The Treatment of Menstrually-Related Mood Disorders With the Gonadotropin Releasing Hormone (GnRH) Agonist, Depot Leuprolide Acetate (Lupron)
Phase: PHASE1
Conditions: Premenstrual Syndrome, Menstruation Disturbances
Sponsor: National Institute of Mental Health (NIMH)

NI N D S Pr ot oc ol Te m plate (re v. 2 4 J ul 0 6)  
 
I R B Pa nel: Bl ue    W hite  
Pr ot oc ol Title  
T he treat me nt of m e nstr uall y-relate d m o o d d is or ders wit h 
t he g o na d otr o pi n releasi n g h or m o ne ( G n R H) a g o nist, de p ot 
le u pr oli de acetate ( L u pr o n) 
Pr ot oc ol N u m ber  
  
  
9 0- M- 0 0 8 8 
Date of T his S u b missi o n/ Versi o n   
 J u ne 1 8, 2 0 1 9 
 
Lea d Ass ociate I n vesti gat or  
Peter J. Sc h mi dt , M. D. 
NI M H/
S B E  
Bl d g  1 0  
R m  3 N 2 4 4  
P h o ne  
3 0 1 -4 9 6 -6 1 2 0  
E -mail  
petersc h mi dt @ mail. ni h. g o v  
 
Ass ociate I n vesti gat ors  
Da vi d R. R u bi n o w, M. D.  
De pt. of 
Ps yc h, 
U N C  
 
9 1 9 -9 6 6 -4 7 3 8  E -mail  
dr u bi n o w @ me d. u nc.e d u 
L y n nette K. Nie ma n  
NI C H D/
P R E B  
Bl d g 1 0 C R C  
R m 1 3 1 4 0  
3 0 1 -4 9 6 -8 9 3 5  E -mail  
nie ma nl @ mail. ni h. g o v  
Pe dr o E. Marti nez, M. D.  
NI M H/  
S B E  
Bl d g 1 0 C R C  
R m 2 6 3 3 0  
3 0 1 -4 0 2 -0 6 1 5  E -mail 
marti ne p @ mail. ni h. g o v  
S ha u -Mi n g Wei, P h D  
NI M H/  
C B D B/  
SI N  
Bl d g. 1 0  
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3 0 1 -5 9 4 -4 7 6 0  E -mail  
s ha u mi n g @ mail. ni h. g o v 
 
 
Researc h C o ntact  
Peter J. Sc h mi dt, M. D.  
NI M H/
S B E  
Bl d g 1 0 C R C  
R m 2 5 3 3 0  
P h o ne  
3 0 1 -4 9 6 -6 1 2 0  
E -mail  
petersc h mi dt @ mail. ni h. g o v  
 
Me dicall y Acc o u nta ble I n vesti gat or  
Pe ter J. Sc h mi dt, M. D. 
NI M H/
S B E  
Bl d g 1 0 
R m 3 N 2 4 4  
P h o ne  
3 0 1 -4 9 6 -6 1 2 0  
E -mail  
petersc h mi dt @ mail. ni h. g o v  
 
T otal re q ueste d accr ual  
   1 0 0 Patie nts (se paratel y descri be patie nt gr o u ps)  
   0     V ol u nteers 
 
H u ma n Researc h Pr otecti o ns Pr o gra m I n vesti gat or a n d Staff Trai ni n g:  
“J ust i n ti me” h u ma n s u bjects pr otecti o n trai ni n g c o urses are re q uire d f or i n vesti gat ors a n d staff 
partici pati n g o n t his pr ot oc ol:  N o ne 
 
Pr oject Uses I o nizi n g Ra diati o n:  
 N o    
 Yes (attac h R S C/ R D S C d oc u me nt ati o n)  
    
 
Me dicall y -i n dicate d o nl y 
    
 
Researc h -relate d o nl y 
    
 
B ot h  

 
 
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IND/IDE 
 No   
 Yes (attach FDA documentation) 
  
Drug/Device/# 34,662 Leoprolide acetate 3.75 mg 
  
Sponsor  NIMH (Maryland Pao, MD is the official representing the Institute) 
 
Durable Power of Attorney  
 
 No  
 Yes 
 
Multi-institutional Project 
 No  
 Yes 
 
Institution_________________ FWA #_________ 
Date of IRB approval_________ (attach IRB documentation) 
 
Data and Safety Monitoring Board 
 No  
 Yes 
 
Technology Transfer Agreement 
 No  
 Yes 
Agreement type and number __________________________ 
 
Samples are being stored 
 
 No  
 Yes 
 
Flesch-Kinkaid reading level of consent form: 
Combined: 11.0 
Genetics: 9.5 
 

 
 
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Precis 
 
This protocol is designed to accompany Clinical Protocol # 81-M-0126, The 
Phenomenology and Biophysiology of Menstrually-Related Mood and Behavioral Disorders.  Its 
original purposes  were as follows: 1) to evaluate the efficacy of the gonadotropin releasing 
hormone (GnRH) agonist depot leuprolide acetate (Lupron) in the treatment of menstrually-
related mood disorders (MRMD) by determining whether mood and behavioral symptoms are 
eliminated when the cyclic secretion of both gonadotropic hormones and gonadal steroids is 
suppressed, and 2) to determine the possible relevance of gonadal steroids to affective state by 
sequentially replacing estradiol and progesterone during continued GnRH suppression in those 
patients whose premenstrual symptoms remit following administration of the GnRH agonist.  We 
observed that GnRH agonist induced ovarian suppression was an effective treatment compared to 
placebo in women with MRMD.  Additionally, women with MRMD but not asymptomatic 
controls (participating in companion protocol # 92-M-0174) experienced a recurrence of mood 
and behavioral symptoms when either estradiol or progesterone (but not placebo) was added 
back.  These data suggest that women with MRMD have a differential sensitivity to the mood 
destabilizing effects of gonadal steroids (1). 
 
Having established that women with MRMD show a differential behavioral response to 
estrogen and progesterone, we now hope to identify the underlying mechanisms and physiologic 
concomitants of the differential behavioral sensitivity by performing studies (described in 
companion protocols) under the three hormonal conditions created by this protocol, and 
comparing results obtained with those seen in normal controls (Protocol # 92-M-0174).  Planned 
studies include the following: cognitive testing, , brain imaging (3D PET, FMRI, MRS) and 
genetic studies including induced pluripotent cells. 

 
 
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Table of Contents 
 
 
  
 
 
 
Page # 
1) 
Background and Scientific Justification 
 
 
 
 
7 
2) 
Study Objectives 
 
  
 
 
 
 
 
17 
3) 
Subjects 
 
 
  
 
 
 
 
 
18 
a. Description of study populations 
 
 
 
18 
b. Inclusion criteria 
 
 
 
 
 
18 
c. Exclusion criteria 
 
 
 
 
 
19 
4) 
Study Design and Methods 
  
 
 
 
 
 
21 
a. Study overview 
 
 
 
 
 
21 
b. Recruitment   
 
 
 
 
 
21 
c. Screening 
  
 
 
 
 
 
22 
d. Study Procedures 
 
 
 
 
 
23 
e. End of Participation  
 
 
 
 
28 
5) 
Management of data and samples 
 
 
 
 
 
28 
6) 
Additional Considerations 
  
 
 
 
 
 
28 
7) 
Risks and Discomforts 
  
 
 
 
 
 
28 
8) 
Subject Safety Monitoring 
  
 
 
 
 
 
36 
9) 
Outcome Measures 
 
  
 
 
 
 
 
37 
10) Statistical Analysis 
 
  
 
 
 
 
 
37 
 
 

 
 
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11) Human Subjects Protection 
  
 
 
 
 
 
38 
a. Subject selection 
 
 
 
 
 
38 
b. Justification for exclusion of children 
 
 
38 
c. Justification for inclusion/exclusion of other vulnerable subjects 
38 
d. Justification of sensitive procedures  
 
 
38 
e. Safeguards for vulnerable populations 
 
 
38 
f. Qualifications of Investigators 
 
 
 
38 
12) Anticipated Benefits  
  
 
 
 
 
 
40 
13) Classification of risk  
  
 
 
 
 
 
40 
14) Consent documents and process 
 
 
 
 
 
40 
15) Data and Safety Monitoring   
 
 
 
 
 
41 
16) Quality Assurance 
 
  
 
 
 
 
 
41 
a. Quality assurance monitor 
 
 
 
 
41 
b. Quality assurance plan 
 
 
 
 
41 
17) Adverse Event and unanticipated problem Reporting  
 
 
42 
18) Alternatives to Participation   
 
 
 
 
 
42 
19) Privacy 
 
 
                                                                           44 
20) Confidentiality 
 
  
 
 
 
 
 
45 
21) Conflict of Interest 
 
  
 
 
 
 
 
45 
22) Technology transfer  
  
 
 
 
 
 
45 
23) Research and Travel Compensation 
 
 
 
 
 
45 
24) References 
 
  
 
 
 
 
 
48 

 
 
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25) Appendix  
 
 
 
 
 
 
56 
Abbreviations: 
MRMD – menstrually related mood disorders 
GnRH – Gonadotropin releasing hormone 

 
 
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1) 
Background and Scientific Justification 
 
Menstrual-related mood disorder (MRMD) is a condition characterized by affective, 
behavioral, and somatic symptoms that are temporally linked to the luteal phase of the normal 
menstrual cycle (2).  The pathophysiologic role of the luteal phase in MRMD is currently 
unclear, as are the roles of the ovarian steroids, estrogen and progesterone.  In a previous study 
(3), truncation of the luteal phase with high doses of the progesterone receptor antagonist 
mifepristone (RU 486) failed to alter the course or severity of the symptoms of MRMD: Both 
affective and somatic symptoms typically associated with MRMD developed during hormonal 
conditions similar to the follicular phase.  This study suggested the lack of causal relevance of 
mid - late luteal phase biology in MRMD.  In contrast ovarian suppression with GnRH agonists 
resulted in the remission of MRMD symptoms in some (4-13) (but not all (14)) trials, suggesting 
the importance of changes in ovarian hormones in the development of MRMD symptoms.  As 
stated previously (3), these data are consistent with MRMD representing a disorder of mood state 
that is triggered by hormone-related events occurring prior to the mid - late luteal phase of the 
menstrual cycle. 
 
In this study (1), we sought to answer three questions: 1) Does ovarian suppression 
eliminate the symptoms of MRMD; 2) Will exogenous administration of estradiol or 
progesterone reverse the effects of ovarian suppression on mood; and 3) Do women lacking a 
history of MRMD respond similarly to women with MRMD during manipulation of gonadal 
steroid levels?  Our findings to date confirm several previous studies reporting the therapeutic 
efficacy of ovarian suppression in women with MRMD (4-12).  Second, our data suggest that 
women with MRMD experience an acute symptom precipitation when ovarian steroids are added 
back under conditions of leuprolide-induced ovarian suppression, similar to the observations of 

 
 
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Muse et al. (15) and Mortola et al. (9).  Third, and of greatest interest, controls showed no 
perturbation of mood in response to either ovarian suppression or to exogenous hormone 
administration.  Given the identical nature of the hormonal manipulations performed in patients 
and controls, it would appear that the mood changes seen in MRMD patients represent an 
abnormal response to otherwise unremarkable hormonal changes. 
Efficacy of Leuprolide vs. Placebo: We observed significant reductions in MRMD symptom 
severity during leuprolide treatment for all symptoms measured on both daily rating scales 
except for the symptom of increased appetite.  We observed that only six of ten (double blind) 
and ten of 18 women (open label or double blind) with MRMD receiving leuprolide met our 
criteria for response.  Thus, we observed response rates between 45 and 60% employing 
relatively conservative criteria.  The reported response rates to selective serotonin reuptake 
inhibitors (SSRI) in women with MRMD (40-60%) (16-25) appear similar to the rates observed 
in trials of GnRH-agonists.  Thus, although the majority of studies would support the short term 
use of GnRH agonists or selective serotonin reuptake inhibitors in this condition, symptomatic 
response is not uniform, and predictors of response are lacking. 
 
The relatively brief period of GnRH agonist administration was well tolerated by both 
women with MRMD and controls.  Despite the occurrence of hot flushes during the leuprolide 
alone conditions, no woman dropped out of the study due to intolerable side effects.  Indeed, we 
observed no adverse mood or behavioral effects during the hypogonadal state induced in this 
protocol, nor did we observe significant changes in weight or blood pressure recordings.  In fact, 
women with MRMD rated themselves on the visual analogue scale ratings as feeling 
significantly better than the controls when they were hypogonadal and less symptomatic than 
during their baseline (pretreated) condition.  We did not observe any woman with MRMD to 

 
 
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meet our criteria for response on placebo, and symptom rating scores were significantly 
decreased in the sample receiving leuprolide compared to those receiving placebo. 
Effects of Hormone Addback: In the second phase of the study we observed the recurrence of 
typical MRMD symptoms, both physical and emotional, in women with MRMD during hormone 
addback.  Symptom recurrence was observed within one to two weeks of exposure to either 
estradiol or progesterone given separately.  The doses of estradiol or progesterone resulted in 
plasma hormone levels comparable to the levels observed during the normal menstrual cycle, and 
there were no differences in plasma hormone levels between women with MRMD and controls. 
 
Our data are consistent with two previous studies by Muse et al. (15) and Mortola et al. 
(9) reporting the return of both physical and emotional symptoms in women with MRMD when 
estrogens or progestins were added back under conditions of GnRH-agonist induced ovarian 
suppression.  We observed significant (or at least a trend level of significance) worsening of 
MRMD symptoms for all symptoms measured in all scales during hormone addback except for 
the symptoms of food cravings and increased appetite.  No differences in symptom severity 
measures were observed between women with MRMD and controls in any symptom during 
leuprolide-induced hypogonadism (with the exception of women with MRMD feeling more 
happy and more relaxed than controls).  Investigators have reported correlations between plasma 
estradiol and/or progesterone levels and symptom severity in women with MRMD (26-30) and, 
additionally, have observed the following differences in plasma hormone levels in samples of 
women with MRMD compared to controls: no differences in levels of both estradiol and 
progesterone (31, 32), high levels of estradiol and low levels of progesterone (29, 33), and high 
levels of estradiol and no differences in progesterone (28).  Our data are consistent with the 
suggested relationship (based on correlative rather than direct data) between MRMD symptom 

 
 
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severity and ovarian steroid secretion.  Additionally, the proposed lag (three to seven days) (27-
29) in the correlation between progesterone levels and symptom onset is also consistent with our 
observations of MRMD symptom recurrence occurring approximately one to two weeks after the 
administration of estradiol or progesterone.  Several women experienced a remission of their 
symptomatic state after 7-10 days of symptoms despite being maintained on the same dose of 
estradiol or progesterone.  This suggests that the onset of MRMD may be triggered by ovarian 
steroids, but the “switching out” of the MRMD state is independent of plasma hormone levels.  
Finally, the variable association between either estradiol or progesterone and symptom return, 
within individual women with MRMD, may provide an explanation for otherwise discrepant 
correlative relationships observed in studies with small sample sizes, since it is unlikely that a 
sample of women with MRMD would uniformly display a link between the same ovarian steroid 
and mood symptoms. 
 
Our data extend the findings of our previous study employing RU 486 (3) in which we 
demonstrated that MRMD symptoms occur independent of the mid - late luteal phase of the 
menstrual cycle.  The observations from this earlier study suggested that MRMD may represent 
either an autonomous mood disorder linked to, but not caused by, menstrual cycle hormones, or, 
alternatively, that hormonal events occurring prior to the mid - luteal phase of the menstrual 
cycle triggered the onset of MRMD symptoms.  The data from the present study of a selected 
sample of leuprolide responders support the latter relationship and is consistent with the 
proposals of other investigators (27, 28) who have suggested that periovulatory changes in either 
estradiol or progesterone secretion may be critical to the onset of MRMD symptoms. 
MRMD Patients Compared with Controls: The most striking finding in this study is the 
differential symptom response in women with MRMD compared to controls.  Women with 

 
 
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MRMD show alleviation of symptoms with ovarian suppression and precipitation of symptoms 
with hormonal addback, while controls show no perturbation of mood with either hormonal 
manipulation.  These observations converge with the demonstration of normal reproductive 
endocrine function in women with MRMD to suggest that normal levels or changes in gonadal 
steroids can trigger an abnormal response - i.e., mood state deterioration - in a susceptible 
population.  Our data suggest that MRMD symptoms occur in a context within which normal 
levels of ovarian steroids (or their neurosteroid metabolites (34)) similar to those measured 
across the normal menstrual cycle may interact with neuroregulatory systems to alter behavior in 
a susceptible group of women.  Identification of the mechanisms underlying the susceptibility to 
these effects will not only assist in the development of more specific treatments for individual 
women with MRMD but additionally will provide a context within which to address the 
relationship between mood dysregulation and changes in reproductive endocrine function in 
conditions such as postpartum depression and depression occurring in the context of the 
perimenopause. 
Background and Justification for Brain Imaging Studies 
 
Recent brain imaging studies in asymptomatic women (i.e., women without MRMD) 
confirm for the first time in humans that physiologic levels of ovarian steroids have the capacity 
to modulate the neurocircuitry thought to be involved in both normal and pathological affective 
states.  First, Berman et al. performed cognition-activated O15PET scans in women during 
conditions of GnRH agonist-induced hypogonadism and gonadal steroid replacement.  They 
observed the elimination of Wisconsin Card Sort-activated regional cerebral blood flow (rCBF) 
in the dorsolateral prefrontal cortex as well as an attenuation of cortical activation in the inferior 
parietal lobule and posterior inferior temporal cortex (bilaterally) during GnRH agonist-induced 

 
 
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hypogonadism (35).  The characteristic pattern of cortical activation re-emerged during both 
estradiol and progesterone addback.  Additionally, they observed a differential pattern of 
hippocampal activation with estradiol increasing and progesterone decreasing activation relative 
to hypogonadism.  This was the first demonstration that ovarian steroids have activational effects 
on rCBF during cognitive stimulation in the brain regions (i.e., PFC) implicated in disorders of 
affect and cognition.  Two recent studies using fMRI and 1HMRS respectively, have extended 
these findings in young women under conditions of GnRH agonist-induced ovarian suppression.  
Compared with baseline, ovarian suppression was associated with decreased activation in the 
prefrontal cortex during verbal memory encoding (but not retrieval) (36).  In the second study 
with 1HMRS, ovarian suppression was associated with an increase in choline concentration (a 
proxy for neuronal metabolism/turn-over) in the dorsolateral prefrontal cortex (37).  Second, 
Goldstein et al. (38) observed an increase in amygdalar activity and arousal (as measured by 
fMRI and skin conductance, respectively) during the late follicular phase of the menstrual cycle 
(higher estradiol levels) compared to the early follicular phase (characterized by relatively low 
estradiol levels).  Third, Protopopescu et al. (39) employed an affective pictures task in an fMRI 
study and observed increased OFC activity (a region that in some studies exerts inhibitory 
control over amygdalar functioning) during the luteal compared with the follicular phase.  
Moreover, preliminary data from these same investigators in women with MRMD 
(Silbersweig, DC, personal communication) suggest a relative loss of OFC activity (decreased 
inhibition) in women with MRMD during the luteal phase.  Notwithstanding the caveat that 
decreased cortical “activity” also could reflect more efficient or optimal function, these data 
suggest that a reduction in OFC inhibition of amygdalar function during the luteal phase is 
associated with MRMD symptoms.  Finally, Dreher et al. (40), have initiated an event-related 

 
 
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fMRI study of reward processing across the menstrual cycle in women with MRMD and 
controls.  The paradigm employed disentangles transient reward error prediction (PFC) from 
sustained response to reward uncertainty (ventral striatum).  Preliminary data in the controls 
demonstrate, for the first time in humans, that ovarian steroids modulate reward system function, 
with increased follicular phase activation of the OFC and amygdala during reward anticipation 
and of the midbrain, striatum, and left ventrolateral PFC during reward delivery.  New analytical 
approaches will allow for testing the hypothesis that the hormonally-induced alteration in 
function includes changes in interregional neural interactions.  These findings then suggest that 
cognitive and affective information processes may serve as probes to identify candidate circuits 
for the mediation of gonadal steroid-dependent affective dysregulation.  Additionally, these 
neuroimaging studies in women suggest that ovarian steroids can influence many neural 
processes and systems relevant to MRMD including arousal, stress-responsivity, and reward 
processing. 
Background and Justification for Induced Pluripotent Cell Study 
We wish to collect an additional sample of venous blood in women who have participated 
(or who currently are participating) in protocols 90-M-0088, titled “The treatment of 
menstrually-related mood disorders with the gonadotropin releasing hormone (GnRH) agonist, 
depot leuprolide acetate (Lupron),” and 92-M-0174, titled “The central nervous system effects of 
pharmacologically induced hypogonadotropic hypogonadism with and without estrogen and 
progesterone replacement.”  Previous findings from these protocols have demonstrated a 
differential behavioral response (i.e., a recurrence of typical mood and behavioral symptoms 
experienced premenstrually) to physiologic levels of the ovarian steroids estradiol and 
progesterone in women with premenstrual dysphoria (PMD) compared with asymptomatic 

 
 
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controls.  The observed differential response appears to be tissue specific since the effects of 
ovarian steroids at several other target tissues does not differ in women with and without PMD 
(e.g., endometrium, pituitary, breast).  The biological basis for this differential behavioral 
response to ostensibly the same physiologic stimulus is unclear; however, it is well established 
that tissue specificity in the response to sex steroids is mediated by factors at the level of cellular 
function.  Receptors for both estradiol and progesterone are widely distributed throughout the 
brain, and recent neuroimaging studies have demonstrated that both estradiol and progesterone 
regulate the activation patterns in brain regions involved with the processes of affective 
adaptation and stress responsivity. 
 
We hypothesize that the capacity for phenotypic differences between women with and 
those without PMD will be preserved in the cellular function of induced pluripotential cells 
(IPCs). Although the phenotypic difference in response to sex steroids is tissue specific, the 
latent capacity for differential expression in response to steroids should be preserved in IPCs and 
expressed in the differentiation of the IPCs into neural elements.  Thus, we plan to obtain T-
lymphocytes from peripheral blood (47) in order to convert these cells into IPCs to establish 
neuronal and glial cell lines in both women with PMD and controls.  This study will be done in 
collaboration with Dr. David Goldman at the NIAAA.  The goal of this project will be to develop 
neurons and glial cells from participants and to characterize their gene expression patterns, 
morphological properties, and cell signaling pathways in response to exposures to physiologic 
levels of estradiol and progesterone.  These experiments, therefore, will allow us to evaluate the 
nature of the differential behavioral response by examining protein expression and changes in 
cellular behaviors associated with the exposure to physiologic levels of either estradiol or 
progesterone across the two different behavioral phenotypes.  The two behavioral phenotypes 

 
 
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will be constituted by those women with PMD whose symptoms remit during ovarian 
suppression and whose symptoms recur during physiologic addback of either estradiol or 
progesterone.  This assures the phenotypic fidelity of the subjects and avoids the false positives 
that would otherwise be generated if diagnoses are established solely on the basis of baseline 
behavioral ratings.  The selection of each woman will occur after completion of the six month 
study to ensure both the proper characterization of the behavioral phenotype and to include 
comparable numbers of women in whom symptoms recur after estradiol and progesterone 
exposure.  To recruit sufficient numbers of women in each group we will contact women who 
have previously participated in these protocols, have met our baseline criteria for PMD or 
asymptomatic controls, and have further demonstrated either the elimination of symptoms during 
GnRH agonist and return of symptoms upon re-exposure to estradiol or progesterone (PMD) or 
the absence of negative behavioral symptoms during both GnRH agonist and ovarian steroid 
addback phases (controls).  Each of these women who is interested in participating will be re-
consented for this study. 
We hypothesize that the T-lymphocytes obtained from women with PMD and those from 
asymptomatic controls can be converted into IPCs and differentiated into model neuronal and 
glial cell lines.  The production of these pluripotential cell lines will retain genetic (or epigenetic) 
variations that will help us understand the differential behavioral response at a cellular level in 
this condition. 
a) Medications Used in Protocol 
 
GnRH is a decapeptide produced by the hypothalamus and causes the anterior pituitary to 
release follicle stimulating hormone (FSH) and luteinizing hormone (LH).  Leuprolide acetate 
(Lupron) is a synthetic nonapeptide that functions as an agonist that is 80 to 100 times more 
potent than synthetic native GnRH in inducing the release of LH (48, 49).  During the first week 

 
 
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of Lupron therapy, there is an initial increase in the pituitary release of LH and FSH leading to a 
transient increase in levels of the gonadal steroids estrone and estradiol in premenopausal 
females.  However, with longterm administration, Lupron decreases the number of GnRH 
receptors and inhibits pituitary secretion of gonadotropins, leading to levels of estrogens similar 
to those observed in post-menopausal women.  These decreases in gonadal steroid levels occur 
within two to four weeks after initiation of treatment.  Lupron is not active when given orally; 
however, following a single injection of depot Lupron, mean peak leuprolide acetate plasma 
concentration was almost 20 ng/ml after four hours and .36 ng/ml at four weeks, levels 
associated with effective gonadotropin suppression.  The plasma half-life of depot Lupron is not 
known; however, the half-life in the non-depot form is approximately three hours. 
 
The administration of 17 beta estradiol via a transdermal system was chosen for this 
study because it has several advantages as described by Cedars and Judd (50).  First, it delivers 
the primary ovarian estrogen, estradiol, into the circulation at a constant rate and results in 
sustained levels of estradiol, constant rates of excretion of estradiol conjugates, and 
estrone/estradiol ratios less than one (as seen in the pre-climacteric period of life).  Thus, 
transdermal estradiol is considered to result in a more physiological form of estrogen 
replacement than occurs with oral estrogens (51).  Second, it delivers sufficient estradiol into the 
circulation to raise estradiol plasma concentrations to levels similar to those of women in the 
early follicular to mid-follicular phases of the menstrual cycle (50, 52-55), levels reported by 
some investigators as the minimum necessary for the relief of menopausal symptoms, in 
particular hot flushes.  Finally, the system can be applied and removed without difficulty, 
allowing for easy adjustment of the dosage in the presence of minor side effects such as nausea 
that may not require complete cessation of the medication.  With the application of the estrogen 

 
 
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patch system twice weekly, patient compliance has been reported to be excellent, and only 
occasional local irritation has been observed (52).  Further, transdermal estradiol can provide 
adequate amounts of estrogen to suppress hot flashes, correct vaginal atrophy, and reduce urinary 
calcium excretion (52) without increasing synthesis of renin substrate.  An increase in renin 
substrate has been suggested to accentuate or initiate the development of high blood pressure in 
susceptible women with other predisposing factors (56), and has been implicated as a factor 
contributing to the association of hypertension with administration of oral conjugated estrogen 
(57). 
 
Progesterone is widely prescribed in gynecologic settings, with proved indications 
including dysfunctional uterine bleeding, endometriosis, mastodynia, galactorrhea and 
precocious puberty (58).  Further, progesterone suppositories have been approved by the IRB for 
administration to patients with MRMD under NIMH protocol # 82-M-0193. 
2) 
Study Objectives 
 
The results of this protocol and its companion protocol (92-M-0174) demonstrate that 
during conditions of GnRH agonist-induced ovarian suppression women with MRMD 
experience a differential behavioral response to physiologic levels of ovarian steroids compared 
with controls.  Our current objectives are to employ this hormone manipulation paradigm to 
investigate the underlying substrates for this differential behavioral response as well as the 
mechanisms mediating the differential risk.  The current study objectives are as follows: 
1) 
To investigate possible differences in the substrate mediating the observed 
differential response, we will employ multimodal imaging paradigms (O15 PET, MRI) to 
examine the neurocircuitry regulated by ovarian steroids in MRMD and controls under the 

 
 
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hormone conditions established in this protocol.  Additionally, we will examine hormone-related 
differences in HPA axis responsivity between women with MRMD and controls. 
2) 
To investigate possible mechanisms underlying the observed differences in 
behavioral response to ovarian steroids we will examine the profile of neurosteroid metabolites 
in plasma using a metabolomics platform to determine if the enzymatic metabolism of 
behaviorally relevant steroids differs in women with MRMD and controls.  Additionally, we will 
employ functional genomics studies in-vitro cell cultures to examine potential differences in 
cellular function in women with MRMD and controls after exposure to physiologic levels of 
ovarian steroids. 
3) 
Subjects 
 
a) Description of Study Population: The subjects of this study will be women who meet 
the criteria for MRMD as described in Protocol # 81-M-0126, “The Phenomenology and 
Biophysiology of Menstrually-related Mood and Behavioral Disorders.”  All patients in this 
protocol will have already participated in Protocol # 81-M-0126 and will have a prospectively 
confirmed and predictable relationship between their mood disorder and the premenstrual phase 
of the menstrual cycle; i.e., a 30% change in severity of symptom self rating scales, relative to 
the range of the scale employed, during the seven days premenstrually compared with the seven 
days post-menstrually in two out of three months of study.  We intend to recruit 100 women with 
MRMD to complete the current study objectives.  Participants who drop out may be replaced. 
 
b) Inclusion criteria: 
• History within the last two years of at least six months with menstrually-related mood 
or behavioral disturbances of at least moderate severity--i.e., disturbances that are 
distinct in appearance and associated with a notable degree of subjective distress; 

 
 
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• Symptoms should have a sudden onset and offset; 
• Age 18-50; 
• Not pregnant and in good medical health; 
• Medication free. 
 
The Schedule for Affective Disorders and Schizophrenia will be administered to all 
patients prior to study entry.  Any patient with a current axis I psychiatric diagnosis will be 
excluded from participating in this protocol. 
 
Prior to treatment, a complete physical and neurological examination will have been 
performed and the following routine laboratory data obtained: 
 
A. Blood 
 
Complete blood count; thyroid function tests; cortisol; renal function tests, such as BUN 
and creatinine; electrolytes; glucose; liver function tests. 
 
B. Urine 
 
Routine urinalysis; urine pregnancy test. 
 
GnRH agonist will not be administered to any subject with significant clinical or 
laboratory abnormalities.  The blood tests and urinalysis will be repeated two weeks after GnRH 
agonist administration to rule out any evidence of acute renal, hepatic or hematologic toxicity. 
 
Additional tests 
 
Results of Pap smear performed within one year of the onset of treatment will be 
obtained. 
 
c) Exclusion Criteria: The following conditions will constitute contraindications to 
treatment with hormonal therapy and will preclude a subject's participation in this protocol: 
• Current Axis I psychiatric diagnosis 

 
 
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• History consistent with endometriosis; 
• Diagnosis of ill-defined, obscure pelvic lesions, particularly undiagnosed ovarian 
enlargement; 
• Hepatic disease as manifested by abnormal liver function tests; 
• History of mammary carcinoma; 
• History of pulmonary embolism or phlebothrombosis; 
• Undiagnosed vaginal bleeding; 
• Porphyria; 
• Diabetes mellitus; 
• History of malignant melanoma; 
• Cholecystitis or pancreatitis; 
• Cardiovascular or renal disease; 
• Pregnancy; 
• Any woman meeting the Stages of Reproductive Aging Workshop Criteria (STRAW) 
for the perimenopause (59).  Specifically, we will exclude any woman with an 
elevated plasma FSH level (> 14 IU/L) and with menstrual cycle variability of 
> 7 days different from their normal cycle length. 
 
Subjects taking birth control pills will be excluded from the study.  Subjects taking 
diuretics, prostaglandin inhibitors, or pyridoxine (putative treatments for MRMD) will similarly 
be excluded from the study, as will patients taking psychotropic agents (e.g., lithium carbonate, 
tricyclic antidepressants).  All subjects will be required to use non-hormonal forms of birth 
control (e.g., barrier methods) to avoid pregnancy during this study. 
• NIMH employees and staff and their immediate family members will be excluded 

 
 
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from the study per NIMH policy.  
       
4) 
Study Design and Methods 
 
a) Study Overview 
 
This outpatient study consists of a baseline period (three months), followed by three 
months of GnRH administration (phase I) and three months of estradiol and progesterone 
replacement (phase II).  Subjects who experience remission of symptoms in Phase I will advance 
to Phase II of the protocol.  Those who do not experience symptom relief in Phase I may opt to 
enroll in another treatment protocol or receive open treatment for a time-limited period. 
Throughout the study participants will have weekly or biweekly visits to the outpatient clinic for 
blood draws and ratings, will complete daily self ratings, and will be scheduled for additional 
procedures and tests as described below. 
 
b) Recruitment 
 
Patients will be sought by advertising for women who suffer severe menstrually-related 
mood disturbances. 
• 
Flyers will be produced with tear-offs.  Posters will not have tear-offs. 
• 
Flyers/poster will be used in color as submitted, or may be printed in black and white.  The 
color of the flyer may vary.  However, color changes will be made proportionally throughout the 
ad and will not be used to change the emphasis of the flyers. 
• 
The size of the flyers/posters may vary, but all parts, including fonts and pictures, will be 
changed proportionately to the rest of that flyer.  Disproportionate changes in size will not be 
used to change the emphasis of the flyer. 
• 
Flyers/posters may be posted on bulletin boards on the NIH campus, and at coffee shops, 
grocery stores, bookstores, libraries, fitness centers, community centers, or placed in venues, such 

 
 
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as at advocacy group offices, in doctor’s office waiting rooms, and retail establishments with 
approval of the venue or in accord with their policy. 
• 
Flyers/posters may be made available at outreach exhibits, speaking engagements, support 
group meetings, parenting groups, professional meetings, and association/trade meetings with 
approval of the venue or in accord with their policy. 
• 
Flyers/posters may be given directly to persons requesting study information. 
• 
Flyers/posters may be posted electronically on websites such as such as NIH or NIMH 
websites, advocacy/parenting group websites such as PTAs, athletic groups or neighborhood 
groups, publications’ websites such as Washington Parent, or Gazette. 
• 
Flyers/posters may be sent electronically to persons requesting study information 
• 
Flyers/posters may be sent electronically to listserv administrators.  SBE will not post directly 
to Listservs.  Rather, an email with the material attached, including the following statement will 
be sent to the administrator of the listserv: 
 
You are receiving the email because your email address is included on this listserv.  The 
purpose of this message is to inform you of an NIMH study that is recruiting subjects.  The 
administrator of this listserv has permitted its use for this distribution. 
 
The administrator has the option of sharing the information with their list.  Examples of types 
of Listservs to be contacted include professional groups, parenting/family, school, sport groups, 
women’s health and fitness.  SBE will retain copies of all correspondence with the administrator 
of each listserv and submit as requested to the IRB. 
• 
IRB-approved advertisements may be placed in local and national print publications of 
newspapers, magazines and support or health care organizations, such as The Washington Post, 
The Express, Washington Parent, Gazette, Washingtonian, Washington Jewish Week and others. 
• 
NIH Record announcements will appear as text in the NIH Record. 

 
 
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• 
NIH employees and staff will not be directly recruited by or through their supervisors or co-
workers to participate in this study. 
 
c) Screening  
 
All patients in this protocol will have already participated in Protocol # 81-M-0126 and 
will have a prospectively confirmed and predictable relationship between their mood disorder 
and the premenstrual phase of the menstrual cycle; i.e., a 30% change in severity of symptom 
self rating scales, relative to the range of the scale employed, during the seven days 
premenstrually compared with the seven days post-menstrually in two out of three months of 
study.  Initial assessments may be performed by instruments such as the Premenstrual Tension 
Syndrome Scale (Steiner-Carroll Scale) (60), Beck Depression Inventory (61), State-Trait 
Anxiety Inventory (62), Hamilton Depression Scale (63), and related psychological measures.  
Additionally, subjects will be asked to fill out symptom self-rating scales (as described in 
screening protocol 81-M-0126), the daily symptom rating scale (Halbreich and Endicott) (64) 
and visual analogue scales (65), on a daily basis.  Symptom ratings, diagnostic interviews, and 
other questionnaires will be collected through an online system using a subject-specific log in 
and password to protect confidentiality (see Appendix I). Both participants and investigators will 
input data into CTDB/CTSS. Participant entered data will be reviewed during the clinic visit. All 
subjects meeting criteria will receive a careful medical screening and will be excluded if there is 
evidence of significant renal, cardiac, hepatic, or other medical disorder.  All patients will 
receive routine physical and laboratory examinations such as urinalysis, hematocrit, hemoglobin, 
BUN, creatinine, liver function tests, electrolytes, and a serum pregnancy test.  Blood specimens 
will also be collected on interview days by routine venipuncture and will be assayed for a 
number of endocrine measures such as estrogen, progesterone, sex hormone binding globulin, 
testosterone, prolactin, cortisol, T4, T3, and TSH. 

 
 
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d) Study Procedures 
 
Baseline 
 
All subjects will have a three month baseline period during which mood and behavioral 
ratings will be obtained.  Urinary pregnancy tests will be performed in all women prior to 
administration of the GnRH agonist to exclude pregnancy.  No pregnant women will be 
continued in the study. 
 
 

 
 
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Phase I 
 
Following the baseline period patients will receive 3.75 mg of GnRH agonist via 
intramuscular injection on a monthly basis in our clinic for a maximum of twenty-four weeks 
(see Figure I).  Subjects will fill out symptom self-rating scales on a daily basis preceding, 
during, and following treatment with GnRH agonist.  Additionally, subjects will be administered 
the following ratings during weekly clinic visits: Beck Depression Inventory, Spielberger State-
Trait Anxiety Inventory, the Rating Scale for Premenstrual Tension (PMTS) (self and rater 
administered versions) and a side effect checklist.  Following the third month of GnRH agonist 
treatment, the results of the trial will be discussed with each patient.  In those subjects who 
continue to evidence cyclical mood and behavioral changes comparable to their menstrually-
related mood disturbances, GnRH agonist administration will be discontinued, and these subjects 
will be offered participation in an alternate treatment protocol.  Those patients who experience a 
complete remission of mood and behavioral disturbances during the treatment with the GnRH 
agonist will be entered into the second phase of this study. 
 
Phase II 
 
Phase II of the study consists of the sequential replacement of estradiol and progesterone 
under double blind (subject and rater) conditions to determine whether these hormones are 
critical in the determination of the patient's premenstrual mood state.  These patients will 
continue to receive GnRH agonist for another 12 weeks.  While continuing on the GnRH agonist, 
patients will be randomized into one of two groups as follows: group I will receive 0.1 mg/day of 
17ß- estradiol via skin patch (Estraderm) for a period of five weeks.  During the fifth week, 
progesterone suppositories (200 mgs twice daily) will be added to provide progesterone 
withdrawal-induced shedding of the endometrium and menses in order to prevent prolonged 

 
 
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exposure of the endometrium to unopposed estrogen.  Following the four weeks of estradiol 
administration and the week of combined estradiol and progesterone, there will be a two week 
washout period when placebo patches and suppositories will be substituted for estradiol and 
progesterone.  Patients will then be administered progesterone (200 mg) suppositories twice 
daily for a period of five weeks following which no progesterone will be taken.  Group II is 
identical to group I except the order of administration of hormones is reversed: progesterone 
suppositories (200 mg BID) will be administered for the first five weeks, followed by a two 
week washout, and then estradiol 0.1 mg/day for five weeks, with the addition of progesterone 
during the fifth week of estrogen treatment.  To maintain double blind conditions all patients will 
use both patches (active or placebo) and suppositories (active or placebo) daily for the 12 weeks 
of phase II.  
 
Blood Drawing 
 
Following the administration of the GnRH agonist, in addition to the completion of daily 
mood and behavioral rating scales, blood samples (50 ml) will be drawn bi-weekly, if possible, 
for 24 weeks of this study (total = 660 ml).  All blood sampling will be obtained in the following 
fashion.  Subjects will arrive at the 4th or 9th floor outpatient clinic; they will be seated or placed 
at bed rest, a scalp vein needle will be placed in the forearm or hand via venipuncture and 
approximately 50 ml of blood will be drawn.  This blood will then be analyzed for several 
measures such as gonadotropins, estradiol, and progesterone to confirm creation of the intended 
hormonal conditions.  Additionally, blood samples will be assayed for hormonal/metabolic 
measures that could distinguish either the symptomatic state in women with MRMD or women 
with from those without MRMD. 
 
 

 
 
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Related Studies 
I. 
Brain Imaging 
 
In an earlier study, we demonstrated that the expected pattern of cognitive task - activated 
cerebral blood flow was eliminated during Lupron-induced hypogonadism and normalized with 
hormone addback.  These group data did not permit us to determine the following: 1) whether 
the disappearance of the normal response during hypogonadism reflects recruitment of new 
neural areas of simple increased variance, and 2) whether women with MRMD differ in their 
activated response from controls.  Subjects in this protocol will be asked to participate in brain 
imaging (as outlined in protocols # 90-M-0014, 91-M-0124) studies during each of the different 
hormonal conditions of this study.  The use of 015 PET and FMRI will enable us to investigate 
the effects of gonadal steroids on cerebral blood flow on an individual basis. 
II 
Genetic Studies 
 
This protocol offers an unparalleled opportunity to identify potential genetic 
contributions to the differential sensitivity to gonadal steroids underlying MRMD because it 
identifies relatively pure phenotypes; i.e., women with estrogen - or progesterone - precipitated 
mood disorders and women for whom the same manipulation of gonadal steroids is without 
effect on mood.  A specific hormonal precipitant for the mood disorder is identified or 
disconfirmed in each subject, thus, dramatically increasing the likelihood of detecting any 
genetic contribution to the differential behavioral response to the same hormonal signal.  Two 
genetic strategies will be employed: candidate gene studies examining polymorphisms in the 
receptors modulating the hormone signal (i.e., estrogen, progesterone, and androgen receptors); 
and establishment of cell lines for genome scanning in the future when polymorphism mapping 

 
 
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microarray technology becomes widely available.  Wherever possible, internal control genotypes 
will be acquired (affected family-based control method). 
Induced Pluripotent Cells.  Samples derived from from peripheral blood cells (47) may be 
utilized for procedures such as special stains, immunohistochemistry, direct immunofluorescence 
or immunoelectron-microscopy for localization of immune deposits, PCR, or establishment of 
cell cultures.  In our protocol, the samples will be used to grow a pluripotent cell lines.   e) End 
of Participation 
 
At the completion of this study, a member of the research team will review the results of 
the study with each woman.  Women with MRMD will be offered participation in other 
evaluation and treatment protocols as indicated or, alternatively, referred for standard treatment 
to a caregiver in the community. 
5) 
Management of Data and Samples: 
 
a) Storage 
 
Samples and data will be stored using codes that we assign.  Data will be kept in 
password-protected computers.  Samples will be kept in locked storage.  DNA samples and cell 
lines will be stored in locked freezers in David Goldman’s laboratory (NIAAA) on Fischer’s 
Lane in Rockville.  Only study investigators will have access to the samples and data. 
 
Data from structured diagnostic interviews and symptom ratings are kept 
in secure research files and electronically on the Branch server space or within the CTDB 
database.  Access to these research files is only available to study investigators. Symptom 
ratings, diagnostic interviews, and other questionnaires will be collected through an 
online system using a subject-specific log in and password to protect confidentiality (see 
Appendix I). 

 
 
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             b) Data (Including Genomic Data) and Sample Sharing Plan:            
This protocol is not subject to the Genomic Data Sharing (GDS) policy. The sharing of  
Genomic data according to the GDS policy is covered under the screening protocol 81-M-0126. 
Data and samples may be shared with dbGaP, collaborating laboratories at NIH or outside of 
NIH and/or submitted to NIH-designated repositories and databases if consent for sharing was 
obtained.  Repositories receiving data and/or samples from this protocol may be open-access or 
restricted access.  
 
Samples and data will be stripped of identifiers and may be coded (“de-identified”) or 
unlinked from an identifying code (“anonymized”). When coded data is shared, the key to the 
code will not be provided to collaborators, but will remain at NIH.  Data and samples may be 
shared with investigators and institutions with an FWA or operating under the Declaration of 
Helsinki (DoH) and reported at the time of continuing review.  Sharing with investigators 
without an FWA or not operating under the DoH will be submitted for prospective IRB approval.  
Submissions to NIH-sponsored or supported databases and repositories will be reported at the 
time of Continuing Review.  Submission to non-NIH sponsored or supported databases and 
repositories will be submitted for prospective IRB approval. 
 
Required approvals from the collaborating institution will be obtained and materials will be 
shipped in accordance with NIH and federal regulations.  Data will not be shared from those who 
completed participation prior to Amendment 32 (FF). 
 6) 
Additional Considerations 
a. Research with investigational drugs or devices N/A 
7) 
Risks and Discomforts 
 
Lupron 

 
 
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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 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 3.75 mgs depot Lupron every month for a period of six months, the most 
common side effects reported to occur 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 ten patients of the original sample of 400 found the side effects to be severe 
enough to discontinue therapy.  Regular menstrual cycle function returned within two months 
following the last injection of depot Lupron (Tapp Pharmaceuticals, personal communication).  
In our experience to date, menstrual cycle irregularity has persisted up to six months after the last 
injection. Blurred vision, lethargy, memory disorder, and numbness have been reported in less 
than 3% of patients receiving the drug.  Thrombophlebitis and/or 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 anorexia.  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 

 
 
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hemoglobin concentration, fatigue, fever, facial swelling, rash, hives, hair loss, and itching.  
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 were observed; however, there is no 
evidence to date that overdosage in humans produces similar adverse effects.  Lupron dosages up 
to 20 mg 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 (86-88).  The FDA recently published a caution about the effects of 
GnRH agonists in elderly males; however, the safe use of these agents in younger adults and 
children was not questioned in the FDA statement. 
 
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 eating, 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 this risk is small. 
 
The relationship between estrogen, both endogenous and exogenous, and the 
development of endometrial carcinoma has been suggested by several different lines of 
investigation (89).  Numerous retrospective case control studies published since 1975 have 
indicated that post menopausal exposure to unopposed estrogens for more than one year results 

 
 
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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 therapy 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 and thus, inferentially, the risk of carcinoma, consists of 12 to 13 days of progestin 
treatment each month when estrogens are administered (90).  There is an increase in 
thromboembolism and stroke in women receiving estrogen therapy (91-98) (and, possibly, 
ovarian and lung cancer (99-102)); however, these complications are unlikely at the dose and 
duration of estrogen therapy employed in this protocol and in the younger age of the women 
participating in this trial.  One study (52) reported no effect of the estrogen patch on the four 
clotting indices previously shown to be altered by oral contraceptive use (90, 103, 104).  
Additionally, recent studies (105, 106) observed that an increased risk of venous 
thromboembolism was associated with oral but not transdermal estrogen compared with 
nonusers (odds ratios = .42 [95% CI, 1.5 to 11.6] and 0.9 [95% CI, 0.4 to 2.1] respectively 
(107)).  Blood pressure, on average, appears to be unaffected by estrogen therapy, although both 
increases and decreases have been reported.  Post menopausal estrogen therapy has been 
observed to increase the relative risk of cardiovascular disease in some (95, 108) but not all 
studies (109-111).  Indeed recent analyses of the Women’s Health Initiative demonstrate that the 
adverse effects of estrogen therapy on cardiovascular outcomes were largely confined to older 
women compared with younger perimenopausal women (98, 112-120).  High doses of oral 
estrogens have been reported to elevate hepatocellular enzyme levels and, less commonly, cause 

 
 
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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 (121-123).  Further, 
most studies have suggested an increased relative risk of breast cancer after four or five years’ 
use (98, 120, 124-136), similar to the risk expected if the onset of menopause was delayed for a 
comparable length of time. 
 
Due to the publicity surrounding the cancellation of the treatment arm of the Women’s 
Health Initiative study (137) that involved the administration of combined conjugated estrogens 
and medroxyprogesterone acetate (Prempro), we have included the following statement in the 
consent documents: 
Adverse Events Related to Combined Hormone Replacement and the Results of the Women’s 
Health Initiative (WHI) 
 
The WHI study demonstrated that continuous administration of one form of estrogen 
(conjugated estrogens) in combination with one form of progesterone (medroxyprogesterone 
acetate) is associated with an increased risk of dementia, heart attacks, stroke, blood clots, and 
breast cancer.  Estradiol, the form of estrogen that we use in this study, is administered as a sole 
agent (with the exception of one week’s combination with progesterone) and, consequently, we 
do not expect that it will pose the increased risks observed with the chronic combination of the 
conjugated estrogens and medroxyprogesterone administered in the WHI study.  Indeed, while 
the estrogen alone arm of the WHI trial was shown to be associated with an increased risk of 
stroke, no increased risk of either heart disease or breast cancer was observed (137, 138). 

 
 
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Estrogens may precipitate migraine headaches, and depression has also been reported to 
occur with the use of estrogens.  In general, considering the dose and duration of treatment that 
we propose to use in this protocol, the risk of developing such side effects is negligible. 
 
Progesterone 
 
Progesterone and the synthetic progestins are widely prescribed, with indications 
including dysfunctional uterine bleeding, endometriosis, mastodynia, galactorrhea, and 
precocious puberty (58).  Side effects reported in women taking progestins are uncommon but 
may include breakthrough bleeding, edema, change in weight (increase or decrease), cholestatic 
jaundice, rash (with or without pruritus), depression of mood, easy fatigue, 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. 
 
Side effects observed in patients receiving combined oral contraceptives include nausea, 
breast soreness, vaginal discharge, fluid retention, hypertension, and clotting abnormalities, 
which have been associated with the estrogen component of the oral contraceptive.  
Thromboembolic disorders including thrombophlebitis, pulmonary embolism, and cerebral and 
coronary thrombosis appear to occur with greater frequency in women taking oral 
contraceptives.  While the increased incidence of these disorders has been associated with the 
estrogen component of the oral contraceptives, it is now believed that the progestogen 
component may, to a lesser extent, contribute to the increased risk.  There are relatively few 
reports associating oral contraceptives with the development of carcinomas (vaginal, uterine, 
hepatic, and mammary) despite the vast use of these agents, although this may reflect the latent 

 
 
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period needed for cellular transformation.  Finally, several reports suggest an association 
between intrauterine exposure to female sex hormones and congenital anomalies. 
 
Symptom Production 
 
Preliminary observations in this protocol (1) suggest that some women may experience a 
recurrence of their typical MRMD symptoms during the hormone addback phase.  These 
symptoms have been similar in severity to those experienced prior to study entry.  However, if 
symptoms are intolerable we will discontinue the study. 
 
Any patient experiencing clinically significant side-effects such as nausea, hypertension, 
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, but the patient's continued involvement with our clinic will not be jeopardized.  
Similarly if menopausal symptoms occurring secondary to GnRH agonist treatment are 
intolerable, drug treatment will be discontinued. 
Blood Drawing 
One discomfort of this study may occur due to the venipuncture and multiple blood 
sampling.  Total blood withdrawal (660 ml) falls within NIH guidelines (550 ml. per eight week 
period). 
 
Potential discomforts in this study could arise from the repeated venipuncture 
(i.e., bruising or pain at site of needle entry) or the completion of rating scales.  The latter should 
take between 5-10 minutes each day and in our experience have not been a source of discomfort 
in the women with whom we have worked. 
Risks Related to Additional Procedures 
 

 
 
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Genetic testing 
Under some circumstances, it can be a risk for genetic information about an individual to 
be known.  Variation in some genes is known to be directly related to risk for certain illnesses.  
Other genes may be shown at some point in the future to be related to illness.  Since the results 
of these genetic tests may allow prediction of risk of illness in some cases, it is possible this 
information could be used against a subject participating in the study.  Although there are no 
physical risks associated with participation in genetic studies, apart from those routinely 
associated with phlebotomy, psychological and social/economic risks associated with genetics 
studies of the kind described here are difficult to define, and remain the subject of heated 
controversy in the ethics community.  The major risk, to the degree that any exists, is that a 
breach of confidentiality regarding genetic studies that resulted in third parties finding out 
genetic information about a person could theoretically place a person at risk for loss of insurance, 
loss of employment, etc. because of genotype-based discrimination.  To our knowledge, no 
person has ever suffered harm for the reasons just described as a result of participating in a 
genetics research study.  Regardless, our written informed consent process will go over these 
risks carefully.  In addition, subjects will have the right to “withdraw” from the research by 
having their DNA sample destroyed.  Finally, all research records containing any subject-
identifying information will be stored under lock and key, or in secured computing environments 
by the CTDB.  Personal identifiers are never associated directly with genotypes in the same data 
file - all genotype information is indexed only to de-identified subject codes.  With these 
safeguards in place, we are confident the research is virtually without psycho-social-economic 
risk to subjects. 
 
 

 
 
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Brain imaging 
The risks related to MRI and PET scanning are described in the consent forms associated 
with the protocols 90-M-0014, and 91-M-0124 under which they will be performed. 
Rating Scales, interviews and cognitive Testing 
 
No discomfort is expected to be associated with the rating scales, or clinical interview 
other than potential stress of answering personal questions.  All clinical assessors have extensive 
experience in clinical psychiatric assessment and will make every effort to implement protocol 
procedures in a sensitive and supportive manner.  Research interviews will be interrupted if 
subjects become distressed or object to answering questions.  Other measures to minimize risks 
include the careful assessment of each subject before the study, and close clinical scrutiny during 
all aspects of the study. 
8) 
Subject Safety Monitoring 
 
Subjects are evaluated by one of the associate investigators.  Medical history and physical 
assessments occur at each clinic visit including interviews, symptom assessments, vital signs, 
and laboratory testing when clinically indicated.  After completing the study, subjects will either 
be discharged from this protocol with a referral to the community, or will be referred to other 
NIMH studies. 
 
Patients will be warned not to become pregnant during the study and will be advised to 
employ barrier contraceptive methods.  Observations from our previous study (1) suggest that 
some women may experience a recurrence of their typical MRMD symptoms during the 
hormone addback phase.  These symptoms have been similar in severity to those experienced 
prior to study entry.  However, if symptoms are intolerable we will discontinue the subject’s 
participation in the study (or the study-specific procedure). 

 
 
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As we are administering doses of estradiol and progesterone designed to produce 
physiologic levels, we expect - and have seen - no unexpected adverse events.  Similarly, we do 
not anticipate unexpected adverse events with the dose of Lupron that we propose to use.  
Nonetheless, we see subjects every two weeks during their clinic visit and advise them in the 
consent form that if they experience side effects, they should notify the investigator immediately.  
Any adverse events will be reported as per NIH policy. 
9) 
Outcome Measures 
 
Current outcome measures include symptom ratings, brain activation and connectivity,  
metabolomic and genomic measures. 
10) 
Statistical Analysis 
 
A responder to Lupron will be defined in the following way: 1) the absence of PMTS 
rating scale scores above ten during any week of phase I (this threshold reflects our clinical 
experience with this rating scale and represents the maximum follicular phase score seen in over 
110 premenstrual syndrome patients followed longitudinally), and 2) the absence of two weekly 
mean scores on anxiety, depression, or irritability scales greater than 2.5 on a six point scale 
within a two month time period (1, 84).  The effects of both estrogen and progesterone 
replacement on mood ratings will be analyzed using similar threshold criteria to define patients 
as responders (recurrence of mood syndrome) or non-responders.  Previous estimates by 
Van Horn et al. (85) in CBDB, NIMH, suggest that 15 women with MRMD and 15 controls 
(recruited through protocol # 92-M-0174) would be required in the brain imaging component of 
this protocol to achieve statistical power of 80% and an alpha = .05.  In our first study we 
observed a response rate to GnRH agonist-induced ovarian suppression of 60% and a recurrence 
rate of mood symptoms during addback of 100%.  Therefore, to study 15 women in the brain 

 
 
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imaging component of this protocol we would need to admit 25 additional women to this 
protocol. 
To recruit sufficient numbers of women in each group for IPCs we will contact women 
who have previously participated in these protocols, have met our baseline criteria for PMD or 
asymptomatic controls, and have further demonstrated either the elimination of symptoms during 
GnRH agonist and return of symptoms upon re-exposure to estradiol or progesterone (PMD) or 
the absence of negative behavioral symptoms during both GnRH agonist and ovarian steroid 
addback phases (controls).  Each of these women who is interested in participating will be re-
consented for this study. 
11) 
Human Subjects Protection 
 a) 
Subject selection: 
 
Subject selection will be equitable.  We will select physically healthy adult female 
individuals.  Male subjects will be excluded as this is a study about menstrually related mood 
disorders which does not apply to men.  The proportion of ethnic minorities (vs. Caucasians) in 
the total sample, will be approximately consistent with the overall U.S. population proportions. 
b) 
Justification for inclusion/exclusion of children: 
We will exclude children or minors because the study population is women with MRMD. 
c) 
Justification for inclusion or exclusion of other vulnerable subjects: 
Pregnant women are excluded due to the risks associated with hormone administration.  
Cognitively impaired subjects and those unable to provide consent are excluded due to the 
rigorous requirements of daily ratings, cognitive testing and weekly study visits. 
d) 
Justification of sensitive procedures: 
N/A 

 
 
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e) 
Safeguards for vulnerable populations: 
 Protections for NIH employees, staff and family members participating in this study include 1) 
assuring that the participation or refusal to participate will have no effect, either beneficial or 
adverse, on the subject’s employment or position at the NIH, 2) giving employees and staff who 
are interested in participating the “NIH Information Sheet on Employee Research Participation” 
prior to obtaining consent, and 3) assuring that there will be no direct solicitation of employees 
or staff.  
f) 
Qualifications of Investigators: 
Peter J. Schmidt, M.D., is an investigator with the Section on Behavioral Endocrinology, 
NIMH.  He has over 20 years experience performing studies that examine the effects of 
reproductive hormones on mood and behavior in women with reproductive endocrine-related 
mood disorders.  He will be allowed to obtain consent. 
 
David R. Rubinow, M.D., is a special volunteer and collaborator within the Section on 
Behavioral Endocrinology, NIMH.  He has over 30 years experience in reproductive 
endocrinology and psychiatry.  He will not be involved in obtaining consent. He does not have 
access to personally identifiable information (PII). 
Lynnette K. Nieman, M.D., is a senior investigator in the Reproductive Biology and 
Medicine Branch, NICHD and has extensive experience with clinical research studies in 
endocrinology and reproductive biology.  She will not be involved in obtaining consent. 
 
Pedro E. Martinez, M.D., is a staff clinician within the Section on Behavioral 
Endocrinology, NIMH and has performed endocrine studies examining the effects of aging and 
reproductive hormones on mood and behavior in both adults and children.  He will be allowed to 
obtain consent. 

 
 
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Shau-Ming Wei, PhD has an extensive experience in experimental design, and she has 
designed and implemented both behavioral and neuroimaging experiments over the past several 
years.  Her graduate training at the NIH/Brown Program included collaborative neuroimaging 
studies on the effects of genotype and reproductive hormones on brain function.  She has worked 
with our program for more than ten years (as part of our ongoing collaborations with Dr. Karen 
Berman’s group), first as a doctoral candidate, then as a postdoctoral fellow. Currently, she is a 
research fellow within our Branch and in the future will be offered a position as a staff scientist. 
Over the last decade Dr. Wei has worked closely with our clinical program and this protocol 
involving the administration of a GnRH agonist with and without ovarian steroid hormone 
replacement. She will be involved in imaging data collection and analysis, and manuscript 
preparation. She will not obtain informed consent. 
 
The Principal Investigator has verified that all individuals working on this protocol 
required to take HRPP training under OHSRP SOP 25 (Training requirements for the NIH 
Human Research Protections Program) have completed all required training. 
12) 
Anticipated Benefits 
 
Menstrually-related mood disorders constitute a condition that causes significant distress 
to a potentially large number of women.  The potential benefit of determining an effective and 
consistent treatment for menstrually-related mood disorders is quite significant, particularly since 
existing therapies successfully treat only two thirds of patients with this disorder.  Further, the 
opportunity to explore potential biological mechanisms underlying both the menstrually-related 
mood disorders and their response to treatment offers the possibility of uncovering some 
etiopathogenic mechanisms involved in these and related mood disorders. 
13) 
Classification of Risk 

 
 
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The overall risks for this study are more than minimal. 
 
There are low risks to individual subjects in the use of medication and procedures under 
the conditions stated in this protocol.  Patients stand to gain effective and scientifically validated 
pharmacologic treatment of a condition that is frequently associated with pronounced 
debilitation.  Lupron is currently available for long term administration.  Finally, patients who 
continue to experience cyclic mood symptoms during treatment with GnRH analogue will be 
unlikely to respond to further hormonal manipulation and would potentially profit from currently 
available psychotropic medication. 
14) 
Consent Documentation and Process 
 
Each patient will receive a verbal and written explanation of the purpose, procedure, and 
potential hazards of this project.  A record of the communication of this information and of the 
consent to participate in this study will be placed in the medical record.  The right of the subjects 
to withdraw from the study or to refuse any procedure will be made clear.  Any patient whose 
symptoms become excessive during either the GnRH alone or estrogen/progesterone replacement 
phases will be offered another medication without completing the sixth month trial.  
Confidentiality of patients will be assured according to the laws of the State of Maryland.  In 
case of published data resulting from the study, care will be taken to protect the anonymity of 
patients. 
 
Consent for NIH employees and staff will not be obtained by coworkers. 
 
15) 
Data and Safety Monitoring 
 
A. 
Data and Safety Monitor 
 
Data and safety will be monitored by the Principal Investigator.   

 
 
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B.        Data and Safety Monitoring Plan 
 
The PI will review data and safety parameters at least annually. The PI will document the 
data and safety review in the research records and at the time of continuing review. 
 
C.        Criteria for stopping the study or suspending enrollment or procedures 
 
The study (or the study-specific procedure) will be stopped if any patient experiences 
clinically significant, unexpected, side-effects from the medication that cannot be relieved with a 
dose reduction.  The PI and IRB will determine if changes are needed for the research to 
continue or if it will be closed. 
 
 
16) 
Quality Assurance 
 
A. Quality Assurance Monitor  
 
Quality assurance will be monitored by the PI, the research team and the NIMH Office of 
Regulatory Oversight (ORO). 
 
B. Quality Assurance Plan  
 
ORO monitors intramural research studies to ensure compliance with GCP, 
organizational policies and regulations.  Audit frequency is determined by the ORO SOP based 
on the study level of risk.  Results of ORO audits are provided to the PI, the Clinical Director 
and the CNS IRB.  As an IND study, this protocol will be subject to GCP audits at study 
initiation and after the first enrolled subject.  Timing of subsequent review will be established by 
ORO but no less frequent than every other year.  
17) 
Reporting of Unanticipated problems, adverse events and protocol deviations 
The Principal Investigator is responsible for detecting, documenting, and reporting unanticipated 
problems, adverse events (AEs), including serious adverse events (SAEs), and deviations in 

 
 
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accordance with NIH policy, IRB requirements, and federal regulations. Relatedness to the 
research of all serious adverse events will be determined by the PI in consultation with the CD. 
Serious unanticipated problems and serious protocol deviations will be reported to the IRB and 
CD as soon as possible and in writing not more than 7 days after the PI first learns of the 
event.  Not serious unanticipated problems and not serious deviations will be reported to the IRB 
and CD as soon as possible and in writing not more than 14 days after the PI first learns of the 
event. Written reports will be submitted in PTMS.  
Deaths will be reported to the Clinical Director within 7 days after the PI first learns of the event.  
It is anticipated that participants in this study will occasionally miss or fail to complete an 
assessment or procedure, such as a study visit, completion of a rating scale, blood draw or other 
laboratory test as a result of an issue by participant, research staff, lab, or phlebotomy. Omissions 
such as these will be considered expected events and not protocol deviations provided they are 
infrequent and do not include data needed to assess safety or the primary study outcome.  
Cumulative proportions of these missed events in the study population will be presented to the 
IRB annually. In addition, the rate of omissions will be monitored by the Investigators. If an 
individual misses more than 15% of the required assessments/procedures or if more than 15% of 
the participants miss completion of the same assessment or procedure, it will be considered a 
deviation and a deviation report will be sent to the IRB within 14 days.  
All adverse events, deviations, and unanticipated problems will be summarized and 
reported at the time of Continuing Review. 
18) 
Alternatives to Participation 
 
Subjects do not receive any treatment in this study or forego any treatment in order to 
participate in this study.  The alternative, therefore, is not to participate. 

 
 
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19) 
Privacy: 
 
All research activities will be conducted in as private a setting as possible. 
20) 
Confidentiality 
 
Samples and data will be stored using codes that we assign.  Data will be kept in 
password-protected computers.  Samples will be kept in locked storage.  Only study investigators 
will have access to the samples and data. 
This study collects sensitive information on medical and psychiatric diagnoses and drug 
and alcohol use. The PI will train study staff regarding obtaining and handling potentially 
sensitive and private information about co-workers through staff discussions and written 
branch/section procedures.  Prior to enrollment, potential participants will be informed that this 
sensitive information will be in their NIH medical record. 
21) 
Conflict of Interest 
 
NIH guidelines on conflict of interest have been distributed to all investigators. There are 
no conflicts-of-interest to report. 
22) 
Technology Transfer 
 
There are no technology transfer agreements associated with this protocol 
23) 
Research and Travel Compensation 
 
Reimbursement of travel and subsistence will be offered consistent with NIH guidelines.  
Compensation will be prorated for parts completed if subjects do not complete the study.  No 
escort fee will be provided. 
 
Employees and staff who participate during work hours must have permission from their 
supervisor. NIH employees and staff must either participate outside of work hours or take leave 
in order to receive compensation.  

 
 
CNS IRB Protocol Template (rev 9.21.11) 
 
 
 
 
 
 
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1) Core Protocol 
Initial evaluation, physical exam (2 hours) 
 
100.00 
Screening phase 
 
 
 
100.00 
Clinic visits (weekly) 2 hour x 13  
 
390.00 
Multiple venipuncture x 13 
 
 
260.00 
Psychological testing x 5 
 
 
100.00 
Symptom rating scales x 6 months  
 
150.00 
Investigational drugs a) Depot Lupron injections 100.00 x 6 = 
600.00 
 
 
b) Skin patches daily x 3 months 
400.00 
 
 
c) Vaginal suppositories daily x 3 months 
400.00 
Total 
 
 
 
 
2500.00 
Blood Volume 
 
Core protocol: 660 mls 
 
 
 

 
 
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24) 
Flow Sheet 
 
 
0         4         8       12
0        4         8        12
Time
(weeks)
Effects of GnRH Agonist & Gonadal Steroid 
Replacement in MRMD
Leuprolide
(3.75 mg IM QM)
Baseline
(3 cycles)
Estradiol 0.1 mg/day
Progesterone 200 mg BID
Placebo/Placebo
Responder
Non-Responder
OR
Leuprolide
(3.75 mg IM QM)
Procedures

 
 
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25) 
References 
 
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Appendix I 
Clinical Trials Database - Security Overview 
There are multiple aspects to the security framework for the Clinical Trials Database (CTDB) and 
Clinical Trials Survey System.  The following features allow for the safe and secure collection of 
research variables: 
• Application Firewall- The NICHD has recently upgraded their application firewall which 
protects both the front end web server and back end database server for the CTDB.  Strict 
policies are in place which control exactly who has pre-defined, limited access to the 
application.  This firewall is a state-of-the-art hardware solution which blocks access to 
everyone but authorized users for the CTDB system. 
• Data Encryption and SSL Certificates - The CTDB system makes use of military grade 
encryption both for the session and the data storage.  The CTSS collects de-identified self-
reported data.  Both systems protect information from interception by encrypting the data 
flow using SSL with a 1024 bit signed certificate.  The entire communication session from 
the time a client requests a connection to the system to the time a user logs out is encrypted 
using a certificate from an industry recognized vendor.  The result is a secure 
communications channel for our partners, providing data confidentiality and integrity.  In 
further, the CTDB program encrypts data stored within the system, thereby providing an 
additional layer or security for the sensitive CTDB clinical data.     
• CTSS HIPAA Requirements - Below is the list of identifiers to be removed for the de-
identification of health information under HIPAA. This is found in 45 C.F.R. 
164.514(a),(b)&(c)  
(A) Names;  
(B) All geographic subdivisions smaller than a State, including street address, city, 
county, precinct, zip code, and their equivalent geocodes, except for the initial three 
digits of a zip code if, according to the current publicly available data from the Bureau of 
the Census:  
(1) The geographic unit formed by combining all zip codes with the same three initial 
digits contains more than 20,000 people; and  
(2) The initial three digits of a zip code for all such geographic units containing 20,000 or 
fewer people is changed to 000.  

 
 
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(C) All elements of dates (except year) for dates directly related to an individual, 
including birth date, admission date, discharge date, date of death; and all ages over 89 
and all elements of dates (including year) indicative of such age, except that such ages 
and elements may be aggregated into a single category of age 90 or older;  
(D) Telephone numbers;  
(E) Fax numbers;  
(F) Electronic mail addresses;  
(G) Social security numbers;  
(H) Medical record numbers;  
(I) Health plan beneficiary numbers;  
(J) Account numbers;  
(K) Certificate/license numbers;  
(L) Vehicle identifiers and serial numbers, including license plate numbers;  
(M) Device identifiers and serial numbers;  
(N) Web Universal Resource Locators (URLs);  
(O) Internet Protocol (IP) address numbers;  
(P) Biometric identifiers, including finger and voice prints;  
(Q) Full face photographic images and any comparable images; and  
(R) Any other unique identifying number, characteristic, or code, except as permitted by 
paragraph (c) of this section 
• Logical Access Controls (Role/Privileges) – Logical access controls are in placed using role 
based security for database access and application account access. Security controls are in 
place to detect unauthorized access attempts. The application is further protected by the 
NICHD firewall and NIH firewall. Inactive user accounts are monitored and removed when 
not needed, and users are disconnected after a specific period of inactivity. Encryption is 
used (1024bit SSL key) and data is HIPPA compliant. Access is monitored and apparent 
security violations are investigated when identified. Insecure protocols are disabled on all 
application servers. Guest and anonymous accounts/access is disabled.  
• Audit Trails – Activity involving access to and modification of sensitive or critical files is 
logged and monitored for possible security violations. Access to these audit trails is strictly 
controlled and can be used to support after-the-fact investigations of how, when and why 
normal operations ceased should this occur. Off-line storage of audit logs is retained for a 
period of at least 1 year. Suspicious activity is investigated and appropriate action is taken 
when warranted.  
• Physical and Environmental Protection – The servers are physically located in a secured 
NIH data center with controlled limited access. All work products from the system including 
Data backup tapes are rotated to off-site storage with must be authorize and are recorded. All 

 
 
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visitors to sensitive areas are escorted with entry codes changed periodically. Fire prevention 
and suppression devices are installed and in working condition. All heating and air-cooling 
systems are periodically checked to ensure proper working condition.  
• Production Input and Output Control – Audit trails are in place to record data changes. 
Only authorized system administrators are allowed access to this data, as well as any data 
backup tapes. Damaged media is sanitized or destroyed, and any hardcopy media is shredded 
when no longer needed.  
• Contingency Planning – All critical data files, database files and web server files have been 
identified. A regularly scheduled data backup solution is in place with identified resources 
supporting critical operations. A comprehensive contingency plan has been developed and 
documented. This plan has been approved by key affected parties. The Contingency 
plan/Disaster recovery plan is regularly tested and adjusted as appropriate.  
• Hardware and Software System Maintenance – Access is limited to the hardware and 
software infrastructure. Restrictions are in place as to who performs maintenance activities. 
Procedures are in place to monitor the use of system resources. All new and revised hardware 
and software are tested and approved before implementation. All system and application 
components are tested, documented and approved prior to promotion to production 
environment. Detailed system specification as prepared and reviewed by management. A 
version control system is in place for all key application and operating system files. The 
systems are actively managed to monitor and reduce vulnerabilities with unnecessary 
services eliminated.  
• Strategic framework – The tactical security framework provides a mechanism whereby the 
Clinical Trials support personnel provide day-to-day operational support activities for the 
regular maintenance of the CTDB system.  These initiatives incorporate application and 
software security.  The CTDB application was designed using the latest Java technology.  
This allows the adaptation of the application to ever-changing business rules within the 
application.  An Oracle 10g relational database provides the repository for the clinical data.  
The use of a robust, industry standard relational database provides a modular architecture 
design of CTDB which allows for the CTDB program to assign role based security to the 
participants in the system.  This allows roles to be defined and implemented for different 
users- such as investigators, study participants, report writes, etc- in order to secure database 

 
 
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access and the application data stored within the system.  This implies that the NICHD 
CTDB partners can implement custom roles and maintain their own clinical data with a high 
level of confidence that the data will not be compromised nor shared with non-participants.  
As technology evolves, this attention to the strategic framework allows us to address 
individual software components and target them for enhancements or upgrades all while 
maintaining the integrity and confidentiality of the CTDB system.  Another example of this 
strategic framework is the reporting interface.  The modular design of CTDB allows provides 
the ability to upgrade to Cognos reporting with the result being more detailed comprehensive 
reporting abilities. The net result is a feature-enhanced system while maintain the strict 
security framework of the system.