Clinical trial NCT01602679
Conditions: Female Reproductive Physiology
Sponsor: University of Virginia
Start date: 2012-05-01; Completion date: 2015-07-31
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The rapidity with which progesterone slows LH (and by inference GnRH) pulse frequency in women is unclear. The investigators hypothesize that progesterone slows LH pulse frequency within 10 hours. The investigators propose to assess this further with a randomized, cross-over, placebo-controlled study. Regularly cycling women without hyperandrogenism will be admitted to the Clinical Research Unit on cycle day 5-9 (mid-follicular phase) for a 10 hour frequent sampling study to observe LH, FSH, estradiol, progesterone, and testosterone. Either oral micronized progesterone suspension or placebo will be administered at 0900 h. During a subsequent menstrual cycle, subjects will undergo another study identical to the first except that oral progesterone will be exchanged for placebo or vice versa in accordance with a crossover design.

Detailed description:
The rapidity with which progesterone slows LH (and by inference GnRH) pulse frequency in women is unclear. The investigators hypothesize that progesterone slows LH pulse frequency within 10 hours. The investigators propose to assess this further with a randomized, cross-over, placebo-controlled study. Regularly cycling women without hyperandrogenism will be admitted to the Clinical Research Unit on cycle day 5-9 (mid-follicular phase) for a frequent sampling study. Beginning at 0900 h, blood for LH, FSH, estradiol, progesterone, and testosterone will be obtained over a 10-hour period. Either oral micronized progesterone (100 mg p.o.) suspension or placebo will be administered at 0900 h. During a subsequent menstrual cycle, subjects will undergo another study identical to the first except that oral progesterone will be exchanged for placebo or vice versa in accordance with a crossover design. The primary endpoint of interest is LH pulse frequency; the investigators will compare LH pulse frequency after progesterone administration to LH pulse frequency after placebo administration.

Arms: arm 1: Participants first received oral micronized progesterone (100 mg p.o.) suspension. After a washout period of approximately 20 days, they then received placebo (matching oral micronized progesterone suspension). arm 2: Participants first received placebo. After a washout period of approximately 20 days, they then received oral micronized progesterone syrup (100 mg p.o.)Placebo contains only inert ingredients and is not expected to exert any direct physiological effects
Interventions: intervention 1: oral micronized progesterone suspension intervention 2: Placebo
Intervention descriptions: intervention 1: oral micronized progesterone (100 mg p.o.) suspension intervention 2: Placebo contains only inert ingredients and is not expected to exert any direct physiological effects

Protocol documents:
Prot_SAP_000.pdf: 
IRB-HSR# 16085: Acute effects of progesterone on LH pulses during the follicular phase 
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IRB-HSR PROTOCOL 
Investigator Agreement 
 
BY SIGNING THIS DOCUMENT, THE INVESTIGATOR CONFIRMS: 
1. I am not currently debarred by the US FDA from involvement in clinical research studies. 
2. I am not involved in any regulatory or misconduct litigation or investigation by the FDA. 
3. That if this study involves any funding or resources from an outside source, or if you will be sharing data 
outside of UVA prior to publication that you will contact the Dean’s office regarding the need for a contract 
and letter of indemnification.  If it is determined that either a contract or letter of indemnification is needed, 
subjects cannot be enrolled until these documents are complete. 
4. The proposed research project will be conducted by me or under my close supervision.  It will be conducted 
in accordance with the protocol submitted to and approved by the IRB including any modifications, 
amendments or addendums submitted and approved by the IRB throughout the life of the protocol.  
5. That no personnel will be allowed to work on this protocol until they have completed the IRB-HSR On-line 
training and the IRB-HSR has been notified. 
6. That all personnel working on this protocol will follow all IRB-HSR Policies and Procedures as stated on 
the IRB-HSR Website http://www.virginia.edu/vprgs/irb/ and on the School of Medicine Clinical Trials 
Office Website:  http://knowledgelink.healthsystem.virginia.edu/intranet/hes/cto/sops/sop_index.cfm 
7. I will ensure that all those delegated tasks relating to this study, whether explicitly or implicitly, are capable 
through expertise, training , experience or credentialing to undertake those tasks.   
8. I confirm that the implications of the study have been discussed with all Departments that might be affected 
by it and have obtained their agreement for the study to take place.  
9. That no subjects will be recruited or entered under the protocol until the Investigator has received the signed 
IRB-HSR Approval form stating the protocol is open to enrollment 
10. That any materials used to recruit subjects will be approved by the IRB-HSR prior to use.  
11. That all subjects will sign a copy of the most current consent form that has a non-expired IRB-HSR 
approval stamp. 
12. That any modifications of the protocol or consent form will not be initiated without prior written approval 
from the IRB-HSR, except when necessary to eliminate immediate hazards to the subjects. 
13. Any significant findings that become known in the course of the research that might affect the willingness 
of subjects to enroll or to continue to take part, will be promptly reported to the IRB.   
14. I will report immediately to the IRB any unanticipated problems involving risk to subjects or to others 
including adverse reactions to biologics, drugs or medical devices.   
15. That any serious deviation from the protocol will be reported promptly to the Board in writing. 
16. That any data breach will be reported to the  IRB, the UVa Corporate Compliance and Privacy Office , UVa 
Police as applicable.  
17. That the continuation status report for this protocol will be completed and returned within the time limit 
stated on the form. 
18. That the IRB-HSR office will be notified within 30 days of a change in the Principal Investigator or of the 
closure of this study. 
19. That a new PI will be assigned if the current PI will not be at UVA for an extended period of time.  
20. All study team members will have access to the current protocol and other applicable documents such as the 
IRB-HSR Application, consent forms and Investigator Brochures. 
21. Signed consent forms and other research records will be retained in a confidential manner.  Records will be 
kept at least 6 years after completion of the study.  


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22. No data/specimens may be taken from UVa without a signed Material Transfer Agreement between 
OSP/SOM Grants and Contracts Office and the new institution.  Original study files are considered 
institutional records and may not be transferred to another institution. I will notify my department 
administration regarding where the originals will be kept at UVa.  The material transfer agreement will 
delineate what copies of data, health information and/or specimens may be taken outside of UVa.  It will 
also approve which HIPAA identifiers may be taken outside of UVa with the health information or 
specimens. 
23. If any member of study team leaves UVa, they are STRONGLY ENCOURAGED to use Exit Checklist 
found on IRB-HSR website at http://www.virginia.edu/provost/facultyexit.pdf. 
 
 The IRB reserves the right to terminate this study at any time if, in its opinion, (1) the risks of further 
experimentation are prohibitive, or (2) the above agreement is breached. 
 
Investigators Experience 
 
Dr. McCartney (Principal Investigator) has 12 years of experience performing clinical research in the field of reproductive 
neuroendocrinology. He has extensive experience with frequent sampling protocols, procedures of the Clinical Research 
Unit, and LH pulse analysis—both in adolescent girls and adult women. He was/is intimately involved with GCRC 
protocols JCM001 (successfully completed) and CRM001 (IRB-HSR# 13368; ongoing), which are very similar to the 
protocol proposed herein. 
 
 
Signatures 
 
Principal Investigator 
 
____________________________ ____________________________ _______ 
Principal Investigator 
Principal Investigator 
Date 
Signature 
Name Printed 
 
Department Chair 
BY SIGNING THIS DOCUMENT THE DEPARTMENT CHAIR AGREES: 
1. To work with the investigator and with the board as needed, to maintain compliance with this 
agreement. 
2. That the Principal Investigator is qualified to perform this study. 
3. That the protocol is scientifically relevant and sound. 
 
___________________________ 
_______________________  
_________ 
Department Chair or Designee  
Department Chair or Designee 
Date 
Signature 
Name Printed 
 
 
The person signing as the Department Chair cannot be the Principal Investigator or a sub-investigator on this 
protocol. 
The Department Chair or Designee signature is ONLY required if this is a new protocol or a modification 
changing the Principal Investigator 
 
 


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Brief Summary/Abstract 
 
The rapidity with which progesterone slows LH (and by inference GnRH) pulse frequency in women is unclear. 
We hypothesize that progesterone slows LH pulse frequency within 10 hours. We propose to assess this 
further with a randomized, cross-over, placebo-controlled study. Regularly cycling women without 
hyperandrogenism will be admitted to the Clinical Research Unit on cycle day 5-9 (mid-follicular phase) for a 
frequent sampling study. Beginning at 0900 h, blood for LH, FSH, estradiol, progesterone, and testosterone will 
be obtained over a 10-hour period. Either oral micronized progesterone (100 mg p.o.) suspension or placebo 
will be administered at 0900 h. During a subsequent menstrual cycle, subjects will undergo another study 
identical to the first except that oral progesterone will be exchanged for placebo or vice versa in accordance 
with a crossover design. The primary endpoint of interest is LH pulse frequency; we will compare LH pulse 
frequency after progesterone administration to LH pulse frequency after placebo administration.  
Background 
 
Through this study, we seek to assess the validity of an important assumption in our overall hypothesis 
regarding how cyclic ovulation is established during puberty—namely, that progesterone acutely reduces 
luteinizing hormone (LH) pulse frequency. 
 
Gonadotropin-releasing hormone (GnRH) stimulates LH and follicle-stimulating hormone (FSH) synthesis and 
secretion from the same gonadotrope cell; nonetheless, LH and FSH levels change differentially throughout 
ovulatory cycles, with FSH predominance in the early follicular phase and LH predominance in the late 
follicular phase. These variations in gonadotropin secretion result in part from different patterns of pulsatile 
GnRH stimulation, with high GnRH pulse frequencies favoring LH synthesis/secretion and low GnRH pulse 
frequencies favoring FSH synthesis/secretion (1). Thus, an ability to reduce GnRH pulse frequency is 
important for the normal cyclic patterns of LH and FSH.  
  
Progesterone appears to be the primary effector of GnRH pulse frequency slowing. GnRH pulse frequency 
slows coincident with progesterone increases in the luteal phase, and administration of progesterone to women 
during the follicular phase also slows GnRH pulse frequency (2). Progesterone’s ability to slow GnRH pulse 
frequency appears to require the permissive presence of estradiol, possibly reflecting estradiol’s ability to 
induce hypothalamic progesterone receptors (3). However, the rapidity with which progesterone suppresses 
GnRH pulse frequency in women remains unknown.  
 
Changes of GnRH pulse frequency are also seen during puberty. Specifically, early puberty is marked by 
relatively high LH (and by inference GnRH) pulse frequency at night, with slowing of LH pulse frequency during 
the day. The cause(s) of these diurnal changes in GnRH pulsatility is (are) unclear, but diurnal changes of sex 
steroids, which also occur during this time, may play an important role. Overnight increases of testosterone 
and estradiol occur in pubertal boys and girls, respectively. Estradiol infusion in peripubertal girls (4), in 
addition to infusions of either testosterone (5, 6) or estradiol (7) in peripubertal boys, mitigates nocturnal 
increases in LH pulsatility. Moreover, in contrast to diurnal changes of LH and estradiol in normal pubertal girls, 
age-matched girls with gonadal dysgenesis exhibit elevated LH pulse frequencies at all time periods (8, 9). 
Thus, diurnal changes of sex-steroids may direct diurnal changes (i.e., daytime slowing) of GnRH pulse 
frequency during puberty.  
 
Since progesterone is the primary effector of GnRH pulse frequency slowing in adult women, and given that 
progesterone increases ~2.3-fold overnight in early pubertal girls (10), we have hypothesized that 
progesterone is a major effector of diurnal (daytime) GnRH pulse frequency slowing in peripubertal girls. We 
have considered the possibility that diurnal changes of progesterone during puberty could alter GnRH pulse 
frequency in “real-time,” with morning increases of progesterone “immediately” suppressing GnRH pulse 


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frequency. However, the rapidity (over hours to days) with which progesterone slows LH pulse frequency in 
normal women remains unknown. This is a critical point: for the above hypothetical model to be viable, these 
sex steroids would have acute actions, effecting GnRH pulse frequency changes over hours rather than days.  
 
To address this issue, our group first performed a study in adults (11). Eight normally cycling women were 
pretreated with transdermal estradiol patches and then admitted to the GCRC. (Pre-treatment with estradiol 
was given to ensure adequate hypothalamic progesterone receptors.) We administered a single dose of 
progesterone at 1800 h and monitored changes (before vs. after progesterone) of LH pulse characteristics. 
Each subject also underwent a GCRC admission where placebo was administered at 1800 h. The 10-hour 
mean progesterone concentration increased from 0.6 ± 0.1 ng/ml before progesterone (0800-1800 h) to 3.9 ± 
0.3 ng/ml after progesterone administration (2200-0800 h). LH pulse frequency decreased significantly after 
both progesterone and placebo administration, with no significant difference between progesterone and 
placebo. (These changes after progesterone and placebo actually reflect sleep-wake differences, which have 
been previously described.) Also of interest, progesterone markedly and significantly increased both LH pulse 
amplitude and mean LH in this study—a reflection of progesterone positive feedback. We concluded that in 
estradiol-pretreated women in the late follicular phase, nocturnal LH pulse frequency is not acutely (within 12 
hours) influenced by progesterone administration.  
 
The apparent absence of rapid progesterone-induced slowing of LH frequency in the adult study above is in 
contrast to animal studies, which suggest a rapid (within 2-6 hours) decrease in LH and GnRH pulse frequency 
after progesterone administration. For instance, in ovariectomized but estradiol-replete ewes, progesterone 
dramatically suppresses GnRH pulse frequency over 12 hours; this effect appears to begin within 2 hours and 
is blocked by the progesterone-receptor antagonist mifepristone (12). Similarly, in bovine females, changes in 
LH pulse frequency are observed within 6 hours of altered progesterone concentrations (13).  
 
Of great interest, several lines of evidence suggest the possibility that sleep-related LH frequency is resistant 
to negative feedback by progesterone, but that LH frequency while awake may remain rapidly suppressed by 
progesterone (14). For example, a recent study by our group (15) was performed to evaluate the effect of 
progesterone on LH pulse frequency in early to mid-pubertal girls. We studied 18 non-obese, non-
hyperandrogenemic Tanner 1-3 girls. Frequent sampling was performed from 1900 to 0700 h. Five subjects 
received oral progesterone (25-50 mg at 1600 and 2000 h), while the remainder did not. In contrast to controls, 
girls receiving progesterone exhibited no LH pulses during waking hours, while nighttime (2300-0700 h) LH 
frequency was similar. Based on this study, we concluded that exogenous progesterone acutely (within 3-7 
hours) suppresses daytime, but not nocturnal, LH pulse frequency in early to mid-pubertal girls, suggesting that 
GnRH pulse frequency is differentially regulated by progesterone depending on sleep status. 
 
In support of the above notion, two studies by Loucks and colleagues suggest that dietary restriction slows 
daytime—but not nighttime—LH pulse frequency in the late follicular phase (16, 17). This suggests that 
daytime and nighttime LH frequency may be differentially affected by experimental maneuvers.  
 
On the basis of the above, we considered the possibility that daytime (or non-sleep-associated) LH frequency 
is acutely responsive to changes in P concentrations in women, even though nighttime frequency is not. This 
formed the basis for IRB-HSR 13368, which involved a protocol identical to that in reference 11 (including 
estradiol-pretreatment and study in the late follicular phase) except that the timing of the sampling and 
progesterone (and placebo) administration is altered by exactly 12 hours (i.e., progesterone and placebo are 
administered at 0600 h instead of 1800 h). This study was designed to test whether or not progesterone 
suppresses daytime LH pulse frequency within 10 hours in estradiol-pretreated women in the late follicular 
phase. Preliminary data to date suggests that daytime LH frequency may not be acutely altered by 
progesterone, although we again see that LH pulse amplitude and mean LH increases markedly within 4 hours 
of progesterone administration. This latter phenomenon is a reflection of progesterone positive feedback, 


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which occurs in the setting of gonadotrope priming with high estradiol concentrations (18-20). Indeed, this 
phenomenon is important for the full expression of the midcycle (preovulatory) LH surge.  
 
The data from IRB-HSR 13368 are important in their own right, and this study will continue until completion. 
However, we are now concerned that this study (IRB-HSR 13368) may possibly include two separate but 
related confounding factors: (a) estradiol pretreatment and (b) study in the later follicular phase. That is, we are 
likely studying the effects of progesterone in a hormonal milieu that is similar to the preovulatory phase of the 
menstrual cycle. Thus, we may be primarily assessing the acute positive feedback effects of progesterone—
which may occur only in the setting of high (preovulatory) estradiol concentrations—rather than the acute 
negative feedback effects of progesterone. For this reason, we now propose a protocol to assess the acute 
effects of progesterone on LH pulse frequency in the midfollicular phase in women who have not received 
pretreatment with exogenous estradiol. 
 
This study is important for a more thorough understanding of normal female reproductive neuroendocrine 
physiology. Perhaps more importantly (from our perspective), it is imperative that we fully assess the validity of 
this important assumption in our overall hypothesis regarding how cyclic ovulation is established during 
puberty. 
 
Hypothesis to be Tested 
 
We hypothesize that administration of progesterone to normally cycling adult women during the follicular phase 
will result in a demonstrable suppression of LH (and by inference GnRH) pulse frequency within 10 hours.  
 
Study Design: Biomedical 
1.  Will controls be used? 
 
This is a cross-over study, so subjects will serve as their own controls.  
 
2. What is the study design?  
 
Double-blind until data analysis (progesterone concentrations are measured, which will disclose 
whether progesterone or placebo was given).  
 
3. 
Does the study involve a placebo? Yes. 
 
►IF YES, provide a justification for the use of a placebo 
 
LH secretory characteristics can be influenced by various factors such as time of day, stress, etc. Thus, 
defining LH secretory characteristics in the absence of progesterone is important for valid inference regarding 
the effects of progesterone.  
Human Participants 
Ages  18-30 y 
Sex 
Female only 
Race All races 
Subjects- see below 
1.  Provide target # of subjects (at all sites) needed to complete protocol. 


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We aim to complete study on 12 subjects.  
 
2.  Describe expected rate of screen failure/ dropouts/withdrawals from all sites.   
 
A 33% completion rate (for both admissions) is expected.  
 
3.  How many subjects will be enrolled at all sites?   Up to 36 
 
4.  How many subjects will sign a consent form under this UVa protocol?    Up to 36 
Inclusion/Exclusion Criteria 
1. List the criteria for inclusion  
 
 
Subjects will be healthy women with regular menstrual cycles and no evidence of hyperandrogenism.  
 
Subjects will be 18-30 years old; we use a cutoff age of 30 years because age-related alterations in the 
hypothalamic-pituitary-ovarian axis is uncommon before age 30 years.   
 
Subjects will be willing to strictly avoid pregnancy (using non-hormonal methods) during the time of 
study and must be willing and able to provide informed consent.  
 
2.  List the criteria for exclusion 
 
 
Pregnancy  
 
Lactation  
 
History of allergy to progesterone 
 
BMI < 18 kg/m2 or > 30 kg/m2 (underweight and obesity can affect hypothalamic-pituitary-ovarian 
function)  
 
Excessive exercise, defined as routine and current engagement in either (a) moderate exercise (e.g., 
brisk walking) exceeding 14 hours per week or (a) vigorous exercise exceeding 7 hours a week. 
 
Clinical hyperandrogenism (primarily hirsutism) 
 
Abnormally elevated free testosterone or DHEAS concentration 
 
A previous diagnosis of diabetes, a fasting glucose ≥ 126 mg/dl 
 
Abnormal TSH (subjects with adequately treated hypothyroidism, reflected by normal TSH values, will 
not be excluded; or, for a new diagnosis of hypothyroidism, further study will at the least be delayed 
pending appropriate treatment) (confirmed on repeat) 
 
Abnormal prolactin (confirmed on repeat) 
 
Evidence of Cushing’s syndrome by history or physical exam 
 
History of venous thromboembolism, breast/ovarian/endometrial cancer  
 
We will exclude women with any other cancer diagnosis and/or treatment (with the exception of basal 
cell or squamous skin carcinoma) unless they have remained clinically disease free (based on 
appropriate surveillance) for five years.  
 
Women with anemia (hematocrit < 36% and hemoglobin level < 12 g/dl) will be treated with iron for a 
maximum of 2 sequential months before the 1st admission and/or before the 2nd admission. If they 
remain anemic after 2 sequential months of ferrous gluconate (325 mg bid), they will then be excluded 
from further participation in the study. 
 
Women with a significant history of cardiac or pulmonary dysfunction (e.g., known or suspected 
congestive heart failure; known or suspected coronary atherosclerosis; asthma requiring systemic 
intermittent corticosteroids; etc.) will be excluded.  


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 
Women with liver enzymes, alkaline phosphatase, or bilirubin > 1.5 times upper limit of normal 
(confirmed on repeat) will be excluded, with the exception that mild bilirubin elevations will be accepted 
in the setting of known Gilbert’s syndrome. 
 
Abnormal sodium or potassium concentrations (confirmed on repeat); bicarbonate concentrations <20 
or >30 (confirmed on repeat) 
 
Women with abnormal renal function (i.e., serum creatinine > 1.4) will be excluded (confirmed on 
repeat) 
 
Due to the amount of blood being drawn in the study, subjects with body weight < 110 pounds will be 
excluded from the study 
 
3.  List any restrictions on use of other drugs or treatments.    
 
Being a study of the acute effects of progesterone on the hypothalamic-pituitary unit, subjects must not take 
hormonal medications (e.g., oral contraceptives) or other medications known to affect the reproductive axis for 
60 days prior to the study and during the study. 
Biomedical Research 
 
1.  What will be done in this protocol?    
 
Interventions in this research study are not expected to directly benefit the volunteers, and all interventions 
(e.g., collection of blood, data, administration of progesterone) are being done solely to answer a research 
question and generate generalizable knowledge.  
 
Studies under this protocol will be performed in normally cycling women from 18 to 30 years old. After informed 
consent is obtained, all potential subjects will undergo a screening history and physical exam. Subjects will 
need to fast for a minimum of 8 hours prior to screening blood draw. After informed consent is obtained, blood 
tests (≤ 16 cc) will be drawn at approximately 0800-1000 h as follows: LH, FSH, progesterone, estradiol, total 
testosterone, sex hormone binding globulin (SHBG), DHEA-S, beta-hCG, TSH, prolactin, CBC, chemistry and 
liver panels, and fasting insulin. BOD POD® will be used to measure total fat mass, fat free mass, and percent 
body fat. Waist and hip circumference will be measured.  
 
If a low hematocrit and hemoglobin with a low or low-normal MCV (i.e., likely related to iron deficiency) is seen 
on screening labs, we will offer 1 month of iron treatment (ferrous gluconate 325 mg bid) with a subsequent 
recheck of hematocrit and hemoglobin. If hematocrit and hemoglobin are still low, we will offer 1 more month of 
iron treatment (ferrous gluconate 325 mg bid) with a subsequent recheck of hematocrit and hemoglobin. Only 
volunteers with a hematocrit ≥ 36% or a hemoglobin ≥ 12 g/dl (after a maximum of two sequential months of 
iron treatment) will be allowed to proceed with frequent blood sampling. Women with anemia will be treated 
with iron for a maximum of 2 sequential months before the first admission. If they remain anemic after two 
sequential months of ferrous gluconate (325 mg bid), they will then be withdrawn from the study. 
 
This study follows a crossover design, with assessment of the acute effects of progesterone and placebo 
(individually) on LH (GnRH) pulsatility (namely frequency); subjects will be randomized to receive either 
progesterone or placebo during the first admission, with subsequent admission occurring during a subsequent 
cycle.  
 
One to 3 days before a scheduled admission, subjects will come to the CRU for an outpatient blood draw for 
beta-HCG (1 cc). If 30 days have elapsed between (a) the most recent hemoglobin and hematocrit and (b) the 
scheduled overnight admission, a hemoglobin and hematocrit will also be drawn at this time (1 cc). Note: a 
hematocrit ≥ 36% or hemoglobin ≥ 12 g/dl in the month before overnight admission is required to participate in 


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the scheduled inpatient (frequent sampling) protocol. If three months have elapsed between (a) the subject’s 
most recent safety labs and (b) the first CRU admission, a chemistry and liver panel will also be obtained at 
this time. 
 
On cycle day 5-9 (mid-follicular phase), women will undergo a 10-h sampling study in the Clinical Research 
Unit (CRU). Subjects will come to the CRU no later than 0700 h (2 h prior to the start of sampling).  
 
NOTE: If not performed 1-3 days before the admission, we will perform beta-HCG, 
hemoglobin/hematocrit (as needed), and safety labs (as needed) on admission to the CRU. 
 
Beginning at 0900 h, blood will be obtained through an indwelling i.v. forearm heparin lock over a 10-h period 
as follows: LH every 10 min (1 ml); progesterone every 30 min for 4 h, then every 2 h (1.5 ml). In addition, the 
following assays will be run in the same blood samples as progesterone: FSH, estradiol, and testosterone 
every 2 h. SHBG will be measured once at 0900 h.  
 
At 0900 h (immediately after the first blood draw at 0900 h), either oral micronized progesterone suspension 
(100 mg p.o.) or placebo suspension will be administered (according to randomization). With exogenous 
progesterone, we aim to achieve mean plasma progesterone concentrations 4-8 ng/ml.  
 
NOTE: The randomization will be balanced (1:1 ratio), with an equal number of (a) subjects receiving 
progesterone during the first admission and (b) subjects receiving placebo during the first admission.  
 
Subjects will not be allowed to sleep during the admission. We will ask women to eat only the food provided by 
the CRU staff. 
 
At the completion of sampling (1900 h), volunteers will be discharged on oral iron (325 mg BID).  
 
The second inpatient admission will be scheduled during a subsequent cycle. One to 3 days before the 
scheduled admission, subjects will come to the CRU for an outpatient blood draw for beta-HCG (1 cc). If 30 
days will have elapsed between (a) the most recent hemoglobin and hematocrit (obtained after the first 
admission) and (b) the scheduled inpatient admission, a hemoglobin and hematocrit will also be drawn at this 
time (1 cc). If three months have elapsed between (a) the subject’s most recent safety labs and (b) the second 
CRU admission, a chemistry and liver panel will also be obtained at this time. 
 
On cycle day 5-9 (mid-follicular phase), women will undergo a 10-h sampling study in the Clinical Research 
Unit (CRU). Subjects will come to the CRU no later than 0700 h (2 h prior to the start of sampling).  
 
NOTE: If not performed 1-3 days before the admission, we will perform beta-HCG, 
hemoglobin/hematocrit (as needed), and safety labs (as needed) on admission to the CRU. 
 
Subjects will undergo another frequent sampling study identical to the first, except that oral progesterone will 
be exchanged for placebo or vice versa in accordance with the crossover design. In this way, we will be able to 
standardize LH pulsatility after progesterone administration to LH pulsatility after placebo administration.  
 
If the subject does not have hematocrit ≥ 36% or hemoglobin ≥ 12 g/dl at the start of or shortly before the 
second CRU admission (i.e., within 30 days, as long as the measurement was after the first admission), we will 
offer 1 month of iron treatment (ferrous gluconate 325 mg bid) with a subsequent recheck of hematocrit and/or 
hemoglobin. If hematocrit and hemoglobin are still low, we will offer 1 more month of iron treatment (ferrous 
gluconate 325 mg bid) with a subsequent recheck of hematocrit and hemoglobin. Only volunteers with 
hematocrit ≥ 36% or hemoglobin ≥ 12 g/dl will be allowed to proceed with the second admission. No more than 
2 months of iron treatment will be given between the first and second CRU admissions. 


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The study will end after the second CRU admission. Subjects will be asked to continue oral iron 
supplementation for at least 30 d after this last overnight admission. 
 
2.  Will any of the NON-RADIOLOGIC treatments/ procedures be done for research purposes only?  yes  
All procedures are being done for research purposes only  
 
►IF YES, (examination(s) are performed for research) check one of the following two options:  
_X____The examination(s) utilize(s) the same techniques, equipment, etc., that would be used if the 
subject were to have the examination(s) performed for clinical care.  There exists the potential for 
the discovery of clinically significant incidental findings.   
• The PI takes full responsibility for the identification of incidental findings:  
• The PI will inform the subjects verbally of all incidental findings that are of clinical 
significance or are of questionable significance.   
• A follow-up letter describing the finding should be provided to the subject with 
instructions to either show the letter to their PC or if the subject has no PCP, the subject 
should be instructed to make an appointment at UVa or at the Free Clinic.   
3.  Will any RADIOLOGIC treatments/examinations be performed for research purposes only? No 
 
4. Will you be using viable embryos? No 
 
5. Will you be using embryonic stem cells? No 
Family History/Pedigree 
 
1.  What kind of information is being sought?  
 
Family history of disorders that have a genetic component and may impact the reproductive axis (e.g., 
PCOS, infertility, metabolic-related disorders such as diabetes and metabolic syndrome, etc.)  
 
2.  What identifiers will be recorded with the info (e.g. names, initials, relationship such as mother, 
father, brother, sister, random number)? Relationship 
 
3.  Does any of the information sought potentially expose the subject or a family member to additional 
risk? No 
 
Specimens:  Will not be used for Genetic Research or Banking 
 
Specimen Information 
1.  Describe the type of specimen to be used: 
Blood (and possibly urine for pregnancy test) 
 
2.  Will the specimen be obtained BEFORE a subject has signed a consent form? No 
 
3.  Will you be using discarded specimens? No 
 


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►IF NO, and taking a blood sample, will blood be taken more than 2 times/week? Yes 
 
►IF NO, and taking a blood sample, check the option(s) below which match the subject 
population. 
 
__X__  healthy, non pregnant adults who weigh at least 110 pounds.  
 
 
__ X __ Amount will NOT exceed 550 cc in an 8 week period 
 
Specimen Labeling 
1.  What information/ HIPAA identifiers will be on the specimen label when it is given to the study team 
(from clinical labs or other source outside the study team) and/or what information will you put on the 
specimen? 
 
Name, medical record number, CRU protocol number, time (date and clock hour) drawn 
 
2.  If the specimen is given to the study team with information on the label will you delete any of the 
information on the specimen label?    
No 
 
►IF YES, list the information that will be deleted.   
 
3.  Will any additional data be linked to the specimen by way of a code?  No 
 
4.  Will the analysis on the specimen be done soon (within 24 hours) after it is collected? 
 
We anticipate that samples obtained outside of the CRU admissions (e.g., during the screening visit) 
will be analyzed by UVA Clinical Labs or Ligand Assay Core will typically be run within 24 hours. 
Samples obtained during CRU admissions will be spun/separated/frozen for later analysis in the Center 
for Research in Reproduction’s Ligand Core. 
 
 
Specimen Shipping 
1.  Do you plan to ship any specimens outside of UVA? No 
Data and Safety Monitoring Plan 
If you have any questions completing this section call 982-4311, 924-8660 or 243-9847 for assistance 
A Sponsor is defined as entity that will receive data prior to publication. 
1.  Definition: 
1.1 How will you define adverse events (AE)) for this study?  
__X__An adverse event will be considered any undesirable sign, symptom or medical or 
psychological condition even if the event is not considered to be related to the investigational 
drug/device/intervention. Medical condition/diseases present before starting the investigational 
drug/intervention will be considered adverse events only if they worsen after starting study 
treatment/intervention.  An adverse event is also any undesirable and unintended effect of research 
occurring in human subjects as a result of the collection of identifiable private information under the 
research.  Adverse events also include any problems associated with the use of an investigational 
device that adversely affects the rights, safety or welfare of subjects. 


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1.2 How will you define serious adverse events? 
__X__A serious adverse event will be considered any undesirable sign, symptom, or medical 
condition which is fatal, is life-threatening, requires or prolongs inpatient hospitalization, results 
in persistent or significant disability/incapacity, constitutes a congenital anomaly or birth defect, 
is medically significant and which the investigator regards as serious based on appropriate 
medical judgment. An important medical event is any AE that may not result in death, be life-
threatening, or require hospitalization but may be considered an SAE when, based upon 
appropriate medical judgment, it may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in the definitions of SAEs.  
__X__Any serious psychological and emotional distress resulting from study participation 
(suggesting need for professional counseling or intervention). 
 
1.3 What is the definition of an unanticipated problem?  
Do not change this answer 
An unanticipated problem is any event, experience that meets ALL 3 criteria below: 
 Is unexpected in terms of nature, severity or frequency given the research procedures that are 
described in the protocol-related documents AND in the characteristics of the subject 
population being studies 
 Related or possibly related to participation in research.  This means that there is a reasonable 
possibility that the incident may have been caused by the procedures involved in the research 
study. 
 The incident suggests that the research placed the subject or others at greater risk of harm 
than was previously known or recognized OR results in actual harm to the subject or others 
 
1.4 What is the definition of a protocol violation?  
Do not change this answer 
A protocol violation is defined as any change, deviation, or departure from the study design or 
procedures of a research project that is NOT approved by the IRB-HSR prior to its initiation or 
implementation, OR deviation from  standard operating procedures, Good Clinical Practices 
(GCPs), federal, state or local regulations. Protocol violations may or may not be under the control 
of the study team or UVa staff. These protocol violations may be major or minor violations. 
 
Additional Information: see the IRB-HSR website at  
http://www.virginia.edu/vpr/irb/HSR_docs/Forms/Protocol_Violations_%20Enrollment_Exceptions
_Instructions.doc 
 
1.5 If pregnancy occurs how will this information be managed? 
 
__X__ Other – Subjects are counseled to take measures to avoid pregnancy during the study, and 
the likelihood of pregnancy will not be altered by these study procedures. Pregnancy cannot be 
considered an adverse event or unanticipated problem related to any of the study procedures. 
Pregnancy would be considered a protocol violation (on the part of the study volunteer). 
 
1.6 What is the definition of a Protocol Enrollment Exception?   


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__X__NA- No outside sponsor 
 
1.7 What is the definition of a data breach? 
Do not change this answer 
A data breach is defined in the HITECH Act (43 USC 17932) as an unauthorized acquisition, 
access, or use of protected health information (PHI) that compromises the security or privacy of 
such information. 
 
Additional Information may be found on the IRB-HSR Website: Data Breach 
2.  Identified risks and plans to minimize risk 
 
 
2.1 What risks are expected due to the intervention in this protocol? 
 
Expected Risks related to study 
participation. 
  
Frequency 
 
Risks of venipuncture 
 
Discomfort 
_X__Occurs frequently 
____Occurs infrequently 
____Occurs rarely 
____Frequency unknown 
Bruising 
_X__Occurs frequently 
____Occurs infrequently 
____Occurs rarely 
____Frequency unknown 
Infection 
____Occurs frequently 
____Occurs infrequently 
____Occurs rarely 
__X_Frequency unknown, but likely to be 
very rare 
Blood clot at the site of intravenous 
catheter insertion 
____Occurs frequently 
____Occurs infrequently 
_X__Occurs rarely 
____Frequency unknown 
Risks of frequent blood draws 
 
Mild anemia 
____Occurs frequently 
____Occurs infrequently 
____Occurs rarely 
__X_Frequency unknown 
      Risk to fetus 
____Occurs frequently 
____Occurs infrequently 
____Occurs rarely 
__X_Frequency unknown – Extremely 
unlikely, as endogenous progesterone 
concentrations are normally very high during 
pregnancy, and we are administering one 


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small dose of progesterone. 
Risks of progesterone 
 
Fluid retention 
____Occurs frequently 
____Occurs infrequently 
____Occurs rarely 
__X_Frequency unknown - Can occur with 
long-term, higher dose progestin 
administration, but very unlikely to occur after 
one small dose of progesterone. 
Sleepiness 
____Occurs frequently 
____Occurs infrequently 
____Occurs rarely -  
__X_Frequency unknown - Unlikely to occur 
after one small dose of progesterone. 
Mood swings 
____Occurs frequently 
____Occurs infrequently 
____Occurs rarely 
__X_Frequency unknown - Can occur with 
long-term, higher dose progestin 
administration, but very unlikely to occur after 
one small dose of progesterone. 
Mild vaginal bleeding 
____Occurs frequently 
____Occurs infrequently 
____Occurs rarely 
__X_Frequency unknown - often occurs after 
longer-term, higher dose progestin 
administration, but very unlikely to occur after 
one small dose of progesterone. 
Risks of iron supplementation 
 
nausea 
____Occurs frequently 
__X_Occurs infrequently 
____Occurs rarely 
____Frequency unknown 
constipation 
____Occurs frequently 
__X_Occurs infrequently 
____Occurs rarely 
____Frequency unknown 
dark stool 
__X_Occurs frequently 
____Occurs infrequently 
____Occurs rarely 
____Frequency unknown 
Risk for early termination of 
study participation if subject 
becomes pregnant 
Subjects are not expected to have any 
alteration of fertility as a result of study 
medications. Therefore, sexually active 
subjects may get pregnant during this 
protocol. If the volunteer becomes pregnant, 
the study and all study medications will be 
discontinued. 


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Violation of subject’s privacy and 
confidentiality 
Minimized due to the requirements of the 
privacy plan in this protocol 
 
2.2   List by bullet format a summary of safety tests/procedures/observations to be performed.  
• 
Risks of venipuncture will be minimized by using proper sterile technique 
• 
Risk of anemia will be reduced in the following manner: Most importantly, blood withdrawal will be carefully 
limited to < 550 cc over an 8 week period of time. Specifically, 16 cc will be withdrawn during screening 
visit, and approximately 155 cc will be withdrawn during each CRU admission (this includes up to 0.5 cc of 
blood wastage per blood draw). Thus, overall blood withdrawal for the entire protocol will be approximately 
325 cc. Also, hemoglobin and hematocrit will be measured and reviewed within 30 days before each CRU 
sampling study. Only volunteers with hematocrit ≥ 36% or hemoglobin ≥ 12 will be allowed to proceed with 
the frequent sampling study.  
• 
A history and physical will be performed at screening. Women with disorder that could be exacerbated by 
mild anemia will be excluded: known or suspected congestive heart failure; known or suspected coronary 
atherosclerosis; asthma requiring systemic intermittent corticosteroids; etc.  
• 
We do not believe that this study poses any risk to a fetus. Nonetheless, risk of fetal exposure to study 
drugs will be reduced by having a serum pregnancy test obtained and reviewed prior to each overnight 
sampling study. If the volunteer is pregnant, the study and all study medications will be discontinued.  
• 
A single small dose of progesterone is not expected to increase the risk of venous thromboembolism or 
cancer. Nonetheless, we will exclude women with a history of venous thromboembolism or 
breast/ovarian/endometrial cancer. 
• 
Risk from iron supplementation will be reduced by instructing subjects to take their iron tablets with food 
and a full glass of water. They will be told to include whole grains and fruits and vegetables in their diet for 
fiber. 
• 
A comprehensive metabolic panel will be performed at screening. Women with liver enzymes, alkaline 
phosphatase, or bilirubin > 1.5 times upper limit of normal (confirmed on repeat) will be excluded, with the 
exception that mild bilirubin elevations will be accepted in the setting of known Gilbert’s syndrome. Women 
with abnormal renal function (i.e., serum creatinine > 1.4) will be excluded. Women with abnormal sodium, 
potassium, or bicarbonate concentrations (confirmed on repeat) will be excluded. 
• 
If three months have elapsed between (a) the subject’s most recent safety labs and (b) an overnight 
admission, a CBC, chemistry and liver panel will be obtained prior to the overnight admission (or on 
admission) to exclude anemia and any other exclusion criteria. 
• 
Subjects will have frequent (at least every 10 minutes) contact with CRU nursing personnel and will be 
asked to report any unusual symptoms occurring during the protocol. 
 
 
2.3 Under what criteria would an INDIVIDUAL SUBJECT’S study treatment or study participation be 
stopped or modified 
__X__At subject, PI or sponsor’s request 
 
Protocol-determined criteria for study withdrawal include pregnancy and persistent anemia despite iron 
supplementation. The PI could also withdraw a subject if it is felt that continuation would be unsafe. The 
subject may withdraw at any time and for any (stated or unstated) reason. 
 
__X__Treatment would be stopped if the subject had a serious adverse event deemed related to 
study, or study drug will be increased if the subject tolerates dosing insert details:_ 
 
Specifically, treatment would be stopped if the subject had a serious adverse event deemed related 
to study. 


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#         
 
2.4 Under what criteria would THE ENTIRE STUDY need to be stopped.   
These are called stopping rules for early termination of the entire study. 
List criteria regardless of whether the study is sponsored or not.  
Be sure to include any criteria for which the UVa PI would halt the study at UVa. 
__X__Per IRB, PI, DSMB, or sponsor discretion 
2.5 What are the criteria for breaking the blind/mask? 
 
__X__Other: specify 
 
The treatment allocation would be unblinded if a serious adverse event occurs during study. Given that 
progesterone concentrations are measured, treatment allocation will be effectively unblinded once a 
participant completes study and blood samples are analyzed. 
 
2.6 How will subject withdrawals/dropouts be reported to the IRB prior to study completion? 
__X__IRB-HSR continuation status form  
 
3.  Adverse Event / Unanticipated Problem Recording and Reporting 
 
3.1 Will all adverse events, as defined in section 1.1, be collected/recorded? No 
►IF NO, what criteria will be used?  
 
__X__Only adverse events deemed related/possibly related to study  
 
3.2 How will adverse event data be collected/recorded? Check all that apply 
__X__Paper AE forms/source documents  
__X__Spreadsheet (paper or electronic) 
 
3.3. How will AEs be classified/graded? Check all that apply 
__X__Mild/Moderate/Severe 
__X__Serious/Not serious Required for all protocols 
 
 
3.4 What scale will the PI use when evaluating the relatedness of adverse events to the study 
participation?   
 
__X__The PI will determine the relationship of adverse events to the study 
 using the following scale: 
 
Related:      
 
AE is clearly related to the intervention 
Possibly related: 
AE may be related to the intervention 
Unrelated:  
 
AE is clearly not related to intervention 
 
3.5 When will recording/reporting of adverse events/unanticipated problems begin? 


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__X__After subject begins study drug/ device placement/intervention /study-related procedure/specimen 
collection 
 
3.6 When will the recording/reporting of adverse events/unanticipated problems end? 
__X__End of study drug/device/intervention/participation  
 
3.7 How will Adverse Events, Unanticipated Problems, Protocol Violations and Data Breaches be 
reported?  Complete the table below to answer this question 
 
Type of Event 
To whom will it 
be reported: 
Time Frame for 
Reporting 
How reported? 
Any internal event resulting 
in death that is deemed 
DEFINITELY related to 
(caused by) study 
participation 
An internal event is one that 
occurs in a subject enrolled 
in a UVa protocol 
IRB-HSR 
Within 24 hours 
IRB Online and phone call 
 
www.irb.virginia.edu/ 
 
Internal, Serious, Unexpected
adverse event  
 
 
IRB-HSR 
Within 7 calendar 
days from the time 
the study team 
received knowledge 
of the event. 
 
Timeline includes 
submission of signed 
hardcopy of AE form. 
IRB Online 
 
www.irb.virginia.edu/ 
 
Unanticipated Problems that 
are not adverse events or 
protocol violations  
This would include a Data 
Breach.   
IRB-HSR 
 
 
Within 7 calendar 
days from the time 
the study team 
received knowledge 
of the event.  
Unanticipated Problem report 
form.  
 
http://www.virginia.edu/vp
rgs/irb/HSR_docs/Forms/R
eporting_Requirements-
Unanticipated_Problems.d
oc ) 
 
  
Protocol Violations 
 (The IRB-HSR only requires 
that MAJOR violation be 
reported, unless otherwise 
required by your sponsor, if 
applicable.) 
 
Or  
 
Enrollment Exceptions 
IRB-HSR 
 
 
Within 7 calendar 
days from the time 
the study team 
received knowledge 
of the event.  
 
Protocol Violation and 
Enrollment Exception Reporting 
Form 
 
 
http://www.virginia.edu/vp
rgs/irb/hsr_forms.html 
 
Go to 3rd bullet from the 
bottom. 
  


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Data Breach  
The UVa 
Corporate 
Compliance and 
Privacy Office, a 
 
 
ITC:  if breach 
involves  
electronic data-  
 
 
 
UVa Police if 
breach includes 
such things as 
stolen 
computers.  
As soon as possible 
and no later than 24 
hours from the time 
the incident is 
identified. 
 
As soon as possible 
and no later than 24 
hours from the time 
the incident is 
identified. 
IMMEDIATELY.  
 
 
UVa Corporate Compliance and 
Privacy Office- Phone 924-9741 
 
 
 
 
ITC:  Information Security 
Incident Reporting procedure,  
http://www.itc.virginia.edu/secur
ity/reporting.html 
 
 
Phone- (434) 924-7166 
  
UVa PI HELD IND 
Life-threatening and/or fatal 
unexpected events related or 
possibly related to the use of 
the investigational agent. 
FDA 
Within 7 calendar 
days of the study 
team learning of the 
event 
Form FDA 3500A (MedWatch) 
or narrative 
Serious, unexpected and 
related or possibly related 
adverse events 
FDA 
Within 15 calendar 
days after the study 
team receives 
knowledge of the 
event 
Form FDA 3500A (MedWatch) 
or narrative 
All adverse events 
FDA 
Annually 
IND annual report 
 
 
 
4.    How will the endpoint data be collected/recorded.  
__X__Source documents 
__X__Database: specify  
5. Data and Safety Oversight Responsibility 
 
5.1. Who is responsible for overseeing safety data for this study ?  
 
__X__DSMB/ DSMC-  If your study is NIH funded, check with the center to determine if they 
require a DSMB for this study. 
 
5.2. What is the composition of the reviewing body and how is it affiliated with the sponsor?   
Members of the study team may NOT also be members of the DMSB. 
 
_____Information may be found in the UVa Cancer Center Institutional DSMP 
 
__x___Other- specify    
William Evans, MD; Mark DeBoer, MD; Guofen Yan, PhD. This DSMB was 
established to oversee studies on NIH R01 grant. The listed individuals have no 
direct affiliation with the NIH and do not directly participate in these studies. 


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5.3. What items will be included in the aggregate review conducted by the PI?  
 
__X__All adverse events 
__X__Unanticipated Problems 
__X__Protocol violations 
__X__Audit results 
_____Application of dose finding escalation/de-escalation rules These should be outlined under 2.4. 
__X__Application of study designed stopping/decision rules 
_____Early withdrawals 
__X__Whether the study accrual pattern warrants continuation/action 
____Endpoint data 
_____Other: (specify) ______ 
 
5.4 How often will aggregate review occur? 
For additional information on aggregate review see: 
www.virginia.edu/vpr/irb/hsr/continuations.html#aggreview 
 
__X__Annually 
 
5.5. How often will a report, regarding the outcome of the review by the DSMB/DSMC, be sent to 
the UVa PI? 
A copy of these reports must be sent to the IRB if applicable as soon as they are received by the PI.  
Do not wait until the next continuation to submit them to the IRB.   
__X__Once a year 
_____Other: specify 
 
5.6. How will a report of the information discussed in question 5.4 OR 5.5 be submitted to the 
IRB?   
__X__Part of IRB-HSR continuation status form 
Payment 
 
1.  Are subjects being reimbursed for travel expenses (receipts /mileage required)? No 
 
2.  Are subjects compensated for being in this study? Yes 
 
2a.  What is the maximum TOTAL compensation to be given over the duration of the protocol? 
 
$225 
 


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2b.  Explain compensation to be given. 
 
Subjects will receive $75 for each completed inpatient admission, and a $75 bonus for 
completing all CRU admissions and outpatient visits in the study. 
 
2c.  Is payment pro-rated (e.g. some compensation is given even if subjects do not complete the 
entire study)? 
 
Yes, subjects completing only one inpatient CRU admission will receive $75. 
 
 
3.  Is money paid from UVa or State funds (including grant funds) or will items such as gift cards be 
distributed through UVa?Yes 
 
3a.  How will the researcher compensate the subjects? 
__X__ Check issued to participant via UVA Oracle or State system  
 
 
3b.  Which category/ categories best describes the process of compensation?  
 
__X__ All compensation will be made via check issued to participant via UVA Oracle or 
State system  
Risk/ Benefit Analysis 
 
1.  What are the potential benefits for the participant as well as benefits which may accrue to society in 
general, as a result of this study? 
 
There will likely be no direct benefits for the participant as a result of this study. A panel of laboratory testing 
will be performed (e.g., at screening), and abnormalities requiring medical evaluation are occasionally 
discovered in this manner.  
 
We believe that the risk of participating in this study is minimal, but the information obtained may help to further 
elucidate the mechanisms involved in modulation of the GnRH pulse generator in health and disease. The 
information obtained via this study will be critical to obtain while pursuing our hypotheses regarding the 
development of ovulatory cycles during puberty and the emergence of neuroendocrine abnormalities in 
adolescents destined to develop PCOS. These hypotheses may be used in developing therapeutic 
interventions for hyperandrogenemic adolescents, a condition felt to represent a forerunner of PCOS. 
 
2.  Analyze the risk-benefit ratio. 
The mechanisms by which cyclic ovulation is established at puberty are incompletely understood. Polycystic 
ovary syndrome (PCOS), the most prevalent reproductive disorder in young women, typically manifests at 
puberty, and it is very likely that the genesis of PCOS occurs at puberty. Enhanced understanding of normal 
neuroendocrine function during puberty and how these normal processes go awry in PCOS will be essential to 
design rational treatment strategies for PCOS. These studies may further elucidate the mechanisms involved 
in modulation of the GnRH pulse generator in adults (and by inference in peripubertal adolescents). Again, we 
believe that the risks involved to individuals in this study are minimal and that the potential benefits to medical 
knowledge are substantial. 


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Bibliography 
 
1. 
McCartney Eagleson CA, Marshall JC. Regulation of gonadotropin secretion: implications for polycystic 
ovary syndrome. Semin Reprod Med 2002; 20: 317-325 
2.  Soules MR, Steiner RA, Clifton DK, Cohen NL, Aksel S, Bremner WJ. Progesterone modulation of 
pulsatile luteinizing hormone secretion in normal women. J Clin Endocrinol Metab 1984; 58: 378-383  
3.  Goodman RL, Bittman EL, Foster DL, Karsch FJ. The endocrine basis of the synergistic suppression of 
luteinizing hormone by estradiol and progesterone. Endocrinology 1981; 109: 1414-1417  
4.  Cemeroglu AP, Kletter GB, Guo W, Brown MB, Kelch RP, Marshall JC, Padmanabhan V, Foster CM. In 
pubertal girls, naloxone fails to reverse the suppression of luteinizing hormone secretion by estradiol. J 
Clin Endocrinol Metab 1998; 83: 3501-3506 
5.  Foster CM, Hassing JM, Mendes TM, Hale PM, Padmanabhan V, Hopwood NJ, Beitins IZ, Marshall JC, 
Kelch RP. Testosterone infusion reduces nocturnal luteinizing hormone pulse frequency in pubertal boys. 
J Clin Endocrinol Metab 1989; 69: 1213-1220 
6.  Kletter GB, Foster CM, Brown MB, Beitins IZ, Marshall JC, Kelch RP. Nocturnal naloxone fails to reverse 
the suppressive effects of testosterone infusion on luteinizing hormone secretion in pubertal boys. J Clin 
Endocrinol Metab 1994; 79: 1147-1151 
7.  Kletter GB, Padmanabhan V, Beitins IZ, Marshall JC, Kelch RP, Foster CM. Acute effects of estradiol 
infusion and naloxone on luteinizing hormone secretion in pubertal boys. J Clin Endocrinol Metab 1997; 
82: 4010-4014 
8.  Cemeroglu AP, Foster CM, Warner R, Kletter GB, Marshall JC, Kelch RP. Comparison of the 
neuroendocrine control of pubertal maturation in girls and boys with spontaneous puberty and in 
hypogonadal girls. J Clin Endocrinol Metab 1996; 81: 4352-4357  
9.  Ross JL, Loriaux DL, Cutler GB, Jr. Developmental changes in neuroendocrine regulation of gonadotropin 
secretion in gonadal dysgenesis. J Clin Endocrinol Metab 1983; 57: 288-293 
10.  McCartney CR, Blank SK, Prendergast KA, Chhabra S, Eagleson CA, Helm KD, Yoo R, Chang RJ, Foster 
CM, Caprio S, Marshall JC. Obesity and sex steroid changes across puberty: evidence for marked 
hyperandrogenemia in pre- and early pubertal obese girls. J Clin Endocrinol Metab 2007; 92: 430-436 
11.  McCartney CR, Blank SK, Marshall JC. Progesterone acutely increases LH pulse amplitude but does not 
acutely influence nocturnal LH pulse frequency slowing during the late follicular phase in women. Am J 
Physiol Endocrinol Metab 2007; 292: E900-6. 
12.  Skinner DC, Evans NP, Delaleu B, Goodman RL, Bouchard P, Caraty A. The negative feedback actions of 
progesterone on gonadotropin-releasing hormone secretion are transduced by the classical progesterone 
receptor. Proc Natl Acad Sci U S A. 1998; 95: 10978-10983 
13.  Bergfeld EG, Kojima FN, Cupp AS, Wehrman ME, Peters KE, Mariscal V, Sanchez T, Kinder JE. 
Changing dose of progesterone results in sudden changes in frequency of luteinizing hormone pulses and 
secretion of 17 beta-estradiol in bovine females. Biol Reprod 1996; 54: 546-553 
14.  McCartney CR. Maturation of sleep-wake GnRH secretion across puberty in girls: potential mechanisms 
and relevance to the pathogenesis of polycystic ovary syndrome. Journal of Neuroendocrinology. 2010; 
22: 701-709. 
15. Collins JS, Marshall JC, McCartney CR. “Differential day-night influence of progesterone on GnRH pulse 
secretion.” Accepted January 4, 2012, for publication in Neuroendocrinology (DOI: 10.1159/000336395) 
16.  Loucks AB, Heath EM. Dietary restriction reduces luteinizing hormone (LH) pulse frequency during waking 
hours and increases LH pulse amplitude during sleep in young menstruating women. J Clin Endocrinol 
Metab 1994; 78: 910-915     
17.  Loucks AB, Verdun M, Heath EM. Low energy availability, not stress of exercise, alters LH pulsatility in 
exercising women. J Appl Physiol. 1998; 84: 37-46 
18. Chang RJ, Jaffe RB. Progesterone effects on gonadotropin release in women pretreated with estradiol. J 
Clin Endocrinol Metab 1978; 47: 119–125 


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19. Liu JH, Yen SS. Induction of midcycle gonadotropin surge by ovarian steroids in women: a critical 
evaluation. J Clin Endocrinol Metab 1983; 57: 797–802 
20.  Nippoldt TB, Khoury S, Barkan A, Kelch RP, Marshall JC. Gonadotrophin responses to GnRH pulses in 
hypogonadotrophic hypogonadism: LH responsiveness is maintained in the presence of luteal phase 
concentrations of oestrogen and progesterone. Clin Endocrinol (Oxf) 1987; 26: 293–301 
 
APPENDIX:  Sponsor 
Sponsor Information 
This study is supported by funding from the University of Virginia’s Department of Endocrinology and 
Metabolism. 
 
.APPENDIX:  Legal/Regulatory 
Recruitment 
The following procedures will be followed: 
• Finders fees will not be paid to an individual as they are not allowed by UVa Policy 
• All recruitment materials will be approved by the IRB-HSR prior to use.   The advertisements will be 
submitted to the IRB after the protocol has been approved. 
• Only those individuals listed as personnel on this protocol will recruit and or conduct the consenting 
process with potential subjects.  
 
Clinical Privileges 
The following procedures will be followed:  
• Investigators who are members of the clinical staff at the University of Virginia Medical Center must 
have been granted clinical privileges to perform specific clinical privileges whether those procedures 
are experimental or standard.  
• The IRB cannot grant clinical privileges.   
• Performing procedures which are outside the scope of the clinical privileges that have been granted 
may result in denial of insurance coverage should claims of negligence or malpractice arise. 
• Personnel on this protocol will have the appropriate clinical privileges in place before performing any 
procedures required by this protocol.  
• Contact the Clinical Staff Office- 924-5871 for further information. 
 
Sharing of Data/Specimens 
Data and specimens collected under an IRB approved protocol are the property of the University of Virginia.  
You must have “permission” to share data/ specimens outside of UVa other than for a grant application and or 
publication.  This “permission” may come in the form of a contract with the sponsor or a material transfer 
agreement (MTA) with others.  A contract/ MTA is needed to share the data outside of UVa even if the data 
includes no HIPAA identifiers and no code that could link the data back to a HIPAA identifier.   
• No data will be shared outside of UVa, beyond using data for a grant application and or publication, 
without a signed contract/MTA approved by the SOM Grants and Contracts office/ OSP or written 
confirmation that one is not needed. 
• No specimens will be shared outside of UVa without a signed contract/MTA approved by the SOM 
Grants and Contracts office/ OSP or written confirmation that one is not needed. 
 


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Prisoners 
If the original protocol/ IRB application stated that no prisoners would be enrolled in this study and 
subsequently a subject becomes a prisoner, the study team must notify the IRB immediately.  The study team 
and IRB will need to determine if the subject will remain in the study.  If the subject will remain in the study, 
the protocol will have to be re-reviewed with the input of a prisoner advocate.  The prisoner advocate will also 
have to be involved in the review of future continuations, modifications or any other reporting such as protocol 
violations or adverse events.   
 
Prisoner- Individuals are prisoners if they are in any kind of penal institution, such as a prison, jail, or juvenile 
offender facility, and their ability to leave the institution is restricted. Prisoners may be convicted felons, or may 
be untried persons who are detained pending judicial action, for example, arraignment or trial. 
For additional information see the OHRP website at  http://www.hhs.gov/ohrp/policy/populations/index.html 
APPENDIX:  Drug Information 
 
1   What is the drug name, manufacturer and IND# if available?    
 
In this protocol, we will use a micronized progesterone suspension (FDA IND number 64,126), which is 
formulated by the UVAHS research pharmacy. This IND was required solely because it is 
formulated/constituted by our investigational pharmacy. The progesterone used to formulate the suspension 
(i.e., Progesterone USP, micronized, for prescription compounding [NDC 39822-6000-3] Mfg: Spectrum 
Chemicals) is FDA approved.  
 
2.   If IND application has been submitted to the FDA, who is the Principal Investigator on the IND?     
 
John C. Marshall, MD, PhD 
 
3.  What is the phase or stage of this study?    
e.g. Phase 1,2 or 3, pivotal, pilot, post-marketing 
 
This study is not being performed to evaluate the effectiveness of micronized progesterone as a therapeutic 
agent, so we do not feel that any of these phases/stages apply to this study.  
APPENDIX:  Recruitment 
Recruitment includes identifying, review of records to determine eligibility or any contact to determine a 
potential subjects interest in the study. 
 
1. How do you plan to identify potential subjects? 
To "identify" a potential subject refers to steps you plan to take to determine which individuals 
would qualify to participate in your study. This does NOT include steps to actually contact those 
individuals. 
If your study involves more than one group of subjects (e.g. controls and cases or subjects and 
caregivers) note below which groups are being identified by the given method.  
Check the methods you plan to utilize: 
 


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a. ____ Chart Review/ Clinic Schedule Review/ Database Review from a database 
established for health care operations (departmental clinical database) or quality 
improvement. 
DHHS: Study team requests Waiver of Consent to identify potential subjects.  
HIPAA- Allowed under Preparatory to Research 
 
b. ____ Review of a database that was established to keep data to be used for future 
research such as the CDR, departmental research database or use of data from a separate 
current active research protocol.     
DHHS: Study team requests Waiver of Consent to identify potential subjects. 
HIPAA- Allowed under Preparatory to Research 
 
NOTE:  The information from which you are obtaining potential subjects must also 
have an IRB protocol approval.  
 
IRB# ________________ 
If obtaining information from the Clinical Data Repository (CDR) insert IRB # 10797. 
 
c. ____ Patients UVa health care provider supplies the UVa study team with the patients 
contact information without patients knowledge.  
DHHS: Study team requests Waiver of Consent to identify potential subjects.  
HIPAA- Allowed under Preparatory to Research 
 
 
d. ____ Patient obtains information about the study from their health care provider.  The 
patient contacts the study team if interested in participating.  
DHHS:  NA 
HIPAA:  Allowed under Health Care Operations 
If this choice is checked, check 3d-INDIRECT CONTACT below.  
 
e. _X_ Potential subjects will not be directly identified. They will respond to an 
advertisement such as a flyer, brochure etc.   
If this choice is checked, check 3d- INDIRECT CONTACT below.  
DHHS & HIPAA:  NA 
 
f. _____  Potential subjects have previously  signed a consent to have their name in a 
registry/database to be contacted for future studies of this type.   
IRB#  of registry/ database:  ________________ 
DHHS & HIPAA:  NA 
 
 
g_X__ Other- explain 
 
We may offer this study as an option for some subjects who responded to 
advertisements for other studies (e.g., IRB-HSR 13368). 
 


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If item # a, b or c is checked above and if this protocol involves the use of protected health 
information you confirm the following to be true: 
The use or disclosure is sought solely to review protected health information as necessary to 
prepare the research protocol or other similar preparatory purposes. 
No PHI will be removed from the UVa covered entity during the review. 
The PHI that the researcher seeks to use or access is necessary for the research purposes. 
 
2. How will potential subjects be contacted? 
To "contact" a potential subjects refers to the initial contact you plan to take to reach a potential 
subject to determine if they would be interested in participating in your study.  This may include 
direct contact by such methods as by letter, phone, email or in-person or indirect contact such as 
the use of flyers, radio ads etc.  
If your study involves more than one group of subjects (e.g. controls and cases or subjects and 
caregivers) note below which groups are being contacted by the given method.    
 
Check the methods you plan to utilize: 
a.____Direct contact of potential subjects by the study team via letter, phone, direct e-
mail. Members of study team ARE NOT health care providers of patients.  
Note:  Letter, phone, direct email scripts must be approved by IRB prior to use.  
See IRB-HSR Website for templates. 
DHHS/HIPAA: Study team requests a Waiver of Consent and Waiver of 
HIPAA Authorization to contact potential subjects.  
 
b.____Potential subjects will be approached while at UVa by a person who is NOT a 
member of their health care team.  
DHHS & HIPAA: Study team requests a Waiver of Consent and a Waiver of 
HIPAA Authorization to contact potential subjects.  
 
You should share the following information with the potential subject:  
1. Your name 
2. Who you are:  physician, nurse etc. at the University of Virginia.    
3. Why you want to speak with them 
4. Ask if you have their permission to explain the study to them 
5. If asked about how you obtained their information use one of the following 
as an option for response.     
• DO NOT USE THIS RESPONSE UNLESS YOU HAVE OBTAINED 
PERMISSION FROM THEIR UVa PHYSICIAN:   
Your doctor, Dr. insert name wanted you to be aware of this research 
study and gave us permission to contact you.    
• We obtained your information from your medical records at UVa.   
Federal regulations allow the UVa Health System to release your 
information to researchers at UVa, so that we may contact you regarding 
studies you may be interested in participating.  We want to assure you that 
we will keep your information confidential.  


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IF THE PERSON SEEMS ANGRY, HESITANT OR UPSET, THANK THEM 
FOR THEIR TIME AND DO NOT ENROLL THEM IN THE STUDY.  YOU 
MAY ALSO REFER THEM TO THE IRB-HSR AT 924-9634. 
 
c.____Direct contact of potential subjects by the study team by approaching in person at 
UVa or via letter, phone, direct e-mail. Members of study team ARE health care 
providers of patients.  
If you are not approaching them in person but using a letter, phone call or direct 
email please note that the letter, phone, direct email scripts must be approved by 
IRB prior to use.  See IRB-HSR Website for templates. 
DHHS:  Study team requests a Waiver of Consent to contact potential subjects 
HIPAA:  Allowed under Health Care Operations.  
 
d._X__ Indirect contact (flyer, brochure, TV, broadcast emails, patient provided info 
about the study from their health care provider and patient contacts study team.) 
DHHS & HIPAA:  NA 
 
3. Will any additional information be obtained from a potential subject during "prescreening"?   
 
Yes 
 
Pre-screening for IRB purposes is the term used to describe activities PRIOR to obtaining Informed Consent and may not 
include any research procedures.   
Pre-screening of potential subjects over the telephone or in person is generally performed to determine their initial eligibility 
for, and, interest in a study and is a common strategy in the recruitment process.  
Questions appropriate for pre-screening address the specific inclusion/exclusion criteria for the study and other issues of 
suitability, for example, an individual's ability to come to the research site multiple times.  
It is not appropriate at this point in the process (i.e. prior to obtaining informed consent/enrollment) to gather information that 
is not directly related to assessing eligibility and suitability (e.g. obtaining complete medical histories, obtaining blood 
specimens for lab tests).  
 
IF YES, submit any documents that will be used to collect pre-screening information so that 
the IRB may confirm what questions will be asked. 
NOTE: To comply with HIPAA regulations only the minimum necessary information may be 
collected at this time.  This means that only questions pertaining to the Inclusion and Exclusion 
Criteria may be asked.   
 
IF YES, 
DHHS study team requests a Waiver of Documentation of Consent for Pre-screening 
questions.  
HIPAA- covered under Health Care Operations 
 
IF YES, Will any of the questions involve health information? 
 
Yes 


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IF YES, will you collect HIPAA identifiers with the health information? 
 
Yes 
 
IF YES, which HIPAA identifiers will be recorded? 
 
Name, MR#, date of birth, age, postal address, telephone number, email address (if 
applicable) 
 
Do you confirm that health information with HIPAA identifiers will not be shared 
outside of UVa until a consent form is signed or only shared in a de-identified 
manner?  
 
Yes 
 
4. Do you plan to ask the subjects to do anything, other than answering questions, for the study 
prior to signing a consent?  
 
Yes 
 
For example: come to the first visit fasting, stop taking medications that may be an exclusion 
criteria, change diet.  As this is still part of pre-screening one is not allowed to gather 
information that is not directly related to inclusion/exclusion criteria or other issues of 
suitability (e.g. is person able to come to UVa for multiple visits)  
NOTE:   
• Only those members of the study team with a DEA# (license to prescribe drugs) are allowed 
to determine if a potential subject may be asked/informed to stop taking a drug which is an 
exclusion criteria.    
• It is recommended that the potential subject notify their health care provider if they plan to 
stop a prescription drug.   
 
 
►IF YES, explain in detail what you will ask them to do. 
 
Tips to Study Team 
• You must document their verbal consent in the study records.  
• If a subject is asked to stop taking a drug, document the date and name of the person 
on the study team giving the verbal order to stop medications (again- must be a 
person with a DEA#) . 
DHHS-  Study team requests the use of Verbal Consent (Waiver of Documentation of 
Consent) for minimal risk screening procedures.  
HIPPA- Covered under Health Care Operations 
 
We will request that subjects come to the screening visit while fasting for at least 8 hours. We 
will tell potential subjects that only subjects who have taken no hormonally-active medications 


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for 2 months prior to the screening visit (and 3 months prior to inpatient study) will be eligible for 
participation. However, we will strongly recommend that potential subjects do not stop 
medications without first consulting with their personal physicians. 
 
5. How will the consenting process take place?    
• Describe the setting for the consent 
• How much time will the consenting process take? 
• How much time will pass between obtaining written consent and initiation of study procedures?  
How will you assess subject understanding? 
• See Protocol Examples:  Consenting Process for examples of how to answer this question.   
 
Potential subjects will be given a consent form (via mail or e-mail) to read at their leisure. If the 
potential subject desires to be involved in the study, a consent and screening visit will be 
scheduled. At the beginning of this visit, the study (including procedures, risks, alternatives) will 
be discussed and any questions will be answered. If the potential subject decides to enter the 
study, they will then sign the consent form, and study screening procedures will begin thereafter. 
 
6. Will subjects sign a consent form for any part of the study?  
 
Yes 
 
7.  Will the study procedures be started the same day the subject is recruited for the study?  
 
Yes, if day of recruitment equates to day of enrollment.  
 
►IF YES, explain in detail why the subject cannot be given more time to make a decision 
to consent.  
 
When a potential subject contacts us (in response to advertisements), they are sent a copy of 
the consent form by mail or email. Subjects are instructed to carefully review the consent form, 
and are encouraged to ask any questions prior to scheduling a screening visit. Thus, by the time 
a consent/screening visit is scheduled, subjects have been given time to consider the study and 
formulate questions about the study. At the screening visit, subjects are lead through a 
discussion of the consent form. Subjects are given the opportunity to ask any additional 
questions during this portion of the screening visit. After the study team has read through the 
entire consent form with the subject, they are then given the opportunity to sign the consent 
form if they are ready to do so. They are also given the option to decline to enroll in the study, or 
take more time (minutes, hours, days, etc. – as long as needed) to review the consent form 
before making a decision regarding enrollment. If the subject decides to enroll in the study on 
the day of the screening visit (most participants have historically chosen this option), then we 
will proceed with the study procedures (namely, screening procedures) outlined above. Note 
that the procedures occurring on that day (i.e., screening procedures) carry minimal risk, and 
subjects may withdraw from the study at any time.   
 
►IF YES, explain in detail what will be done to assure the potential subject has enough 
time to make an informed decision. 
 
Please see answer immediately above. 


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8. Do you need to perform a “dry run” of any procedure outlined in this protocol?   No 
 
APPENDIX:  Pharmacy-Investigational Drugs/Biologics  
 
1.   What is the name of the investigational drug/biologic?    
 
Micronized progesterone  
 
2. Where will the subjects be seen for the administration/dispensing of the drug?     
__X__  Inpatient Unit:  specify:_____ 
A single dose of micronized progesterone solution will be administered in the CRU 
 
3.  What dose will be utilized in this study?    
 
A single dose of 100 mg.  
 
Note that progesterone is a naturally-occuring sex-steroid produced by the ovaries (primarily) and adrenal 
glands. Moreover, we administer a single dose, and achieved peak concentrations are much less than those 
observed in the normal luteal phase. 
 
4. What will be the frequency of dosing in this study?    
 
Single dose at 0900 during the frequent sampling admission 
 
5.  What will be the duration of dosing in this study?    
 
Single dose 
 
6.  What route of administration will be utilized?   Oral 
 
7.  Will drug need to be prepared by the UVa Investigational Drug Service (IDS)?     
__X__  YES 
_____  NO- Drug will be prepared and/or administered per package insert 
 
►IF YES, complete the following information under 7a-7d.  
If you need assistance completing this section contact the Investigational Pharmacists at 982-1048 
7a.  Concentration 
__X__ Standard 
_____  Non- Standard-  specify   
 
7b.  Diluents 
__X__ Standard 
_____  Non- Standard-  specify   
 
7c.  Stability after prepared 


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__X__ Standard 
_____  Non- Standard-  specify   
 
7d. Special storage requirements 
__X__ Standard 
_____  Non- Standard-  specify   
 
8.  Are there any special handling instructions mandated by the study (e.g. weighing hazardous 
materials)?   No 
 
9.  Does the protocol provide provisions for dose titration, dose reductions, and or re-challenged (if drug 
is stopped), etc.?   No 
 
 
10.  How will missed doses be handled?     
 
Since the single dose is given by CRU nurses on a well-defined schedule, missed doses should not be 
an issue. 
 
11.  Will a comparator (active or placebo) be utilized in the protocol?    
 
Yes 
 
►IF YES, comparator is: 
_____  Active FDA approved drug:   provide name and dose of drug  
__X__  Placebo:  describe 
 
The UVAHS research pharmacy provides a solution that is identical to the micronized progesterone 
suspension, with the exception that progesterone is not included.  
 
12.  Does this study involve research on a drug, biologic, supplement or food additive?     
 
No. This study is not being performed to evaluate the effectiveness of micronized progesterone as a 
therapeutic agent. Instead, progesterone is being used as a physiological probe (i.e., to answer questions 
about normal physiology).  
 
►IF YES, is this study investigator initiated?    
 
If yes, answer questions # 13 and 14 
 
If no, answer question # 13 only. 
 
13    Are you using a drug/supplement/ food additive in a manner not approved by the FDA?     
 
In this protocol, we will use a micronized progesterone suspension (FDA IND number 64,126), which is 
formulated by the UVAHS research pharmacy. This IND was required solely because it is 
formulated/constituted by our investigational pharmacy. No risk is expected on the basis of the way the 
progesterone suspension is made (and minimal potential risk is associated with progesterone administration). 


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The progesterone used to formulate the suspension (i.e., Progesterone USP, micronized, for prescription 
compounding [NDC 39822-6000-3] Mfg: Spectrum Chemicals) is FDA-approved.  
 
IF YES, answer questions 13a-13f 
You may reference the non-IRB protocol to answer these questions. 
 
13a.  Describe pertinent animal data that is available regarding the toxicity/safety of this drug.    
 
N/A 
 
13b. Describe pertinent human data that is available regarding the toxicity/safety of this drug.    
 
As described above, the IND was required solely because the micronized progesterone is 
formulated/constituted by our investigational pharmacy. No risk is expected on the basis of the 
way the progesterone suspension is made (and minimal potential risk is associated with 
progesterone administration). The progesterone used to formulate the suspension is FDA-
approved. There are no published data regarding the safety of this specific formulation of 
micronized progesterone suspension, but our group has used this formulation successfully in 
numerous clinical research protocols. Adverse events that we have observed with longer term 
use of micronized progesterone solution (i.e., three times a day dosing for a week) include mild 
somnolence and irregular menstrual bleeding: these are known to be possible side effects of 
micronized progesterone.  
 
13c. Have there been any human deaths associated with this drug?    
 
To our knowledge, no. 
 
13d. In how many humans has this drug been used previously?    
 
Various forms of micronized progesterone (e.g., Prometrium®) are FDA-approved. It is used 
clinically for a number of indications, including dysfunctional uterine bleeding, prevention of 
endometrial hyperplasia, luteal support, etc. We do not know how many women have used this 
drug, but the numbers are substantial.  
 
13e. If this protocol will be used in children describe any previous use of this drug with children of 
a similar age range.   N/A 
 
14.  Do the following criteria apply?  
 
_____  The investigation is intended to be reported to FDA as a well-controlled study in support of a 
new indication for use or intended to be used to support any other significant change in the labeling for 
the drug; 
 
_____  If the drug that is undergoing investigation is lawfully marketed as a prescription drug product, 
the investigation is intended to support a significant change in the advertising for the product; 
 


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_____  The investigation does involve a route of administration or dosage level or use in a patient 
population or other factor that significantly increases the risks (or decreases the acceptability of the 
risks) associated with the use of the drug product. 
 
If Not checked- explain why you believe the risk to subjects is not increased:   
As described above, the IND was required solely because the micronized progesterone is formulated/constituted 
by our investigational pharmacy. No risk is expected on the basis of the way the progesterone suspension is made 
(and minimal potential risk is associated with progesterone administration). The non-progesterone ingredients of 
the suspension are innocuous. The progesterone used to formulate the suspension is FDA-approved. The 
progesterone (in the micronized progesterone) is chemically identical to progesterone made by ovaries, and the 
achieved concentrations will be less than that observed in the luteal phase of the normal menstrual cycle. Our 
group has used this formulation successfully in numerous clinical research protocols. 
 
_X_  The investigation will be conducted in compliance with the requirements for institutional review 
set part in part 21CFR56 and with the requirements for informed consent set forth in part 21CFR50 ; and   
This item must be checked. 
 
_ X _ The investigation will be conducted in compliance with the requirements of 21CFR312.7 
(Promotion and charging for investigational drugs) 
 This item must be checked. 
 
15.  Is this a post-marketing study?      No 
 
APPENDIX:  Privacy Plan for Studies With Consent 
1.  Answer the questions below (1a-1e) to describe your/central registry’s plan to protect the 
identifiable data from improper use and disclosure.   
 
1a.  How will data be stored? 
__X__  Data, which may include health information, or other highly sensitive data will be 
stored with HIPAA identifiers.   
 
1b. Will specimens be stored at UVa? 
If YES, the following security precautions will be implemented:  
• Specimens will be kept in a locked freezer/ or locked room 
• __X__ Access to the freezer/room will be limited to authorized personnel.  
Specimens with HIPAA identifiers will never be shared outside of UVa 
without the written permission of the subject.  
 
1c.  Will any of the data be stored electronically at UVa? 
 
►IF YES, will it include any HIPAA identifiers with health information or other 
highly sensitive data? 
 
►IF YES, where will it be stored?  
__X__  a Health Systems Computing Services (HS/CS) managed server that is 
configured to store data regulated by HIPAA. 


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1d. Will any of the data be stored in hard copy format at UVa (e.g.- on paper) ?  yes 
 
►IF YES, where will it be stored?  
 
__X__ case report forms will be stored in a secure area with limited access.  
 
1e.  The following procedures will also be followed.  
• Only investigators for this study and clinicians caring for the patient will have access 
to the data.  They will each use a unique log-in ID and password that will keep 
confidential.  
• Each investigator will sign the University’s Electronic Access Agreement forward the 
signed agreement to the appropriate department as instructed on the form. 
If you currently have access to clinical data it is likely that you have already signed 
this form.  You are not required to sign it again.  
• UVa Institutional Data Protection Standards will be followed 
http://itc.virginia.edu/security/dataprotection.  Identifiable data is classified as 
“Highly Sensitive”, de-identified data is classified as “Moderately Sensitive”.   
• If identifiable data (data with health information and HIPAA identifiers) is transferred 
to any other location such as a desktop, laptop, memory stick, CD etc. the researcher 
must follow the University’s  “Electronic Storage of Highly Sensitive Data Policy”. 
Additional requirements may be found in the Universities Requirements for Securing 
Electronic Devices.  
• If identifiable health information is taken away from the UVa Health System, Medical 
Center Policy # 0218 will be followed.  
• The data will be securely removed from the server, additional computer(s), and 
electronic media according to the University's Electronic Data Removal Policy.  
• The data will be encrypted or removed if the electronic device is sent outside of UVa 
for repair according to the University's Electronic Data Removal Policy. 
• If PHI will be faxed, researchers will follow the Health System Policy # 0194.     
• If PHI will be emailed, researchers will follow the Health System Policy # 0193 and 
UVa Institutional Data Protection Standards . 
• The data may not be analyzed for any other study without additional IRB approval.  
• If you are using patient information you must follow Health System Policy  # 0021. 
 
 
Summary of Requirements to Comply with UVa Health System, Medical Center and 
University Policies and Guidance as noted above: 
 
Highly Sensitive Data is: 
-personal information that can lead to identify theft if exposed or 
-health information that reveals an individual’s health condition and/or history of health services 
use.  
 
PHI- a type of Highly Sensitive Data, is health information combined with a HIPAA identifier 
 


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• LIMIT- Limit the HIPAA identifiers to the minimal amount needed- e.g. use initials 
instead of name, use a code instead of initials, limit amount/type of health information 
collected, and collect and share only those items you state you will in this protocol.  
• SECURE- Secure Highly Sensitive Data 
o Because single-use electronic devices and media, such as desktops, laptops, memory 
sticks, CDs, smartphones etc., can be easily lost or stolen, the University strictly 
limits the circumstances under which Highly Sensitive Data may be stored on them. 
In accordance with the University’s Electronic Storage of Highly Sensitive Data 
Policy, you must obtain written approval from your Department AND VP or Dean 
prior to moving data to single use devices or media by using the Highly Sensitive 
Data Storage Request Form. 
  You additionally are responsible for applying all security safeguards covered 
in that policy, including but not limited to password protecting and encrypting 
any document on a single access electronic device.  
 If you use your smartphone to send email and your phone is not managed was 
not purchased and/or set up for you by the Health System, you cannot send 
Highly Sensitive Data via email.   
 In addition, do not use Outlook Web to send your email if it contains 
sensitive data.   
 Also, you are not allowed to auto forward your email to outside email 
systems like Gmail or Yahoo.   
 Do not save any email attachment containing Highly Sensitive Data to 
a single use device.   
 You are allowed to access Highly Sensitive Data stored on the University or 
Health Systems network via a VPN, however you cannot download any of the 
information onto your desktop or laptop. 
 Store files containing Highly Sensitive Data on a network drive specifically 
designated for storing this type of data, e.g. high-level security servers 
managed by Information Technology Services or the “F” and “O” managed 
by Heath Systems Computing Services.  You may access it via a shortcut icon 
on your desktop, but you are not allowed to take it off line to a local drive.  
 If data will be collected and/or viewed via a website, it is critical that the 
website and associated data file are set up in a highly secured manner. Do not 
attempt without assistance from:  
University Side:    ITCmicrosystems@virginia.edu 
Health System:   Web Development Center:   (434-243-6702) 
o Encrypt any electronic file containing Highly Sensitive Data that is not on a network 
drive specifically designated for this purpose.  . See encryption solutions guidance.  
o Password protect any electronic device containing Highly Sensitive Data. 
o Lock up hard copies of Highly Sensitive Data. 
• PROTECT- Protect Highly Sensitive Data 
o Do not leave a hard copy file open on your desk when not using it and secure your 
computer when not attended. 
o Have discussions in private. 
o If you lose Highly Sensitive Data, you must report it in accordance with the 
Information Security Incident Reporting Policy. 


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o Do not share Highly Sensitive Data with those not on the study team or those who 
do not have a need to know. 
o Do not share with sponsor unless subject has already signed a consent form or 
IRB has approved waiver of consent.  
o If faxing Highly Sensitive Data  
 Verify fax numbers before faxing, and use fax cover sheets with a 
confidentiality statement.  
 If printing to a central printer, ensure that names and identifiers on the 
documents are given to the correct patient. 
o Highly Sensitive Data may not be stored in a Drop Box. 
o If you plan to store data in the Cloud, you must consult with UVa Information 
Technology Services (ITS) to verify all essential security measures are in place.  
If you have a contract to use the cloud, the contract must include required security 
measures as outlined by ITS.   
o DO NOT email health information with name, medical record number or Social 
Security number to or from an email address that does not have an *HS in the 
address.  May use subject initials if within the UVa HIPAA covered entity:  The 
"UVA HIPAA covered entity" includes the hospital, health system, School of 
Medicine School of Nursing and the VP for Research Office.   
o Be aware:  PHI collected without consent/ HIPAA authorization will NOT be 
allowed to leave UVa in an identifiable form unless the disclosure is tracked with 
Health Information Services.   
o Any Highly Sensitive Data sent outside of UVa (e.g. to sponsor) that was 
obtained under a consent must be encrypted and password protected.   
o If your electronic device is sent outside of UVa for repair, all institutional data, 
whether Highly Sensitive or not, must be either encrypted or removed.  
o If transporting Highly Sensitive Data in paper format from one UVa building to 
another, take the following steps to protect it: 
1. Put paper inside a closed container such as a briefcase, or sealed 
envelope to limit the chance of a losing a piece. 
2. Do not leave Highly Sensitive Data unattended in a public area if it is 
not locked up.  
o When the study is complete, all electronic files containing Highly Sensitive Data 
must be stored on a network drive specifically designated for that purpose.  They 
may not be stored on a single use device such as a CD. 
• STOP, THINK and BE CAREFUL- 
o If this was your Highly Sensitive Data how would you want it protected?  
o There are significant monetary fines to the individual and the institution for loss 
or misuse of sensitive data. 
o Your job may also be on the line. 
 
 
2.  Describe your/central registry’s plan to destroy the HIPAA identifiers at the earliest opportunity 
consistent with the conduct of the research and in accordance with any stipulations in the research 
sponsor contract and UVa records management guidelines. 
 


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__X__The HIPAA identifiers (except full dates and or address information if needed) will be destroyed 
as soon as all publications are complete.  
This wording would allow the researcher to keep HIPAA identifiers until all queries/ request for 
additional information from publisher are addressed 
 
3.  Do you confirm that you will not reuse the identifiable data (HIPAA identifiers or health information) 
or disclose any of this information to any other person or entity except as outlined in this protocol, except 
as required by law, for authorized oversight of the research study, or use it for other research unless 
approved by the IRB-HSR?  Yes 
 
This means that after the study is closed at UVa: 
 
• You cannot contact the subject by any method (you cannot call them, send a letter, talk to them in 
person about the study, etc) without additional IRB approval 
• You cannot use the data for any research that is not already described in your IRB protocol 
without additional IRB approval (if you change your hypothesis you must modify your protocol)  
• You cannot share your research data with another researcher outside of your study team without 
additional IRB approval 
• Any health information with HIPAA identifiers will be shredded or discarded by using recycling 
bins for confidential material found in clinic settings.  For large item disposal of confidential 
material contact Environmental Services at 2-4976 or University Recycling at 2-5050.  
TABLE A:  HIPAA Identifiers (Limited Data Set)  
1.  Name 
2.  Postal address information, other than town or city, state, and zip code 
3.  Telephone numbers 
4  Fax numbers 
5.  Electronic mail addresses 
6.  Social Security number 
7.  Medical Record number 
8.  Health plan beneficiary numbers 
9.  Account numbers 
10.  Certificate/license numbers 
11.  Vehicle identifiers and serial numbers, including license plate numbers 
12.  Device identifiers and serial numbers 
13.  Web Universal Resource Locators (URLs) 
14.  Internet Protocol (IP) address numbers 
15.  Biometric identifiers, including finger and voice prints 
16.  Full face photographic images and any comparable images  
17.  Any other unique identifying number, characteristic, code that is derived from or related to information 
about the individual (e.g. initials, last 4 digits of Social Security #, mother’s maiden name, first 3 letters of last 
name.)