Clinical trial NCT04225221
Conditions: Bulimia Nervosa
Keywords: bulimia nervosa binge eating eating disorder estrogen
Sponsor: University of North Carolina, Chapel Hill
Start date: 2020-02-24; Completion date: 2022-04-04
Enrollment: 10 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This pilot study experimentally manipulates ovarian hormones to examine the direct impact of estrogen (E2) and progesterone (P4) on binge eating symptom burden and the behavioral reward response in women with bulimia nervosa (n=15). This is completed by taking medications that change ovarian hormone levels. This line of research could lead to the development of pharmacological interventions developed to target specific areas of the brain, brain receptors, or pathways identified to be involved in the mechanism underlying ovarian hormone change and binge eating.

Detailed description:
Eating disorders (EDs) affect 15 million women in the United States and have one of the highest mortality rates of any mental illness. Despite this, the underlying neurobiology remains poorly understood. EDs predominantly occur in women, and the frequency of certain symptoms change in a predictable pattern over the menstrual cycle; specifically, symptom changes appear to be triggered by normal fluctuations in the ovarian hormones estradiol (E2) and progesterone (P4).

The objective of this study is to examine the direct and mechanistic role of E2 and P4 on binge eating in women with bulimia nervosa (BN; n = 15). The experimental design parallels an established design developed to determine the hormonal triggers of premenstrual dysphoric disorder and depression: temporarily stopping the menstrual cycle using a Gonadotropin-releasing hormone (GnRH) agonist (Lupron) and addback E2 and P4 independently in a double-blind crossover design. The overarching hypothesis is that BN represents a hormone-sensitive phenotype, and this sensitivity is modulated by E2's effects on aspects of the reward response such that reward-motivated behaviors increase in the context of low E2. This line of research will provide direction for future research addressing neuroendocrine, neurobiological, and brain activity and function in BN. To date, there are no medications that have been developed specifically for the treatment of individuals with BN.

Our specific aims are to:

Aim 1: Quantify the direct effect of E2 and P4 on binge eating in women with BN.

Aim 2: Determine the effect of E2 on reward response in women with BN.

Aim 3: Examine the association between reward response and binge eating before and after E2 addback.

Arms: arm 1: Participants are randomly assigned to treatment Sequence A: after achieving hormone suppression using Lupron, participants begin the addback period and take study medications for 8 weeks. During the 8 week period, participants will take placebo or estradiol or progesterone. Participants will not know when or for how long they are on active medication (i.e., estradiol or progesterone) or inactive (i.e., placebo) medication. When active medication is administered, participants randomized to treatment sequence A will receive estradiol addback first, followed by progesterone.

Estradiol and progesterone are never given simultaneously. Participants are on active medication for a total of 4 weeks. arm 2: Participants are randomly assigned to treatment Sequence B: after achieving hormone suppression using Lupron, participants begin the addback period and take study medications for 8 weeks. During the 8 week period, participants will take placebo or estradiol or progesterone. Participants will not know when or for how long they are on active medication (i.e., estradiol or progesterone) or inactive (i.e., placebo) medication. When active medication is administered, participants randomized to treatment sequence B will receive progesterone first followed by estradiol.

Estradiol and progesterone are never given simultaneously. Participants are on active medication for a total of 4 weeks.
Interventions: intervention 1: Estradiol intervention 2: Micronized progesterone intervention 3: Leuprolide Acetate intervention 4: Placebo Oral Capsule
Intervention descriptions: intervention 1: During estradiol administration, 2mg of estradiol is given twice daily via oral capsule. intervention 2: During progesterone administration, 200mg of progesterone is given twice daily via oral capsule. intervention 3: Initial 3.75 mg intramuscular injection administered approximately Day 6 of menstrual cycle and then monthly thereafter for a total of 3 months. intervention 4: Placebo is administered during the addback phase when participants are not taking active medication. Placebo is given so that medication administration occurs throughout the entire 8-week addback period in order to blind participants to when and for how long they are on the active medication.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
Study Protocol  
 
Ovarian Hormones, Reward Response, and Binge Eating in Bulimia 
Nervosa: An Experimental Design 
 
 
 
 
 
NCT Number NCT04225221 
 
Document Date 11/11/2021 


Ovarian Hormones, Reward Response, and Binge Eating in Bulimia Nervosa: An 
Experimental Design 
 
Principal Investigator: 
Jessica H. Baker, PhD 
UNC Department of Psychiatry 
101 Manning Drive, CB 7160 
Chapel Hill, NC 
27599-7160 
984-974-3794 
Study Physician and Co- 
Investigator: 
Steven Young, MD, PhD 
UNC Department of Obstetrics & Gynecology 
101 Manning Drive, CB 7570 
Chapel Hill, NC 
27599- 7570 
Funding Sponsor: 
National Institute of Mental Health 
6001 Executive Boulevard, Room 6200, MSC 9663 
Bethesda, MD 20892-9663 
Study Product: 
Estradiol 
Active ingredient: micronized estradiol 
Chemical name: estra-1,3,5,(10)-triene-3, 17β-diol 
Lupron Depot 
Active ingredient: leuprolide acetate for depot suspension 
Chemical name: 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L- 
seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L- 
prolinamide 
Progesterone 
Active ingredient: micronized progesterone 
Chemical name: pregn-4-ene-3, 20-dione 
IRB Protocol Number: 
IRB# 19-2343 
IND Number: 
Exempt 
Study Personnel: 
Principal Investigator: Jessica Baker, PhD 
Co-Investigator and Study Physician: Steven Young, MD, PhD 
Co-Investigator: Crystal Edler Schiller, PhD 
Biostatistician: Kai Xia, PhD 
Data Manager: Russel Dean, MS 
OBGYN: Lauren Schiff, MD 
Study Coordinator: Jennifer White 
Initial version:   8/06/19 
Last updated:   11/11/21 
 
 


2 
 
Table of 
Contents 
 
Study Summary..................................................................................................................1 
1 Introduction.....................................................................................................................3 
1.1 Background ..............................................................................................................3 
1.2 Investigational Agent ...............................................................................................7 
1.3 Preclinical Data ......................................................................................................10 
1.4 Clinical Data to Date ..............................................................................................10 
1.5 Dose Rationale and Risk/Benefits ..........................................................................12 
2 Study Objectives ...........................................................................................................19 
3 Study Design .................................................................................................................19 
3.1 General Design .......................................................................................................19 
3.2 Outcome Variables .................................................................................................19 
4 Subject Selection and Withdrawal ..............................................................................21 
4.1 Inclusion Criteria ...................................................................................................21 
4.2 Exclusion Criteria ...................................................................................................21 
4.3 Subject Recruitment and Screening .......................................................................22 
4.4 Early Withdrawal of Subjects ................................................................................23 
5 Study Drug.....................................................................................................................25 
5.1 Description .............................................................................................................25 
5.2 Treatment Regimen ................................................................................................25 
5.3 Method for Assigning Subjects to Treatment Groups ............................................25 
5.4 Preparation and Administration of Study Drug ......................................................26 
5.5 Subject Compliance Monitoring ............................................................................26 
5.6 Prior and Concomitant Therapy .............................................................................26 
5.7 Packaging ..............................................................................................................26 
5.8 Blinding of Study Drug (if applicable)...................................................................26 
5.9 Receiving, Storage, Dispensing and Return ...........................................................26 
6 Study Procedures ..........................................................................................................28 
7 Statistical Plan ...............................................................................................................34 
7.1 Sample Size Determination ....................................................................................34 
7.2 Statistical Methods .................................................................................................34 
7.3 Subject Population(s) for Analysis .........................................................................38 
8 Ethical Considerations................................................................................................38 
9 Study Finances ............................................................................................................38 
9.1 Funding Source.....................................................................................................38 
9.2 Conflict of Interest................................................................................................38 
9.3 Subject Stipends or Payments ..............................................................................38 
10 References ....................................................................................................................40 
11 Appendices...................................................................................................................52 
Appendix A. Study Procedures Flow Chart .................................................................53 
Appendix B. COVID Response………………………………………………………54 
 
 
 
 
 
 
 


3 
 
Protocol Updates: 
 
November 11, 2021: Updated medication dispense protocol to 
require second pharmacist verification  
 
October 20, 2021: Updated pharmacy medication dispense procedures  
 
August 12, 2021: Updated exclusion criteria “pregnancy related excessive vomiting and high blood 
pressure.” 
 
April 22, 2021: Approval to provide participants with mileage reimbursement for study visit travel 
 
March 29, 2021: IRB approval to hire clinical trial recruitment company 
 
November 13, 2021: Update BMI to <35 
 
October 8, 2020: Additional COVID protocols  
 
July 27, 2020: COVID protocols and procedures  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


4 
 
 
List of Abbreviations 
 
AE 
Adverse Event 
BAS 
Behavioral approach system 
BIS 
Behavioral Inhibition system 
BMI 
Body Mass Index 
BN 
Bulimia Nervosa 
CBT 
Cognitive Behavior Therapy 
CHD 
Coronary Heart Disease 
CMP 
Comprehensive Metabolic Panel 
CRF 
Case Report Form 
DA 
Dopamine 
DSMB 
Data and Safety Monitoring Board 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
DVT 
Deep Vein Thrombosis 
E2 
Estradiol 
EDs 
Eating Disorders 
EC 
Ethics Committee 


5 
 
 
EPT 
Combined Estrogen and Progestin Treatment (EPT) 
ERT 
Estrogen Replacement Therapy 
FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
GnRH 
Gonadotropin-Releasing Hormone 
HIPAA 
Health Insurance Portability and Accountability Act 
HCG 
Human Chorionic Gonadotropin 
IDAS 
Inventory of Depression and Anxiety Symptoms 
IDS 
Investigational Drug Service 
IM 
Intramuscular 
IRB 
Institutional Review Board 
IVF 
In Vitro Fertilization 
LH 
Luteinizing Hormone 
NIH 
National Institutes of Health 
P4 
Progesterone 
PHI 
Protected Health Information 


6 
 
 
PMDD 
Premenstrual Dysphoric Disorder 
PMS 
Premenstrual Syndrome 
SAE 
Serious Adverse Event 
SCID 
Structured Clinical Interview for DSM-5-TR Axis-I Disorders 
UNC 
University of North Carolina at Chapel Hill 


1 
 
Study Summary 
 
Title 
Ovarian Hormones, Reward Response, and Binge Eating in 
Bulimia Nervosa: An Experimental Design 
Short Title 
Neurobiology of Binge Eating 
Protocol Number 
IRB# 19-2343 
Phase 
II 
Methodology 
Double-blind, placebo-controlled, longitudinal comparison study 
Study Duration 
4 months 
Study Center(s) 
Single-center 
Objectives 
Proof-of-concept pilot study: examine the direct impact of ovarian 
hormones (i.e., E2 and P4) on binge eating and the behavioral 
reward response in women with BN 
Number of Subjects 
15 
Diagnosis and Main 
Inclusion Criteria 
A current DSM-5 diagnosis of BN, age 18-42, BMI < 35, and a 
regular menstrual cycle for at least three months; not pregnant, not 
lactating and in general good health, no medications or medical 
history contraindicated for use with study medications, no history 
of suicide attempts or bipolar/psychotic disorder, no current 
substance use disorder 
Study Product, Dose, 
Route, Regimen 
Study Product: 
Estradiol 
Active ingredient: micronized estradiol 
Chemical name: estra-1,3,5,(10)-triene-3, 17β-diol 
Lupron Depot 
Active ingredient: leuprolide acetate for depot suspension 
Chemical name: 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L- 
seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L- 
prolinamide 
Progesterone 
Active ingredient: micronized progesterone 
Chemical name: pregn-4-ene-3, 20-dione 


2 
 
Dose: 
Drug 
Dosage 
Formulation 
Estradiol 
2 mg bid 
Oral capsule 
Lupron Depot 
3.75 mg/month 
Intramuscular 
injection 
Progesterone 
200 mg bid 
Oral capsule 
 
Route: 
Drug 
Route of Administration 
Estradiol 
Oral 
Lupron Depot 
Intramuscular injection 
Progesterone 
Oral 
 
 
 
Regimen: 
Induced Hypogonadism. After a baseline period, participants will 
receive their first injection of the gonadotropin-releasing hormone 
(GnRH) agonist leuprolide acetate (Lupron) 3.75 mg/month via 
intramuscular injection, which is administered to produce a stable 
hypogonadal condition (after the initial “flair”). Lupron is 
administered at monthly intervals thereafter for a total of 3 doses. 
 
Addback. After 6-weeks of Lupron-alone treatment (i.e., 
hypogonadism), physiological plasma levels of E2 and P4 will be 
attained via micronized E2 and P4 tablets for two weeks (with 
continued Lupron administration), respectively. E2 and P4 will be 
administered in a double-blind, cross-over design with a 2-week 
washout period in-between E2 and P4 administration. E2 will be 
administered at a dose of 2 mg bid (i.e., a total of 4 mg per day). 
P4 will be administered at a dose of 200 mg bid (i.e., a total of 400 
mg per day). The blood levels that we expect to achieve and 


3 
 
 
sustain in each woman will be approximately 500 pg/ml of E2 and 
30-40 ng/ml of P4. 
Duration of 
administration 
3 months 
Reference therapy 
Placebo 
Statistical 
Methodology 
A 2 x 2 double-blind crossover design, with 2-sequence, 2-period 
and 2-treatment will be implemented 
 
 
 
 
1 
Introduction 
 
This document is a protocol for a human research study. This study is to be conducted according to US and 
international standards of Good Clinical Practice (FDA Title 21 part 312 and International Conference on 
Harmonization guidelines), applicable government regulations and Institutional research policies and 
procedures. 
 
 
1.1 
Background 
 
EDs are serious mental health conditions affecting 15 million women in the United States1 and have one of the 
highest mortality rates of any mental illness,2 yet the underlying neurobiology remains poorly understood. EDs 
predominantly occur in women,3 and the frequency of certain symptoms change in a predictable pattern over the 
menstrual cycle.4 Specifically, symptom change appears to be triggered by  normal fluctuations in the ovarian 
hormones E2 and P4;5, 6 this is particularly evident for binge eating. In women with BN, high levels of E2 are 
associated with reduced binge-eating whereas high levels of P4 are associated with increased binge-eating5 
during a normal menstrual cycle. Thus, we have hypothesized BN represents a hormone sensitive phenotype: 
women with BN display differential sensitivity to normal changes in ovarian hormones.4, 7 Unraveling the 
neurobiology of BN has the potential to open innovative avenues for treatment for this life-impairing illness. 
 
Decades of preclinical work confirms E2 has a direct, protective effect on food intake, binge-type behaviors, and 
weight-related constructs.8-10 No comparable experimental designs have been conducted in humans. 
Cumulatively, it appears that low E2 or P4 antagonized E2 (both E2 and P4 are high) are risky milieus for binge 
eating.11 The exact hormone milieu that is “risky” may depend on the level of pathology present: subsetting a 
community sample into DSM-defined binge eaters vs. non- binge eaters showed a significant inverse main 
effect for E2.12 This suggests that for those with higher levels of pathology, low E2 may be the catalyst for 
symptom exacerbation. In contrast, the follicular and ovulatory phases may be protective: across all studies, 
binge-eating frequency is lowest during these phases.5, 6, 13-15 During the follicular phase, E2 is rising in 
preparation for ovulation and reaches peak levels at ovulation whereas P4 is low and relatively stable. Finally, 
two recent case reports show manipulation of E2/P4 directly effects symptomatology. The introduction of a P4- 
only hormonal contraceptive relapsed gains made in treatment for BN, which was reversed upon stopping the 
medication.16 Impressively, complete recovery from subclinical binge eating disorder was also achieved 
following surgical ovarian suppression (i.e., bilateral salpingo-oophorectomy and hysterectomy) treatment for 
PMDD,17 which results in the absence of E2/P4. This could suggest that, unlike animals, hypogonadism may 
result in symptom relief for humans: hormone sensitivity may reflect sensitivity to changing levels vs. the 
presence (or absence) of acute levels. This is corroborated by the fact menopause (i.e., hypogonadism) does not 


4 
 
result in increased ED symptoms, yet the menopause transition (i.e., chaotic changes in ovarian hormones) 
does.18 
To date, the effects of ovarian hormones on eating behaviors have been inferred from animal studies and from 
changes in behavior occurring with presumed and measured levels of hormones during the menstrual cycle. 
Although animal studies established that E2 controls eating behaviors,8, 9 studies have limitations: it is unclear if 
animal studies can translate to human behavior and observational human studies cannot conclude causality or 
tease apart the effects of E2 and P4 given the presence of both. Moreover, the neurobiological mechanisms 
underlying why ovarian hormones are responsible for symptom fluctuation remains unknown. E2 has 
pronounced effects on certain neuropathways19-21 and neurotransmitters22, 23 and in particular, may influence 
binge eating through its effect on reward processes that are altered in BN.24-26 Women with BN show reduced 
brain activation in dopamine-related reward pathways,27 increased reward sensitivity,28, 29 and inhibitory control 
deficits30 compared with healthy controls, which together, may result in increased reward-motivated behaviors 
(e.g., binge eating). Indeed, E2 replacement in ovariectomized rats decreases food reward-motivated behavior31 
and, in women, delay gratification is inversely associated with E232 whereas E2 suppression reduces reward 
responsivity.33 Together, this suggests E2 neuromodulation of aspects of the reward response may be 
responsible for changes in binge eating observed across the menstrual cycle. 
Indeed, women with BN tend to be more sensitive to reward,28, 29, 34-36 display a preference for smaller rewards 
now vs. larger rewards later (i.e., delay discounting),37-40 and have inhibitory control deficits associated with 
impulsivity.30, 41-43 Certain aspects of reward processing and the reward response are powerfully modulated by 
E2,22, 44 albeit the direction is inconsistent with some studies showing a beneficial effect31, 45, 46 and others a 
worsening47-49 effect. This directionality appears to, in part, differ by the aspect of reward addressed.22, 50 
Regardless, some work suggests that E2 replacement in ovariectomized rats decreases food-reward behavior31 
and in women, reward sensitivity is heightened during the late luteal phase,51 which is marked by a steep 
decline in E2 and P4, and risk taking behavior and impulsivity are lowest when E2 levels are highest.46, 52-54 
Reward-motivated behavior related to choice (vs. action) has a more consistent inverse association with E2: 
delay discounting is greater in females than males in animals50, 55, 56 yet E2 may attenuate delayed discounting 
and inhibition in humans and animals.22, 32, 45, 57 
Individual characteristics may determine if E2 has a beneficial or worsening effect, which could also account 
for inconsistences observed in the direction of the effect of E2 on reward-motivated behaviors such as binge 
eating. Specifically, dopamine has an established effect on multiple aspects of reward22, 23, 44, 58 and there is 
evidence that the effect of E2 may be dopamine activity dependent.59-63 Preclinical studies established that E2 
enhances dopamine activity,64-66 but at its highest levels E2 may inhibit dopamine.23 Also, dopamine appears to 
have an inverted U effect: an optimal amount of dopamine results in maximal function whereas insufficient or 
excessive levels lead to dysfunction,58, 67, 68 suggesting that the effect of E2 on dopamine [reward] motivated 
behaviors depends on baseline dopamine.23, 46, 60, 69 Specifically, E2 is beneficial for subgroups with lower 
baseline dopamine (enhancing activity to the optimal level) and worsening for subgroups with higher baseline 
dopamine (leading to an excessive amount of dopamine). Corroborating this, the beneficial effect of E2 on 
delay discounting is driven by COMT genotype, which is often used as a proxy for baseline dopamine activity: 
declines in delay discounting during high E2 were observed among COMT Val allele carriers,32 the allele 
associated with less dopamine activity. This is highly relevant for BN:70, 71 BN is associated with decreased 
dopamine activity,72-74 reduced brain activation in dopamine-related reward pathways,27, 75 and possibly a higher 
frequency of gene alleles associated with decreased dopamine;71, 76 though this is inconsistent,77 unconfirmed by 
genome-wide studies, and perhaps an indirect and/or interactive association.78-80 Thus, because women with BN 
represent a subgroup of the population with low dopamine activity, low E2 may detrimentally affect the reward 


5 
 
response and further promote reward-motivated behavior 
via dopamine withdrawal, whereas high E2 is beneficial 
by enhancing dopamine activity to an optimal level, in 
turn decreasing the reward response and reward 
behaviors. 
 
Together, we hypothesize women with BN are a hormone 
sensitive phenotype with precursory impaired dopamine 
 
 
 
 
 
 
Protective 
Effect 
 
 
 
 
 
E2 
DA 
Reward 
Response 
 
Low DA 
Activity 
 
 
 
 
E2 
DA 
Reward 
Response 
 
 
 
 
 
Risky 
Effect 
activity, leading to increased reward response (e.g., 
reward-related inhibitory control deficits, heightened 
reward sensitivity, impaired delay discounting) and 
therefore, increased engagement in reward-motivated 
Binge eating 
 
Figure 1. Hypothesized cycle of the effect of E2 on binge eating 
behavior, which is modulated by cycling E2 (Figure 1). Decreasing E2 triggers a cascade of neurobiological 
events leading to the onset of or increased engagement in reward-motivated behaviors (i.e., binge eating) in 
vulnerable women (i.e., low dopamine activity). While others made postulations regarding reward-related 
inhibitory control,24, 34, 81 few considered the effect of E225, 82-84 Although some,85 but not all,5 studies suggest 
dysregulated hormone levels in women with BN, we do not hypothesize physiologically aberrant ovarian 
hormone levels are a precursor to BN, rather behavioral reactions to normal hormone changes are dysregulated 
in women with [or at risk for] BN due to an underlying sensitivity to this change. Currently, research in this area 
focuses on E2 and overlooks P4; assuming that the effect of P4 is indirect and not causal. However, we could be 
overlooking an important etiological construct given P4 also directly impacts dopamine levels,86 which are at 
the core of our hypothesized model. 
 
The objective of this proposal is to examine the direct and mechanistic role of ovarian hormones on binge eating 
in women with BN (n = 15). Our overarching hypothesis is that BN represents a hormone sensitive phenotype 
and this sensitivity is modulated by E2’s effects on aspects of the reward response such that reward-motivated 
behaviors increase in the context of low E2. For the first time in humans, we propose an experimental design 
that parallels animal models to directly manipulate ovarian hormones: temporarily stopping the menstrual cycle 
using a GnRH agonist and addback E2 and P4 independently in a double-blind crossover design. This utilizes 
an established design developed to determine the hormonal triggers of premenstrual dysphoric disorder PMDD 
and depression.87-89 We propose this proof-of-concept study to obtain empirical evidence supporting our 
overarching hypothesis and the utility of this experimental design in a BN population. The experimental design 
proposed here is the only way to confidently explore the direct impact of ovarian hormones on binge eating in 
BN. Observational designs provide insight but cannot quantify the mechanism in which ovarian hormones 
impact binge eating. Further, the impact of E2 on neurocircuitry contributing to BN has been deprioritized by 
research to date.25 Successful completion of the proposed aims will provide guidance in regard to if (and how) 
E2 and P4 directly affect binge eating in BN. This will not only provide the empirical direction needed for the 
investigators to complete larger, hypothesis-driven mechanistic trials, but will provide direction for future 
research addressing neuroendocrine, neurobiological, and brain activity and function in BN. 
 
Rationale for experimental manipulation in BN population: the direct benefit to participants will be limited and 
we are not conducting a clinical treatment trial but a mechanistic clinical trial (as defined by the NIH). 
However, we do hypothesize a beneficial effect will be observed during some treatment arms, in particular 
during the E2 condition. Additionally, as described above, one case study showed complete recovery from 
subclinical binge eating disorder following surgical ovarian suppression via a bilateral salpingo-oophorectomy 
and hysterectomy for PMDD.17 Compared with this surgery, ovarian suppression through an intervention such 
as Lupron is much less invasive. Thus, if our hypotheses are correct an obvious treatment implication could be 
the direct manipulation of ovarian hormones with the medications used here or the use of treatments that buffer 
the impact of these hormones on neurobiological function. Explicating the mechanism through which E2 


6 
 
inhibits (and/or P4 exacerbates) binge eating behavior could lead to the development of interventions based  
upon this mechanistic understanding. To date, there are no medications that have been developed specifically 
for the treatment of individuals with BN. Further, if a beneficial effect is observed for a specific treatment 
condition, follow-up clinical treatment trials could be conducted—for example, by beginning to explore the 
dosages at which a beneficial effect is observed and effectiveness when used in combination with other 
treatments (e.g., CBT). Additionally, one goal for this line of research is to further our mechanistic 
understanding of eating disorders/binge eating in order to develop more personalized approaches to treatment. 
Although we hypothesize that menstrual exacerbation of binge eating is due to an underlying sensitivity to 
normally fluctuating ovarian hormones, some women with an eating disorder may experience this sensitivity to 
a greater degree—or this sensitivity may not be present across all eating disorder subtypes. Thus, our larger 
studies (R01) and subsequent follow-up studies will aim to identify predictors of hormone sensitivity: women 
who binge eat who may benefit from the direct manipulation of ovarian hormones or treatments that buffer the 
impact of these hormones on neurobiological function. With this line of research, we hope to enable discovery 
of novel neural treatment targets and therapeutics to ultimately prevent illness expression. 
 
The major benefit of this study is to aid in understanding the underlying neurobiological mechanisms in BN, 
leading to larger trials ultimately aimed at creating novel, individualized therapeutics. This line of research 
could lead to the development of medications that have less risk for side effects than the ones used here; for 
example, pharmacological interventions developed to target specific areas of the brain, brain receptors, or 
pathways identified to be involved in the mechanism underlying ovarian hormone change and binge eating. This 
pilot study will lay the groundwork for this line of research. For example, results from this pilot study and the 
larger mechanistic trial could lead to therapeutics that are developed to selectively target specific receptors in 
the brain or specific regions in the brain to alleviate binge eating (notably, in our future trials we plan to include 
an fMRI component), and other symptomatology, in BN. There is a major disconnect between the significant 
public health impact of BN and our knowledge about the neurobiology of the disorder. Further, patients with 
BN struggle with barriers to treatment and a fragmented health care system. Although psychotherapy is 
typically the first treatment of choice for BN,90, 91 it is not readily accessible or affordable.92,93 For those who 
receive evidence-based treatment, the effectiveness of psychotherapy varies across individuals94 and over 60% 
of BN patients do not reach symptom abstinence from psychotherapy alone.95 Moreover, there is only one FDA 
approved pharmacological treatment (Fluoxetine) for BN and innovative avenues for pharmacological treatment 
have been overlooked. Given that the cost per abstinent patient for Fluoxetine is nearly half that for 
psychotherapy ($12,146 vs. $20,317),96 innovative avenues for pharmacological treatment must be pursued, 
which could improve treatment accessibility and outcome for BN. Implementing high risk research, yet that has 
the significant potential for high reward is the first step in opening doors for innovative new treatments to be 
developed. Prior to study participation, all subjects will complete informed consent so that they can make 
a fully informed and educated decision regarding the possible risks associated with study participation. 
Women who participate in this study will received personalized feedback regarding their individual response to 
the experimental arms. Study participants will obtain personalized feedback at study completion of the study 
about any changes in BN symptoms observed during the experimental phases from the study PI. This 
individual-level feedback could provide an area of treatment for the participant to pursue and identify potential 
triggers for symptom exacerbation for that specific individual. We have also observed many altruistic benefits 
in our past eating disorder studies. Specifically, we frequently receive feedback from study participants that 
they are excited to participate in research studies that contribute to a better understanding of what causes an 
eating disorder, regardless of a direct benefit for them, in hopes that someone else in the future may not have to 
suffer. 


7 
 
 
 
1.2 
Investigational Agent 
 
Estradiol 
 
Description 
Estradiol Tablets USP for oral administration contain 2 mg of micronized estradiol per tablet. Estradiol (17β- 
estradiol) is a white, crystalline solid, chemically described as estra-1,3,5,(10)-triene-3, 17β-diol. The structural 
formula is: 
 
 
 
Figure 2. Structural formula for estra-1,3,5,(10)-triene-3, 17β-diol. 
 
Inactive Ingredients: Colloidal silicon dioxide, corn starch, dibasic calcium phosphate, lactose monohydrate, 
magnesium stearate, and sodium starch glycolate. In addition, the 1 mg also contains FD&C blue no. 1 
aluminum lake and D&C red no. 27 aluminum lake. The 2 mg also contains FD&C blue no. 1 aluminum lake 
and FD&C yellow no. 5 (tartrazine) aluminum lake. 
 
Pharmacology 
Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive 
system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of 
metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more 
potent than its metabolites, estrone and estriol at the receptor level. 
 
The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 
500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous 
estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral 
tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating 
estrogens in postmenopausal women. 
 
Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen 
receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate 
the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), 
through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in 
postmenopausal women. 
 
LUPRON DEPOT 
 
Description 
Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone 
(GnRH or LH-RH). The analog possesses greater potency than the natural hormone. The chemical name is 5- 


8 
 
oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide 
acetate (salt) with the following structural formula: 
 
 
 
Figure 3. Structural formula for leuprolide acetate (5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L- 
leucyl-L-arginyl-N-ethyl-prolinamide acetate). 
 
 
LUPRON DEPOT is available in a prefilled dual-chamber syringe containing sterile lyophilized microspheres 
which, when mixed with diluent, become a suspension intended as a monthly intramuscular injection. 
 
 
The front chamber of LUPRON DEPOT 3.75 mg prefilled dual-chamber syringe contains leuprolide acetate 
(3.75 mg), purified gelatin (0.65 mg), DL-lactic and glycolic acids copolymer (33.1 mg), and D-mannitol (6.6 
mg). The second chamber of diluent contains carboxymethylcellulose sodium (5 mg), D-mannitol (50 mg), 
polysorbate 80 (1 mg), water for injection, USP, and glacial acetic acid, USP to control pH. During the 
manufacture of LUPRON DEPOT 3.75 mg, acetic acid is lost, leaving the peptide. 
 
 
Pharmacology 
Leuprolide acetate is a long-acting GnRH analog. A single monthly injection of LUPRON DEPOT 3.75 mg 
results in an initial stimulation followed by a prolonged suppression of pituitary gonadotropins. 
 
 
Repeated dosing at monthly intervals results in decreased secretion of gonadal steroids; consequently, tissues 
and functions that depend on gonadal steroids for their maintenance become quiescent. This effect is reversible 
on discontinuation of drug therapy. Leuprolide acetate is not active when given orally. Intramuscular injection 
of the depot formulation provides plasma concentrations of leuprolide over a period of one month. 
 
PROGESTERONE 
 
Description 
PROMETRIUM (progesterone, USP) Capsules contain micronized progesterone for oral administration. 
Progesterone has a molecular weight of 314.47 and a molecular formula of C21H30O2. Progesterone (pregn-4- 
ene-3, 20-dione) is a white or creamy white, odorless, crystalline powder practically insoluble in water, soluble 
in alcohol, acetone and dioxane and sparingly soluble in vegetable oils, stable in air, melting between 126° and 
131°C. The structural formula is: 


9 
 
 
Figure 4. Structural formula for progesterone, USP (pregn-4-ene-3, 20-dione) 
 
 
Progesterone is synthesized from a starting material from a plant source and is chemically identical to 
progesterone of human ovarian origin. PROMETRIUM Capsules are available in multiple strengths to afford 
dosage flexibility for optimum management. PROMETRIUM Capsules contain 200 mg micronized 
progesterone. 
 
 
The inactive ingredients for PROMETRIUM Capsules 100 mg include: peanut oil NF, gelatin NF, glycerin 
USP, lecithin NF, titanium dioxide USP, D&C Yellow No. 10, and FD&C Red No. 40. 
The inactive ingredients for PROMETRIUM Capsules 200 mg include: peanut oil NF, gelatin NF, glycerin 
USP, lecithin NF, titanium dioxide USP, D&C Yellow No. 10, and FD&C Yellow No. 6. 
 
 
Pharmacology 
PROMETRIUM Capsules are an oral dosage form of micronized progesterone which is chemically identical to 
progesterone of ovarian origin. The oral bioavailability of progesterone is increased through micronization. 
 
Summary of Previous  Human Experience 
 
The proposed monthly 3.75-mg injection of leuprolide acetate (Lupron Depot) is FDA-approved for use to treat 
endometriosis and uterine fibroids. Lupron has also been widely researched to treat a variety of medical 
conditions in actively ill women, including ovarian epithelial tumor cells97, insulin resistance98, endometrial 
stromal sarcoma99, and infertility100 as well as in healthy women. Several studies have also investigated the use 
of Lupron and hormone addback (as is being completed here) to treat the symptoms of premenstrual syndrome 
and PMDD,87, 101-103which has resulted in combined Lupron and estrogen/progestin supplementation as a 
recommended long-term treatment for premenstrual syndrome.104, 105 Notably, there is a significant association 
between PMDD and PMS and BN: women with PMDD are 7-times and with PMS 2-times more likely to have 
a BN diagnosis,106 suggesting that an underlying pathophysiology may exist. 
 
Infertile women undergoing IVF routinely receive luteal supplementation of 600 mg progesterone daily along 
with 6 mg oral micronized estradiol107 in combination with GnRH agonists (e.g., Lupron). GnRH agonist 
treatment combined with hormone addback (i.e., high-dose estradiol and progesterone supplementation) has 
been previously studied in large randomized controlled trials for the purpose of IVF.107-112 Of particular 
relevance to our study, researchers induced a hypogonadal state using 3.75 mg Decapeptyl, followed by high- 
dose (800 mg) oral progesterone treatment in 32 women without an adverse event.111 Damario et al. (1999) also 
reported the use of combined Lupron treatment, 9 mg oral micronized estradiol, and 100 mg i.m. progesterone 
in 238 women presenting for IVF. 


10 
 
Dr. Schiller’s research lab at UNC and research team’s at the NIH have examined the combined administration 
of Lupron and estradiol and/or progesterone in premenopausal women in several studies without a significant 
adverse event.113-117 Moreover, the same drug protocol proposed in the current study has been employed 
previously by Dr. Schiller’s research lab at UNC and research teams at the NIH.87, 117, 118 Notably, the hormone 
challenge we are using in this protocol has been truncated in length in order to decrease participant burden. 
Previous studies conducted at NIH indicate hypogonadism can be fully induced within 2 months and reliable 
symptom change occurs within 2 weeks of E2/P4 addback.87, 118 As such, compared with the original protocol, 
the challenge has been shortened by 2 months yet still is able to capture maximal symptom change. Taken 
together, a large number of women in the population have previously received combined Lupron with 
high-dose oral E2 and P4 supplementation either as part of medical care, a research study, or standard 
IVF treatment without serious side effects or adverse events. 
 
 
Status of Drug in Other Countries 
 
To our knowledge, the proposed drugs have not been withdrawn from investigation or marketing in any other 
country. 
 
 
1.3 
Preclinical Data 
 
 
Decades of preclinical work confirms E2 has a direct, protective effect on food intake, binge-type behaviors, 
and weight-related constructs whereas P4 may antagonize the effect of E2.8-10 
 
 
1.4 
Clinical Data to Date 
 
Hormone Challenge Protocol. Dr. Schiller’s research lab has employed similar hormone regimens to elicit 
symptoms of depression and is currently conducting an experimental study with a similar design to elicit 
irritability in healthy women. Team’s at the NIH developed the protocol used here to address the hormonal 
mechanisms underlying PMS/PMDD. All participants will undergo the same hormonal challenge but in a 
double-blind cross-over design. Subjects will be randomly assigned to receive E2+P4 or P4+E2 based on the 
randomization table created by the study biostatistician. 
 
Recruitment and Retention. The investigative team has experience recruiting clinical populations for eating 
disorders research (i.e., Dr. Baker) and for reproductive hormone challenges (e.g., Dr. Schiller). In Dr. 
Schiller’s most recent hormone challenge study, participants were recruited based on the following: targeted 
social media advertising (57%), university-wide mass emails (10%), Craigslist advertising (10%), 
ResearchMatch.org (7%), a UNC Center for Women’s Mood Disorders research registry (7%), flyers (3%), 
Join the Conquest (3%), and referral from a friend in the study (3%). 
 
Dr. Schiller’s successful completion of a previous study (N=30) involving a similar hormone challenging plus a 
neuroimaging component demonstrates both the feasibility and ability to recruit and retain women to participate 
in hormone challenge studies. Importantly, the current protocol is less invasive. It is possible that recruiting 
women with BN willing to undergo the hormone experimentation will be more challenging, thus, we have built 
in additional retention plans: a) the hormone challenge has also been truncated in order to decrease participant 
burden given previous studies indicate hypogonadism can be fully induced with significant behavioral changes 
observed in 6-weeks and reliable symptom change occurs within 2 weeks of E2/P4 addback;87, 118 b) we do not 
require participants to not be in treatment to participate in the study. However, we request that subjects make no 
changes to their treatment protocol for the duration of the study. While this does introduce a potential confound, 


11 
 
even in treatment, we would expect to see changes in binge eating during the hormone challenge if indeed 
ovarian hormones have a direct impact on binge eating—continuing treatment would not negate this effect; c) a 
unique aspect of our study, we will provide participants with individual feedback regarding any changes 
observed in binge eating during the hormone manipulation after study termination. Women can take advantage 
of this optional session with Dr. Baker to review their own data in relation to hormone changes and observed 
changes in binge eating. This represents real-time, personalized information about the participant’s individual 
response to hormones. This may be helpful to women as they pursue treatment. 
 
Use of the Hormone Challenge Protocol in BN and preliminary data. There is compelling evidence an 
experimental design is the next logical step in ovarian hormone research in BN. Preclinical work confirms E2 
has a direct, protective effect on food intake, binge-type behaviors, and weight-related constructs. Additionally, 
observational studies implicate ovarian hormones in neurobiology such that E2 is inversely and P4 is positively 
associated with binge eating in women with BN.5, 6 Cumulatively, for women with higher levels of binge eating 
pathology, findings indicate that E2 has a potential protective effect and P4 an exacerbating effect on binge 
eating. However, observational work in this area is limited: 1) both E2 and P4, albeit at differing levels, are 
present throughout the menstrual cycle: given the presence of both (and other hormones such as FSH and LH), 
the specific effects of each cannot be isolated, which is vital given that E2 and P4 may have opposite effects on 
binge eating; 2) there is a lack of ovarian suppression: in order to directly target and manipulate hormone 
sensitivity, the removal of both hormones must occur; 3) there is no randomization or manipulation: thus, 
causal, mechanistic conclusions cannot be made. Only with an experimental design can we begin to unravel the 
independent and mechanistic effects of ovarian hormones on BN symptoms—providing formative information 
about the nature of the hormone trigger on binge eating. 
 
Co-I Schiller’s early work on the effects of ovarian hormones on binge eating in women with BN provides the 
foundation for this study.5 Increased binge eating was observed during the mid-luteal and premenstrual phases 
of the menstrual cycle compared with the follicular and ovulatory phases with mean Z-scores for binge-eating 
frequency as follows: ovulatory -.37, follicular -.30, premenstrual -.08, mid-luteal .61. Symptom fluctuation was 
attributable to change in E2 and P4: increases in binge eating were associated with decreases in E2 (-.13(0.05), 
t(142.89) = -2.82, p<.01) and increases in P4 (.15(0.04), t(142.55) = 3.49, p<.001), controlling for the effect of 
the other. Further, women with BN did not have different E2 and P4 profiles compared with women without BN5 
supporting our hypothesis: women with BN do not exhibit abnormal hormone levels, rather their behavioral 
reactions to normal ovarian hormone fluctuations are dysregulated. 
 
Additionally, Dr. Schiller’s pilot work of E2 treatment in midlife women 
suggests E2 has a direct effect on appetite: three weeks of E2 treatment 
significantly reduced appetite in those with major depression 
(t=3.88,p<.001) and those without depression (t=2.70, p<.015; see Graph) 
suggesting a Cohen’s d=2.3. Finally, work at the NIH using this hormone 
challenge provides insight into changes in food intake during the challenge 
and proves its utility. In women with PMS, a significant increase in food 
cravings was reported from week 2 of the menstrual cycle (M=1.6,SD=.7) 
to week 4 (M=3.3,SD=1.5), which was entirely eliminated 
by the GnRH agonist (M=1.7,SD=.7 at week 4), but not placebo.87 This suggests a strong effect (Cohen’s 
d=1.51) of the GnRH agonist on food cravings. In a related protocol (GnRH agonist followed by combined 
E2+P4), women with PMDD had a significant increase in food cravings transitioning from hypogonadism to 
E2+P4.118 
Pilot work by PI Baker provides further insight into the protective effect of E2 against dysregulated eating. In 
midlife women receiving estrogen replacement or placebo during the menopause transition, a moderate negative 
correlation was observed between loss of control eating and treatment group (r= -.32;unpublished data119) 
indicating a direct effect of E2 on loss of control eating such that lower levels of loss of control eating were 


12 
 
observed in women receiving E2 replacement. Dr. Baker’s unpublished work further corroborates the 
association between ovarian hormones and ED as well as her experience in this area: a positive correlation was 
observed between binge eating and premenstrual symptoms (PMS; r=.24, p<.01) in college women (n=448) 
indicating that higher binge eating scores were associated with increased PMS, which by definition are ovarian 
hormone sensitive symptoms. Dr. Baker’s published work shows pubertal development predicts ED 
symptoms120 and some of the same genes are responsible for age of menarche and ED symptoms.121 
 
 
1.5 
Dose Rationale and Risks/Benefits 
 
 
Dose Rationale 
 
We use the same dose of each drug administered in previous published studies using this hormone challenge. 
We replicate the dosage used for these studies as they were able to reliable induce hypogonadism, physiological 
levels of E2 and P4, and measurable behavior change. Moreover, based on these published data87, 118 we have 
shortened the protocol given that hypogonadism was reliably induced and measurable behavior change 
observed within 6-weeks of the first dose and maximal symptom change was observed with two weeks of E2 
and P4 administration.87, 118 Thus, the drug protocol, including the route of administration, dosage, dosage 
regimen, and dosage period, mirrors a truncated version of previous studies. Further, each medication is being 
used for their intended use (e.g., ovarian suppression). 
 
This proposal is to support mechanistic work and not to support a new indication, dose, or route of 
administration, and not to support clinical use or treatment in a new population. 
 
Risks/Benefits 
 
We do not expect serious adverse side effects associated with the hormonal manipulations outlined in this 
protocol for the following reasons: First, the doses of Lupron, estradiol and progesterone, and the duration for 
which they will be administered in this protocol, will result in plasma hormone levels comparable to those 
commonly used for in vitro fertilization (IVF) protocols lasting 1-3 months. Therefore, based on current IVF 
procedures we do not anticipate any adverse incidents arising from the proposed doses of estradiol and 
progesterone.122, 123 Second, no serious adverse reactions or events were encountered in past studies conducted 
with similar and more invasive protocols used in Dr. Schiller’s research lab or labs at the NIH. Third, 
comparable extended, uninterrupted gonadal steroid treatment (such as oral contraceptives) for 6 to 12 weeks 
has been shown to be well-tolerated.124 Fourth, we have truncated the length of the protocol compared with the 
initial studies using this hormone challenge. 
 
Relevant studies in the EDs literature also indicate that an ED population would not be at increased risk for 
negative side effects or the decreased acceptability of such side effects. A relevant study in humans addressed 
the effectiveness of an oral contractive (synthetic E2/P4: 30 μg of ethinyl estradiol and 3 mg of drosperinone) 
for 3-months for the treatment of ED symptoms in women with BN.125 The oral contraceptive reduced meal- 
related hunger and gastric distention and, for a subset of women only, it also reduced BN symptomatology. No 
serious adverse effects were reported.125 Additionally, women and adolescents with low weight EDs, which are 
at heightened risk for severe medical complications, have been given oral contraceptives, physiological estrogen 
replacement, and progesterone, ranging from periods of time from 3-months to 18-months, without noted 
serious adverse events.126-130 For example, in a study examining 18-months of physiological estrogen 
replacement in girls with anorexia nervosa compared with healthy controls, the most frequent (>25%) side 
effects were: bloating (32%), irritation at estrogen patch site (31%), breast tenderness (25%), and 
nausea/vomiting (25%).127 Notably, for many of the reported side effects, girls receiving placebo reported side 


13 
 
effects at a similar rate to those girls receiving estradiol replacement. In a second, related study, of oligo- 
amenorrheic athletes who were randomized to an oral contraceptive, estradiol patch plus progesterone, or 
placebo for 12-months, the most common side effects noted from the patch (~4%) were bloating and 
headaches.126 Finally, having an ED is not a recognized contraindicated population for use of these medications 
and the presence of an ED does not appear to have been an exclusionary criterion for the clinical trials of 
Lupron, specifically.131 Given the high comorbidity with PMS/PMDD,106 it is highly probable women with a 
current or past history of BN or binge eating have indeed been given these medications as part of routine 
treatment or in a research study. Our study is not testing the effectiveness of these medications for the 
treatment of binge eating but to further our mechanistic understanding of the disorder—which, in the future, 
could lead to new treatments or innovative targets to prevent illness expression. 
 
Finally, any changes observed in ED symptoms that occur during E2 and P4 addback specifically would not be 
expected to surpass the subjects baseline levels of symptom expression. We do not expect symptom levels to 
significantly surpass baseline levels of severity (i.e., prior to hormone manipulation) given that the participants 
endogenous E2 and P4 levels are present and in flux during their natural menstrual cycle. For example, for 
women with PMS, a decrease in sadness was observed from baseline to hypogonadism. Although sadness 
increased with E2 and P4 addback (which is expected based on the hypothesized pathophysiology of PMS), the 
average-mean levels of sadness were lower at addback compared with mean scores observed during their 
natural menstrual cycle, prior to the manipulation.87 Relatedly, oligo-amenorrheic athletes who were 
randomized to estrogen replacement showed a stabilization (i.e., no change) in ED symptoms compared with 
placebo, whereas girls on placebo showed an increase in symptoms over a one year period.126 Second, 
physiologically relevant steroid hormones (E2 and P4) will be administered and hormone levels attained; thus, 
the E2 and P4 arms will mimic the presence of these hormones during a natural menstrual cycle—and thus, 
again, would not be expected to cause significant increases in symptomatology that surpass baseline levels. 
However, the E2 and P4 addback arms will allow us to directly manipulate hormone levels and remove 
additional confounds, while also attaining physiologic hormone levels. Third, we have truncated the 
experimental design to the minimal length of time necessary to elicit symptom change for each phase. Finally, 
as mentioned above, no adverse reactions or events were encountered in past studies conducted that were 
developed to induce symptoms of depression. Here, we are not selecting individuals with a past (or current) 
history of a mood disorder, which has been done in previous studies using this experimental design.87 Although 
we are selecting individuals who have current BN and manipulating their symptoms, their symptomatology is 
already present at baseline; we are not directly causing their symptoms, and thus, symptoms are not expected to 
be more severe throughout the hormone challenge compared with the baseline levels that were already present 
at study enrollment. 
 
As described below, the most serious potential adverse side effects associated with the pharmacological 
interventions used here would likely be considered: DVT/blood clots (although a causal relationship has not 
been established) and bone loss (which is reversible upon stopping the medication). Notably, there is no 
evidence to suggest women with BN are at increased risk for DVT/blood clots.132 Further, whereas low weight 
EDs are at risk for bone loss, women with BN, who are of normal weight and above, may not be at this same 
risk.133-135 The risk for bone loss in EDs is directly related to the loss of estrogen that can occur at a low weight 
status and with menstrual cycle irregularities (i.e., amenorrhea),133l, 134 which are more common in anorexia 
nervosa. Notably, the current proposal requires participants to have a regular menstrual cycle and normal BMI 
for study inclusion. 
 
We describe the adverse effects of Lupron, E2, P4, and combined Lupron+E2+P4 below. 
 
Lupron:  The most frequent adverse effect of Lupron is hot flushes (flashes) reportedly occurring in 4-89% of 
patients receiving the drug. Lupron-induced hot flushes have ranged in severity from occasional mild flushing 


14 
 
to frequent sweating. Episodes of flushing appear to decrease with continued therapy in most patients receiving 
Lupron; however, in at least one study, the incidence of hot flushes did not appear to decrease with continued 
therapy. In a recently completed study of 400 women of reproductive age with either uterine fibroids or 
endometriosis who each received 3.75mg depot Lupron every month for a period of six months, a timeframe 
longer than the current protocol, the most common side effects were as follows: 1) hot flashes of mild to 
moderate intensity (89%); 2) headache (22%); 3) nervousness or irritability (11%); and 4) insomnia (10%). 
Local irritation at the injection site was complained of in less than 10% of the patients in this sample, and there 
was a mean decrease in bone density, as measured by bone densitometry, of 3.4 to 4.0%, which totally reversed 
after the medication had been discontinued for six months. Approximately 10 patients of the original sample of 
400 found the side effects to be severe enough to discontinue therapy (2%). In the majority of women regular 
menstrual cycle function returned within two months following the last injection of depot Lupron (Tapp 
Pharmaceuticals, personal communication). Complete reversibility of fertility suppression has been observed 
for administration of Lupron for periods of up to 24 weeks131—much longer then the use of Lupron proposed in 
this study. 
 
Blurred vision, myalgias, lethargy, memory disorder, and numbness have been reported in less than 3% of 
patients receiving the drug. Thrombophlebitis, pulmonary embolus, and congestive heart failure have occurred 
rarely in patients receiving Lupron, but a causal relationship to the drug has not been established. Adverse GI 
effects occurring in 2% or more of patients receiving Lupron include nausea and/or vomiting, constipation, and 
loss of appetite (non-eating disorder related food intake). Diarrhea and a sour or unusual taste in the mouth have 
been reported less frequently. Other adverse effects of Lupron occurring in less than 3% of patients include 
decreased hematocrit and hemoglobin concentration, fatigue, fever, facial swelling, rash, hives, hair loss, and 
itching. In 20 PMS patients and 20 controls, Lupron was well tolerated (no dropouts) with the most common 
side effects being hot flushes and a decrease in libido. Limited information is available on the acute toxicity of 
Lupron. Following subcutaneous administration of Lupron in rats at dosages 250-500 times the usual human 
dosage, dyspnea, decreased activity, and local irritation at the injection site wereobserved; however, there is no  
evidence to date that overdosage in humans produces similar adverse effects. Lupron dosages up to 20mg daily 
for up to two years have not produced unusual adverse effects in humans. There has been one report of an 
anaphylactic reaction in a patient following administration of a GnRH agonist. Recent longitudinal follow-up 
studies of girls and boys receiving GnRH agonists as a treatment for precocious puberty report the development 
of normal reproductive function, skeletal growth, and fertility.136,137 
 
Estradiol: Nausea is the most common side effect of estrogen administration. At conventional replacement 
doses, higher than those employed in this protocol, this complaint seldom interferes with food intake (i.e., non- 
eating disordered), and no weight loss has been reported. Breast engorgement, endometrial hyperplasia, and 
bleeding are also common side effects of estrogen administration. Pre-existing fibroid tumors of the uterus may 
enlarge under the effects of estrogen; however, at the dosage and for the duration of estrogen administration in 
this protocol (2-weeks) this risk is quite small. 
The relationship between estrogen, both endogenous and exogenous, and the development of 
endometrial carcinoma has been suggested by several different lines of investigation.138 Numerous retrospective 
case control studies published since 1975 have indicated that post-menopausal exposure to unopposed estrogens 
for more than one-year results in a two to 12-fold increased relative risk for endometrial cancer. A relationship 
between the dose and duration of estrogen use and the risk for endometrial cancer has also been shown, the risk 
being increased after one to four years of estrogen use and rising also with the dosage employed. However, the 
addition of progesterone to estrogen replacement therapy (ERT) appears to decrease the risk of endometrial 
hyperplasia and endometrial cancer to equal or below that of women receiving no hormonal treatment. Recent 
studies suggest that the optimal regimen to prevent hyperplasia during long term ERT and thus, inferentially, 
the risk of carcinoma, consists of 12 to 13 days of progesterone treatment each month when estrogens are 


15 
 
administered.139 There is an increase in thromboembolism in women receiving non-contraceptive estrogen 
therapy.140-142 Additionally, some but not all studies report an increase in risk of stroke143, 144 in older women 
taking estrogen therapy. However, these complications are unlikely at the dose and duration of estrogen 
replacement employed in this protocol (2-weeks), and in the younger age group (18-42) of women who 
participate in this study. One study122 reported no effect of the estrogen patch on the four clotting indices 
previously shown to be altered by oral contraceptive use.145, 146 Blood pressure, on average, appears to be 
unaffected by estrogen therapy, although both increases and decreases have been reported. In observational 
studies, post-menopausal estrogen therapy has been observed to lower the relative risk of cardiovascular disease 
in some but not all studies.143, 147 In contrast, randomized controlled trials in older postmenopausal 
women (e.g., Women’s Health Initiative [WHI]) report an increased risk of cardiovascular disease.148 
Emerging data suggest that these disparities in findings may be related to the timing of initiation of 
estrogen therapy in relation to the proximity of menopause. Subgroup analyses of the combined estrogen and 
progestin (EPT) arm of the WHI demonstrated a significant interaction between coronary heart disease (CHD) 
risk and time since initiation of EPT, with an increased risk in the early years following initiation and a 
decreased risk in later years. Additionally, the increased risk of CHD was observed in older but not younger 
perimenopausal women.149-152 High doses of oral estrogens have been reported to elevate hepatocellular enzyme 
levels and, less commonly, cause cholestatic jaundice. The risk for gall stones and hepatocellular adenomas has 
been reported to be increased in association with oral contraceptive use, and although uncommon these 
complications may also occur with the use of replacement doses of estrogen.153, 154 Estrogen therapy also may 
increase the risk of urinary incontinence in older postmenopausal women.155 Further, most studies have 
suggested an increased relative risk of breast cancer after four or five years' use,156-160 similar to the risk 
expected if the onset of menopause was delayed for a comparable length of time.  
Women and adolescents with low weight EDs, which are at heightened risk for severe medical 
complications, have been given physiological estrogen replacement for periods ranging from 3-months to 18-
months, without any noted serious adverse events.126-130 In a study examining 18-months of physiological 
estrogen replacement in girls with anorexia nervosa compared with healthy controls, the most frequent (>25%) 
side effects were: bloating (32%), irritation at estrogen patch site (31%), breast tenderness (25%), and 
nausea/vomiting (25%).127 For a majority of the reported side effects, girls receiving placebo reported side 
effects at a similar rate to those girls receiving estradiol replacement. Notably, the experimental arm of E2 
addback is time-limited, lasting only 2-weeks. Thus, any side effects that may occur are expected to be minimal 
and transient in nature.  
  
Progesterone: Progesterone and the synthetic progestins are widely prescribed to women in the population, with 
indications including dysfunctional uterine bleeding, endometriosis, mastodynia, galactorrhea, and precocious 
puberty.162 Progestin contraceptives are also widely used. Side effects reported in women taking progestins may 
include breakthrough bleeding, edema, change in weight (increase or decrease), cholestatic jaundice, rash (with 
or without pruritus), depression, easy fatigue and sedation, lack of initiative, and chloasma. Since progestins are 
often used in women with antecedent menstrual irregularity, it is not clear whether the breakthrough bleeding 
represents an effect of the medication or refractoriness to treatment. In the large majority of patients, 
menstruation occurs predictably following withdrawal of progestins and is usually more regular than in 
spontaneous cycles. In a recent study, an average dose of 1750mg of oral micronized P4 was given to 
59 women with PMS for a period of three months and was well tolerated by this sample. The side effects 
reported on progesterone were lightheadedness, fatigue, forgetfulness, and headaches. These were very mild 
and caused no dropouts. 
 
Women and adolescents with low weight eating disorders have been given physiological estrogen replacement 
with cyclic progesterone for up to 18-months, without any noted serious adverse events.126-130 
 
Given the short timeframe of P4 addback in this study (2-weeks), we expect the risk for any side effects to be 
minimal and any side-effects that are experienced will be brief.  


16 
 
Lupron,  Estradiol, and Progesterone Combined  Administration: The proposed monthly 3.75-mg injection of 
leuprolide acetate (Lupron Depot) is FDA-approved for use in premenopausal women to treat endometriosis and 
uterine fibroids.163 Lupron has also been widely researched and used to treat a variety of medical conditions, 
including ovarian epithelial tumor cells,97insulin resistance,98 endometrial stromal sarcoma,99infertility,100 and 
premenstrual syndrome and premenstrual dysphoric disorder.101-103  Combined Lupron and estrogen/progestin 
supplementation is a recommended long-term treatment for premenstrual syndrome.104, 105 Women undergoing 
IVF to treat infertility routinely receive luteal supplementation of 600 mg progesterone daily along with 6 mg 
oral micronized estradiol107 in combination with GnRH agonists (e.g., Lupron). 
 
GnRH agonist treatment combined with hormone addback (i.e., high-dose estradiol and progesterone 
supplementation) has been previously studied in large randomized controlled trials for the purpose of IVF to 
treat infertility.107, 109-111 Several studies have examined the use of combined Lupron treatment (1 mg daily or 
3.75 mg monthly), oral micronized estradiol (max doses ranged from 4 mg to 9 mg daily), and either oral (900 
mg daily), vaginal (90-600 mg daily), or i.m. (50-200 mg daily) progesterone administration in >1800 
women.108, 109, 111, 164-172 
 
Dr. Schiller’s research lab at UNC and labs at NIH have examined the combined administration of Lupron 
and estradiol and/or progesterone in premenopausal women in several studies without a serious adverse 
event.113-117 Thus, a large number of women have previously received combined Lupron with high-dose oral 
estradiol and progesterone supplementation either as treatment for a medical condition, a research study, or 
routine IVF treatment without serious adverse events. It is possible that women with BN or who binge eat 
may have taken part, as assessing for an eating disorder is not necessarily common practice during medical 
evaluations. 


17 
 
Below we describe the adverse events reported in a recent protocol completed by Dr. Schiller that entailed a 
more invasive study design and higher doses of E2/P4.  This protocol was classified as IND exempt by the 
FDA. 
 
Table 2. Medication Regimens in a previous IND Exempt Protocol and the Proposed Protocol 
Previous  IND Exempt Protocol 
Proposed  Protocol 
Phase 
1: 
Hypogonadism 
2: Low Dose 
Addback 
3: High 
Dose 
Addback 
4: High Dose 
Withdrawal 
1: 
Hypogonadism 
2: Addback 
3: Addback 
Duration 
Lupron 
Estrace 
Prometrium 
4 weeks 
3.75 mg IM 
dose #1 
Placebo 
Placebo 
2 weeks 
3.75 mg IM 
dose #2 
2 mg bid 
200 mg bid 
6 weeks 
3.75 mg IM 
dose #3 
5 mg bid 
400 mg bid 
4 weeks 
3.75 mg IM 
dose #4 
Placebo 
Placebo 
6 weeks 
3.75 mg IM 
dose #1,2 
Placebo 
Placebo 
2 weeks 
3.75 mg IM 
dose #3 
2 mg bid 
2 weeks 
200 mg bid 
 
 
Below (Table 3) is a list of the adverse events that occurred in the previous, IND exempt protocol conducted at 
UNC by Dr. Schiller described above. All of the symptoms summarized in Table 3 were either transient and 
remitted without intervention or were addressed either by consolidating the dose to nighttime or by decreasing 
the dose of estradiol by 2 mg or progesterone by 200 mg, depending on the symptom. The adverse events 
reported in purple most replicate the experimental arms proposed here. Dizziness was the most common 
reported side effect and side effects were more common during the addback conditions compared with the 
Lupron-only condition. In the current protocol, the addback conditions are only 4-weeks total (2-weeks each) 
whereas in the previous protocol they were 8-weeks total. Few adverse events were reported as “severe.” 
Importantly, there were no serious adverse events in this study and no subjects were discontinued due to an 
adverse event. 
 
 
Table 3. Adverse Events in a Previous IND Exempt Protocol 
1: Hypogonadism 
2: Low Dose Addback 
Cognitive: 
Drowsiness 
1 
1 
Sedation 
3 
Dizziness 
1 
5 
Lightheadedness 
1 
Memory impairment 
Psychological: 
Depression 
2 
Anxiety 
1 
Irritability 
2 
Mood Swings 
1 
Trouble concentrating 
1 
Night Terrors 
1 
Gastrointestinal: 
Nausea 
1 


18 
 
 
Diarrhea 
1 
Upset Stomach 
Constipation 
1 
Heart Burn 
1 
1 
Cardiac: 
Transient Heart Palpitations* 
1 
Chest Pain* 
1 
Arrhythmia* 
1 
Bradycardia* 
1 
Menstrual: 
Spotting 
1 
Prolonged menstrual bleeding 
Heavy menstrual bleeding 
Breast Tenderness 
2 
2 
Vaginal itching 
Cramps 
Physical/Somatic: 
Weight Gain 
Hot Flashes 
1 
Headache 
3 
1 
Hair Loss 
Cracked Nipple 
1 
Rash on legs 
1 
Tingling 
1 
Dry Mouth 
1 
Frequent Urination 
1 
Hip pain 
1 
TOTAL 
18 
27 
Note: Bolded individual symptoms were rated as severe. Headaches were rated as severe two times and all other bolded symptoms were rated as 
severe only once. All others symptoms were rated minimal, mild, or moderate. 
*Symptoms were determined by an independent physician to be a result of participant’s excessive physical training for Iron Man combined with poor 
self-care (i.e., working 3rd shift, sleeping 4 hours/night, and poor diet) rather than the study. All symptoms resolved when participant reduced 
training schedule and increased time available for sleep. 


19 
 
2 
Study Objectives 
 
 
The objective of this study is to examine whether BN is an ovarian hormone sensitive phenotype and whether 
this hormone sensitivity is modulated by reward processing by directly manipulating ovarian hormone levels in 
women with BN (n = 15), using an established experiential design. For the first time in humans, we propose an 
experimental design that parallels animal models to directly manipulate ovarian hormones: temporarily stopping 
the menstrual cycle (i.e., hypogonadism) and then adding back E2 and P4 independently in a double-blind 
cross-over design in order to examine the direct effect of E2 and P4 on the BN symptom of binge eating. 
Participants will complete behavioral tasks and self-report questionnaires of reward processing and response 
during each phase of the experimental design. Our overarching hypothesis for the following aims is that BN 
represents a hormone sensitive phenotype and this sensitivity is displayed as an impaired reward response 
within the context of low E2 such that E2 addback will be beneficial for all outcomes of interest. We plan to 
accomplish the objectives of this application by pursuing the following specific aims: 
 
 
Aim 1: Quantify the direct effect of E2 and P4 on binge eating in women with BN. 
 
Aim 2: Determine the effect of E2 on reward response and related correlates (e.g., behavioral inhibition) in 
women with BN during behavioral tasks and through self-report questionnaire. 
Aim 3: Examine the association between reward response (defined in Aim 2) and binge eating before and after 
E2 addback. 
 
 
3 
Study Design 
 
 
3.1 
General Design 
 
 
This single-site study will include 8 study visits in total and a reproductive hormone challenge. Participants will 
undergo screening and consent (T0), a baseline assessment (T1), testing at the end of each experimental phase 
(T2-T4), and a follow-up assessment 8-weeks post-intervention (T5). Brief testing to examine side effects will 
also occur in addition to the end-of-phase primary study visits. During the hormone challenge, subjects will 
have an equal number of brief check-in visits (n=3) and end-of-phase study visits (n=3) The study timeline is 
depicted in Figure 5, and the specific procedures that will take place are outlined in Table 4 and detailed below 
in Section 6. 
 
 
3.2 
Outcome Variables 
 
The primary outcomes for the Specific Aims are: 1) binge eating, and 2) reward response. 
 
 
Binge eating will be defined as: 1) the EPSI subscale binge eating score obtained at each study visit (T1-T4), 
which represents symptoms over the previous week; 2) a weekly average based on daily frequency obtained 
from the DSRP. For both the subscale score and weekly average, the primary outcome is the last week of each 
phase of the hormone challenge to capture the period of time with maximal symptom change. 
Reward response and related correlates will be defined by the Monetary Incentive Delay (MID),174 the Delayed 
Discounting (DD) and Go No/Go behavioral tasks, and the BIS/BAS and SPSRQ self-report questionnaires. 
MID operationalizes reward response as motivated behavior: the average speed of responses to reward vs. non-


20 
 
P 
Lupron 
P 
E2 
P 
P4 
reward trials during a reward task. DD operationalizes reward response as “delay gratification”: the tendency to 
choose small, immediate rewards over larger, delayed rewards. The task determines the rate of devaluation over 
time for the larger, delayed reward, which is defined as the k parameter. We use behavioral tasks of monetary 
reward vs. food because the value of food is dependent on hunger state202, 203 and it reduces the confounding 
effect of the task provoking symptoms.34 The Go/No Go Task is a behavioral measure of inhibitory control. 
Inhibitory control is defined by the response accuracy of the go no/go trials with fewer errors (“go” response on 
a “no/go” trial) indicating better inhibitory control. 
The BIS/BAS and SPSRQ will be included as self-report measures relevant to the reward response. The 
BIS/BIAS will be used to assess behavioral inhibition and activation. The SPSRQ will be used to assess 
sensitivity to reward. As described in the statistical analysis plan below, reward response will be examined 
within the E2 arm of the study.  
 
Figure 5. Within-Subject Hormone Challenge (study visits occur every 2 weeks) 
 
 
Phase 
Screening  hypogonadism   Addback 
Addback  
Follow-up 
 
Month 
0 
 
 
 
 
 
Medication 
1 
2 
3 
4 
5 
6 
 
 
Assessments   T0 
T1 
T2 
T3 
T4 
T5


21 
 
 
 
4 
Subject Selection  and Withdrawal 
 
 
4.1 
Inclusion Criteria 
 
 
Participants will be women aged 18-42 with a current BN. Only participants capable of giving informed consent 
and understanding the risks associated with the study will be enrolled. Participants will be compensated upon 
completion of the study. 
Inclusion Criteria. 
1) Current BN  
2) Aged 18-42 
3) A regular menstrual cycle for at least three months; 
4) BMI < 35 
5) Free of medication that impacts ovarian hormones or is contraindicated for use with study interventions 
 
 
4.2 
Exclusion Criteria 
 
Patients will not be permitted to enter this protocol if they have important abnormalities including any of the 
following: 
· 
peanut allergy 
·   
endometriosis (an illness related to abnormal tissue growth around the uterus) 
·   
enlargement of the ovaries 
·   
liver disease 
·   
breast cancer (self or family history) 
·   
a personal or family history of blood clots  
·   
undiagnosed/abnormal vaginal bleeding 
·   
porphyria (a rare genetic blood disorder) 
·   
diabetes mellitus 
· 
osteoporosis or osteopenia  
·   
malignant melanoma (a type of skin cancer) 
·   
gallbladder or pancreatic disease 
·   
heart or kidney disease 
·   
cerebrovascular disease (stroke) 
·   
currently smoking >10 cigarettes daily 
· 
epilepsy or history of seizures 
·   
a history of suicide attempts or bipolar disorder/psychotic episodes 
· 
current substance misuse 
· 
frequently use diuretics or laxatives 
·   
recurrent migraine headaches with aura 
·      
history of pregnancy-related deep vein thrombosis 
·       
irregular menstrual cycle  
·       
body mass index (BMI) greater than 35 
· 
currently pregnant, planning to become pregnant, or lactating 
·       
taking any medication or have any other medical history that is contraindicated for the medications used 
in this study  
· 
unwilling to use barrier contraceptive during the study 


22 
 
·          Any condition or symptoms considered by the study team to detrimentally impact subject safety. 
·          First degree relative (immediate family) with breast cancer that occurred before menopause, or breast 
cancer presenting in both breasts, or if you have multiple family members (greater than three relatives) with 
breast cancer.  
 
 
4.3 
Subject Recruitment and Screening 
 
 
Methods of recruiting for this study include: 
 
We will utilize recruitment methods that have been highly successful in the past including: 
 
1) Recruiting directly from the UNC Center of Excellence for Eating Disorders (CEED) outpatient 
treatment and research program: CEED evaluates between 200-220 new patients per year and has an 
excellent track record of successful recruitment of women with EDs for research studies.175 Specifically, we 
will recruit women from the CEED via flyers, brochures, and direct recruitment by speaking with women who 
expressed interest in research on their referral form. In a recent clinical treatment trial for BN,175 214 women 
contacted study staff and completed the phone screen and 80% were randomized. 
 
2) Established research registries at CEED and within the Department of Psychiatry at UNC: CEED 
houses a research registry, which any member of the community (including current CEED patients) can join and 
consent to be contacted about future studies. There are currently 535 individuals signed up for the registry, 81 of 
whom self-report a BN diagnosis. CEED also has a registry of previous research study participants who 
consented to be re-contacted for future studies. Additionally, Dr. Schiller has an established registry of 
individuals (3,000+) who previously completed online screening questionnaires for her hormone manipulation 
studies who agreed to be contacted for future studies. 
 
3) Targeted social media and website advertisements (e.g., Facebook; ResearchMatch.org; Craigslist): In 
past studies, we have found social media to be an extremely effective strategy for recruitment at CEED.176, 177 
 
4) Large-scale research registries: UNC houses two large-scale research registries available to researchers: 
The Carolina Data Warehouse (CDW), a central data repository containing clinical, research, and administrative 
data sourced from the UNC Health Care System, and the website Join the Conquest. Within CDW currently, 
557 female patients aged 18-35 have a diagnosis of BN within the medical record, with 151 of these diagnoses 
being made since 2017. 
 
5) Flyers, brochures, and mass emails: these will be disbursed in UNC Hospitals, across the university, across 
the larger community, and with established community partners who allow us to advertise and recruit for active 
studies (e.g., local medical offices). 
 
6) NC TraCS Research Recruitment Service: We will capitalize on the TraCS Research Recruitment 
Service’s expertise in enrolling members of communities historically under-represented in research. 
 
7) TrialFacts Clinical Trial Recruitment: As of March 2021, we will also work with the clinical trial 
recruitment/marketing company TrialFacts. During recruitment and initial screening process, direct interaction 
occurs between the individual and TrialFacts, not study staff. The TrialFacts website specifically informs 
individuals that they are a distinct company from the trial site and a distinct organization from the site 
conducting the research study. Individuals consent to provide their data to TrialFacts, receive communication 
from TrialFacts, and for TrialFacts to provide us with their contact information. TrialFacts are the owners of the 


23 
 
data they collect and it does not become part of the research study data. TrialFacts primarily recruits via social 
media avenues (facebook, youtube, instagram etc). Individuals are self-identified by responding to the 
advertisements. Once an individual self-identified by TrialFacts is determined as potentially eligible for our 
study, contact information is provided to us by Trialfacts - only at this point does our study team begin/initiate 
any contact (i.e., phone call) with this individual.  
 
Eligibility screening will include: 
● An initial phone or online screening that includes questions about past medical and mental health history 
to assess potential participants eligibility based on the criteria listed in sections 4.1 and 4.2. 
● Participants will undergo a Clinical and Health Screening process to determine whether they are healthy 
enough to participate in this study. 
● All participants will receive a pregnancy test. No pregnant women will be entered into the study, 
because the study drugs (Lupron, estrogen, and progesterone) may be associated with birth defects. 
 
 
4.4 
Early Withdrawal of Subjects 
 
 
4.4.1 
When and How to Withdraw Subjects 
 
 
• Participants with significant clinical/laboratory abnormalities will not be enrolled/discontinued from the 
study prior to GnRH agonist administration. 
• Participants deemed at elevated suicide risk at enrollment will not be enrolled in the study. 
• If a subject is deemed at elevated suicide risk at any point after enrollment, they will be discontinued 
from the study protocol. 
• Any subject experiencing clinically significant side effects that cannot be relieved will be discontinued. 
• If menopausal-like symptoms occurring secondary to GnRH agonist treatment are intolerable, drug 
treatment will be discontinued. 
• Any subject experiencing > 50% increase in BN symptom severity, as indicated by the frequency of 
binge eating and/or purging behaviors, during the medication protocol will be assessed for 
discontinuation. Continuing/discontinuing will, in part, depend on subject safety, whether the increase 
in severity is likely a direct result of the study protocol, and if the subject is in current, study approved 
treatment, for their eating disorder. 
 
Participant safety will be managed in several ways. First, risk is managed through study eligibility criteria. 
Although we do not expect the hormone manipulation to elevate suicide risk based on previous studies,87, 88, 117, 
118 as an added measure of safety, we exclude subjects who have a history of elevated suicide risk. Specifically, 
exclusionary criteria include a history of a suicide attempt. Second, risk is also managed by the truncated 
hormone regimen. The protocol has been shortened to only the amount of time necessary for each condition to 
elicit symptom change. 
 
Third, to ensure safety of the participant’s enrolled in the study we will monitor risk daily, throughout the study 
protocol. Once enrolled, subjects will complete a daily questionnaire that assesses the presence and intensity of 
behavioral (e.g., binge eating frequency) and mood symptoms. This will include items related to suicide risk. 
The questionnaire will be completed online by subjects, and ratings will be transmitted to the study team in real- 
time. Members of the study team will receive immediate notification if a subject endorses active risk on the 
study form. Subjects will be contacted directly by Dr. Baker and a safety assessment will be conducted. Any 
subject that is deemed at elevated suicide risk will be followed-up for at least three days with The Hamilton 
Rating Scale for Depression and the Beck Scale for Suicidal Ideation (SSI). Anyone scoring > 20 on the 


24 
 
Hamilton (indicating severe depressive symptoms178) for three days will be considered to have severe mood 
symptoms and be discontinued from the protocol. The SSI does not have a defined cutoff ( > 6 is suggested as 
high risk for psychiatric patients with a suicide attempt history179); thus, total scores and item-level responses 
will be examined for severity and change. If a subject does not complete the daily form, a member of the study 
staff will contact them and conduct a safety assessment over the phone. 
Fourth, to further ensure the safety of enrolled subjects, participants will complete bi-weekly assessments of 
change in physical symptoms, mood, suicide risk, and eating disorder symptoms throughout the hormone 
manipulation—this is in addition to the daily assessment. Mood symptoms and suicide risk will be monitored 
by administering the Inventory of Depression and Anxiety Symptoms (IDAS). The IDAS will be scored 
immediately and if IDAS suicidality risk scores > 8 are observed (mean score observed in non-psychiatric 
community sample; we use this mean to conservatively evaluate risk180), then the Hamilton Rating Scale for 
Depression and SSI will be administered as described above. BN symptoms (e.g., binge eating, purging) will be 
monitored at bi-weekly appointments with the Eating Disorder Examination Questionnaire (EDEQ). The EDEQ 
will be scored during bi-weekly visits and scores will be compared with baseline levels and previous study 
visits. Dr. Baker will follow-up with any participant with a >50% increase in symptoms as indicated by the 
EDEQ questions regarding frequency of binge eating and purging behaviors. 
 
We are not conducting a clinical treatment study and thus are not providing care or management of the subject’s 
BN symptoms. We will not provide treatment or pay for treatment/medical costs for subjects who are 
discontinued from the study or in need of medical care during the course of the study. However, we will ensure 
subjects have appropriate treatment contacts before terminating contact with the subject. 
 
Notably, no serious adverse reactions or events were encountered in past studies conducted with this protocol. 
No subjects to date have been discontinued from a study protocol due to heightened suicide risk. Indeed, this is 
true of similar experimental designs that have been longer in nature and selected individuals with a history of a 
mood disorder. It is possible that women with current BN may be at increased risk; however, this risk is 
decreased by excluding women with a significant suicide history. Additionally, previous studies implementing 
this hormone regimen have shown that E2 and P4 addback are the conditions which negatively impact mood87, 
118 (i.e., depressive symptoms worsen). In the current study these conditions are brief, lasting only 2-weeks. 
Thus, any impact on mood that may occur is expected to be transient. 
 
Any patient experiencing clinically significant side effects such as nausea, vomiting, or extreme fluid retention 
from the medication will have the dose titrated to achieve relief of the symptoms. If adequate relief cannot be 
achieved in this manner, drug treatment will be discontinued. Similarly, if menopausal-like symptoms 
occurring secondary to GnRH agonist treatment are intolerable, drug treatment will be discontinued. 
 
Should an adverse event occur, we will comply with the NIMH reporting requirements for adverse events. As 
Principal Investigator, Dr. Baker will be responsible for the documentation, investigation, and follow-up of all 
study-related adverse events. All adverse events will be reported according to the NIMH expectations and 
reporting timeframes and provided to the study Program Officer in writing. Dr. Baker will also be responsible to 
report any individual occurrence of an adverse event to the Chair of the DSMB according to the guidelines 
established at the initial DSMB meeting. All moderate or severe adverse events will be reported to the UNC 
IRB within 7 calendar days. The NIMH Program Officer will be notified of any study modifications or 
suspension imposed by the DSMB or local IRB in response to an adverse event. 
 
The determination of when and how to withdrawal subjects will be overseen by the study’s Data and Safety 
Monitoring Board and will be reported to the UNC Biomedical IRB. 
 
 


25 
 
5 
Study Drug 
5.1 
Description 
 
Drug 
Dosage 
Formulation 
Estradiol 
2 mg bid (total of 4 mg/day) Oral capsule 
Lupron Depot 
3.75 mg/month 
Intramuscular injection 
Progesterone 
200 mg bid (total of 400 
mg/day) 
Oral capsule 
 
 
 
5.2 
Treatment Regimen 
 
 
Regimen 
 
Induced Hypogonadism. After a screening period, participants will receive their first injection of the 
gonadotropin-releasing hormone (GnRH) agonist leuprolide acetate (Lupron) 3.75 mg/month via i.m. injection, 
which is administered to produce a stable hypogonadal condition (after the initial “flair”). The first Lupron 
injection will be administered at approximately day six of the participants’ first menstrual cycle. After 4-weeks 
of Lupron alone, participants will begin taking two capsules daily of either placebo, estradiol, or progesterone 
for 8-weeks. They will be told at some points during this final 8-week period of the study, the pills will be 
active medication and at some points they will be placebo. Subjects will be blinded to when medication 
switches to active medication; all participants will first receive 2-weeks of placebo. After 2-weeks of placebo, 
the end-of-phase Lupron assessment (T2) will occur and placebo capsules will be switched to active medication 
in a double blind, cross over design. 
 
Addback. After 6-weeks of Lupron-alone treatment (i.e., hypogonadism), physiological levels of E2 or P4 will 
be attained via oral micronized E2 (2mg b.i.d) or P4 (200mg b.i.d), respectively (along with continued Lurpon 
administration), with a 2-week washout period in-between. Placebo pills continue during the washout. The 
blood levels that we expect to achieve and sustain in each woman will be approximately 500 pg/ml of estradiol 
and 30-40 ng/ml of progesterone. 
 
 
5.3 
Method for Assigning Subjects to Treatment Groups 
 
All subjects will receive the same drug protocol in a double-blind, cross over fashion. The study biostatistician 
will create a randomization table. Subjects will be randomized into two arms by permutated block of small size 
2 with 1:1 ratio and maximum imbalance of 1. We will also restrict E2-P4 group to have the n = 8 and P4-E2 to 
have n=7 because the response from E2-P4 group is the primary phase of interest. The pre-generated 
randomization sequence will be uploaded to REDCap, with assignment group information coded. REDCap will 
randomly assign a possible number from table when a subject is entered. Study personnel will only receive that 
randomization number and will not receive information on the coded assignment group, so not only will they 
not know what group a subject is in, but they won't know which subjects have been similarly assigned. We will 


26 
 
not store any information on what assignment groups codes actually correspond to in REDCap, further ensuring 
that randomization remains concealed. 
 
 
5.4 
Preparation and Administration of Study Drug 
 
All study drugs will be stored, prepared, and dispensed from the UNC Investigational Drug Service (IDS). 
 
Assigned Study Pharmacist: 
Investigational Drug 
Service Department of 
Pharmacy UNC Hospitals 
CB 7600, Room 3001 
101 Manning Drive 
Chapel Hill, NC 27514 
 
 
5.5 
Subject Compliance Monitoring 
 
We will monitor participants’ compliance with the drug regimen through self-report. Compliance will also be 
monitored by having participant’s return any missed pills during the study visits. 
 
 
5.6 
Prior and Concomitant Therapy 
 
Women are required to be free of any medications that influence ovarian hormones or are contraindicated for 
use with the study medications; however, prior medication usage will not preclude participation in the study. 
 
 
5.7 
Packaging 
 
The UNC Investigational Drug Service will receive the active drug from their Pharmacy storeroom and will 
provide the capsules for blinding. 
 
 
5.8 
Blinding of Study Drug (if applicable) 
 
Placebo and active medication will be in like-colored capsules with identical labeling. Subjects will take two 
capsules daily during each phase once oral medication administration begins. 
 
 
5.9 
Receiving,  Storage, Dispensing and Return 
 
The UNC Investigational Drug Service will receive the study drugs from the UNC Pharmacy Storeroom and 
will dispense the drug to the PI or study coordinator to deliver to participants. Any unused drug will be returned 
to the UNC Investigational Drug Service. 
 
5.9.1 
Receipt of Drug Supplies


27 
 
To dispense medications, IDS sets up a standing medication order in the electronic medical record for each 
study. When a medication is needed, the project coordinator will pull up the order, enter the participant’s subject 
ID number and confirm they provided informed consent. Within the order there is also a comment box to 
provide additional information to the pharmacy. When oral medications are dispensed, the project coordinator 
will note in this box if the medication dispensed is to be active hormone or placebo. The order is then forwarded 
to Co-Investigator Young for review and signature. Only an MD has the ability to sign off on an order. Orders 
are sent electronically to IDS who then dispenses the study medication according to the study protocol.  
 
According to IDS protocol, prior to the first oral medication release, IDS is provided with the participant’s 
randomization number. The research coordinator will be primarily responsible for picking up the prescription 
from IDS. Upon receipt, the coordinator will check the medication to ensure the prescription is for the correct 
participant. The research coordinator will be blinded to the sequence of the medication (E2 and P4). 
 
5.9.2 
Storage 
 
Lupron, Estradiol, and Progesterone will be stored at 20° to 25° C in a temperature-controlled facility. 
 
5.9.3 
Dispensing of Study Drug 
 
Drugs will be dispensed in tight, light-resistant containers and defined in the USP, with a child-resistant closure. 
Regular study drug reconciliation will be performed to document drug assigned, drug consumed, and drug 
remaining. This reconciliation will be logged on the drug accountability form and signed and dated by the study 
team. 
 
5.9.4 
Return or Destruction of Study Drug 
 
At the completion of the study, there will be a final reconciliation of drug shipped, drug consumed, and drug 
remaining.  This reconciliation will be logged on the drug reconciliation form, signed and dated.  Any 
discrepancies noted will be investigated, resolved, and documented prior to return or destruction of unused 
study drug.  Drug destroyed on site will be documented in the study files. 


28 
 
Procedure 
T0 
T1 
T2 
T3 
T4 
T5 
Check-in 
Eligibility and Enrollment 
Informed Consent 
x 
Demographics 
x 
SCID-5 
x 
GYN Exam/Medical History 
x 
Venipuncture 
x 
 
 
 
 
 
Saliva Samples 
 
x 
x 
x 
x 
x 
Side Effects & Adherence 
x 
x 
x 
 
x 
Self-report Questionnaires 
IDAS* 
x 
x 
x 
x 
x 
x 
x 
EDEQ* 
x 
x 
x 
x 
x 
x 
x 
EPSI 
x 
x 
x 
x 
x 
x 
x 
BIS/BAS 
x 
x 
x 
x 
x 
x 
SPSRQ 
x 
x 
x 
x 
x 
x 
Behavioral Tasks 
MIDT 
x 
x 
x 
x 
DD 
x 
x 
x 
x 
Go/No Go 
x 
x 
x 
x 
PANAS 
x 
x 
x 
x 
24-hour Food Intake 
x 
x 
x 
x 
*used to monitor subject safety only 
6 
Study Procedures 
 
Overview. This single-site study will include 8 study visits and the reproductive hormone challenge (Figure 5). 
The experimental protocol will last approximately 3-months. Participants will undergo screening and consent, a 
baseline assessment, testing at the end of each experimental phase, brief testing to examine side effects and 
protocol adherence, and a follow-up assessment 8-weeks post-intervention. 
 
The study timeline is depicted in Figure 5 in Section 3, and the specific procedures that will take place are 
outlined in Table 4 and detailed below. 
 
Participants. Women between the ages of 18-42 with a current DSM-5 diagnosis of BN. Our primary research 
question does not require a control group and requires a within-subjects design. All participants will undergo 
the same hormonal challenge but in a 
Table 4. Study Visit Procedures  
double-blind cross-over design. Subjects 
will be randomly assigned to receive 
E2+P4 or P4+E2 based on the 
randomization table created by the study 
biostatistician. 
Hormone Administration. The hormone 
administration protocol replicates a 
design used by co-investigators,87, 117 
with slight modifications made based on 
previous study findings in order to 
reduce the burden of the protocol and the 
risk for side effects. The hormone 
challenge consists of three study phases: 
1) hypogonadism; 2) E2 addback; 3) P4 
addback. Lupron administration begins 
at T1 and continues throughout the 
duration of the challenge. Medication 
administration (placebo or addback) 
begins after 4-weeks of Lupron-alone. 
This is done in order to add an additional 
blind to participants as to whether they 
are on active medication vs. placebo. 
Because the end-of-phase assessments 
are longer in duration than the check-in 
visits, it is possible a subject could 
detect when active mediation begins 
based on the timing of the change from 
check-in visits to end-of-phase 
assessments if medication administration 
begins with the first dose of Lupron. 
This also standardizes each study phase 
to be 2-weeks in length as the first 
month of Lupron is not a study phase of 
interest, yet a ‘waiting period’ for 
ovarian suppression to occur. 


29 
 
Induced Hypogonadism. At T1, participants will receive their first injection of the gonadotropin- 
releasing hormone (GnRH) agonist leuprolide acetate (Lupron) 3.75 mg/month via i.m. injection, which is 
administered to produce a stable hypogonadal condition (after the initial “flair”). The first Lupron injection will 
be administered at approximately day six of the participants’ first menstrual cycle and monthly thereafter. 
Subjects will be on Lupron alone for 6-weeks. Previous studies using this experimental design show significant 
change in behavioral measures of interest after 6-weeks.87 
During the first month of GnRH agonist administration, participants will not receive any other 
medication. After 4-weeks of Lupron alone, all participants will receive 2-weeks of placebo capsules (blinded to 
the participant) and continue daily capsules throughout the duration of the study. Subjects will be told at some 
points the medication will be active and at other points it will be placebo. Subjects will not know when 
medication is active vs. placebo. An end-of-phase (T2) assessment will occur before addback, 2-weeks after 
medication administration begins. 
Addback. After 6-weeks of Lupron-alone treatment (i.e., hypogonadism), physiological levels of E2 or 
P4 will be attained via oral micronized E2 (2mg b.i.d) or P4 (200mg b.i.d), respectively (along with continued 
Lurpon administration), with a 2-week washout period in-between. Placebo pills continue during the washout. 
Each addback phase will be 2-weeks (compared with 4-weeks) as previous studies using this experimental 
design have shown significant symptom change can be obtained within 2-weeks.87 Subjects will be randomized 
to receive E2 followed by P4 or P4 followed by E2. The study biostatistician will create a randomization table 
and study investigators will be blinded to the randomization order. End-of-phase assessments will occur at the 
end of E2 and P4 addback (T3/T4). 
 
Once medication administration begins, subjects will be instructed to take pills twice daily, at approximately the 
same time each day. To improve medication compliance, we will recommend subjects schedule a daily reminder 
on their phone to take the study medication each day. The daily assessments will also ask participant’s whether 
they took the study medication each day. 
 
Clinical Assessments. Measures used to obtain primary outcomes and monitor subject safety are shown in 
Table 4. Study visits will occur every 2-weeks. Participants will attend end-of-phase assessments at the end of 
each hormone phase as well as check-in visits to monitor symptoms. There will be an equal number of end-of-
phase assessments and check-in visits (3 each) during the hormone challenge. All study measures are 
empirically valid and reliable. 
 
Clinical Interviews 
a)  SCID-5: Structured Clinical Interview for DSM-5181 will be administered by trained study staff at 
T0, and supervised by Dr. Baker, to confirm eligibility and BN diagnosis. Based on DSM-5 criteria, 
the interview guides trained interviewers in determining whether a psychiatric diagnosis is present 
or absent. 
 
Self-report Questionnaires 
Self-report questionnaires will be completed through secure, encrypted, online survey (i.e., Qualtrics), and 
scored by standard conventions. During the reproductive hormone challenge, (i.e., T1-T4) self-report 
questionnaires will be modified to represent symptomatology over the previous week only, in order to capture 
the period of time with maximal or minimal pathology during each hormone manipulation phase.  
 
Primary outcome measures are bolded. Non-bolded measures are included to replicate the projected protocol 
for the larger mechanistic trial we will conduct based off of these pilot data but will not be examined as 
outcomes in the current study.


30 
 
a)  Demographics: at baseline, subjects will be asked to self-report relevant demographic information in 
order to address eligibility and to characterize the sample: age, race, ethnicity, marital status, 
education level, and participation in any current treatment for BN. 
b)  Adverse Life Events Checklist: will be completed at baseline only to obtain information on the 
number of adverse life events experienced by the participant as previous studies have suggested that 
ovarian hormone sensitivity is greater in women with a history of adverse life events.182 Respondents 
indicate varying levels of exposure to each type of potentially traumatic event. A count score will be 
obtained which indicates the number of negative adverse life events experienced. It will be 
completed at baseline only and we plan to include it in our follow-up clinical trial.  
a) UPPS-P: The UPPS-P Impulsive Behavior Scale183 is a 59-item self-report questionnaire that 
assesses distinct dimensions of impulsivity. Here we include the negative urgency, lack of 
premeditation, and sensation seeking subscales. It will be completed at baseline only and we plan to 
include it in our follow-up clinical trial.  
b)   Inventory of Depression and Anxiety Symptoms (IDAS):184 is a 64-item questionnaire that 
comprehensively assesses anxiety and depression symptoms, including ill temper, dysphoria, 
appetite change, lassitude, well-being, and suicidality. The IDAS is only used to monitor 
subject safety. 
c)   EDEQ: the Eating Disorder Examination Questionnaire,185 will be used to monitor subject safety. 
Items include frequency of specific behaviors (e.g., binge eating, purging) as well as a subscale score.  
d)   EPSI: the Eating Pathology Inventory186 is a 45-item self-report questionnaire assessing various 
aspects of eating disorder symptomatology and will be included in order to obtain a more detailed 
examination of symptoms compared with frequency counts only. The EPSI includes eight subscales; 
however, we only include the following subscales in the current project: binge eating, body 
dissatisfaction, cognitive restraint, purging, excessive exercise, and restricting. A majority of the 
previous studies to date examining symptom change over the menstrual cycle have focused on 
symptom-scores, including pilot data from our own group using the EPSI.177 
e)   BIS/BAS Scales: the Behavioral Inhibition/Behavioral Activation Scales187 is a 24-item measure 
designed to measure behavioral inhibition and behavioral activation. It is comprised of four 
subscales: BIS, Reward Responsiveness, Drive, and Fun Seeking, and 20 items total that assess 
behavioral inhibition and behavioral activation. Primary outcomes of interest are reward 
responsiveness, behavioral inhibition, and behavioral activation. The BIS/BAS scales are associated 
with neural markers of psychopathology. 
f) SPSRQ: The Sensitivity to Punishment/Sensitivity to Reward Questionnaire188 is a 48-item self- 
report questionnaire used to assess sensitivity to reward and sensitivity to punishment. 
g)  The Food Cravings Questionnaire (FCQ): the Food Cravings Questionnaire,189, 190 includes an 
assessment of both trait-cravings and state-cravings. Only the craving as a physiological and 
preoccupation with food subscales will be given. The FCQ will be included in our larger, 
follow-up clinical trial. 
h)  Three-Factor Eating Questionnaire-Hunger Subscale: The TFEQ-Hunger subscale191 will be used to 
assess changes in self-reported hunger across the experimental design. Hunger will be included in 
the larger mechanistic trial given previous studies show in change in appetite, including our own 
pilot work, with E2 administration. The TFEQ will be included in our larger, follow-up clinical trial. 
i) EEI: The Eating Expectancies Inventory (EEI) will be given at T2-T5. The EEI measures learned 
expectations about eating and contains five subscales. We include the eating helps manage negative 
affect, eating is useful as a reward, and eating leads to feeling out of control subscales. It will be 
included in our follow-up, larger clinical trial.  


31 
 
 
Scoring for Primary Outcome Self-Report Questionnaires 
Scale 
Likert Scale Minimum Score Maximum Score 
EPSI 
5 point 
Binge eating 
0 
32 
BIS/BAS 
4 point 
Behavioral inhibition 
7 
28 
Fun seeking 
4 
16 
Reward responsiveness 
5 
20 
SPSRQ 
2 point(T/F) 
Sensitivity to reward 
0 
24 
 
 
 
Reward Response Behavioral Tasks 
 
a)  Monetary Incentive Delay Task (MIDT)174: Two event-related MID runs consist of 6-second trials 
during which women will be presented with a cue shape, a fixation crosshair (for variable duration), 
the target, and performance (win/loss/neutral) feedback. Cues indicate whether it is an incentive 
(gain, loss) or non-incentive trial. In incentive trials, women can gain or lose money by pressing a 
button during target presentation; difficulty is based on individual reaction times. MID defines 
reward response as the average speed of responses to reward vs. non-reward trials during a reward 
task. 
b)  Delayed Discounting (DD) Task: The DD task192 is used to understand how subjects make a 
choice between an immediate, smaller reward and a larger reward given after a time delay. 
Discounting is assessed across 4 time delays: 2, 30, 180, and 365 days later. Delays are presented in 
a mixed fashion. Questions are posed to participants asking whether they would prefer to receive a 
given amount of money immediately or a larger amount after a delay. The amount of money 
available immediately is adjusted with each trial to calculate an indifference point for each delay 
periods. Discounting rates of hypothetical and real reward tasks are comparable.193-195 DD defines 
reward response as the tendency to choose small, immediate rewards over larger, delayed rewards. 
The task determines the rate of devaluation over time for the larger, delayed reward, which is 
defined as the indifference point.192 The k parameter will be obtained and used as the primary 
outcome.  
c)  Go No/Go Task: A behavioral Go No/Go Task will be used as a measure of inhibitory control. Each 
trial consists of one stimulus indicating either “go” (response) or “no/go” (do not respond). The 
response accuracy of each no/go trial is used as the indicator for inhibitory control such that fewer 
errors (“go” response on a “no/go” trial) signifies better inhibitor control. 
d)  Positive Affect Negative Affect Schedule: The PANAS180 is a 10-item questionnaire that measures 
current positive and negative affect. The measure will be given to subjects prior to the behavioral 
tasks to include as a potential covariate in statistical analyses. Items are answered according to a 1 to 
5 Likert scale and then summed to create the positive and negative affect subscales with scores 
ranging from 10 to 50. 
e)  24-hour Food Intake: We will ask women to self-report their food intake for the 24-hours prior to 
study appointments. Detailed information will be obtained so that estimated caloric intakes can be 
determined based on the provided information as well as the number of meals and snacks eaten. 
 
Daily Symptom Assessment 
 


32 
 
a)  Daily Rating Form:36 20-item questionnaire that assesses the presence and intensity of physical and 
mood symptoms that accompany ovarian hormone changes, will be used to assess daily symptoms 
and safety. This will be completed by subjects online (i.e., Qualtrics) each morning starting at T0 
and ending at T4. Thus, there will be 17 weekly scores for each participant. The form will be slightly 
modified to include BN symptom ratings (e.g., binge eating frequency). Ratings are 
transmitted to the study team in real-time, which is essential for monitoring changes 
throughout the study and ensuring participant safety. 
 
Assessment Schedule. 
Eligibility. Interested participants will initially complete an online screening survey to assess potential 
eligibility. No more information than required to determine an accurate representation of eligibility will be 
collected. This can also be completed by telephone interview if needed. Women who screen eligible on the 
survey and are interested in participating in the study will be contacted by a member of the study staff to 
schedule a review consent and schedule a screening assessment. 
Screening. At this initial screening visit (T0), consent forms will be reviewed, eligibility confirmed, and 
a Clinical and Health Screening will be completed. Women will be required to have a GYN exam within the 
past year. Women who have had this exam completed already will be asked to provide medical records for 
review. Women who have not had this exam within the past year can go to their own provider to complete the 
exam—providing the records for review—or can be scheduled to see the study GYN (Dr. Schiff). This 
screening will include a laboratory panel (CMP, CBC, pregnancy test). After enrollment (if eligible), 
participants will complete the Daily Rating Form for one natural menstrual cycle. This form will be completed 
each morning, throughout the study duration. We expect the completion of the Daily Rating Form to take <5 
minutes. The Daily Rating Form will also be used to monitor subject safety regarding changes in mood and 
eating disorder symptoms throughout the protocol. 
Baseline (T1) and end-of-phase assessments (T2-T4). Prior to beginning the reproductive hormone 
challenge, participants will complete a baseline assessment (T1) including self-report questionnaires and 
behavior tasks. Most procedures will be repeated at the end of each experimental phase: after 6-weeks of 
Lupron (T2); after 2-weeks of E2/P4 (T3/T4). After the baseline assessment, subjects will complete three end-
of-phase assessments. 
Check-in Visits. In additional to the Daily Rating Form, subjects will have study visits (either end-of- 
phase or check-in visits) every two weeks. Check-in visits will be completed in order to assess side effects and 
protocol adherence. Two check-in visits will occur during Lupron only before medication administration begins 
and one will occur during medication administration (after the washout period). The number of check-in visits 
and end-of-phase assessments are standardized across the study protocol. The same adherence, monitoring, and 
side-effect checks will occur at every study visit once medication administration begins. Along with monitoring 
side effects and adherence, this information will be used for protocol development in our future studies. From 
these visits, we can pinpoint when ovarian suppression has occurred, and thus, the protocol could be modified 
for future studies based on this information. 
Medication Administration and Study Visits. The first dose of Lupron will be given at T1 and 
monthly thereafter. Medication administration (placebo, E2, or P4) will begin after 4-weeks of Lupron alone. 
Subjects will be blinded as to whether capsules contain placebo, E2, or P4. Investigators will be blinded to the 
order of E2 and P4. Subjects will be told that at some points the medication will be active and at other points the 
medication will be inactive. Once medication administration begins, participants will have four remaining study 
visits; three end-of-phase assessments and one check-in visit. The behavioral tasks that are part of the end-of- 
phase assessments are the primary difference between the end-of-phase visits and the check-in visit (we believe 
participants would be unlikely to notice small differences in the type and number of self-report questionnaires 
given). Participants will be told that, over the final 8-weeks of the study, they will attend three long study visits 
and one short study visit, and the addition of the behavioral tasks to the study visit will be randomly scheduled. 
They will be informed of the next study visit type at their current study visit. Although the assignment of the 
behavioral tasks is not random, this is done in order to decrease the likelihood that the participant would detect 


33 
 
whether they are on inactive or active medication by the timing and duration of the study visits. Given the 
significant length of time the addition of the behavioral tasks adds to the study visits (~ 60 minutes), it would 
add significant and unreasonable participant burden to add the behavioral tasks to the post-washout period visit, 
with no empirical/scientific justification to do so given we are not addressing symptom change on the 
behavioral tasks during the washout period. 
Follow-up. Eight weeks after study completion a brief follow-up assessment, via online self-report 
questionnaire, will be completed by participants. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


34 
 
7 
Statistical Plan 
 
Mr. Russ Dean is the database manager and Kai Xia, PhD, is the biostatistician who will complete the statistical 
analyses. 
 
 
7.1 
Sample Size Determination 
 
This is a pilot study to obtain pilot data for larger studies. Previous observational studies in humans suggest at 
least a moderate effect of ovarian hormones on binge eating with an effect size approximating d = 1.5,5, 196, 19] 
including Dr. Schiller’s pilot work described above. Additionally, Dr. Schiller’s pilot work of E2 treatment in 
midlife women indicates d = 2.3 for the effect of E2 replacement decreasing appetite in women with and 
without major depression whereas other published work showed d = 1.51 for the effect of Lupron on 
decreasing food cravings in women with PMS.87 Because we are directly manipulating ovarian hormones with 
an experimental design, which removes other potential confounds found in observational studies, we expect that 
the effect sizes from observational studies are an underestimate. 
 
According to a power estimation for Aims 1 and 2, with a projected sample of n = 15, an effect size of .77 is 
required to detect a treatment difference at a two-sided .05 significance level at 80% power (calculated based 
off of projected sample size and desired power). Additionally, based on n = 15 and estimated effect size of 1.5 
for E2 on binge eating (the average effect size observed in previous studies),5, 196, 197   a power estimation for 
Aim 1 (our primary aim) estimates our power at significance of .05 is > 90%. Thus, despite the smaller sample 
size of this pilot study, power analyses indicate we should have sufficient power based on hypothesized effect 
sizes (which are empirically based) for E2 on binge eating. 
 
 
7.2 
Statistical Methods 
 
Statistical analyses are completed using the most recent version of R. Primary outcome measures, as described 
below, are binge eating and aspects of the reward response. Methods are modeled after similar, successfully 
implemented studies.87, 117 All measures included are empirically valid, and well-established, thus, measures 
will be scored according to standard conventions and scoring procedures. Descriptive statistics and graphics 
will be used to screen for errors, outliers, and potential influential observations and to check distributional 
assumptions. Where appropriate statistical estimates will be tabulated. We first complete analysis without 
covariates. As appropriate, relevant covariates may also be included in data analysis (e.g., negative affect, self-
reported food intake). 
 
 
PRIMARY OUTCOMES 
 
Binge eating will be defined as: 1) the EPSI subscale binge eating score obtained at each study visit (T1-T4), 
which represents a continuous score of symptoms over the previous week (higher scores indicate more 
symptoms); 2) a weekly average based on daily frequency obtained from the DSRP. For both the subscale score 
and weekly average, the primary outcome is the last week of each phase of the hormone challenge to capture the 
period of time with maximal symptom change. 
 
Reward response will be defined by the Monetary Incentive Delay (MID),174 the Delayed Discounting (DD), 
and Go No/Go behavioral tasks and the BIS/BAS and SPSRQ self-report questionnaires. MID operationalizes 
reward response as motivated behavior: the average speed of responses to reward vs. non-reward trials during a 
reward task. 


35 
 
DD operationalizes reward response as “delay gratification”: the tendency to choose small, immediate rewards 
over larger, delayed rewards. The task determines the rate of devaluation over time for the larger, delayed 
reward, which is defined as the k parameter. We use behavioral tasks of monetary reward vs. food because the 
value of food is dependent on hunger state202, 203 and it reduces the confounding effect of the task provoking 
symptoms.34 
The Go/No Go Task is a behavioral measure of inhibitory control. Inhibitory control is defined by the response 
accuracy of the go no/go trials with fewer errors (“go” response on a “no/go” trial) indicating better inhibitory 
control. 
 
The BIS/BAS and SPSRQ will be included as a self-report measures of reward response. Specifically, we will 
include the reward responsiveness, behavioral inhibition, and fun seeking subscales of the BIS/BAS as self-
report correlates of the reward response. The SPSRQ will be used to assess sensitivity to reward. 
 
Hypothesis. Our overarching hypothesis for the following aims is that BN represents a hormone sensitive 
phenotype and this sensitivity is displayed as an impaired reward response within the context of low E2 such 
that E2 addback will be beneficial for all outcomes of interest (i.e., binge eating, aspects of the reward 
response). As such, our null hypothesis is that there is no effect of E2 on binge eating or the reward response. 
For all hypothesis tests, we will use the Benjamini-Hochberg Procedure to correct for multiple comparisons. 
 
 
Aim 1: Quantify the direct  effect of E2 and P4 on binge eating in women with BN. 
 
Dependent variables: EPSI binge eating subscale score; DSRP binge eating weekly average. 
Independent variables: Treatment sequence, treatment condition, and selected covariates 
 
The two longitudinal measures of binge eating (i.e., EPSI subscale score and DSRP weekly average) will be fit 
to linear mixed effect models with subject-specific random intercept assuming an unstructured covariance 
among different time points. Such a covariance allows different variance and covariance parameters to be 
estimated for each time point allowing for potential increasing or decreasing variability in outcomes during each 
of the follow-up time points for each outcome and will include fixed effect predictors such as binary treatment 
sequence (E2-P4 or P4-E2) and treatment condition of categorical variable with three levels: Lupron-alone, E2, 
or P4, where effect size and standard error of fixed effect parameters will be estimated in the described model 
followed by t-test. Study hypotheses comparing outcomes between group outcomes of E2 vs. Lupron-alone, E2 
vs. P4, and P4 vs. Lupron-alone, will be tested using contrasts test through t-test of least squares means estimate 
in the context of the main effects model. 
 
Along with the primary contrasts of interest described above, additional contrasts between each end point of 
treatment condition (Lupron-alone, E2, or P2) and baseline (T1), which occurs prior to medication 
administration, will be tested using the statistical model just described above. 
Aim 2: Determine the effect of E2 on reward response  and related correlates (e.g., 
behavioral inhibition) in women with BN. 
 
Dependent variables: Behavioral measures of reward response, self-report measures of reward response. 
Independent variables: Treatment sequence, treatment condition, and selected covariates  
 
Behavioral measures of reward response (MID, DD) and related correlates (Go No/Go, BIS/BAS, SPSRQ) will 
be fit to linear mixed effect models as described above with binary treatment sequence (E2-P4 or P4-E2), 
treatment condition, and covariates as independent variables and reward response as dependent variables. The 
contrasts between E2 and baseline (T1) or Lupron-alone (T2) will be tested in the same model. 
 


36 
 
For the behavioral tasks, beneficial impacts of E2 are defined as an accelerated speed of response to rewards 
and improvement in reward learning during the MID, higher indifference points during the DD task, and fewer 
errors on the Go No/Go Task. For self-report questionnaires, a decrease in scores represents a beneficial 
response as higher scores indicate more “pathological” responses. 
 
Aim 3: Examine the association between reward response  (defined in Aim 2) and binge eating 
before and after E2 addback. 
 
Null hypothesis: There is no association between reward response and binge eating before and after E2 addback 
Alternative hypothesis: There is an association between reward response and binge eating before and after E2 
addback. 
 
We will explore Pearson correlations between change in self-reported reward responses and change in binge 
eating between baseline and E2 addback. Binge eating will be defined by the EPSI subscale score. Reward 
response will include the BIS/BAS reward responsiveness subscale, and SPSRQ reward sensitivity subscale. 
Specifically, a change score will be created that signifies the amount and direction of change that occurred in 
binge eating and reward responses between baseline and E2 addback for each subject. A Pearson correlation 
will then be examined between binge eating and reward response change scores. 
 
If Aims 1 and 2 alternative hypotheses are supported, we will conduct a tertiary exploration to address whether 
changes in reward behavior mediate the link between E2 addback and changes of binge eating.  A four-step 
mediation analysis (Baron & Kenny 1986) will be applied to preliminarily investigate the mediation effect of 
reward-motivated behavior on changes of binge eating. An approximated t-test will be used to test the 
significance of the mediation effect. 
 
Missingness. We will use multiple imputation to correct for data determined to be missing at random. Data for 
any dropouts will be compared with data for those who complete the study to determine the extent to which 
excluding their data will introduce selection bias, and selection bias will be identified as a weakness in any 
resulting publications or presentations. 
 
 
Sensitivity Analysis. In addition to the statistical tests described above, we will use sensitivity analyses to 
evaluate the robustness of the main results of the study to reasonable perturbations of the statistical methods and 
assumptions used and to help ensure reproducibility of the main results. Sensitivity analysis will address the 
inclusion/exclusion of questionable data values (i.e., outliers), the use of alternative methods of coping with 
missing values and dropouts, and modeling assumptions. We will additionally examine whether associations 
differ based on the severity (e.g., DSM-5 mild, moderate, severe, extreme) of baseline binge eating and purging 
frequency.


37 
 
 
7.3 
Subject Population(s) for Analysis 
Most studies addressing the impact of ovarian hormones on binge eating have included heterogenous samples. 
While this increases generalizability, findings may be less robust or inconsistent because associations between 
variables of interest may differ by sub-groups within these populations. Specifically, we hypothesize these 
individuals would vary in their baseline dopamine activity which, in turn, would affect whether E2 has a 
beneficial or worsening effect on symptoms: the behavioral effect of E2 would not be consistent unless 
individual differences in dopamine are accounted for. This may account for why when samples are separated by 
high and low pathology (with higher pathology predicted to represent low dopamine), low E2 is consistently the 
catalyst for increased symptomatology.5, 12 Thus, the sample for this proof of concept study is focused on a 
clinical population of BN, a sub-group proxy for low baseline dopamine. 
 
8 
Ethical Considerations 
 
This study is to be conducted according to US and international standards of Good Clinical Practice (FDA Title 
21 part 312 and International Conference on Harmonization guidelines), applicable government regulations and 
Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent Ethics Committee 
(EC) or Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the 
study conduct.  The decision of the EC/IRB concerning the conduct of the study will be made in writing to the 
investigator and a copy of this decision will be provided to the sponsor before commencement of this study. The 
investigator should provide a list of EC/IRB members and their affiliate to the sponsor. 
 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study. See Attachment 
for a copy of the Subject Informed Consent Form. This consent form will be submitted with the protocol for 
review and approval by the EC/IRB for the study. The formal consent of a subject, using the EC/IRB- approved 
consent form, must be obtained before that subject undergoes any study procedure. The consent form must be 
signed by the subject or legally acceptable surrogate, and the investigator-designated research professional 
obtaining the consent. 
 
9 
Study Finances 
 
 
9.1 
Funding  Source 
 
This study is financed through a R21 grant from the National Institutes of Health. 
 
 
9.2 
Conflict of Interest 
 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial gain 
greater than the minimum allowable by their institution, etc.) will have the conflict reviewed by a properly 
constituted Conflict of Interest Committee with a Committee-sanctioned conflict management plan that has 
been reviewed and approved by the study sponsor prior to participation in this study.  All UNC investigators 
will follow the University conflict of interest policy. 
 
 
9.3 
Subject Stipends  or Payments 
 


38 
 
Participants will be compensated $900 upon completion of the study according to the schedule below. For study 
visits that occur at UNC, parking vouchers will be provided as well as mileage reimbursement for study. 
Payment is processed through the UNC Department of Psychiatry. 
 
Long Study Visits 
Clinical Health Screening Visit 
$20 
Long Visit 1 (before medication administration) 
$50 
Long Visit 2 (during medication administration) 
$75 
Long Visit 3 (during medication administration) 
$75 
Long Visit 4 (during medication administration 
$75 
Other Study Activities 
GYN exam 
$30 
Screening phase (1 menstrual cycle) 
$30 
Short Clinic Visits (3 visits, $20/each) 
$60 
Lupron Injection (3 injections, $5/each) 
$15 
Completion of daily survey and medication adherence during 
hormone challenge ($5.00/day for 91 days) 
$455 
Follow-up Survey 
$15 
 
 
 
 
 
 
 
 


39 
 
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51 
 
15 Appendices 
 
Appendix A. Flow Chart of Study Procedures 
 
Appendix B. COVID Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


52 
 
P 
Lupron 
P 
E2 
P 
P4 
Appendix A. Study Procedures Flow Chart 
 
 
 
 
 
Figure 5. Within-Subject Hormone Challenge (study visits occur every 2 weeks) 
 
 
Phase 
Screening  hypogonadism   Addback 
Addback  
Follow-up 
 
Month 
0 
 
 
 
 
 
Medication 
1 
2 
3 
4 
5 
6 
 
 
Assessments   T0 
T1 
T2 
T3 
T4 
T5 
 
P = placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


53 
 
Appendix B. COVID Response 
 
Due to the COVID-19 pandemic, this study will be modified as described below. These procedures are 
only in response to the COVID-19 pandemic. If we are able to begin recruitment, enrollment, and 
study visits ‘as usual,’ study procedures will resume as described in the original protocol.  
 
All remote portions of study visits will be conducted via WebEx calls. All scheduled WebEx 
visits will be password protected and only those with the password can enter the call. WebEx has 
been approved by the UNC ITS as secure programs for PHI and sensitive information and the School 
of Medicine specifically recommends the use of WebEx for research study visits. WebEx is HIPPA 
complaint, ISO/IEC 27001:2013 certified, and approved for the transmission of PHI. Visits will be 
password protected and only those with the password can enter the study visit. Although Internet 
access is not a specific inclusion/exclusion criteria, because COVID19 requires converting many 
aspects of this study to virtual visits, we acknowledge participants will need to have access to the 
Internet.  
 
Overview:  
Recruitment will be conducted as described, we will make no changes to our recruitment procedures 
or methods. We previously created a modification for participants who appear eligible on a study 
screener to be added to a research study waiting list and will be re-contacted once the study is able to 
resume in-person visits. Once our revised study protocol is IRB approved, we will no longer create 
this waiting list and study enrollment will begin as described in this revised, COVID19 protocol 
addendum.  
 
This current addendum includes our plans to begin enrolling participants and the updated measures to 
prevent against the spread of SARS-CoV-2. We have altered study activities to make many of them 
remote. When contact is essential for certain activities, we have included procedures to protect 
participants and our study team. We are limiting the number of study personnel that conduct in-person 
visits to two individuals— the Clinical Translational Research Center nurse and coordinator. Both will 
be dressed in personal protective equipment (PPE) and will follow procedures to prevent the 
opportunity of transmission.  
 
PPE. During all interactions with participants, participants will be given a surgical mask and the study 
personnel will wear scrubs, gloves, and a surgical mask. Eye protection will be worn during Lupron 
injection and during blood draws. All items will be immediately removed as soon as possible after the 
study visit and washed or thrown away.  
COVID screening. A COVID health check will be completed with all participants 24 hours prior to 
study visit. If this is not completed, the study visit will not occur. In addition, a departmental Qualtrics 
survey will be completed by research personnel prior to any study visits or interactions with human 
subjects, regardless of the location.  
Preventive procedures. Study personnel, additionally, will follow preventive procedures. All 
equipment that will be shared between a participant and research staff (except paper) will be cleaned 
immediately prior to the study visit, immediately after use, and upon returning to CEED. 
Social distancing. Distance will be maintained between people any time closer contact is not 
absolutely required (e.g., blood draws). As allowable, study visits will be scheduled as in-home. If a 
subject prefers to come to the hospital for a study visit, this request will be considered. As much of a 
study visit that can be completed without being in person will occur remotely in order to decrease 
interaction with subjects.  


54 
 
 
Study Activities 
Recruitment & Eligibility 
Distance. Due to the need to complete as many study visits offsite as possible, we have expanded our 
radius for in-home study visits to a radius of approximately 45 miles or 1-hour of UNC Hospitals (as 
described in the consent form). Although this change is in response to COVID19, for fairness, this will 
remain a permanent change to the study protocol. 
 
Eligibility Screening:  We will screen individuals remotely via Qualtrics and telephone as described 
in the original protocol. This includes screening individuals via phone or online Qualtrics screener. As 
previously approved, we were screening participants and adding them to a waitlist to be contacted 
once in-person visits resumed. Now that we are planning in-person visits, the individuals that were on 
the waitlist will be contacted to confirm study eligibility. A portion of the phone/clinic eligibility 
screener will be used to confirm eligibility. These participants will only be asked the menstrual cycle 
status and eating behaviors sections of the screener. In the event study activities need to be suspended 
again due to COVID19, we will resume use of the waitlist. This waitlist is a password-protected 
document that contains the potential subjects’ name, temporary ID, and contact information.   
 
Enrollment: If participants are deemed eligible based on their screening, we will follow-up with a 
remote Informed Consent (T0a) and a remote Clinical Health Screening and SCID Interview (T0b) 
visit. T0b will be scheduled after informed consent is obtained and the signed consent forms are 
received by study staff. No study procedures will be conducted until the signed consent forms are 
received by study staff. We also added 3 questions to the T0 questionnaires survey that assess the 
impacts of COVID-19 on eating behaviors. 
 
Informed consent. The informed consent documents have been modified to reflect the changes to the 
study protocol outlined below. Dr. Jessica Baker or her trained study coordinator will obtain informed 
consent from those individuals who pass the initial screening and are interested in participating. 
Notably, the informed consent process during COVID (virtual/remote) will mirror the procedures for 
an in-person visit, the major difference being the visit will occur remotely via WebEx and the consent 
forms will be mailed, reviewed, signed, and mailed back. Participants will not review the consent 
documents on their own, but will be walked through the forms, verbatim, as would be completed 
during an in-person visit.  
 
Two copies of the consent forms will be mailed to the person in unmarked envelopes. For any 
participant that does not receive this most recent consent form, they will be given the COVID-19 
Consent Addendum. This document includes text from the updated study consent form that discusses 
COVID-19 exposure risks and the measures that may be taken to prevent exposure.  
Consent forms will be reviewed remotely during WebEx (or telephone if necessary) and will be 
returned to study staff signed in a pre-paid envelope. The participant will be given multiple 
opportunities to ask questions. Prior to signing the consent form, participants will be asked the consent 
quiz to ensure understanding of the consent form. We will obtain contact information and social 
security number verbally from the participant after the consent process. Contact information and social 
security number are only required if the participant consents to participant in the study. Future studies 
consent will also only be obtained verbally.  


55 
 
Regarding WedEx, it is HIPPA complaint, ISO/IEC 27001:2013 certified, and approved for the 
transmission of PHI. Visits will be password protected and only those with the password can enter the 
study visit. UNC SOM specifically recommends the use of WebEx for virtual research study visits. 
Study Procedures and COVID19 Study Visit Modifications: 
 
Screening Period Prior to Medication Administration. Prior to medication administration, 
participants complete a screening period which examines their eating disorder symptoms daily, during 
1 menstrual cycle. No changes have been made to this aspect of the protocol as the original protocol 
included completing this screening virtually/remotely through daily Qualtrics surveys.  
 
Study Questionnaires. A majority of study questionnaires were already completed through Qualtrics 
so this is easily converted to remote completion. Two surveys, IDAS and EDE-Q, have moved from 
paper and pencil versions to Qualtrics during COVID-19. These are used to monitor safety throughout 
the duration of the study and will be scored automatically for study staff to review within the survey 
flow. When the study returns standard procedures, we will keep the option of completing these in 
Qualtrics or completing them in their paper/pencil versions. The Delay Discounting questionnaire has 
now been added to T1-T5 Qualtrics surveys. This would have previously been completed via a paper 
and pencil survey, but now will be completed electronically via Qualtrics. This will remain a 
permanent change. The COVID Stress Scale (CSS) has been added to the electronic questionnaires for 
each in person visit that includes in-person behavioral tasks (T1, T2, T3, T4) to assess distress in 
relation to COVID-19 during tasks. 
 
Side Effect Checks and Interviews. The side effects and adherence interview will be conducted via 
interview through WebEx. Participants responses to the daily surveys will continue to be monitored 
daily and participants endorsing any concerning symptoms will be followed up with by the PI (as 
outlined in the original protocol). 
 
Behavioral Tasks. Behavioral tasks must be completed in person due to the software used (i.e., E-
prime). Although a remote option for E-prime is available, it is not ideal for tasks that are based on 
response time this could vastly differ across computers and operating systems. Using our computer 
standardizes this. The remote version also saves the data directly to the participants computer and 
requires it to be transferred to the study staff. This would also require participants have access to an 
appropriate computer. 
 
Before using the study laptop, the research coordinator will thoroughly wipe down the entire laptop, 
especially the parts that are frequently touched. When setting up the tasks for the participant, the 
coordinator will wear gloves. Directions will be given to the participant at a distance, and the 
participant and coordinator will remain 6 feet apart whenever possible during this task. The Pre-
Behavioral Task Food Intake Questionnaire will be completed with the participant by the study 
coordinator. In the event we must stop completing behavioral tasks in person, we will use the software 
application Millisecond as a back-up. Notably, our initial IRB approval proposed to use Millisecond; 
however, we converted to E-prime given we intend to include fMRI imaging in our future studies and 
UNC imaging center uses E-prime to run imaging tasks.  
 
Millisecond allows for psychological tasks to be administered online, on any device able to download 
the application, and provides centralized and secure storage for data. Their servers are protected by 
high-end firewall systems, and scans are performed regularly to ensure that any vulnerabilities are 
quickly found and patched. All services have quick failover points and redundant hardware, with 
complete backups performed nightly. Data are stored redundantly across data centers for resiliency 
and availability during disasters. Millisecond provides each customer a unique username and strong 


56 
 
password that must be entered each time a customer logs on. The user remains authenticated only for 
the duration of the session and is automatically logged off after 30 minutes of inactivity. This system 
ensures that customer data can only be accessed by authenticated and authorized users. Customer data 
are processed and stored in world-class data center facilities in Oregon, USA. Data are not moved 
around to other locations. The data centers are housed in nondescript facilities. Physical access is 
strictly controlled both at the perimeter and at building ingress points by professional security staff 
utilizing video surveillance, intrusion detection systems, and other electronic means. Authorized staff 
must pass two-factor authentication a minimum of two times to access data center floors. All visitors 
and contractors are required to present identification and are signed in and continually escorted by 
authorized staff. The servers reside behind high-availability firewalls and are monitored using state of 
the art systems for detection and prevention of various threats including denial of service, man in the 
middle, IP spoofing, port scanning, and packet sniffing. Automated network security audits using the 
industry standard SSAE-16 method are conducted to the standards and requirements of the SANS/FBI 
security test, the U.S. Department of Homeland Security's published recommendations and the 
Payment Card Industry Data Security Standard. Millisecond encrypts all data in transit by enforcing 
Transport Layer Security (TLS) encryption (also known as HTTPS). Millisecond encrypts all data at 
rest using the industry standard AES-256 cypher. Millisecond deploys the general requirements set 
forth by many Federal Acts, including the FISMA Act of 2002. They meet or exceed the minimum 
requirements as outlined in FIPS Publication 200. HITECH (Health Information Technology for 
Economic and Clinical Health Act) updated HIPAA rules to ensure that data are properly protected 
and best security practices followed. Millisecond safeguards all customer data, and uses secure data 
centers to ensure the highest protection as per HITECH requirements. 
Medication administration. Medication will be administered similar to our original protocol as in 
person contact is required (i.e., Lupron injection). However, for any study visits where giving the 
study participant their next set of oral medications is the only in-person activity needed, the study 
coordinator will pass off the pills directly to the participant during a drive by the participant’s house. 
Alternatively, the participant can drive by the hospital and the research assistant will give them the 
pills when they pull up to the hospital. If the visit is already requiring in-person contact for another 
reason (i.e. Lupron injection or behavioral tasks), the personnel that is involved in the visit will give 
the participant the study pills. 
Blood draws. Due to significant safety concerns regarding in-person contact and biological specimen 
processing and handling, all study blood draws will be removed from the protocol except those that are 
for labs in order to determine if participant is healthy and can participate in the study (T0). If the 
participant attends the research study gynecological exam (which must be conducted in person and 
cannot be modified), this will be collected during the exam. If they instead provide their own 
gynecological records, the blood draw for labs will be performed by the coordinator at the 
participant’s home or at the hospital.  
Saliva samples. Saliva samples will now be collected for E2 and P4 assay. This will be collected by 
the participant in their home. All saliva sample materials will be given to participants with instructions 
during the first in-person contact during (T1) to be completed remotely. We have created collection 
documents and a log for participants to complete in. At visit T4, all tubes will be collected from the 
participant and taken back to the UNC Core laboratory for storage. Consent forms have been modified 
to reflect this change. 
End of Study Feedback. We have expanded the information participants will be provided at the end 
of study participation. All participants who completed the study have the option to learn how their 
eating behaviors changed in response to the study medications. However, given the current pandemic 
we have expanded this to include a more comprehensive report vs overview as this detailed 
information could be immediately beneficial. This report will include how eating behaviors changed 
but now also include a discussion of (1) how this may translate to natural menstrual cycles (e.g., high 


57 
 
or low risk periods for symptoms); (2) strategies that can be used to manage symptoms; (3) triggers 
that may suggest a high risk period of the menstrual cycle is forthcoming (e.g., ovulation, 
mensuration); (4) additional resources and recommendations that may be useful based on the 
participants individual response. This will remain a permanent change to the study protocol. We have 
added additional text regarding this for interested participants on the study website and as part of the 
Qualtrics and phone/clinic screen. 
 
COVID Risk. If a participant has direct or secondary contact with any suspected or confirmed cases 
of COVID-19 or experience any known symptoms of COVID-19, the study team will reschedule any 
scheduled in person study visits until the case is confirmed negative or until the subject has 
quarantined for at least 14 days from the first symptom.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ICF_001.pdf: 
 
 
 
Informed Consent 
 
Ovarian Hormones, Reward Response, and Binge Eating in Bulimia 
Nervosa: An Experimental Design 
 
 
 
 
 
NCT Number NCT04225221 
 
Document Date 07/13/2021 


19-2343 
Adult Consent Form 
Page 1 of 18 
University of North Carolina at Chapel Hill 
Consent to Participate in a Research Study 
Adult Participants 
 
Consent Form Version Date: July 13, 2021 
IRB Study # 19-2343 
Title of Study: Neurobiology of Bulimia Nervosa 
Principal Investigator: Jessica Baker, Ph.D. 
Principal Investigator Department: Psychiatry 
Principal Investigator Phone number: 984-215-5519 
Principal Investigator Email Address: orched@unc.edu 
Co-Investigators: Steven Young, MD, PhD; Crystal Schiller, PhD; Kai Xia, PhD 
Funding Source: National Institutes of Health (NIH) 
 
CONCISE SUMMARY 
The purpose of this study is to examine the role of the ovarian hormones’ estrogen and 
progesterone in eating behaviors and the response to reward in women with an eating disorder. 
The information we learn from this study may help us better understand the role ovarian 
hormones may have in the development of an eating disorder. After a one-month screening 
period, study participants will take study medications for 3-months. The study medications will 
change estrogen and progesterone levels. While taking the study medications, participants will 
complete self-report questionnaires and behavioral tasks. The study medications are not being 
used to treat your eating disorder. They will help us understand how changing your hormone 
levels changes your eating behaviors. 
Study appointments will occur every 2-weeks while taking the study medications. There will be 
8 study visits and one follow-up survey. Some study visits will last approximately 45 minutes 
and some visits will last up to 3 hours. You will also be asked to complete an online survey 8-
weeks after you stop taking the study medications. After study completion, interested 
participants can meet with the study Principal Investigator, Dr. Baker, to obtain a comprehensive 
report on how their eating behaviors changed when taking the study medications.  
There are risks associated with taking the study medications as described in detail below. Some 
risks include: dizziness, breast tenderness, nausea, vaginal bleeding, headache, fatigue, and 
changes in mood.  
Participation in this research study is voluntary. If you are interested in learning more about the 
study, please continue reading below.  
What are some general things you should know about research studies?  
You are being asked to take part in a research study. To join the study is voluntary. 
You may refuse to join, or you may withdraw your consent to be in the study, for any reason, 
without penalty. 


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Research studies are designed to obtain new knowledge. This new information may help people 
in the future.  You may not receive any direct benefit from being in the research study. There 
also may be risks to being in research studies. Deciding not to be in the study or leaving the 
study before it is done will not affect your relationship with the researcher, your health care 
provider, or the University of North Carolina-Chapel Hill. If you are a patient with an illness, 
you do not have to be in the research study in order to receive health care. 
 
Details about this study are discussed below.  It is important that you understand this information 
so that you can make an informed choice about being in this research study.  
 
You will be given a copy of this consent form. You should ask the researchers named above, or 
staff members who may assist them, any questions you have about this study at any time. 
 
What is the purpose of this study? 
The purpose of this research study is to determine the role of ovarian hormones (estrogen and 
progesterone) in eating behaviors and the response to reward in women with the eating disorder 
bulimia nervosa. We will investigate the role of these hormones on eating behaviors by using a 
hormone “challenge.” The hormone challenge involves two phases. During phase one, you will 
receive Lupron, a medicine that will temporarily turn off your ovaries during the study. Lupron 
reduces the levels of estrogen and progesterone in your blood. During phase two, you will 
continue to receive Lupron and you will take pills that contain estrogen or progesterone or 
placebo. A placebo is a medication without any active ingredients. You will take the pills daily 
for 8-weeks and will not know whether the pills contain estrogen, progesterone, or placebo. You 
will begin taking these pills one month after your first dose of Lupron. After the hormone 
challenge, you will stop taking all study medications and your hormone levels will return to 
normal.  
 
You will complete self-report questionnaires throughout the hormone challenge. At randomly 
scheduled times during the hormone challenge, you will also complete behavioral tasks related to 
reward. This will help us understanding how changing your hormone levels impacts your eating 
behaviors and how you respond to rewards.  
 
Previous studies have shown that estrogen and progesterone play a role in food intake and 
overeating. It remains unclear why changes in estrogen and progesterone cause changes in food 
intake and overeating in some women and not others. You are being asked to participate because 
you are a woman between the ages of 18 and 42 with bulimia nervosa and have monthly periods. 
 
Are there any reasons you should not be in this study? 
You should not be in this study if any of the following apply to you: 
 
· 
peanut allergy 
·   
endometriosis (an illness related to abnormal tissue growth around the uterus) 
·   
enlargement of the ovaries 
·   
liver disease 
·   
breast cancer (self or family history) 


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·   
a personal or family history of blood clots  
·   
undiagnosed/abnormal vaginal bleeding 
·   
porphyria (a rare genetic blood disorder) 
·   
diabetes mellitus 
· 
osteoporosis or osteopenia  
·   
malignant melanoma (a type of skin cancer) 
·   
gallbladder or pancreatic disease 
·   
heart or kidney disease 
·   
cerebrovascular disease (stroke) 
·   
currently smoking >10 cigarettes daily 
· 
epilepsy or history of seizures 
·   
a history of suicide attempts or bipolar disorder/psychotic episodes 
· 
current substance misuse 
· 
frequently use diuretics or laxatives 
·   
recurrent migraine headaches with aura 
·      
history of pregnancy-related deep vein thrombosis 
·       
irregular menstrual cycle  
·       
body mass index (BMI) greater than 35 
· 
currently pregnant, planning to become pregnant, or lactating 
·       
taking any medication or have any other medical history that is contraindicated for the 
medications used in this study  
· 
unwilling to use barrier contraceptive during the study 
 
In addition, you will not be permitted to participate if you have a first degree relative (immediate 
family) with breast cancer that occurred before menopause, or breast cancer presenting in both 
breasts, or if you have multiple family members (greater than three relatives) with breast cancer.  
 
If you are using birth control you can join the study, but you must enter a washout period (i.e. 
stop taking the birth control and instead use a barrier contraceptive) and have 3 regular periods 
before you can begin the study procedures.  
 
We also ask that you do not change any mental health treatment you may be receiving 
throughout the duration of the study (e.g., start or stop psychotherapy).  
 
How many people will take part in this study? 
There will be approximately 15 people in this research study. 
 
How long will your part in this study last? 
This study will include 8 visits over the course of 5 months. You will have study visits every 2-
weeks. Study visits will range from approximately 45 minutes to 3 hours. Most study visits may 
be able to take place at your home provided that you live within 45 miles of UNC Hospitals. The 
hormone challenge will last 3-months. Prior to beginning the hormone challenge, we will track 
your eating behaviors for one menstrual cycle. Eight-weeks after the completion of the hormone 
challenge, we will ask you to complete questionnaires regarding your eating behaviors, mood, 
and experiences in the study. During specific time points during the protocol (described below), 
we will also collect blood and/or saliva samples from you. A portion of these samples will be 
stored for future use. We will store these samples indefinitely.  


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What will happen if you take part in the study? 
 
1. Clinical and Health Screening: 
 
You will undergo a screening process to determine if you are eligible for the study. In order to 
protect you from adverse medication effects and ensure you are healthy enough to participate in 
the study, you will be screened with a medical and psychiatric history and have laboratory tests 
completed. During the initial screening you will be asked questions about your physical and 
mental health as well as questions about any symptoms you may be experiencing now. You will 
also be asked to complete questionnaires about your eating behaviors, personality, mood 
symptoms, and trauma history. You may choose not to answer any or all of the questions for any 
reason. As part of the Clinical Health and Screening, approximately 2 tablespoons (about 30 mls) 
of blood will be drawn to test your liver and kidney function and electrolytes. If you are eligible 
for the study, the results of your laboratory tests will appear in your UNC Health Care medical 
record. 
 
You will receive a pregnancy test prior to enrolling in the study. You may not participate in this 
study if you are pregnant because the study drugs (Lupron, estrogen, and progesterone) may be 
associated with birth defects. The study will cover the cost of the pregnancy test. However, a 
negative pregnancy test does not rule out the presence of a very early pregnancy. If you enroll in 
the study, you will need to use barrier contraceptive methods (diaphragm or condom or both) for 
the entire time you are in this study. To prevent pregnancy, we strongly recommend that you also 
continue barrier contraception until you have three regular menstrual cycles after the study has 
ended. 
 
We also require that you have had a gynecological exam within the last year and PAP smear 
within the past 3 years. If you have not, this can be completed with the study gynecologist or you 
can have this exam with your own doctor, provided you are willing to release these medical 
records to the study investigators for review. If you choose to have the exam conducted by your 
own provider, there may be a cost associated with the exam. The research study will not cover 
the costs of this exam. If you have had a gynecological exam within the past year and PAP smear 
in the past 3 years, you can forgo the gynecological exam if you are willing to provide study 
investigators with the medical records for review. If you have the exam with the research study 
gynecologist, the appointment and results will become part of your UNC Health Care medical 
record. 
 
During this initial period, you will also complete a screening period during which we will track 
your eating behaviors for one menstrual cycle. To do this, you will be asked to complete a short 
questionnaire each morning. Completing this questionnaire should take less than 5 minutes. 
 
2. Hormone Procedures: 
 
For this study we will use a hormone “challenge.” The hormone challenge involves two phases. 
During phase one, you will receive Lupron, a medicine that will temporarily turn off your 
ovaries during the study. Lupron reduces the levels of estrogen and progesterone in your blood. 


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During phase two, you will continue to receive Lupron and you will take pills that contain 
estrogen or progesterone or placebo. A placebo is a medication without any active ingredients. 
You will take the pills daily for 8-weeks and will not know whether the pills contain estrogen, 
progesterone, or placebo. You will begin taking these pills one month after your first dose of 
Lupron. After the hormone challenge, you will stop taking all study medications and your 
hormone levels will return to normal. You will complete self-report questionnaires throughout 
the hormone challenge. At randomly scheduled times during the hormone challenge, you will 
also complete behavioral tasks related to reward. This will help us understanding how changing 
your hormone levels impacts your eating behaviors and how you respond to rewards.  
 
Once you are determined eligible for the study and finish the screening period, we will ask you 
to have an injection of 3.75mg Lupron into a muscle, once a month for three months. Prior to 
your first Lupron injection, you will attend a “long study visit” which will last up to 3-hours. At 
this visit you will complete study questionnaires and behavioral tasks related to your response to 
reward. After you finish the study procedures, you will receive your first injection of Lupron. 
You will then have study appointments every two weeks after the first Lupron injection. During 
the first month of Lupron, you will have two clinic visits that will last approximately 45 minutes.  
 
Four weeks after the first Lupron injection, we will ask you to begin taking two pills daily that 
contain estrogen or progesterone or placebo (i.e., capsules with no active ingredients). You will 
take the pills daily for 8-weeks. You will not be aware of the real nature (hormones versus 
placebo) of the pills you are taking, but you will know that during the 8-week period you will 
receive a total of 4-weeks of active medication, which will be either estrogen or progesterone 
(you will never receive both estrogen and progesterone at the same time). During the active 
medication period, you will receive 4 mg of estrogen (17-beta estradiol) or 400 mg of 
progesterone. You will not be aware of the exact time the capsules are switched from placebo to 
active medication or vice versa.  
 
During medication administration you will continue to have study appointments every 2-weeks, 
for a total of four visits. Three of these visits will be long study visits and one visit will be a 
clinic visit. The long study visits will be randomly assigned across the 8-week medication period. 
You will receive your study visit schedule (i.e., when your long study visits will take place) for 
the 8-week medication period once you begin taking study medications. 
 
The medications being used in this study (Lupron, Estrogen capsules, Progesterone capsules) are 
approved by the FDA and are being used within that approval for this study. 
 
3. Blood and Saliva Samples: 
 
Blood and saliva samples will be taken at specific times during the course of the study. All blood 
samples will be drawn in the following way: you will be asked to sit down and a small plastic 
tube (catheter) will be placed in an arm vein, the blood sample will be drawn, and the catheter 
removed. During the clinical health screening visit approximately 30 ml (2 tablespoons) of your 
blood will be drawn. At specific times during the course of the study you will also provide saliva 
samples (2mL) by drooling into a cup. Estrogen and progesterone levels will be assessed from 


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the saliva samples. A portion of the saliva samples will be saved for the future assay of appetite 
hormones. 
 
After completing the hormone challenge, we will ask you to complete an online follow-up 
survey 8-weeks after your last study visit. At the end of the study, we will discuss the study 
results and their meaning with you. 
 
Is this study providing treatment for an eating disorder? 
No, this research study is not providing you with treatment. The purpose of this research study is 
to determine the role of estrogen and progesterone on eating behaviors and the response to 
reward in women with bulimia nervosa.  
 
Even though you will be taking medications, we are not examining the potential for the study 
medications as treatment for an eating disorder. Participating in this study does not serve as a 
replacement for eating disorder treatment or continued medical monitoring. The study 
investigators will not be your treatment providers but are conducting a research study and 
monitoring your safety while you are enrolled in the study. Because an eating disorder can be 
associated with negative medical side effects, it is important that you have a physician who is 
regularly monitoring your risk for these side effects. If you do not have a primary care physician, 
we can provide you with referrals. If you are in need of any medical care or treatment during the 
course of the research study, you will be referred to your own treatment provider. The research 
study will not cover the costs of any treatment that you need during the course of the study. 
Although there are some exceptions (e.g., certain medications), you can be in this study while 
you are receiving treatment (e.g., therapy) for an eating disorder. However, we ask that during 
the course of the research study you do not start, stop, or change your treatment. If your 
treatment does change, we ask that you notify the investigators immediately.  
 
What are the possible benefits from being in this study? 
Research is designed to benefit society by gaining new knowledge. There is little chance you will 
benefit from being in this research study. However, you may learn about your sensitivity to 
changes in estrogen and progesterone levels and how your eating behaviors change in response 
to estrogen and progesterone, which may be useful for you. 
 
What are the possible risks or discomforts involved from being in this study? 
1). Lupron (leuprolide acetate 3.75mg) causes the ovaries to stop working while it is being 
administered. Lupron may cause the same side effects that are seen when the ovaries stop 
functioning permanently (menopause). The most common side effect of Lupron is hot flushes 
(flashes), occurring in 4% to 89% of women taking the medication. However, episodes of 
flushing often decrease with continued use of the medication. Skin irritation may also occur at 
the site of injection. The most common side effects of Lupron are headaches (10% of patients) 
and breast tenderness (6% of patients). A majority of the side effects reported by patients were of 
minimal, mild, or moderate severity. Your menstrual periods may be irregular for 2-6 months 
after the last Lupron injection. Side effects are reversible after the Lupron treatment is stopped. 
You should not conceive a pregnancy until 3-months after the last Lupron injection. 
 
Other more common side effects associated with Lupron include:  


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Page 7 of 18 
• Vaginal inflammation (19% of patients) 
• Changes in mood (16% of patients) 
• Muscle aches (13% of patients) 
• Trouble sleeping (10% of patients) 
• Decreased libido (6% of patients) 
• Dizziness (6% of patients) 
 
Less frequent side effects include: 
• Blurred vision  
• Memory problems  
• Diarrhea/Constipation  
• Nausea  
• Hair loss  
• Facial swelling and/or itching  
 
More rare but serious risks: Thrombophlebitis, pulmonary embolus, and congestive heart 
failure have occurred rarely in patients receiving Lupron, but a causal relationship to the drug has 
not been established. You may also experience a slight decrease in bone density (thinning of the 
bones). The decrease in bone density is usually reversible and should not be related to an 
increased risk of bone fracture because of the short time you will receive Lupron treatment. You 
should not be in this study if you have osteoporosis. 
 
Given the dose and length of time you will be given Lupron, the risk of developing severe side 
effects is small. Nevertheless, you will be monitored closely to see if side effects develop, and 
the medication will be stopped if side effects become intolerable. 
 
2) Estrogen capsules (Estrace, Micronized 17-beta-estradiol) – The risk of developing side 
effects is small because of the dosage and short period of time that you will receive estrogen 
treatment.  
 
The more common side effects associated with estrogen are:  
• Breast tenderness or enlargement (29% of patients) 
• Headache (18% of patients) 
• Abdominal cramps (16% of patients) 
• Fluid retention (swelling/bloating) (10% of patients) 
 
Less frequent side effects include: 
• Increased blood pressure 
• Dizziness 
• Vomiting 
• Vaginal bleeding 
• Depression  
• Nausea 
• Darkening of the skin - in the rare event that you experience spotty skin darkening, it may 
not disappear completely 


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There is a significantly increased risk of stroke following estrogen therapy in individuals with 
migraine with aura, as compared to individuals without aura, and as such, women with a history 
of recurrent migraine with aura will not be allowed to participate in this study. 
  
3) Progesterone capsules (Micronized progesterone) - Progesterone is commonly used to treat a 
variety of gynecological disorders. Side effects are not common and are usually mild.  
 
The more common side effects associated with progesterone are:  
• Vaginal bleeding consistent with a heavy period (20 to 30% of patients) 
• Dizziness (24% of patients) 
• Abdominal cramps (20% of patients) 
• Headache (16% of patients) 
• Breast tenderness (16% of patients) 
• Viral infection (12% of patients) 
• Joint pain (12% of patients) 
• Changes in mood (11% of patients) 
• Fluid retention (swelling/bloating) (10% of patients) 
• Drowsiness/fatigue (10% of patients) 
Less frequent side effects include: 
• Vaginal discharge 
• Jaundice 
• Chest pain 
• Weight change 
• Depression 
• Decreased sexual desire 
• Skin color changes 
• Diarrhea or flatulence 
 
More rare but serious risks: Estrogen use increases the risk of certain medical problems 
including gallbladder problems, blood clots, and it may increase the risk of certain types of 
cancer and a stroke. However, this risk is minimized because of the dose and the short period of 
time estrogen is used in this study. This risk is also influenced by age with women over 50 years 
of age being at risk.  
 
Lupron, estrogen, and progesterone may also cause an increase in birth defects if they are taken 
during pregnancy. Therefore, you should not become pregnant during this study. A pregnancy 
test will be given prior to enrollment, and you will not be allowed to participate if you are 
pregnant. The study will cover the cost of the pregnancy test. However, a negative pregnancy test 
does not rule out the presence of a very early pregnancy.  
 
If you experience symptoms such as severe mood symptoms, nausea, vomiting, or extreme fluid 
retention (bloating or swelling) from any of the study medications, you will have the dose 
adjusted until you feel relief. If you do not feel relief, then drug treatment will be discontinued. If 
significant vaginal bleeding or any other gynecological problem occurs, we will arrange for a 


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visit with a UNC gynecologist, which may include using an ultrasound that is inserted vaginally. 
If you experience marked discomfort during the insertion of the ultrasound probe, then the 
procedure will be discontinued. Otherwise, there are no additional associated risks or discomforts 
with the ultrasound probe. If the gynecologist finds any abnormality during the ultrasound, 
further testing may occur. The research study will not cover the costs of treatment or medical 
exams; you will need to cover these costs. You will not be reimbursed for any expenses your 
insurance does not cover. If you do not have insurance, you may be asked to cover the costs of 
these expenses yourself. If breakthrough bleeding occurs and is intolerable, you will be 
withdrawn from hormone replacement (which should precipitate a period).  
 
You will be followed closely to see if side effects develop from the medications. If you 
experience medication side effects during the study, the dose will be changed, but you must not 
change your medication dose without consulting the investigator. If adequate relief cannot be 
achieved by changing the dose, the drug will be stopped. Dropping out of the study will not 
interfere with any medical treatment you were receiving at UNC Hospitals. 
 
5) Eating behavior changes –Given your own estrogen and progesterone levels fluctuate during 
your menstrual cycle, we expect that any changes in eating behaviors that may occur with the 
study medications would mimic changes that you may or may not observe during your menstrual 
cycle. However, there is still a risk and it is possible your eating behaviors will worsen during 
the course of the study. If you experience a significant worsening in your eating disorder (e.g., 
overeating, binge eating, purging), we ask that you inform us immediately. We will also assess 
your eating behaviors each day during the study and at your bi-weekly visits. If you experience 
severe and distressing changes in your eating behavior that interfere with your safety in the 
study, then you will not be allowed to continue in the study. We will provide you with treatment 
referrals, including referrals to the UNC Center of Excellence for Eating Disorders or providers 
within the community. The research study will not cover any costs associated with this treatment.  
 
6) Mood changes – If you have a history of depression, you may be at higher risk for developing 
mood symptoms during the study. If you have never experienced an episode of depression in the 
past, then your risk of developing mood symptoms during this study are very low, but this risk 
still exists. If you experience any depression symptoms, including thoughts about death or 
suicide, we ask that you inform us immediately. We will assess your mood each day during the 
study and at your bi-weekly visits. The majority of participants complete the daily mood rating 
every day, and if you miss a day, we will contact you to do a safety assessment over the phone. If 
you experience severe mood symptoms or suicidal thoughts, then you not be allowed to continue 
in the study. We will provide you with treatment referrals, including referrals to UNC providers 
or providers within the community. If a treatment provider cannot see you in a timely fashion, 
Dr. Baker will provide short-term care (up to 3 sessions) at no cost to you. Otherwise, the 
research study will not cover any costs associated with treatment.  
 
Given the relatively brief nature and moderate severity of any mood symptoms that you may 
experience during this study, we do not anticipate that your mood symptoms will adversely 
impact you. Nonetheless, we cannot guarantee the absence of effect, nor can we anticipate every 
risk that may result from your participation in this study. 
 


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7) Clinical interviews and self-report questionnaires contain questions regarding sensitive 
personal information. It’s possible you may become upset or embarrassed when discussing 
current or past distressing life events. You have the right to not answer any question you are not 
comfortable answering.  
 
8) Blood drawing - You may experience some discomfort or temporary pain at the site of the 
needle entry. There is a small risk of fainting and local infection. 
 
9) There may be uncommon or previously unknown risks. If you have any symptoms or 
unexpected side effects during this protocol, please call the study investigators right away. 
 
Addendum for Patients with a History of Episodic Headaches: Lupron and estrogen treatment 
have been reported to aggravate migraine headaches. If you have a history of recurrent migraine 
headaches with aura you may not participate in this study. Once Lupron is injected into your 
body its effects last for about four weeks and you may experience an increase in headache 
frequency while under its influence. If this does happen, we will do our best to manage the pain. 
If your headaches become severe enough to require repeated medication, we may decide with 
you to discontinue your participation in this study. 
  
Addendum for Patients with a History of Epilepsy: There is some evidence that estrogen may 
increase the potential for seizures in some people. If you have a history of seizures, you may not 
participate in the study. Progesterone has been shown to have the opposite effect. The likelihood 
of inducing seizures in someone who has been seizure-free should be very low. However, this 
possibility exists. If you develop a seizure, your participation in the study will be stopped, and 
after assuring that you are medically stable, we will return you to the care of your primary 
physician for any follow up that will be required.  
 
Addendum for COVID-19: You may experience the potential risk to COVID-19 exposure during 
in-person study visits where Lupron injections or blood draws occur when study staff will need 
to maintain less than 6ft distance. Our study team and UNC will be taking every precaution 
possible to protect you and the study team from COVID-19, including virtual video or telephone 
visits when possible, with limited in-person contact to every degree possible. During the in-
person visits we will require masks at all times which will be provided to you by the study team, 
maintaining 6ft distance when possible, COVID-19 prescreening for yourself and staff at various 
timepoints including the day of the study visit, frequent cleaning with 90% alcohol or 1:10 
Bleach solution, cleaning between each subject, handwashing requirements every hour for you 
and all staff,  and  before and after any contact with any subject. While the study team will be 
taking every pre-caution possible to protect yourself and the study staff there may still be a risk 
of COVID-19 exposure due to the possibility of the COVID-19 virus lingering in spaces from 
asymptomatic carriers.  
If you have direct or even secondary contact with any suspected or confirmed cases of COVID-
19 or experience any known symptoms of COVID-19, the study team will reschedule your study 
visit until the case is confirmed negative or until you’ve quarantined for at least 14 days from the 


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first symptom. This may affect your ability to continue to participate in the study. If you 
experience any symptoms of COVID-19 including but not limited to: cough, fever, sore throat, 
shortness of breath, loss of smell or taste, vomiting, diarrhea, shaking with chills, etc. you will be 
asked to notify the study team immediately and contact your Primary Care Provider and your 
local COVID-19 hotline to get tested for COVID-19. We will not cover the cost of the COVID-
19 test. The study team and UNC are not responsible for any care or treatment of COVID-19. 
 
What are the risks to a pregnancy or to a nursing child? 
You may not take part in this study if you are pregnant, nursing, or planning to get pregnant. You 
will take a pregnancy test to make sure that you are not pregnant before starting the study. You 
will also take a urine pregnancy test prior to each Lupron injection, which will be paid for by the 
research study. A negative pregnancy test does not rule out the presence of a very early 
pregnancy. Pregnant women cannot participate because the study medications may have adverse 
effects on an unborn child. You will need to use barrier contraceptive methods (diaphragm or 
condom or both) while you are in this study. We strongly recommend that you continue barrier 
contraception until you have had at least three regular and consecutive menstrual periods after 
the study has ended. If you become pregnant during the study, you should notify the researcher 
right away.  
 
What if we learn about new findings or information during the study?  
You will be given any new information gained during the course of the study that might affect 
your willingness to continue your participation.  
 
How will information about you be protected? 
You will not be identified in any report or publication about this study. Although every effort 
will be made to keep research records private, there may be times when federal or state law 
requires the disclosure of our records, including personal information. This is very unlikely, but 
if disclosure is ever required, UNC-Chapel Hill will take steps allowable by law to protect the 
privacy of your personal information.  In some cases, your information in this research study 
could be reviewed by representatives of the University, research sponsors, or government 
agencies (for example, the FDA) for purposes such as quality control or safety. Your identity 
will be protected by assigning you an ID number and omitting your name and other identifying 
information from scientific reports of the study. We may use de-identified data and/or specimens 
from this study in future research without additional consent. Information you provide as part of 
this study, including saliva samples, survey results, and clinical interview responses, may also be 
included in a database for future research or scientific reports or shared with scientists not 
affiliated with this study or UNC. No personal identifying information will be shared with these 
scientists and your individual identity will not be revealed. Researchers using these databases or 
information cannot learn your identity.  
 
Because this study is funded by the National Institute of Mental Health (NIMH), researchers will 
share your de-identified information so that it can be used by other scientists for future studies. 
Your coded information will be submitted to the NIMH Data Archive (NDA) at the National 
Institutes of Health (NIH). NDA is a large database where de-identified study data from many 
NIMH studies is stored and managed. De-identified study data means that all personal 


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information about you (such as name, address, birthdate, and phone number) is removed and 
replaced with a code number. All data placed into the NDA will be coded and de-identified by 
the researchers at UNC and NDA will never receive the code or any other information that would 
enable the identification of the individuals who are the source of the data. Sharing your de-
identified study data helps researchers learn new and important things about mental health and 
substance use more quickly than before. 
 
During and after the study, the study researchers will send de-identified study data about your 
health and behavior obtained from this study to the NDA. Other researchers across the world can 
then request your de-identified study data for other research. Every researcher (and institutions to 
which they belong) who requests your de-identified study data must promise to keep your data 
safe and promise not to try to learn your identity. Experts at the NIH who know how to keep 
your data safe will review each request carefully to reduce risks to your privacy. Sharing your 
study data does have some risks, although these risks are rare. Your study data could be 
accidentally shared with an unauthorized person who may attempt to learn your identity. The 
study researchers will make every attempt to protect your identity. 
 
You may not benefit directly from allowing your study data to be shared with NDA. The study 
data provided to NDA may help researchers around the world learn more about mental health 
and how to help others who have problems with mental health and substance use. 
NIMH will also report to Congress and on its website about the different studies using NDA 
data. You will not be contacted directly about the study data you contributed to NDA. You may 
decide now or later that you do not want your study data to be added to the NDA. You can still 
participate in this research study even if you decide that you do not want your data to be added to 
the NDA. If you know now that you do not want your data in the NDA, please tell the study 
researcher today. If you decide any time after today that you do not want your data to be added to 
the NDA, call or email the study staff who conducted this study, and they will tell NDA to stop 
sharing your study data. Once your data is part of the NDA, the study researchers cannot take 
back the study data that was shared before they were notified that you changed your mind. If you 
would like more information about NDA, this is available on-line at http://nda.nih.gov.  
 
Identifiable data collected about you as part of this study and the file that links your ID number 
with your data will be accessible only to those working on this study at UNC, including research 
assistants and the Principal Investigator, Dr. Baker. All computer files are kept on secure 
computers on a secure network. If the researchers learn that you or someone else is in serious 
danger of harm (such as in cases of child abuse), they may make disclosures to protect you 
and/or the other persons. 
 
Audio recordings of your clinical interviews will be identified by your study ID number only and 
stored on a secure computer accessible only to members of our research team. The recordings 
will be destroyed at the end of the study.  Only your research ID number will be tape recorded 
along with your interview.  You may request to have the audio recording turned off if you are 
uncomfortable with recording your interview.  
 
Check the line that best matches your choice: 
_____ OK to audio record me during the study 


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_____ Not OK to audio record me during the study 
  
A copy of this consent form will be given to you. 
 
What is a Certificate of Confidentiality?  
This research is covered by a Certificate of Confidentiality from the National Institutes of 
Health. With this Certificate, the researchers may not disclose or use information, documents or 
biospecimens that may identify you in any federal, state, or local civil, criminal, administrative, 
legislative, or other proceedings in the United States, for example, if there is a court subpoena, 
unless you have consented for this use. 
 
The Certificate cannot be used to refuse a request for information from personnel of a federal or 
state agency that is sponsoring the study for auditing or evaluation purposes or for information 
that must be disclosed in order to meet the requirements of the federal Food and Drug 
Administration (FDA). 
 
The Certificate of Confidentiality will not be used to prevent disclosure as required by federal, 
state, or local law, such as mandatory reporting requirements for child abuse or neglect, disabled 
adult abuse or neglect, communicable diseases, injuries caused by suspected criminal violence, 
cancer diagnosis or benign brain or central nervous system tumors or other mandatory reporting 
requirement under applicable law. The Certificate of Confidentiality will not be used if 
disclosure is for other scientific research, as allowed by federal regulations protecting research 
subjects or for any purpose you have consented to in this informed consent document. 
 
You should understand that a Certificate of Confidentiality does not prevent you from 
voluntarily releasing information about yourself or your involvement in this research. If an 
insurer, employer, or other person obtains your written consent to receive research information, 
then the researchers may not use the Certificate to withhold that information. 
 
By signing this informed consent document, you agree that some of the information generated by 
participating in this study may be included in your medical record (e.g., results of lab tests and 
the gynecological exam) and that this information may be viewed by other physicians or 
caregivers who provide healthcare services to you. This will allow the doctors caring for you to 
know what tests you may be receiving as a part of the study and know how to take care of you if 
you have other health problems or needs during the study.  
 
Under North Carolina law, researchers are required to report information about the abuse or 
neglect of a child or disabled adult to local or state authorities. 
 
Will you receive results from research involving your specimens? 
Most research with your blood or saliva specimens is not expected to yield new information that 
would be meaningful to share with you personally. There are no plans to re-contact you or other 
subjects with information about research results. The use of your samples may result in 
commercial profit. You will not be compensated for the use of your samples other than what is 
described in this consent form. 
 


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What will happen if you are injured by this research? 
All research involves a change that something bad might happen to you. If you are hurt, become 
sick, or develop a reaction from something that was done as part of this study, the researcher will 
help you get medical care, but the University of North Carolina at Chapel Hill has not set aside 
funds to pay you for any such injuries, illnesses, or reactions, or for the related medical care. Any 
costs for medical expenses will be billed to you or your insurance company. You may be 
responsible for any co-payments and your insurance may not cover the costs of study related 
injuries.  
 
If you think you have been injured from taking part in this study, call the Principal Investigator at 
the phone number provided on this consent form. They will let you know what you should do.  
 
By signing this form, you do not give up your right to seek payment or other rights if you are 
harmed as a result of being in this study. 
 
What if you want to stop before your part in the study is complete? 
You can withdraw from this study at any time, without penalty. The investigators also have the 
right to stop your participation at any time. This could be because you have had an unexpected 
reaction, or have failed to follow instructions, or because the entire study has been stopped. 
 
Will you receive anything for being in this study? 
You may receive up to $900 for your participation in this study. Only those participants who 
complete all aspects of the study as outlined below will receive the full $900. If you are 
withdrawn from the study by study staff, you will receive compensation for those study activities 
you completed. With the exception of the Clinical Health Screening Visit, you will receive a 
majority of the study compensation upon study completion according to the schedule below. 
However, you will receive a portion of the ‘long study visit’ compensation at that study visit. 
The exact amount that you receive during this visit will be determined based upon your 
responses to one of the behavioral tasks. Any payment provided for participation in this study 
may be subject to applicable tax withholding obligations.  
 
If you are required to travel at least 10 miles to attend the study visits for the 3 Lupron injections 
at UNC, you will be provided travel/mileage reimbursement at 0.56cents per mile, for a 
maximum of 100 miles. For any study visits you attend at UNC, you will also receive vouchers 
to park in the Dogwood Deck at UNC Hospitals as instructed by the research team. This should 
cover the cost of your parking. If you choose to have the gynecological visit with the research 
study gynecologist this will occur at the UNC Hillsborough Hospital campus. If you are required 
to travel at least 10 miles to attend the gynecological appointment, you will also be provided 
travel/mileage reimbursement at 0.56cents per mile, for a maximum of 100 miles. 
 
At the end of the study, you can choose to receive feedback regarding your individual response 
to the hormone challenge from the study Principal Investigator. 
 
Long Study Visits 
 


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Clinical Health Screening Visit  
$20 
Long Visit 1 (before medication administration) 
$50 
Long Visit 2 (during medication administration) 
$75 
Long Visit 3 (during medication administration) 
$75 
Long Visit 4 (during medication administration) 
$75 
Other Study Activities  
GYN exam  
$30 
Screening phase (1 menstrual cycle)  
$30 
Short Clinic Visits (3 visits, $20/each) 
$60 
Lupron Injection (3 injections, $5/each) 
$15 
Completion of daily survey and medication adherence 
during hormone challenge ($5.41/day 84 days) 
$455 
Follow-up survey  
$15 
 
In addition, for each daily survey you complete, you will be entered into a drawing to receive 
one of three $20 gift cards. Each participant in this study has approximately a 20% chance to win 
a gift card, and the more daily surveys you complete, the more chances you have to receive the 
additional gift card.  
 
Your name, address, and U.S. tax payer identification number (SSN or ITIN) are required to 
process payments and/or to report taxable income to the IRS.  You must complete a W-9 (for 
U.S. persons) or W-8BEN and the Foreign Vendor Withholding Assessment with supporting 
documents (for non-resident aliens) in order to receive payment for participation. 
 
U.S. person participants must complete Form W-9 in order to receive payment for 
participation. If payment by UNC equals or exceeds $600 per calendar year for U.S. persons, 
UNC will report the amount to the Internal Revenue Service on Form 1099.  Nonresident alien 
participants must complete Form W-8BEN and the Foreign Vendor Withholding Assessment 
with supporting documents in order to receive payment for participation. Payments to 
nonresident alien participants may be subject to tax withholding and are generally reported to the 
Internal Revenue Service on Form 1042-S. This information will not be linked to any of the 
study data and will only be used for payment purposes. 
 
If you do not provide your SSN or ITIN, or complete the appropriate documentation noted 


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above, we cannot issue you a payment for participation.  However, you may still choose to 
participate in this study. 
 
Will it cost you anything to be in this study? 
If you enroll in this study, you may have costs, including transportation to the appointments at 
UNC as well as any incidental expenses, such as childcare costs, if you have children. There will 
be no other costs to you for participating. 
 
What if you are a UNC student? 
You may choose not to be in the study or to stop being in the study before it is over at any 
time. This will not affect your class standing or grades at UNC-Chapel Hill. You will not be 
offered or receive any special consideration if you take part in this research. 
 
What if you are a UNC employee? 
Taking part in this research is not a part of your University duties, and refusing will not affect 
your job. You will not be offered or receive any special job-related consideration if you take part 
in this research. 
 
Who is sponsoring this study? 
This research is funded by the National Institute of Mental Health (NIMH). This means that the 
research team is being paid by the sponsor for doing the study. The researchers do not, however, 
have a direct financial interest with the sponsor or in the final results of the study. 
 
What if you have questions about this study? 
You have the right to ask, and have answered, any questions you may have about this research. If 
you have questions about the study (including payments), complaints, concerns, or if a research-
related injury occurs, you should contact the researchers listed on the first page of this form. 
 
What if you have questions about your rights as a research participant? 
All research on human volunteers is reviewed by a committee that works to protect your rights 
and welfare.  If you have questions or concerns about your rights as a research subject, or if you 
would like to obtain information or offer input, you may contact the Institutional Review Board 
at 919-966-3113 or by email to IRB_subjects@unc.edu. 
 
ClinicalTrials.gov Registration 
A description of this clinical trial will be available on www.clinicaltrials.gov, as required by U.S. 
Law. This website will not include information that can identify you. At most, the website will 
include a summary of the results. You can search this website at any time. 
Participant’s Agreement: 
 
I have read the information provided above.  I have asked all the questions I have at this time.  I 
voluntarily agree to participate in this research study. 


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______________________________________________________ 
Signature of Research Participant 
 
____________________ 
Date 
 
______________________________________________________ 
Printed Name of Research Participant 
  
 
 
______________________________________________________ 
Signature of Research Team Member Obtaining Consent 
 
____________________ 
Date 
 
______________________________________________________ 
Printed Name of Research Team Member Obtaining Consent 
  


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Required information for NIMH NDA data deposit: 
 
Participant’s Full Legal Name as it appears on Birth Certificate: 
 
______________________________________________________ 
 
____________________ 
 Participant’s Location of Birth as Identified on Birth Certificate: 
 
______________________________________________________ 
 
____________________