Clinical trial NCT00594217
Conditions: Normal PCOS
Keywords: PCOS
Sponsor: University of Virginia
Start date: 2007-11-29; Completion date: 2020-01-18
Enrollment: 85 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The rapidity with which progesterone (P) suppresses daytime lutenizing hormone (LH) (and by inference gonadotropin releasing hormone (GnRH)) pulse frequency is unknown. We propose to assess this further using a randomized, cross-over, placebo-controlled study. Ovulatory women will begin E2 patches on day 4-8 of the cycle, while women with PCOS will begin E2 patches either on day 4-8 of the cycle or at least 8 weeks post-menses. After 3 d of E2 administration, women will undergo a 24-h sampling study in the GCRC. Beginning at 2000 h, blood for LH, FSH, E2, P, and T will be obtained over a 24-h period. After 10 h of sampling, either oral micronized P (100 mg p.o.) suspension or placebo suspension will be administered (according to randomization). At the completion of sampling, E2 patches will be discontinued. During a subsequent menstrual cycle (or after at least 3 weeks in oligomenorrheic PCOS), subjects will undergo another GCRC study identical to the first (including pretreatment with E2) except that oral P will be exchanged for placebo or vice versa in accordance with the crossover design. We will assess the acute effects of progesterone on LH frequency, with secondary endpoints being mean LH, LH pulse amplitude, and mean follicle-stimulating hormone (FSH). We propose two primary hypotheses: (1) administration of P (at 0600 h) to normally cycling adult women during the follicular phase will result in a demonstrable suppression of daytime LH (and by inference GnRH) pulse frequency within 12 hours; (2) administration of P (at 0600 h) to women with PCOS will result in less suppression of daytime LH pulse frequency than in ovulatory women without PCOS. A secondary hypothesis is that augmentation of LH amplitude after P administration will be less in PCOS compared to normal controls.

Detailed description:
Studies under this protocol will be performed in normally cycling women and in women with PCOS from 18 to 35 years old. Criteria for PCOS will be (a) clinical and/or biochemical evidence of hyperandrogenism, (b) oligomenorrhea, and (b) the absence of clinical or biochemical evidence of other potential causes of hyperandrogenism and/or oligomenorrhea. 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 0800-0900 h as follows: LH, FSH, progesterone (P), estradiol (E2), total testosterone, SHBG, 17-OHP, androstenedione, DHEA-S, beta-hCG, TSH, prolactin, CBC, chemistry and liver panels, hemoglobin A1c, fasting insulin, and fasting glucose. Additionally, BOD POD® will be used to measure total fat mass, fat free mass, and percent body fat. Waist and hip circumference will be measured.

This study follows a crossover design, with assessment of the acute effects of P and placebo (individually) on GnRH pulse frequency; subjects will be randomized to receive either P or placebo during the first GCRC admission, with subsequent GCRC study occurring during a subsequent cycle.

Women will begin E2 patches (0.1 mg/d per patch, 2 patches \[delivering a total of 0.2 mg/d\] placed on the abdomen and changed every 2 d) on the evening of day 4-8 of the study cycle (controls or PCOS) or \>= 8 weeks post-menses (PCOS only). These patches will be continued for a total of 4 d, with GCRC admission occurring on day 3 of E2 administration. Exogenous E2 administration will standardize hypothalamic exposure to E2 and help ensure the presence of sufficient hypothalamic P receptors.

Four to 5 days before a scheduled GCRC admission, subjects will come to the GCRC for an outpatient blood draw for P and beta-HCG (2 cc). If 30 days will have elapsed between (a) the most recent hemoglobin and hematocrit and (b) the scheduled GCRC admission, a hemoglobin and hematocrit will also be drawn at this time (1cc).

After 3 d of E2 administration, women will undergo a 24-h sampling study in the GCRC. Estradiol administration (E2 patches) will continue throughout the GCRC admission. Subjects will be admitted to the GCRC at 1800 h (2 h prior to sampling). Beginning at 2000 h, blood will be obtained through an indwelling i.v. forearm heparin lock over a 24-h period as follows: LH every 10 min (1 ml); P every 30 min (1 ml); FSH, E2, and T every 2 h (assays to be run in same samples as LH and P). SHBG, fasting insulin, and fasting glucose (i.e., fasting since 2200 h) will be run on the 0600 h sample (extra 2 cc drawn). (Subjects will fast from 2200 to 0600 h.) After 10 h of sampling (i.e., at 0600 h), either oral micronized P (100 mg p.o.) suspension or placebo suspension will be administered (according to randomization). With exogenous P, we aim to achieve mean plasma P concentrations 4-8 ng/ml. Subjects will not be allowed to sleep during the day (i.e., from 0600 to 2200 h). Subjects will be encouraged to sleep from 2200 to 0600. Sleep will be formally evaluated (extraoculograms, electroencephalograms, wrist actigraphy, etc.). At the completion of sampling, E2 patches will be discontinued. Volunteers will be discharged on oral iron (325 mg BID). We will ask women to eat only the food provided by the GCRC.

Subjects will undergo another GCRC study identical to the first (including pretreatment with E2, outpatient blood draw 4-5 days before admission, etc.), except that oral P will be exchanged for placebo or vice versa in accordance with the crossover design. (Subjects will again begin E2 patches on the evening of cycle day 4-8 \[controls or PCOS\] or \>= 8 weeks post-menses \[PCOS only\].) In this way, we will be able to standardize any change in GnRH pulse frequency after P administration to any change in GnRH pulse frequency after placebo administration.

The study will end after the second GCRC admission. Subjects will be asked to continue oral iron supplementation for at least 30 d after this last GCRC admission.

Arms: arm 1: PCOS women: women were considered to have PCOS if they had evidence of clinical and/or biochemical hyperandrogenism plus oligo-/amenorrhea in the absence of other identifiable causes. arm 2: Normal control women: women with regular menstrual cycles without evidence of hyperandrogenism.
Interventions: intervention 1: oral micronized progesterone suspension intervention 2: Placebo
Intervention descriptions: intervention 1: oral micronized progesterone suspension, single 100 mg oral dose intervention 2: Placebo contains only inert ingredients and is not expected to exert any direct physiological effects

Protocol documents:
Prot_SAP_001.pdf: 
IRB-HSR# 13368: Determining the rapidity with which exogenous P suppresses daytime LH 
(GnRH) pulse frequency in women during the follicular phase of the menstrual cycle (CRM001) 
 
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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, and 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. 


IRB-HSR# 13368: Determining the rapidity with which exogenous P suppresses daytime LH 
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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.  If the current PI is leaving UVa permanently, a new PI will be assigned PRIOR to the 
departure of the current PI.  
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.  
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 18 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. 
 
 
 
 
 
 
 
 
 
 
 
 
 


IRB-HSR# 13368: Determining the rapidity with which exogenous P suppresses daytime LH 
(GnRH) pulse frequency in women during the follicular phase of the menstrual cycle (CRM001) 
 
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Signatures 
 
Principal Investigator 
 
____________________________ 
____________________________ 
_______ 
Principal Investigator 
Principal Investigator 
Date 
Signature 
Name Printed 
 
 
The Principal Investigator signature is ONLY required if this is a new protocol, a 5 year update or 
a modification changing the Principal Investigator. 
 
 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


IRB-HSR# 13368: Determining the rapidity with which exogenous P suppresses daytime LH 
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Brief Summary/Abstract 
The rapidity with which progesterone suppresses daytime LH (and by inference GnRH) pulse frequency is 
unknown. We propose to assess this further using a randomized, cross-over, placebo-controlled study. 
Normally-cycling women and women with PCOS (both pretreated with estradiol) will undergo a 24-h 
sampling study. After 10 h of sampling, either oral micronized progesterone (100 mg p.o.) suspension or 
placebo suspension will be administered (according to randomization). During a subsequent menstrual 
cycle, subjects will undergo another study identical to the first (including pretreatment with estradiol) 
except that oral progesterone will be exchanged for placebo or vice versa in accordance with the 
crossover design. We will assess the acute effects of progesterone on LH frequency, with secondary 
endpoints being mean LH, LH pulse amplitude, and mean FSH. We hypothesize that (1) administration of 
progesterone (at 0600 h) to adult women during the follicular phase will result in a demonstrable 
suppression of daytime LH (and by inference GnRH) pulse frequency within 12 hours; and (2) 
administration of progesterone (at 0600 h) to women with PCOS (during the follicular phase) will result 
in less suppression of daytime LH pulse frequency than in controls.  
Background 
1. Provide the scientific background, rationale and relevance of this project.   
It remains unknown how rapidly progesterone (P) affects gonadotropin releasing hormone (GnRH) pulse 
frequency slowing in normal women or in women with PCOS. Through this study, we are pursuing this 
question to confirm an important assumption in our overall hypothesis regarding how cyclic ovulation is 
established during puberty.   
 
GnRH stimulates LH and 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 (1-7). These 
variations in gonadotropin secretion result in part from different patterns of pulsatile GnRH stimulation, 
with fast GnRH pulse frequencies favoring LH and slow GnRH pulse frequencies favoring FSH synthesis 
and secretion (8-12).  
 
In ovulatory women, LH (and by inference GnRH) pulse frequency slows from one pulse every 
60-90 min in the follicular phase to approximately one pulse every 4-6 h during the luteal phase. Luteal 
slowing of GnRH pulse frequency increases FSH synthesis, but high luteal levels of estradiol (E2) and 
inhibin prevent FSH release from the gonadotrope (13, 14); when E2 and inhibin concentrations fall 
during the luteal-follicular transition (i.e., when inhibition of FSH secretion is removed), an increasing 
GnRH pulse frequency leads to the early follicular monotropic rise of FSH. Thus, the ability to slow GnRH 
pulse frequency during the luteal phase appears to be important for the early follicular rise in plasma 
FSH and, therefore, follicular development.  
 
Progesterone appears to be the primary effector of GnRH pulse frequency slowing. GnRH pulse 
frequency slows coincident with P increases in the luteal phase, and administration of P to women 
during the follicular phase also slows GnRH pulse frequency (15), although the rapidity with which this 
occurs is unknown. Progesterone’s ability to slow GnRH pulse frequency appears to require the 
permissive presence of E2 (16, 17), possibly reflecting E2’s ability to induce hypothalamic P receptors 
(18-21).  
 
Changes of GnRH pulse frequency are also seen during puberty. During childhood, the 
hypothalamic-pituitary-gonadal axis is quiescent with low plasma LH and FSH levels, low LH pulse 
amplitude, and slow LH (GnRH) pulse frequency (i.e., detectable pulses approximately every 3-6 h), and 
high FSH:LH ratio (22-26). Reactivation of this axis at puberty is heralded by sleep-entrained 


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amplification of LH (GnRH) pulsatility, with nocturnal increases in both LH pulse amplitude and 
frequency (23, 24, 27-34). 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, likely play a major role. Overnight 
increases of testosterone (T) (35-38) and E2 (25, 39, 40) occur in pubertal boys and girls, respectively. E2 
infusion in peripubertal girls (41), in addition to infusions of either T (42, 43) or E2 (33) in peripubertal 
boys, mitigates nocturnal increases in LH pulsatility. Moreover, in contrast to diurnal changes of LH and 
E2 in normal pubertal girls, age-matched girls with gonadal dysgenesis exhibit elevated LH pulse 
frequencies at all time periods (34, 44). Thus, diurnal changes in sex-steroids appear to direct diurnal 
changes in GnRH pulse frequency.  
 
Since P is the primary effector of GnRH pulse frequency slowing in adult women, and with data 
that suggests that P increases 2.3-fold overnight in early pubertal girls (45), we believe that P may be the 
major effector of diurnal GnRH pulse frequency slowing in peripubertal girls.  
 
It is unclear what functional significance underlies these diurnal variations in GnRH pulsatility 
during puberty; however, by analogy to adult women, we suggest that diurnal slowing during puberty 
may be important for enhancement of FSH synthesis and corresponding follicular development. 
Original hypothesis regarding the development of ovulatory cycles in peripubertal girls: We initially 
proposed that in normal pubertal adolescent girls, sleep-entrained increases of LH pulsatility drive 
production of sex steroids (P and E2), which in turn suppress pulsatile GnRH (LH) secretion during the 
subsequent day. (Progesterone production may also be of adrenal origin under diurnal ACTH control.) 
These diurnal decreases in GnRH pulse frequency enhance FSH production and are therefore important 
for follicular development. Increasing FSH production results in escalating waves of follicular 
development and corresponding increases in E2 production. Estradiol concentrations eventually become 
adequate to trigger an LH surge, and the (ovulatory) follicular remnant is transformed into a corpus 
luteum that secretes great quantities of P and E2; thus occurs the first luteal phase. Later anovulatory 
cycles are associated with small increases in P, which appear to be adequate to reduce GnRH pulse 
frequency in normal women (46).  
 
These processes have major implications for normal pubertal development and for aberrations 
of this process that appear to occur in adolescents destined to develop PCOS. Hyperandrogenism during 
adolescence, felt to represent a forerunner of PCOS, is associated with disordered LH secretion. Results 
from our group (IRB-HSR# 8588, JCM010) suggest that the GnRH pulse generator is relatively resistant to 
the feedback actions of P and E2 in some hyperandrogenemic adolescents (47), similar to that described 
in women with PCOS (48, 49). If this is indeed the case, then the aforementioned sequence of events at 
puberty would be quite different in hyperandrogenemic adolescents. As puberty begins, nocturnal 
increases of LH (and possibly ACTH) pulsatility would drive production of P and E2. However, these 
relatively low sex steroid concentrations would be insufficient to overcome GnRH pulse generator 
resistance, and a relatively rapid GnRH pulse frequency would persist throughout the following day. 
Persistently rapid GnRH pulses would be expected to result in both LH excess, which would stimulate 
excessive androgen production, and relative FSH deficiency, which would hinder normal follicular 
development. These hypotheses are consistent with available data. 
The rapidity (over hours to days) with which P slows LH pulse frequency in normal women remains 
unknown. This is a critical point: for the above hypothesis regarding the control of diurnal changes in 
GnRH pulsatility during puberty to be viable, these sex steroids would have acute actions, effecting 
GnRH pulse frequency changes over hours rather than days. An earlier study by this group (48) 
chronicled the time course of LH pulse frequency suppression in response to P and E2 administration 
during the follicular phase in normal women. Maximal suppression (to approximately 80% of baseline) 
occurred on day 10 (P < 0.05 vs. day 1). Although LH pulse frequency decreased by a mean of 50% by  


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day 5, this did not reach statistical significance, likely a reflection of the small number (n=5) of subjects 
studied. Subsequent review of the raw data revealed that 4 of 5 women had clear suppression of LH 
pulse frequency (67% reduction on average) and a characteristically luteal LH pulse pattern by day 5 (the 
earliest observation after initiation of P); LH pulse frequency slowed from 6 to 1 pulses/8 h by day 3 in 
one such subject. These data strongly suggest that P reduces GnRH pulse frequency within 3-5 d. Further 
data in a man revealed that 100 mg oral P suspension (which increased plasma P from < 1 to 10 ng/ml 
over 2 h) reduced LH by 40% within 3 h and T by 50% over 6 h.  
 
In a recent study of 8 normally cycling women (nearly identical to the current study), we 
administered a single dose of P at 1800 h and monitored changes (before vs. after P) of LH pulse 
characteristics. Each subject also underwent a GCRC admission where placebo (PBO) was administered 
at 1800 h. A manuscript describing our findings has been published (50). The 10-hour mean P 
concentration increased from 0.6 ± 0.1 ng/ml before P (0800-1800 h) to 3.9 ± 0.3 ng/ml after P 
administration (2200-0800 h; P < 0.01). LH pulse frequency (based on both [a] LH pulse counts over 10 
hours and [b] ten-hour mean LH interpulse intervals) decreased significantly after both P and placebo 
administration, with no significant difference between P and placebo (Figure 1, next page). In contrast, 
mean LH, LH amplitude, and mean FSH increased significantly within 4 hours of P administration, but not 
after placebo.  
 
 
 
We concluded that in E2-pretreated women in the late follicular phase, (1) nocturnal LH pulse 
frequency is not acutely (within 12 hours) influenced by P administration; (2) an acute increase in P 
causes pronounced augmentation of gonadotropin pulse amplitude within 4 hours; and (3) LH pulse 
frequency slows overnight during the second half of the follicular phase.  
The absence of P-induced slowing of LH frequency is in contrast to animal studies that suggest a 
rapid (within 2-6 hours) decrease in LH and GnRH pulse frequency after P administration. For instance, 
in ovariectomized but E2-replete ewes, P dramatically suppresses GnRH pulse frequency over 12 h; this 


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effect appears to begin within 2 h and is blocked by the 
progesterone-receptor antagonist mifepristone (RU-486) (51). 
Similarly, in bovine females, changes in LH pulse frequency are 
observed within 6 h of altered P concentrations (52). Although 
species differences may account for this discordance, we have 
considered an alternative explanation. 
Nocturnal, sleep-related slowing of LH pulse frequency 
during the early follicular phase is well described. Our data 
(above) and several studies by Loucks and colleagues (53-55) 
suggest that late follicular LH pulse frequency also slows by 20-
30% during sleep. Nocturnal slowing of LH frequency in the early 
follicular phase (and presumably in the late follicular phase) 
appears to be specifically related to sleep and is likely driven by 
higher CNS systems.  
These nocturnal changes in LH pulse frequency are 
interesting in light of what is observed during puberty. In early 
pubertal girls (and boys), nocturnal LH frequency increases 
compared to daytime LH frequency. It is generally believed that 
the overnight increase of LH pulsatility during puberty is driven by 
higher CNS systems.  
Of particular interest, our preliminary data in peripubertal 
girls suggests that nocturnal LH frequencies in early pubertal girls, 
late pubertal girls, and the 8 adult women studied under JCM016 
are very similar, while late evening LH frequencies (i.e., from 
1900-2300 h – a surrogate for daytime frequency) are varied 
(Figure 2). These data are consistent with the notion that higher 
CNS systems may in large part determine nocturnal GnRH pulse 
frequency during puberty and in adults. Accordingly, sleep-
associated (and presumably CNS-driven) LH frequency may be 
similar in pubertal girls and adult women, with daytime frequencies being controlled by other factors.  
In addition, two of the aforementioned studies by Loucks and colleagues reported that dietary 
restriction slows daytime—but not nighttime—LH pulse frequency in the late follicular phase (53, 55). 
This suggests that daytime and nighttime LH frequency may be differentially affected by experimental 
maneuvers.  
On the basis of the above observations, we have 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 would be consistent with the notion that CNS control of 
nocturnal LH frequency may override hormonal control, at least in the short-term. We would like to test 
this hypothesis by using a protocol identical to the earlier JCM016 protocol except that the timing of the 
sampling and P (and PBO) administration is altered by exactly 12 hours (e.g., P and PBO are 
administered at 0600 h instead of 1800 h). 
 
 
We will also study women with PCOS in this protocol, primarily to assess for potential 
abnormalities of acute negative feedback by P (i.e., the rapidity with which P slows LH pulse frequency). 
But as a secondary aim, we will also assess for abnormalities of positive feedback (i.e., P-induced 
increases of LH amplitude and mean LH).  


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As mentioned above, studies demonstrate that the GnRH pulse generator is relatively resistant to the negative 
feedback effects of longer-term administration of P in adults with PCOS (48, 49). In women taking combined oral 
contraceptives, LH (GnRH) pulse frequency is increased in PCOS compared to controls (49). Similarly, in a study where 7 
days of exogenous P and E2 were given (to achieve physiologic concentrations) to women with PCOS and controls, LH 
pulse frequency was suppressed by 60% in controls, but by only 25% in PCOS (48). Similar findings are observed 
prenatally-androgenized sheep (56), an animal model of PCOS. In adult PCOS, this relative resistance of the GnRH pulse 
generator to P negative feedback appears to be mediated by T excess, as it is reversed by the androgen-receptor blocker 
flutamide (57). Mouse studies also reveal that DHT impairs the ability of P to slow GnRH firing rate (58). This effect of 
androgens may reflect reduced basal and E-induced P receptors in the hypothalamus (59). Thus, we expect that P will be 
less effective (in reducing LH frequency) in PCOS compared to controls. 
 
 
We are unaware of any studies investigating the positive feedback effects of P in PCOS, a potentially important factor 
contributing to ovulatory dysfunction. As described above, our earlier study (50) disclosed a rapid (within 4 h) and 
pronounced augmentation of gonadotropin secretion after oral P 
administration in E2-pretreated women. Similar findings have been described previously (60-62). These effects of P on 
gonadotropin secretion appear to be related, at least in part, to augmentation of GnRH-stimulated release of 
gonadotropins from pituitary gonadotropes (62, 63). On the basis of these data, it is generally held that the late follicular 
rise in P—which begins ~12 h before the LH surge (61, 64)—is an 
important mechanism contributing to the midcycle LH surge. However, relative resistance to the positive feedback 
effects of P could represent another mechanism by which ovulatory function is reduced in PCOS. That is, we hypothesize 
that LH amplitude and mean LH will not increase after P administration to the degree observed in controls. 
Hypothesis to be Tested 
We propose two primary hypotheses: (1) administration of progesterone (at 0600 h) to normally cycling adult women 
during the follicular phase will result in a demonstrable suppression of daytime LH (and by inference GnRH) pulse 
frequency within 12 hours; (2) administration of progesterone (at 0600 h) to women with PCOS (during the follicular 
phase) will result in less suppression of daytime LH pulse frequency than in ovulatory women without PCOS. We will also 
assess the acute effects of progesterone on mean LH, LH pulse amplitude, and mean FSH. A secondary hypothesis is that 
LH augmentation after progesterone administration will be less in PCOS compared to normal controls. 
 
Study Design: Biomedical 
1.  Will controls be used?Yes 
►IF YES, explain the kind of controls to be used. 
This is a cross-over study; thus, when evaluating the effects of progesterone vs. placebo, subjects will 
serve as their own controls. Also, the data from women with PCOS will be compared to data in normal 
women (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 


IRB-HSR# 13368: Determining the rapidity with which exogenous P suppresses daytime LH (GnRH) pulse 
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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: 18-35 
Sex: 
Female 
Race: All Races 
 
Subjects- see below 
INSTRUCTIONS: For question 1-4 below insert an exact #.  Ranges or OPEN is not allowed.  This # 
should be the maximum # you expect to need to enroll (i.e. sign consent) If you are only collecting 
specimens the number of participants should equate to the # of specimens you need.  If you are 
collecting only data from a chart review the number should designate the number of subjects whose 
medical records you plan to review.  Age/ Sex/Race criteria should designate the demographics of 
participants from whom you will obtain the specimen/data. 
1.  Provide target # of subjects (at all sites) needed to complete protocol. 
Twelve ovulatory subjects and twelve women with PCOS are needed to complete the protocol.  
(Update at time of 5-year renewal April 2017: we have completed study of all required controls, and we are 
nearing completion of study in women with PCOS.) 
 
2.  Describe expected rate of screen failure/ dropouts/withdrawals from all sites.   
We anticipated that approximately one-third would fail screening, and that one-third would either dropout or 
withdraw from the study.  Since the study inception, 81 subjects have been enrolled in the study.  To date, 59 of 
those subjects enrolled have either dropped out or been withdrawn from the study, ~ 73%.   
 
3.  How many subjects will be enrolled at all sites?    
N/A – this is a single site study 
 
4.  How many subjects will sign a consent form under this UVa protocol?     
90 subjects will sign a consent form under this protocol.  (Notably, we will stop recruiting when we have 
obtained complete and interpretable data for 12 women with PCOS and 12 controls). (Update at time of 5-year 
renewal April 2017: we have completed study of all required controls, and we are nearing completion 
of study in women with PCOS.) 
 
5. Provide an estimated time line for the study. 
We anticipate 100% enrollment in two years and 50% completion of data analysis in five years. 
(Update at time of 5-year renewal April 2017: We anticipate completion of the study no later than 2019.) 
 
 
 
 


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Inclusion/Exclusion Criteria 
1.  List the criteria for inclusion  
Criteria for inclusion: 
 
Subjects will be healthy women in two groups: (1) women with regular menstrual cycles and no evidence of 
hyperandrogenism, and (2) women with PCOS (defined as clinical/biochemical evidence of hyperandrogenism 
plus oligomenorrhea, but with no evidence for other endocrinopathies).  
 
Subjects will be 18-35 years old; we use a cutoff age of 35 years because early menopause at this age is very 
rare, and the risk of DVT with estrogen use may increase beyond this age.   
 
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 
Criteria for exclusion: 
 
We will exclude women with a history of any disorders that may potentially be complicated by hormonal 
treatment, such as DVT and breast, ovarian, or 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/or a 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 history of any disorders that may potentially be complicated by long-term iron supplementation, 
such as hemochromatosis and polycythemia vera, will be excluded.   
 
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.  
• 
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) 
 
Pregnant and breast-feeding women will be excluded.  
 
A history of allergy to progesterone or estradiol will constitute grounds for exclusion. 
 
Women with a BMI greater or equal to 40 kg/m2. 
• 
Virilization 
• 
A total testosterone > 150 ng/dl in women with PCOS (which suggests the possibility of a virilizing neoplasm) 
(confirmed on repeat) 
• 
Elevated DHEAS (mild elevations may be seen in PCOS, and elevations < 1.5 times the upper limit of normal will 
be accepted in PCOS) (confirmed on repeat) 
• 
Follicular 17-hydroxyprogesterone > 300 ng/dl, which suggests the possibility of congenital adrenal hyperplasia 
(if elevated during the luteal phase and there is a concern about the possibility of congenital adrenal 
hyperplasia, the 17-hydroxyprogesterone may be collected during the follicular phase, or >60 if 
oligomenorrheic). NOTE: If a 17-hydroxyprogesterone > 300 ng/dl is confirmed on such repeat testing, an ACTH 
stimulated 17-hydroxyprogesterone < 1000 ng/dl will be required for study participation. 
• 
A previous diagnosis of diabetes, a fasting glucose ≥ 126 mg/dl, or a hemoglobin A1c > 6.5% 


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• 
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 (mild elevations may be seen in PCOS, and elevations < 1.5 times the upper limit of normal 
will be accepted in this group) (confirmed on repeat) 
 
Evidence of Cushing’s syndrome by history or physical exam 
Due to the amount of blood being drawn in the study, subjects with body weight < 110 lbs. will be excluded from the 
study 
 
3.  List any restrictions on use of other drugs or treatments. 
Being a study of reproductive hormonal effects 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 90 days prior to 
the study and during the study. 
Statistical Considerations 
1. 
Is stratification/randomization involved?Yes 
►IF YES, describe the stratification/ randomization scheme. 
The subjects will be randomized to receive either progesterone or placebo during the first CRU admission. This 
randomization will be generated by the CRU biostatistician using the PROC PLAN procedure of SAS version 9.3 
(SAS Institute Inc., Cary NC).  
 
►IF YES, who will generate the randomization scheme?  
__X___ UVa Statistician.   Jim Patrie 
 
2.  What are the statistical considerations for the protocol?  
This is a randomized, placebo-controlled, cross-over study. 
 
3.  Provide a justification for the sample size used in this protocol.   
Sample size/statistical power: The primary endpoint will be the change in LH pulse frequency (over 10 h) attributable to 
P. The null hypothesis is that 10-h (1000-2000 h) LH frequency after P administration will be the same as 10-h (1000-
2000 h) LH frequency after placebo administration. Estimates of within-subject variability utilized in the calculation 
(column 2 of table below) were based on our preliminary data. Assuming that 12 women in both groups complete both 
CRU admissions (placebo admit, P admit), we list in column 3 (table) the estimates for the minimum detectable absolute 
difference between the mean 
change in 10-h LH pulse 
frequency that would provide ≥ 
80% statistical power. 
 
4.  What is your plan for primary variable analysis? 
Data analysis plan: 10-h LH pulse frequency will be analyzed using hierarchical mixed-effects ANOVA models. Each 
ANOVA model will be structured to examine whether exogenous P affects LH frequency. In the ANOVA model, “subject” 
will be a blocking factor, while the treatment condition (placebo, P) will be modeled as highest within-subject level 
factor, and the measurement assessment time (10-h baseline sampling period, 10-h post-treatment sampling period) 
will be modeled as the lowest within-subject level factor. Treatment by measurement assessment time interaction will 
also be modeled. We will use linear-contrasts of the ANOVA least-squared means to test our a priori research 
hypothesis. Specifically, we will test whether the change in mean LH frequency from the baseline state to the post-
Endpoint 
Within-subject 
standard deviation 
Minimum detectable P 
effect on LH frequency 
Change in LH pulse-interval (min) 
20.6 
16.7 
Change in # of LH pulses / 10-h 
1.24 
1.0 


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treatment state differed depending on whether placebo or P was administered at 0600 h. 95% confidence interval 
construction (for the estimation of the true magnitude of P effect) will be based on the t-distribution. Traditional 
residual diagnostics will be conducted to evaluate model goodness of fit. If LH frequency data fail to adhere to equal 
variance and normality assumptions of linear mixed-effects models, the data will be analyzed using a generalized linear 
mixed-effect-model in a similar format, with the exception that LH pulses as will be modeled as counts utilizing either a 
Poisson or a Negative-Binomial distribution. Similar statistical procedures will be used to compare the effects of P in 
controls vs. PCOS: in the ANOVA model, PCOS status (no, yes) will be a between-subject factor, while the treatment 
(placebo, progesterone) will be a within-subject factor.   
 
5.  What is your plan for secondary variable analysis?  
Secondary outcome variables (30-min measurements of P; 2-h measurements of P, FSH, E, T; LH pulse amplitude) will be 
analyzed via hierarchical mixed-effect ANOVA models (models/procedures identical to those above). 
 
6. Have you been working with a statistician in designing this protocol?Yes 
IF YES, what is their name?  James Patrie (Department of Public Health Sciences) 
 
 
7.  Will data from multiple sites be combined during analysis?  No 
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 estradiol and 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 and in women with PCOS from 18 to 35 
years old. Criteria for PCOS will be (a) clinical and/or biochemical evidence of hyperandrogenism, (b) oligomenorrhea, 
and (b) the absence of clinical or biochemical evidence of other potential causes of hyperandrogenism and/or 
oligomenorrhea. 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 0800-0900 h as follows: LH, FSH, progesterone (P), estradiol (E2), total 
testosterone, SHBG, 17-OHP, androstenedione, DHEA-S, beta-hCG, TSH, prolactin, CBC, chemistry and liver panels, 
hemoglobin A1c, fasting insulin, and fasting glucose. Additionally, 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 low 
hemoglobin with a low or low-normal MCV (i.e., likely related to iron deficiency) is seen, 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/or 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 level ≥12 
g/dl (after a maximum of 2 sequential months of iron treatment) will be allowed to proceed with frequent blood 
sampling (see below). Women with anemia 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 participation in the study. 
 


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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. 
 
 
This study follows a crossover design, with assessment of the acute effects of P and placebo (individually) on 
GnRH pulse frequency; subjects will be randomized to receive either P or placebo during the first overnight admission, 
with subsequent overnight study occurring during a subsequent cycle.  
 Women will begin E2 patches (0.1 mg/d per patch, 2 patches [delivering a total of 0.2 mg/d] placed on the 
abdomen and changed every 2 d) on the evening of day 4-8 of the study cycle (controls) or ≥ 4 days post-menses (PCOS). 
These patches will be continued for a total of 4 d, with overnight admission occurring on day 3 of E2 administration. 
Exogenous E2 administration will standardize hypothalamic exposure to E2 and help ensure the presence of sufficient 
hypothalamic P receptors.  
Four to 5 days before a scheduled overnight admission, subjects will come to the CRU or alternate UVA clinical 
unit for an outpatient blood draw for P and beta-HCG (2 cc). If 30 days will 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 (1cc).  Note:  A hematocrit ≥ 36% or hemoglobin ≥ 12 g/dl in the month before overnight admission is 
required to participate in the scheduled inpatient (frequent sampling) protocol. 
After 3 d of E2 administration, women will undergo a 24-h sampling study in the CRU, alternate UVA hospital unit, 
or off-site hotel. Estradiol administration (E2 patches) will continue throughout the overnight admission.  Subjects will 
be admitted to the CRU, alternate UVA hospital unit, or hotel at 1800 h (2 h prior to sampling). Beginning at 2000 h, 
blood will be obtained through an indwelling i.v. forearm heparin lock over a 24-h period as follows: LH every 10 min (1 
ml); P every 30 min (1 ml); FSH, E2, and T every 2 h (assays to be run in same samples as LH and P). SHBG, fasting insulin, 
and fasting glucose (i.e., fasting since 2200 h) will be run on the 0600 h sample (extra 2 cc drawn). (Subjects will fast 
from 2200 to 0600 h.) After 10 h of sampling (i.e., at 0600 h), either oral micronized P (100 mg p.o.) suspension or 
placebo suspension will be administered (according to randomization). (NOTE: the study coordinator will pick up the 
P/placebo from the research pharmacy to send to the CRU, alternate UVA hospital unit, or hotel the evening before 
administration.) With exogenous P, we aim to achieve mean plasma P concentrations 4-8 ng/ml. Subjects will not be 
allowed to sleep during the day (i.e., from 0600 to 2200 h). Subjects will be encouraged to sleep from 2200 to 0600. 
When possible, sleep will be formally evaluated (extraoculograms, electroencephalograms, wrist actigraphy, etc.) footnote 
1. At the completion of sampling, E2 patches will be discontinued. Volunteers will be discharged on oral iron (325 mg 
BID). We will ask women to eat only the food provided by the CRU staff.   
         Subjects will undergo another overnight study identical to the first (including pretreatment with E2, outpatient 
blood draw 4-5 days before admission, etc.), except that oral P will be exchanged for placebo or vice versa in accordance 
with the crossover design. (Subjects will again begin E2 patches on the evening of cycle day 4-8 [controls] or ≥ 4 days 
post-menses [PCOS].) In this way, we will be able to standardize any change in GnRH pulse frequency after P 
administration to any change in GnRH pulse frequency after placebo administration.  
 
If the subject does not have hematocrit ≥ 36% or hemoglobin ≥ 12 g/dl shortly before the second scheduled 
overnight 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/or 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/or hemoglobin. Only volunteers 
with hematocrit ≥ 36% or hemoglobin level ≥ 12 g/dl (after a maximum of 2 sequential months of iron treatment) will be 
                                                 
1 Update at time of 5-year renewal April 2017: With regard to the formal sleep evaluation, we have had difficulties obtaining formal 
polysomnography because of scheduling difficulties with a sleep technician, primarily related to (a) limited availability of sleep 
technicians for CRU studies and/or (b) increased competition for sleep technicians. For this reason, we have been unable to perform 
formal sleep studies for the past several years. However, we will routinely perform wrist actigraphy. We will use the Motionlogger Basic-
L wrist actigraphy unit (Ambulatory Monitoring, Inc.), which is a watch-like device that contains an accelerometer. This device captures 
subject movement data, which allows estimation of sleep periods. This watch-like device will be worn on the wrist by the research 
participant during the CRU admission. There are no known risks associated with wrist actigraphy. 


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allowed to proceed with the second overnight admission. If three months have elapsed between (a) the subject’s most 
recent safety labs and (b) the second 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.  
      The study will end after the second overnight admission. Subjects will be asked to continue oral iron 
supplementation for at least 30 d after this last overnight admission. 
 
 
ADDITIONAL NOTE: As this is a study to determine the effects of acute progesterone administration on LH hormone 
regulation, it is important to study subjects during the follicular phase (a time when progesterone should be low, < 1.0), 
rather than during the luteal phase (when progesterone is high). For ovulatory control subjects, the timing of the luteal 
phase is predictable, so admission usually occurs around menstrual cycle day 7-11 (during the follicular phase). 
However, subjects with polycystic ovary syndrome have infrequent/irregular ovulation and infrequent/irregular luteal 
phases, so it is harder to predict when they will be in the luteal phase. For this reason, overnight admission is scheduled 
at a time that is ≥ 7 days since their last menses began; and a progesterone level is checked within 1-5 days before the 
overnight admission, to help rule out the possibility that women will be studied during the luteal phase (i.e., when 
progesterone levels are high).  Following completion of the second overnight admission, samples will be assayed in the 
Center for Research in Reproduction Ligand Assay Core Lab for progesterone and LH.  If it is found that a subject had a 
high progesterone level (> 1.0 ng/mL) prior to administration of progesterone/placebo syrup at 6am during either of 
their study admissions, the subject will be asked to repeat that particular study admission at a time when they are in 
the follicular phase of their cycle (progesterone < 1.0 ng/mL). The subject would be asked to wait the appropriate 8 
weeks before scheduling the repeat study admission, so as not to put the subject at undue risk for anemia.  The exact 
timing of the repeat study admission will depend on the subject’s menstrual cycle.  We would obtain all of the 
appropriate safety labs prior to studying the subject for a final study admission (to ensure subject safety). And to 
prevent a repeat occurrence of catching the subject in the wrong phase of her cycle, a progesterone would be checked 
one to two days before admission. Importantly, in such a situation, subjects would not be obligated to repeat the study 
admission, and they would receive $300 for completing the study even if they do not repeat the admission. However, if 
they indeed complete the extra admission, we would offer additional compensation of $100 for completion of this extra 
study admission, consistent with compensation for each overnight admission under this protocol.      
 
2. List the procedures, in bullet form, that will be done for RESEARCH PURPOSES as stipulated in this 
protocol.ALL 
 
3.  Do you confirm that, except for blood draws through a peripheral site, that all invasive procedures will 
be performed by a licensed health care provider under the supervision of an MD?  
NA, this study only involved blood draws by a licensed health care provider within the UVA hospital system. 
 
4. Will you be using data/specimens in this study that were collected previously, with the use of a research 
consent form, from another research study?No 
 
5.  Will any of the procedures listed in item # 2 have the potential to identify an incidental finding? This 
includes ALL procedures, assessments and evaluations that are being done for RESEARCH PURPOSES that 
may or may not be considered investigational. Yes 
►IF YES, 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:  


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• 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.   
 
6.  Do any of the procedures listed above, under question # 2, utilize any imaging procedures for RESEARCH 
PURPOSES?No 
 
7. Will you be using viable embryos?No 
 
8. Will you be using embryonic stem cells?No 
 
9. If this protocol involves study treatment, explain how a subject will be transitioned from study 
treatment when they have completed their participation in the study.  NA  
 
10. Will your study involve measures used to screen or assess for depression and/or suicidality for research 
purposes? No 
      
11. Where will the study procedures be done? 
 
_X___  UVa , but not medical center facilities: Clinical Research Unit (Barringer) 
 
12. If the study involves medical risk and study procedures will be done outside of the UVa Medical Center 
what is your plan to protect the subjects in case of a medical emergency? 
_____ MD, RN, onsite during procedures 
__X___ Individual trained in CPR on site during procedures 
__X__ AED and Individual trained to use it onsite  
_____ Call 911 
__X__  Other : Call Study staff 
 
13. Are any aspects of the study kept secret from the participants?  No 
 
14. Is any deception used in the study?No 
Family History/Pedigree 
 
1.  What kind of information is being sought?  
Family history (no questionnaire is being used). 
 
2.  What identifiers will be recorded with any of the following info (e.g. names, initials, relationship such as 
mother, father, brother, sister, random number)?Relationship status. 
 
3. Will HIPAA identifiers will recorded?No 


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4.  Does any of the information sought potentially expose the subject or a family member to additional risk?  
No 
 
Specimens  
 
Specimen Information 
1.  Describe the type of specimen to be used:Blood 
 
2.  Will the specimen be obtained BEFORE a subject has signed a consent form? No 
 
3.  Will you be using discarded specimens? No 
 
►IF NO, where will blood be drawn?  
__X___ in the clinical research unit (CRU) 
 
►IF NO, who will draw the blood? 
__X___ a member of the study team who is an individual licensed to practice medicine or 
osteopathy, a nurse practitioner, or a physician assistant employed by UVa School of Medicine 
 
►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 
_____ Amount to exceed 550 cc in an 8 week period 
 
►IF NO, will blood ONLY be obtained via a peripheral blood stick?Yes 
 
 
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 #, CRR protocol #, date of birth, 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 
 
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? 
 
Yes and No.  See the explanation below. 


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Samples from the screening exam that are analyzed by UVA clinical labs will generally be run within 24 
hrs.  
 
►IF NO, where will the specimen be stored until analysis is done?  
Some samples from the screening exam (e.g., TSH, LH, FSH, P, Testosterone, E2 and insulin) and all samples 
from the inpatient admissions will be analyzed and stored in the UVA Center for Research in Reproduction 
Ligand Core lab Suhling Building, Rooms 6918 & 6921, IBC #132-02.  
 
Specimen Shipping 
1.  Do you plan to ship any specimens outside of UVA?No 
 
Specimen Security 
The following security precautions will be implemented:  
• Specimens will be kept in a locked freezer/ or locked room 
__X___ Specimens will be stored with HIPAA identifiers.  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.  
Data and Safety Monitoring Plan 
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 subject s. 
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.  
1.3 What is the definition of an unanticipated problem?  
Do not change this answer 


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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 are the definitions of a protocol violation and/or noncompliance?  
Do not change this answer 
A protocol violation is defined as any change, deviation, or departure from the study design or 
procedures of research project that is NOT approved by the IRB-HSR prior to its initiation or 
implementation.  Protocol violations may be major or minor violations.   
 
Noncompliance can be a protocol violation OR deviation from standard operating procedures, 
Good Clinical Practices (GCPs), federal, state or local regulations.   Noncompliance may be serious 
or continuing.  
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__  Unanticipated Problems- will follow Unanticipated Problem recording and reporting 
procedures outlined in section 3. Note that pregnancy could not be deemed to be 
related/possibly related to this study, as none of the procedures increases likelihood of 
pregnancy, and subjects are specifically required to avoid pregnancy. 
 
1.6 What is the definition of a Protocol Enrollment Exception?   
__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? 
 


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Expected Risks related to study 
participation. 
  
Frequency 
 
Risks associated with 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 draw 
 
Anemia 
____Occurs frequently 
____Occurs infrequently 
____Occurs rarely 
__X__Frequency unknown 
      Risk to Fetus 
Unknown risk to fetus 
Risk of Progesterone 
 
Fluid retention 
May occur with longer-term P administration, but this would 
not be expected after one dose of P. 
Sleepiness 
____Occurs frequently 
____Occurs infrequently 
__X__Occurs rarely 
____Frequency unknown 
Mood swings 
Occurs with longer-term P administration, but rare after one 
dose of P. 
Mild vaginal bleeding 
Generally occurs shortly after discontinuation of a one-week 
course of exogenous P and E2.  We do not expect the same to 
occur after only one dose of P.  
 
Risk of Estradiol 
 
Local skin irritation at the site of E2 
patch application 
May occur in approximately 15-20% of subjects 
Deep Vein Thrombosis 
____Occurs frequently 


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____Occurs infrequently 
____Occurs rarely 
__X__Frequency unknown, however occurs very rarely with 
long-term estrogen use (as with oral contraceptive pills), so 
would expect to be exceedingly rare with the short term 
administration in this protocol. 
Mild nausea 
____Occurs frequently 
__X__Occurs infrequently 
____Occurs rarely 
____Frequency unknown 
Swelling or breast tenderness 
____Occurs frequently 
__X__Occurs infrequently 
____Occurs rarely 
____Frequency unknown 
Hot flashes 
____Occurs frequently 
____Occurs infrequently 
__X__Occurs rarely 
____Frequency unknown 
Risk of Iron Supplementation 
 
nausea 
____Occurs frequently 
__X__Occurs infrequently 
____Occurs rarely 
____Frequency unknown 
constipation 
____Occurs frequently 
__X__Occurs infrequently 
____Occurs rarely 
____Frequency unknown 
dark or black stools 
__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 decreased infertility as a 
result of study medications (i.e., this short course of physiologic 
E2 and P will not provide contraception).  Therefore, sexually 
active subjects may get pregnant during this protocol.  If the 
volunteer becomes pregnant, the study and all study 
medications will be discontinued. 
Reproductive Risks 
Specify potential reproductive risks 
 
Minimized due to the requirements of this protocol.   
Violation of subject’s privacy and 
confidentiality 
Minimized due to the requirements of the privacy plan in this 
protocol 
 


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2.2   List by bullet format a summary of safety tests/procedures/observations to be performed that will 
minimize risks to participants:   
• 
  Risks of venipuncture will be minimized by using proper sterile technique 
 
• 
Risk of anemia will be reduced in the following manner: A hemoglobin and hematocrit will be obtained and reviewed 
prior to each CRU sampling study, and only volunteers with a hematocrit ≥ 36% or a hemoglobin ≥ 12 will be allowed 
to proceed with the frequent sampling study. The one exception to this rule is that those subjects documented to 
have a hematocrit ≥ 36% or Hemoglobin ≥ 12 g/dl in the month before overnight admission will not be required to 
have a repeat hematocrit and hemoglobin on overnight admission. 
 
• 
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 history and physical will be performed at screening. Women with a history of any disorders that may potentially be 
complicated by long-term iron supplementation, such as hemochromatosis and polycythemia vera, will be excluded.  
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. We will exclude women with a history of any disorders that may potentially be complicated by 
hormonal treatment, such as DVT and breast, ovarian, or endometrial cancer. 
 
• 
Risk from use of estradiol patch will be reduced by instructing subjects to rotate sites of their E2 patch to avoid skin 
irritation and/or rash. 
 
• 
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 <20 or >30 (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 who are asked to repeat a study admission at a time when they are in the follicular phase of their cycle will 
be asked to wait the appropriate 8 weeks to schedule the repeat study admission so as not to put the subject at 
undue risk for anemia.  All appropriate safety labs will be obtained prior to studying the subject for a final study 
admission to ensure subject safety.  
 


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• 
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. 
To minimize the risk of having >500 ml of blood drawn within 48 hours: 
A hemoglobin level will be drawn within 30 days prior to the visit at which the blood will be 
drawn.  The blood will not be drawn if the levels do not meet the criteria below: 
 Hematocrit at least 36% and/or a hemoglobin level at least 12 g/dl  
 
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 (see below) 
•  If the volunteer is pregnant, the study and all study medications will be discontinued.  
• Estradiol will be discontinued and the study stopped if side effects (e.g., nausea, breast tenderness) become 
problematic. 
• If subjects remain anemic (HCT < 36% and hemoglobin < 12) after 2 sequential months of ferrous gluconate 
(325 mg bid), they will then be excluded from participation in the study. 
 
_____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 
 
_____Refer to the non- IRB Protocol (Sponsor's, Investigator-Initiated, CTEP protocol etc.) 
 
2.4 Under what criteria would THE ENTIRE STUDY need to be stopped?   
INSTRUCTIONS; 
• 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. 
• Check all that apply. 
__X___Per IRB, PI, DSMB, or sponsor discretion 
Two (2) subjects having serious, unexpected related or possibly related Adverse events. 
 
2.5 What are the criteria for breaking the blind/mask? 
__X___Other: If a severe adverse event occurs within 24 hours after administration of 
progesterone/placebo. 
 
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? 
►IF NO, what criteria will be used? No 
 
__X___Only adverse events deemed related/possibly related to study  


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_____Only adverse events that are deemed serious  
 
_____Only adverse events that are deemed related AND serious  
 
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 
_____Database  Specify name/type of database   Answer/Response: 
 
3.3. How will AEs be classified/graded? Check all that apply 
_____World Health Organization Criteria (WHO) 
_____NCI Common Toxicity Criteria, Version 2.0/ NCI Common Terminology Criteria, Version 3.0 
_____NCI CTCAE Version 4.0 
__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?  Check all that apply. 
 
__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? 
__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  
_____ 30 days post study drug/device/intervention 
_____ Subject completes intervention and follow up period of protocol 
 
3.7 How will Adverse Events, Unanticipated Problems, Protocol Violations and Data Breaches be 
reported?  Complete the table below to answer this question 
 


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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, 
related/possibly related, 
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/vprgs
/irb/HSR_docs/Forms/Reportin
g_Requirements-
Unanticipated_Problems.doc ) 
Protocol 
Violations/Noncompliance 
The IRB-HSR only requires that 
MAJOR violation be reported, 
unless otherwise required by 
your sponsor, if applicable. 
 
OR 
 
Enrollment Exceptions 
See definition- only allowed if 
there is a commercial sponsor 
or a DSMB that has granted 
the enrollment exception.  
IRB-HSR 
 
 
Within 7 calendar 
days from the 
time the study 
team received 
knowledge of the 
event.  
 
Protocol Violation, 
Noncompliance and 
Enrollment Exception 
Reporting Form 
 
 
http://www.virginia.edu/vprgs
/irb/hsr_forms.html 
 
Go to 3rd bullet from the 
bottom. 
  
Data Breach  
The UVa 
Corporate 
Compliance and 
Privacy Office 
 
 
 
ITC:  if breach 
involves  
electronic data  
 
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 
UVa Corporate Compliance and 
Privacy Office- Phone 924-9741 
 
 
 
 
ITC:  Information Security 
Incident Reporting procedure,  
http://www.itc.virginia.edu/se
curity/reporting.html 
 


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Police if breach 
includes items 
that are stolen: 
 
Stolen on UVA 
Grounds 
 
OR  
 
Stolen off UVa 
Grounds- contact 
police 
department of 
jurisdiction of last 
known location of 
PHI 
time the incident 
is identified. 
 
IMMEDIATELY.  
 
 
 
 
 
 
 
 
 
UVa Police-Phone- (434) 924-
7166 
 
4.    How will the endpoint data be collected/recorded. Check all that apply 
__X___Protocol specific case report forms  
_X___Source documents 
5. Data and Safety Oversight Responsibility 
 
5.1. Who is responsible for overseeing safety data for this study?  
 
__X___DSMB/ DSMC 
 
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. 
 
__X___Other- William Evans, MD; Mark DeBoer, MD; Guofen Yan, PhD. (This internal (UVA) DSMB 
has monitored this study since its inception.  
 
5.3. What items will be included in the aggregate review conducted by the PI?  
Check all that apply. 
 
__x___NA- PI is not the overall person overseeing the safety data for this study.     
__X___All adverse events 
__X___Unanticipated Problems 
__X___Protocol violations/Issues of noncompliance 
_____Audit results 
_____Application of dose finding escalation/de-escalation rules  


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These should be outlined under 2.4. 
_____Application of study designed stopping/decision rules 
_____Early withdrawals 
_____Whether the study accrual pattern warrants continuation/action 
_____Endpoint data 
_____Other: Specify   Answer/Response: 
 
5.4 How often will aggregate review occur? 
For additional information on aggregate review see: 
www.virginia.edu/vpr/irb/hsr/continuations.html#aggreview 
_____NA- PI is not the overall person overseeing the safety data for this study.     
_____Per Enrollment/Events 
__X___Annually 
_____Semi-Annually 
_____Quarterly 
_____Monthly 
 
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__Annually 
 
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 
INSTRUCTIONS: 
 
What is the difference between compensation and reimbursement? 
 
A reimbursement is used when the subject is paid back for travel expenses such as mileage, lodging, food 
while traveling. Receipts or mileage must be submitted for a reimbursement.  
Compensation is "payment" for things such as time, discomfort, inconvenience. 


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Total possible compensation should reflect the true value of the total possible dollar amount per participant 
for one year involvement in the study whether it be cash, check, gift card, goods, etc. or a combination of 
these items. 
 
Retention “Gifts”- gifts may be given to a subject periodically during the study to remind them they are in the 
study.  Sponsors may provide such items as water bottles, birthday cards etc. to the subject.  NOTE:  Cash or 
gift cards are NOT allowed as retention items.  
 
1.  Are subjects being reimbursed for travel expenses? 
INSTRUCTIONS: 
• If subject will NOT submit receipts for actual expenses (e.g. hotel, food, you MUST answer this NO.  
• If subjects will have mileage/distance traveled, calculated and confirmed *via Mapquest for 
example, this questions should be answered YES 
• Reimbursements must be paid with Oracle Expenditure types found under the Travel Heading.   
• For instructions on how to process a reimbursement please see "Goods and Services Procurement 
Guide" at  http://www.procurement.virginia.edu/main/.  You may also call the Procurement Help 
Desk at 924-4212.   
• The money will not be reportable to the IRS as income, but will be withheld if the subject owes 
money to the state. 
Yes 
 
►IF YES, explain rate/ amount/ upper limits of reimbursements. 
When round trip travel exceeds 50 miles (one way), we will make available travel reimbursement in the amount 
of $25 per trip.  (Total travel reimbursement not to exceed $75 for the entire study). 
 
►IF YES, Do you confirm you are aware of the following procedures to follow for reimbursements?  
INSTRUCTIONS 
• Subject will submit receipts for actual expenses (e.g. hotel, food) 
• Reimbursements must be paid with Oracle Expenditure types found under the Travel 
Heading.   
• For instructions on how to process a reimbursement  see "Goods and Services 
Procurement Guide" at  http://www.procurement.virginia.edu/main/.  You may also call 
the Procurement Help Desk at 924-4212.  The money will not be reportable to the IRS as 
income, but will be withheld if the subject owes money to the state. 
• Reimbursements may not be done with gift cards 
Yes 
• Subject will submit receipts for actual expenses (e.g. hotel, food, actual mileage). 
• Reimbursements must be paid with Oracle Expenditure types found under the Travel 
Heading.  For instructions on how to process a reimbursement see "Goods and Services 
Procurement Guide" at http://www.procurement.virginia.edu/main/.  You may also call 
the Procurement Help Desk at 924-4212.  The money will not be reportable to the IRS as 
income, but will be withheld if the subject owes money to the state. 


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• Reimbursements may not be done with gift cards 
 
2.  Are subjects compensated for being in this study?Yes 
 
►IF YES, answer the following questions (2a-2d).  
2a. What is the maximum TOTAL compensation to be given over the duration of the protocol? 
$300.00 in most circumstances (although total compensation of $400 is possible [see below]) 
 
2b. Explain compensation to be given. 
Subjects will receive $100 for each completed inpatient admission (normally, the study involves 2 
inpatient admissions), and a $100 bonus for completing all the admissions and outpatient visits in the 
study.  If a subject completes the first two study admissions and is asked by the study team to repeat 
one of those overnight studies, she will be compensated an additional $100 for this extra overnight 
admission. 
 
2c. Is payment pro-rated? 
Yes. Subjects completing only one of two inpatient study admissions will receive $100. 
 
2d.  Is money paid from UVa or State funds (including grant funds) or will items such as gift cards be 
distributed through UVa? 
INSTRUCTIONS 
Examples of when to say no: 
• Researcher is using their own personal funds to compensate participants. 
• Compensation is coming from a UVa Foundation and therefore not subject to UVA financial 
policies and procedures. 
Examples of when to say yes: 
• Sponsor, via a grant or contract, sends money to OSP/ SOM Grants and Contracts office to 
cover cost of compensation to be given to subjects.  Subjects are then paid via Oracle system 
• UVA researcher purchases gift cards for distribution to subjects and there is NO outside 
sponsor. 
• Sponsor purchases gift cards/ debit cards and sends to UVa for study team to distribute to the 
subjects.   
Yes 
►IF YES, answer the following questions [2d(i)-2d(ii)]. 
2d(i).  How will the researcher compensate the subjects? 
 
___X__ 
Check issued to participant via UVA Oracle or State system  
 
2d(ii).  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  


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The preferred method  
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 are no direct benefits for the participant as a result of this study.  The investigators judge that the risk of 
participating in this study is minimal and that the information obtained may help to further elucidate the mechanisms 
involved in modulation of the GnRH pulse generator in health and disease. Volunteers may rarely receive the diagnostic 
benefits of laboratory evaluation without charge. Also, the information obtained via this study will be critical to obtain 
while pursuing our hypotheses regarding (1) the development of ovulatory cycles during puberty and (2) 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.  Do the anticipated benefits justify asking subjects to undertake the risks?   
NA. There are no direct benefits for the participant as a result of this study.  The risk/benefit ratio is acceptable. 
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Goji K 1993 Twenty-four-hour concentration profiles of gonadotropin and estradiol (E2) in prepubertal 
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Wu FC, Butler GE, Kelnar CJ, Huhtaniemi I, Veldhuis JD 1996 Ontogeny of pulsatile gonadotropin 
releasing hormone secretion from midchildhood, through puberty, to adulthood in the human male: a 
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Metab 81:1798-1805 
27. 
Dunkel L, Alfthan H, Stenman UH, Perheentupa J 1990 Gonadal control of pulsatile secretion of 
luteinizing hormone and follicle-stimulating hormone in prepubertal boys evaluated by ultrasensitive 
time-resolved immunofluorometric assays. J Clin Endocrinol Metab 70:107-114 
28. 
Oerter KE, Uriarte MM, Rose SR, Barnes KM, Cutler GB, Jr. 1990 Gonadotropin secretory dynamics 
during puberty in normal girls and boys. J Clin Endocrinol Metab 71:1251-1258 
29. 
Dunkel L, Alfthan H, Stenman UH, Tapanainen P, Perheentupa J 1990 Pulsatile secretion of LH and 
FSH in prepubertal and early pubertal boys revealed by ultrasensitive time-resolved 
immunofluorometric assays. Pediatr Res 27:215-219 
30. 
Wennink JM, Delemarre-van de Waal HA, van Kessel H, Mulder GH, Foster JP, Schoemaker J 1988 
Luteinizing hormone secretion patterns in boys at the onset of puberty measured using a highly 
sensitive immunoradiometric assay. J Clin Endocrinol Metab 67:924-928 
31. 
Wu FC, Borrow SM, Nicol K, Elton R, Hunter WM 1989 Ontogeny of pulsatile gonadotrophin secretion 
and pituitary responsiveness in male puberty in man: a mixed longitudinal and cross-sectional study. J 
Endocrinol 123:347-359 
32. 
Hale PM, Khoury S, Foster CM, Beitins IZ, Hopwood NJ, Marshall JC, Kelch RP 1988 Increased 
luteinizing hormone pulse frequency during sleep in early to midpubertal boys: effects of testosterone 
infusion. J Clin Endocrinol Metab 66:785-791 
33. 
Kletter GB, Padmanabhan V, Beitins IZ, Marshall JC, Kelch RP, Foster CM 1997 Acute effects of 
estradiol infusion and naloxone on luteinizing hormone secretion in pubertal boys. J Clin Endocrinol 
Metab 82:4010-4014 
34. 
Cemeroglu AP, Foster CM, Warner R, Kletter GB, Marshall JC, Kelch RP 1996 Comparison of the 
neuroendocrine control of pubertal maturation in girls and boys with spontaneous puberty and in 
hypogonadal girls. J Clin Endocrinol Metab 81:4352-4357 
35. 
Boyar RM, Rosenfeld RS, Kapen S, Finkelstein JW, Roffwarg HP, Weitzman ED, Hellman L 1974 Human 
puberty. Simultaneous augmented secretion of luteinizing hormone and testosterone during sleep. J 
Clin Invest 54:609-618 
36. 
Albertsson-Wikland K, Rosberg S, Lannering B, Dunkel L, Selstam G, Norjavaara E 1997 Twenty-four-
hour profiles of luteinizing hormone, follicle-stimulating hormone, testosterone, and estradiol levels: a 
semilongitudinal study throughout puberty in healthy boys. J Clin Endocrinol Metab 82:541-549 
37. 
Wu FC, Butler GE, Kelnar CJ, Sellar RE 1990 Patterns of pulsatile luteinizing hormone secretion before 
and during the onset of puberty in boys: a study using an immunoradiometric assay. J Clin Endocrinol 
Metab 70:629-637 
38. 
Goji K, Tanikaze S 1993 Spontaneous gonadotropin and testosterone concentration profiles in 
prepubertal and pubertal boys: temporal relationship between luteinizing hormone and testosterone. 
Pediatr Res 34:229-236 
39. 
Ankarberg C, Norjavaara E 1999 Diurnal rhythm of testosterone secretion before and throughout 
puberty in healthy girls: correlation with 17beta-estradiol and dehydroepiandrosterone sulfate. J Clin 
Endocrinol Metab 84:975-984 


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40. 
Mitamura R, Yano K, Suzuki N, Ito Y, Makita Y, Okuno A 2000 Diurnal rhythms of luteinizing hormone, 
follicle-stimulating hormone, testosterone, and estradiol secretion before the onset of female puberty 
in short children. J Clin Endocrinol Metab 85:1074-1080 
41. 
Cemeroglu AP, Kletter GB, Guo W, Brown MB, Kelch RP, Marshall JC, Padmanabhan V, Foster CM 
1998 In pubertal girls, naloxone fails to reverse the suppression of luteinizing hormone secretion by 
estradiol. J Clin Endocrinol Metab 83:3501-3506 
42. 
Foster CM, Hassing JM, Mendes TM, Hale PM, Padmanabhan V, Hopwood NJ, Beitins IZ, Marshall JC, 
Kelch RP 1989 Testosterone infusion reduces nocturnal luteinizing hormone pulse frequency in 
pubertal boys. J Clin Endocrinol Metab 69:1213-1220 
43. 
Kletter GB, Foster CM, Brown MB, Beitins IZ, Marshall JC, Kelch RP 1994 Nocturnal naloxone fails to 
reverse the suppressive effects of testosterone infusion on luteinizing hormone secretion in pubertal 
boys. J Clin Endocrinol Metab 79:1147-1151 
44. 
Ross JL, Loriaux DL, Cutler GB, Jr. 1983 Developmental changes in neuroendocrine regulation of 
gonadotropin secretion in gonadal dysgenesis. J Clin Endocrinol Metab 57:288-293 
45. 
McCartney CR, Blank SK, Prendergast KA, Chhabra S, Eagleson CA, Helm KD, Yoo R, Chang RJ, Foster 
CM, Caprio S, Marshall JC 2007 Obesity and sex steroid changes across puberty: evidence for marked 
hyperandrogenemia in pre- and early pubertal obese girls. J Clin Endocrinol Metab 92:430-436 
46. 
Clayton RN, Royston JP, Chapman J, Wilson M, Obhrai M, Sawers RS, Lynch SS 1987 Is changing 
hypothalamic activity important for control of ovulation? Br Med J (Clin Res Ed) 295:7-12 
47. 
Chhabra S, McCartney CR, Yoo RY, Eagleson CA, Chang RJ, Marshall JC 2005 Progesterone inhibition of 
the hypothalamic gonadotropin-releasing hormone pulse generator: evidence for varied effects in 
hyperandrogenemic adolescent girls. J Clin Endocrinol Metab 90:2810-2815 
48. 
Pastor CL, Griffin-Korf ML, Aloi JA, Evans WS, Marshall JC 1998 Polycystic ovary syndrome: evidence 
for reduced sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by 
estradiol and progesterone. J Clin Endocrinol Metab 83:582-590 
49. 
Daniels TL, Berga SL 1997 Resistance of gonadotropin releasing hormone drive to sex steroid-induced 
suppression in hyperandrogenic anovulation. J Clin Endocrinol Metab 82:4179-4183 
50. 
McCartney CR, Blank SK, Marshall JC 2007 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 292:E900-906 
51. 
Skinner DC, Evans NP, Delaleu B, Goodman RL, Bouchard P, Caraty A 1998 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 95:10978-10983 
52. 
Bergfeld EG, Kojima FN, Cupp AS, Wehrman ME, Peters KE, Mariscal V, Sanchez T, Kinder JE 1996 
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 54:546-553 
53. 
Loucks AB, Heath EM 1994 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 78:910-915 
54. 
Loucks AB, Thuma JR 2003 Luteinizing hormone pulsatility is disrupted at a threshold of energy 
availability in regularly menstruating women. J Clin Endocrinol Metab 88:297-311 
55. 
Loucks AB, Verdun M, Heath EM 1998 Low energy availability, not stress of exercise, alters LH 
pulsatility in exercising women. J Appl Physiol 84:37-46 


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56. 
Robinson JE, Forsdike RA, Taylor JA 1999 In utero exposure of female lambs to testosterone reduces 
the sensitivity of the gonadotropin-releasing hormone neuronal network to inhibition by progesterone. 
Endocrinology 140:5797-5805 
57. 
Eagleson CA, Gingrich MB, Pastor CL, Arora TK, Burt CM, Evans WS, Marshall JC 2000 Polycystic 
ovarian syndrome: evidence that flutamide restores sensitivity of the gonadotropin-releasing hormone 
pulse generator to inhibition by estradiol and progesterone. J Clin Endocrinol Metab 85:4047-4052 
58. 
Pielecka J, Quaynor SD, Moenter SM 2006 Androgens increase gonadotropin-releasing hormone 
neuron firing activity in females and interfere with progesterone negative feedback. Endocrinology 
147:1474-1479 
59. 
Foecking EM, Szabo M, Schwartz NB, Levine JE 2005 Neuroendocrine consequences of prenatal 
androgen exposure in the female rat: absence of luteinizing hormone surges, suppression of 
progesterone receptor gene expression, and acceleration of the gonadotropin-releasing hormone 
pulse generator. Biol Reprod 72:1475-1483 
60. 
Chang RJ, Jaffe RB 1978 Progesterone effects on gonadotropin release in women pretreated with 
estradiol. J Clin Endocrinol Metab 47:119-125 
61. 
Liu JH, Yen SS 1983 Induction of midcycle gonadotropin surge by ovarian steroids in women: a critical 
evaluation. J Clin Endocrinol Metab 57:797-802 
62. 
Nippoldt TB, Khoury S, Barkan A, Kelch RP, Marshall JC 1987 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) 26:293-301 
63. 
Lagace L, Massicotte J, Labrie F 1980 Acute stimulatory effects of progesterone on luteinizing hormone 
and follicle-stimulating hormone release in rat anterior pituitary cells in culture. Endocrinology 
106:684-689 
64. 
Hoff JD, Quigley ME, Yen SS 1983 Hormonal dynamics at midcycle: a reevaluation. J Clin Endocrinol 
Metab 57:792-796 
 
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.  They will be submitted to 
the IRB after the IRB-HSR has assigned an IRB-HSR # to the protocol. 
• Only those individuals listed as personnel on this protocol will recruit and or conduct the 
consenting process with potential subjects.  
 
Retention Incentives 
Any item used by the sponsor/ study team to provide incentive to a subject to remain in the study, other than 
compensation identified in the Payment section, will be submitted to the IRB for review prior to use.  The IRB-
HSR will provide the study team with a Receipt Acknowledgement for their records.  Retention incentive items 
are such things as water bottles, small tote bags, birthday cards etc.  Cash and gift cards are not allowed as 
retention incentives.  
 
Clinical Privileges 


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The following procedures will be followed:  
• Investigators who are members of the clinical staff at the University of Virginia Medical Center must 
have the appropriate credentials and been granted clinical privileges to perform specific clinical 
procedures 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 credentials and clinical privileges in place before 
performing any procedures required by this protocol.  
• Contact the Clinical Staff Office- 924-9055 or 924-8778 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. 
 
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 
 
Compensation in Case of Injury  
If a subject requests compensation for an injury, the study team should notify the IRB-HSR (924-
9634/2439847) the UVa Health System Patient Relations Department (924-8315).  As a proactive courtesy, the 
study team may also notify UVa Health System Patient Safety and Risk Management (924-5595). 
 
On request, the study team should provide  the Risk Management Office with the following 
information/documents: 


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• Subject Name and Medical Record Number 
• Research medical records 
• Research consent form 
• Adverse event report to IRB 
• Any letter from IRB to OHRP 
 
Subject Complaints  
During a research study, the study team may receive complaints from a subject.  If the study team is uncertain 
how to respond to a complaint, or is unable to resolve it with the subject, the study team may contact the IRB-
HSR (924-9634/243-9847), the UVa Health System Patient Relations Department (924-8315). 
 
Request for Research Records from Search Warrant or Subpoena 
If the study team receives a request for research records from a search warrant or subpoena, they should 
notify UVa Health Information Services at 924-5136. It is important to notify them if information from the 
study is protected by a Certificate of Confidentiality.   
 
APPENDIX:  Drug Information 
1   What is the drug name, manufacturer and IND# if available?    
Micronized progesterone suspension (i.e., Progesterone USP, micronized, for prescription 
compounding [NDC 39822-6000-3] Mfg: Spectrum Chemicals and Laboratory Products). This protocol is 
under IND# 64, 126. 
 
We will also be using commercially available estradiol patches (0.1 mg/d), which are provided by the 
UVAHS research pharmacy. This protocol is under IND# 64, 126.   
 
2.   If IND application has been submitted to the FDA, who is the Principal Investigator on the IND?     
John C. Marshall 
 
3.  What is the phase or stage of this study?   NA 
APPENDIX:  Recruitment 
Recruitment includes identifying, review of records to determine eligibility or any contact to determine a 
potential subjects interest in the study. 
 
*The UVa HIPAA covered entity is composed of the  UVa VP Office of Research, the Health System, School of 
Medicine, School of Nursing, Nutrition Services (Morrisons), the Sheila C. Johnson Center, the Exercise and 
Sports Injury Laboratory and the Exercise Physiology Laboratory.   
 
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. 


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• 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: 
 
a.____ Chart Review/ Clinic Schedule Review/ Database Review from a database established for 
health care operations (departmental clinical database) or an Improvement Project (e.g.  
Performance Improvement, Practice Improvement, Quality Improvement).   
 
If you plan to obtain data from the UVa Enterprise Data Warehouse (EDW) please see option b 
below.   
 
DHHS: Study team requests Waiver of Consent to identify potential subjects.  
 
HIPAA: Allowed under Preparatory to Research if PHI to be accessed.  
 
IMPORTANT 
Keep in mind that PHI in the medical record may only be accessed by individuals who 
work under the UVa HIPAA covered entity; which means they meet one of the following 
criteria: 
--a UVa student working in the UVa HIPAA Covered Entity*   
--a faculty or staff member in a PAID appointment in  the UVA HIPAA Covered Entity* 
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.     
If you plan to obtain data from the UVa Enterprise Data Warehouse (EDW) you are required 
to submit your request to the CDR.  The CDR staff will work with the EDW to obtain the data 
you need.   
DHHS: Study team requests Waiver of Consent to identify potential subjects. 
 
HIPAA: Allowed under Preparatory to Research if PHI to be accessed.  
 
IMPORTANT 
Keep in mind that PHI in the medical record may only be accessed by individuals who 
work under the UVa HIPAA covered entity; which means they who meet one of the 
following criteria: 
--a UVa student working in the UVa HIPAA Covered Entity*   
--a faculty  or staff member in a PAID appointment in  the UVA HIPAA Covered Entity* 
 
The information from which you are obtaining potential subjects must also have an IRB 
protocol approval.  If this item is checked, enter the IRB # below.  
 
IRB# ________________ 
If obtaining information from the Clinical Data Repository (CDR) insert IRB # 10797 


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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 if PHI will be shared by the health care 
provider.  
 
IMPORTANT 
Keep in mind that PHI may only be given to individuals who work under the UVa HIPAA 
covered entity; which means they meet one of the following criteria: 
--a UVa student working in the UVa HIPAA Covered Entity*   
--a faculty or staff member in a PAID appointment in the UVA HIPAA Covered Entity* 
 
d. ____ Patient obtains information about the study from their health care provider.  The 
patient contacts the study team if interested in participating. (Health care provider may 
or may not also be the a member of the study team) 
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. ____ Other: Specify   Answer/Response: 
 
 
If item # a, b or c is checked above and if this protocol involves the use of protected health 
information do you confirm the following to be true? n/a 
• 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. 
• The PHI that the researcher seeks to use or access is necessary for the research 
purposes. 


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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 below 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.  Information 
will not be collected from psychotherapy notes.  
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.  
 
IMPORTANT:   
Keep in mind that if PHI was collected during the identification phase that 
contact with potential subjects may only be performed by individuals who work 
under the UVa HIPAA covered entity; which means they meet one of the 
following criteria: 
 a UVa student working in the UVa HIPAA Covered Entity*   
 a faculty  or staff member in a PAID appointment in  the UVA HIPAA Covered 
Entity* 
 
b.____Potential subjects will be approached while at UVa Hospital or Health Clinic by a 
person who is NOT a member of their health care team.  Information will not be 
collected from psychotherapy notes.  
DHHS & HIPAA: Study team requests a Waiver of Consent and a Waiver of HIPAA 
Authorization to contact potential subjects.  
 
IMPORTANT:   
Keep in mind that contacting individuals in a clinical setting may only be performed by 
individuals who work under the UVa HIPAA covered entity; which means they  meet one 
of the following criteria: 
a UVa student working in the UVa HIPAA Covered Entity*   
a faculty  or staff member in a PAID appointment in  the UVA HIPAA Covered Entity* 


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You should share the following information with the potential subject:  
• Your name 
• Who you are:  physician, nurse etc. at the University of Virginia.    
• Why you want to speak with them 
• Ask if you have their permission to explain the study to them 
• If asked about how you obtained their information use one of the following as an 
option for response.     
o 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.    
o We obtained your information from your medical records at UVa.   
o 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.  
• 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 contacting potential 
subjects 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 either the patient contacts study 
team or gives their healthcare provider permission for the study team to contact them.) 
The indirect method used (flyer, brochure, TV, broadcast emails) must be approved by 
the IRB prior to use.    The IRB does not need to review any type of script to use when 
the potential subject responds to the indirect method.   
 
DHHS & HIPAA:  NA 
 
 


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e. ____  Potential subjects are not patients.  The study does not include obtaining 
subjects health information.   Subjects will be contacted directly via email, phone, 
letter or presentation in group setting with consent then obtained individually in a 
private setting.  
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.  
HIPPA:  NA 
 
3. Will any additional information be obtained from a potential subject during "prescreening"?   
Pre-screening for IRB purposes is the term used to describe activities PRIOR to obtaining Informed 
Consent and may not include any research procedures.  
  
The activities may involve 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).  
An additional telephone script is not required, for this pre-screening process, in addition to any 
scripts required under Recruitment question # 2.   
Yes 
 
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.  
 
HIPPA: 
HIPAA does not apply if: 
--no PHI is collected or 
--if PHI is collected from a potential subject  by an individual from a department that is not part of 
the HIPAA covered entity. 


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HIPAA does apply if the collection occurs by individuals* who work in a department that is part of 
the HIPAA covered entity.   
 
In this case the collection will be covered under Health Care Operations/ 
 
These individuals are those that meet one of the following criteria:  
--a UVa student working in the UVa HIPAA Covered Entity*   
--a faculty  or staff member in a PAID appointment in  the UVA HIPAA Covered Entity* 
 
IF YES, Will any of the questions involve health information?Yes 
 
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?  
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.   
Yes 
 
►IF YES, explain in detail what you will ask them to do. 
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 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 
 


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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:  
If the individual, obtaining consent, works under the HIPAA Covered Entity this is covered under 
Health Care Operations 
If the individual obtaining consent does not work under the HIPAA covered entity, HIPAA does 
not apply.  
 
5. How will the consenting process take place with either the prospective subject, the subject’s 
legally authorized representative or parent/legal guardian of a minor ( if applicable)?    
HIPPA:  
If the individual, obtaining consent, works under the HIPAA Covered Entity consenting is 
covered under Health Care Operations. 
 
If the individual obtaining consent does not work under the HIPAA covered entity, HIPAA does 
not apply.  
 
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 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 YES, explain in detail why the subject cannot be given more time to make a decision to 
consent.  
Potential subjects are given a copy of the consent form prior to their screening visit.  Subjects 
are instructed to review the consent form, and are encouraged to ask any questions prior to 
scheduling a screening visit.  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, decline to enroll 
in the study, or take more time to review the consent form before making a decision whether 
or not to enroll.  If the subject decides to enroll in the study on the day of the screening visit, 


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then we will proceed with the study procedures outlined in the study visit above, unless the 
subject objects.   
 
Therefore, the study team feels that the subject is under no pressure to give consent at the 
screening visit without having ample opportunity to review the consent form.  In addition, 
subjects are given the option to decline consent or delay study procedures at any point during 
this initial visit. 
 
►IF YES, explain in detail what will be done to assure the potential subject has enough time 
to make an informed decision. 
Potential subjects are given a copy of the consent form prior to their screening visit.  Subjects 
are instructed to review the consent form, and are encouraged to ask any questions prior to 
scheduling a screening visit.  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, decline to enroll 
in the study, or take more time to review the consent form before making a decision whether 
or not to enroll. 
 
8.  Is there the potential to recruit economically or educationally disadvantaged subjects, or other 
vulnerable subjects such as students or employees?Yes 
 
IF YES, what protections are in place to protect the rights and welfare of these subjects so 
that any possible coercion or undue influence is eliminated?   
Potential subjects are given the opportunity to read the consent at their leisure prior to the 
study staff knowing if they are economically or educationally disadvantaged or a student or 
employee of Uva. 
9. Do you need to perform a “dry run” of any procedure outlined in this protocol?   No 
10.  Is the study regulated by the Department of Defense (DoD)?No 
 
 
APPENDIX:  Pharmacy-Investigational Drugs/Biologics  
1.   What is the name of the investigational drug/biologic?    
Micronized progesterone suspension (i.e., Progesterone USP, micronized, for prescription 
compounding [NDC 39822-6000-3] 
 
2. Where will the subjects be seen for the administration/dispensing of the drug?     
__X___  Inpatient Unit: Subjects will be given medication at 0600h during one of their inpatient study 
admissions (randomized with placebo). 
 
3.  What dose will be utilized in this study?    
100 mg 
 
4. What will be the frequency of dosing in this study?    


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Subjects will be given a single dose of 100 mg progesterone suspension during the study.  Subjects will receive 
either progesterone or placebo during each inpatient admission at 0600h.  If subjects receive placebo during 
the first inpatient admission, they will receive progesterone during the second inpatient admission (and vice 
versa).   
 
5.  What will be the duration of dosing in this study?    
Subjects will be given a single dose of progesterone during the study. 
 
6.  What route of administration will be utilized?   PO 
 
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 
 
7b.  Diluents 
___X__ Standard 
 
7c.  Stability after prepared 
__X___ Standard 
 
7d. Special storage requirements 
__X___ Standard 
 
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?     
Missed doses are not expected in this study, since the subject will receive this dose during their inpatient 
study admission. 
 
11.  Will a comparator (active or placebo) be utilized in the protocol?   Yes 
 
►IF YES, comparator is: 
__X___  Placebo:  At each inpatient admission, subjects will receive either a single dose of 
progesterone or a single dose of placebo, determined by randomization.  The study is set up as a cross-


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over design, such that subjects receiving placebo during admission 1, will receive progesterone at 
admission 2, and vice versa.  Placebo suspension is made up with the same formulation as the 
micronized progesterone suspension minus the active ingredient. 
 
12.  Does this study involve research on a drug, biologic, supplement or food additive?   yes 
 
13    Are you using a drug/supplement/ food additive in a manner not approved by the FDA?     
Yes 
 
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.    
There are no specific data regarding animal toxicity/safety of the UVAHS’s progesterone suspension. 
 
13b. Describe pertinent human data that is available regarding the toxicity/safety of this drug.    
There are no published data regarding human toxicity/safety of the UVAHS’s progesterone suspension. 
However, the progesterone used to formulate the suspension (i.e., Progesterone USP, micronized, for 
prescription compounding [NDC 39822-6000-3] Mfg:Spectrum Chemicals and Laboratory Products) is 
FDA approved. Of course, progesterone is a natural sex-steroid, and we administer a short-course (< 1 
day) of physiologic amounts in this protocol. We have used this progesterone suspension in other 
protocols, and we have thus far administered the progesterone suspension to > 50 subjects. The only 
adverse event that we felt was unusual (but can occur with progesterone) was mild somnolence with 
longer term use (several days): the somnolence abated when the progesterone dose was decreased. 
Other uncommon reported adverse events, which were not unexpected, involved temporary irregular 
menstrual bleeding. 
 
13c. Have there been any human deaths associated with this drug?    
None known. 
 
13d. In how many humans has this drug been used previously?    
We have thus far administered the progesterone suspension to > 50 subjects. 
 
13e. If this protocol will be used in children describe any previous use of this drug with children of a 
similar age range.    
NA 
 
14.  Do the following criteria apply? Check all that 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; 
 


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_____  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; 
 
_____  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:   
o Regarding micronized progesterone suspension, 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, at worst, 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. 
o Regarding transdermal estradiol use: Transdermal estradiol is being used to standardize estradiol levels prior 
to progesterone/placebo administration. The doses employed will achieve physiological levels appropriate 
to the late follicular phase (i.e., estradiol levels will not be supraphysiological). The estradiol used in this 
study is chemically identical to estradiol made by ovaries, and the achieved concentrations will be similar to 
that observed in the late follicular phase of the normal menstrual cycle. Our group has used transdermal 
estradiol successfully in numerous clinical research protocols. With this in mind, we believe that the use of 
transdermal estradiol in this study will be associated with minimal potential risk (at worst). 
 
__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 
 
 
Privacy Plan 
The following procedures must be followed.  
• The data will be secured per the Data Security Plan of this protocol. 
• Only investigators for this study and clinicians caring for the patient will have access to data.  They will each use 
a unique login ID and password that will keep confidential.   The password should meet or exceed the standards 
described on the Information Technology Services (ITS) webpage about The Importance of Choosing Strong 
Passwords. 
• Each investigator will sign the University’s Electronic Access Agreement forward the signed agreement to the 
appropriate department as instructed on the form. 


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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 University  Data Protection Standards will be followed 
http://www.virginia.edu/informationsecurity/dataprotection.   
• If identifiable data 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 University's Requirements for Securing Electronic Devices.  
• If identifiable data is taken away from the UVa Health System, Medical Center Policy # 0218 will be followed.  
• Data will be securely removed from the server/drive, additional computer(s), and electronic media according to 
the University's Electronic Data Removal Policy.  
• 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 University Data Protection 
Standards . 
• 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. 
• Both data on paper and stored electronically will follow the University's Record Management policy and the 
Commonwealth statute regarding the Destruction of Public Records. 
If you have a question or concerns about the required security standards contact ISPRO at 
 it-security@virginia.edu 
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 identity theft if exposed or 
-data that reveals an individual’s health condition and/or history of health services use.  
Protected Data (PHI) a type of Highly Sensitive Data, is data combined with a HIPAA identifier  
Identifiable Data under HIPAA regulations is considered to be Highly Sensitive Data at UVa. 
A Limited Data Set (LDS) under HIPAA regulations is considered to be Moderately Sensitive Data at UVa. The only HIPAA identifiers 
associated with data: dates and or postal address information limited to town or city, state, and zip code.   
Will not include subjects age if older than 89 or subjects DOB if older than 89.   


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Highly Sensitive Data 
(Identifiable Health Info per HIPAA )  
Moderately Sensitive Data  
(Limited Data Set and De-identified data per 
HIPAA) 
General Issues  
General Issues 
Discussions in private 
Do not share with those not on the study team or 
those who do not have a need to know. 
 
Do not share with those not on the study team or 
those who do not have a need to know 
Password protect  
Password protect 
Physically secure (lock) hard copies at all times if not 
directly supervised.  
If not supervised hard copies must have double 
protection (e.g. lock on room OR cabinet AND in 
building requiring swipe card for entrance).    
 
Physically secure (lock) hard copies at all times if 
not directly supervised.   
For electronic documents turn off File Sharing; turn 
on firewalls; use up to date antivirus and 
antispyware; delete data securely. 
 
For electronic documents turn off File Sharing; turn 
on firewalls; use up to date antivirus and 
antispyware; delete data securely. 
 
Encrypt 
See Encryption Solutions Guidance  
Files on Health System Network drives are 
automatically encrypted.  If not stored there it is study 
teams responsibility to make sure data are encrypted. 
 
If device sent out for service or repair, encrypt or 
remove data AND contract for repair using a UVa 
Purchase order. 
If device sent out for service or repair, encrypt or 
remove data AND contract for repair using a UVa 
Purchase order. 
Store files on a network drive specifically designated 
for storing this type of data, e.g. high-level security 
server/drives 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 such as the 
desktop of your computer (e.g. C drive) or to an 
individual  Use Device*.  May access via VPN 
 
Do not share with sponsor or other outside group 
before consent is obtained or the IRB has granted 
appropriate approvals and contract/ MTA is in place  
Do not share with sponsor or other outside group 
before consent is obtained or the IRB has granted 
appropriate approvals and contract/ MTA is in 
place 
If collected without consent/ HIPAA authorization 
will NOT be allowed to leave UVa HIPAA covered 
entity unless disclosure is approved by the IRB and 
the disclosure is tracked in EPIC  
If collected without consent/ HIPAA authorization 
will NOT be allowed to leave UVa HIPAA covered 
entity unless disclosure is approved by the IRB and 
an MTA is in place prior to sharing of data 


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Highly Sensitive Data 
(Identifiable Health Info per HIPAA )  
Moderately Sensitive Data  
(Limited Data Set and De-identified data per HIPAA) 
Electronic Data Collection & Sharing  
Electronic Data Collection & Sharing 
(e.g. smart phone app, electronic consent using 
tablet etc.) 
MUST consult with ISPRO or Health System Web 
Development Office: 434-243-6702 
 University Side:    
IT-Security@virginia.edu  
 Health System: Web Development Center:   
 
Individual-Use Device  
Individual-Use Device 
Do not save to individual-use device* without 
written approval of your Department AND VP  
or Dean.   
If approval obtained, data must be password  
protected and encrypted. 
 
Do not save an email attachment containing 
HSD to an individual use device  
( e.g. smart phone)  
 
E Mail 
E Mail 
Do not share via email with Outlook Web/ or 
forward email using other email vendors like 
Gmail/ Yahoo  
 
Do not send via email on smart phone unless 
phone is set up by Health System  
 
Email may include name, medical record 
number or Social Security number only if 
sending email to or from a person with * HS in 
their email address. 
NOTE: VPR & IRB staff do not meet this criteria!  
In addition to sharing LDS, may include initials if 
persons sending and receiving email work within the 
UVa HIPAA covered entity.** 
FAX 
FAX 
Verify FAX number before faxing 
Verify FAX number before faxing 
Use Fax Cover Sheet with Confidentiality 
Statement 
Use Fax Cover Sheet with Confidentiality Statement 
Verify receiving fax machine is in a restricted 
access area 
Verify receiving fax machine is in a restricted access 
area 
Verify intended recipient is clearly indicated 
Verify intended recipient is clearly indicated 
Recipient is alerted to the pending transmission 
and is available to pick it up immediately 
Recipient is alerted to the pending transmission and 
is available to pick it up immediately 


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Highly Sensitive Data 
(Identifiable Health Info Per HIPAA 
Moderately Sensitive Data 
(Limited Data Set and Deidentified data per HIPAA 
Electronic Data Collection & Sharing 
Electronic Data Collection & Sharing 
(e.g. smart phone app, electronic consent using 
tablet etc…) 
MUST consult with ISPRO or Health System 
Web Development Office: 434-243-6702 
University Side:    IT-Security@virginia.edu  
Health System: Web Development Center:   
Contract must include required security 
measures. 
 
May be Stored in Qualtrics 
MAY NOT be stored in places like UVaBOX, UVa 
Collab or QuestionPro 
May also NOT be stored I n non-UVA licensed 
cloud providers, such as Dropbox, Google Drive, 
SkyDrive, Survey Monkey etc.. 
May be stored in places like UVaBox, UVaCollab, 
Qualtrics  
May NOT be stored in non-UVa licensed cloud 
providers, such as Dropbox, Google Drive, SkyDrive, 
Survey Monkey, etc. 
LOST OR STOLEN 
LOST OR STOLEN 
Must report in accordance with protocol in 
accordance with the Information Security 
Incident Reporting Policy 
Any data breach will also be reported to the IRB 
of record in the report meets the criteria of an 
Unanticipated  Problem 
Must report in accordance with protocol/ in accordance 
with the Information Security Incident Reporting Policy. 
 
Any data breach will also be reported to the IRB of 
Record if the report meets the criteria of an 
Unanticipated Problem.   
 
*  Individual Use Device – examples include smart phone, CD, flash (thumb) drive, laptop, C drive of your computer,  
**The UVa HIPAA covered entity is composed of the UVa VP Office of Research, the Health System, School of 
Medicine, School of Nursing, Nutrition Services (Morrison’s), the Sheila C. Johnson Center, the Exercise and Sports 
Injury Laboratory and the Exercise Physiology Laboratory.   
 
 
 

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Consent of an Adult to Be in a Research Study 
In this form "you" means a person 18 years of age or older who is being asked to volunteer to participate in 
this study.  
Participant’s Name______________________________Medical Record # ___________________________ 
Principal Investigator: 
Christopher R. McCartney, MD 
University of Virginia 
Center for Research in Reproduction 
PO Box 800391 
Charlottesville, VA 22908    Telephone:  (434) 243-6911 
 
Sponsor: 
University of Virginia, Department of Endocrinology and Metabolism 
 
What is the purpose of this form? 
This form will help you decide if you want to be in the research study. You need to be informed about the 
study, before you can decide if you want to be in it. You do not have to be in the study if you do not want to. 
You should have all your questions answered before you give your permission or consent to be in the study.  
 
Please read this form carefully.  If you want to be in the study, you will need to sign this form. You will get a 
copy of this signed form.   
 
Who is funding this study?  
This study is being funded by the University of Virginia’s Department of Endocrinology and Metabolism. 
 
Why is this research being done? 
This is a study about how the normal menstrual cycle is controlled, and how the menstrual cycle can become 
abnormal in women with polycystic ovary syndrome (PCOS). In order to understand these things, we will study 
several hormones in the blood.  Hormones are substances made in the body that are sent directly out into the 
bloodstream to increase or decrease the function of certain organs, glands, or other hormones.  We will study 
the interactions of the luteinizing hormone (LH), gonadotropin-releasing hormone (GnRH), progesterone, and 
estrogen.  
 
When progesterone and estrogen do not work normally, GnRH pulses remain fast: this occurs in PCOS and can 
contribute to abnormal menstrual cycles, inability to ovulate (release an egg from the ovary), and problems 
with fertility (ability to conceive and have children).   
 
This study is being done to learn how quickly progesterone slows luteinizing hormone pulses. This will be done 
by measuring your luteinizing hormone pulses before and after you take a single dose of progesterone. For 


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scientific reasons, your luteinizing hormone pulses will also be measured before and after you take a single 
dose of an inactive cherry-flavored syrup (placebo).  
 
During this study, you will take one dose of progesterone. This dose of progesterone will produce 
progesterone levels that are lower than the levels your ovaries normally produce during the second half of the 
menstrual cycle.  
 
The progesterone used in this study is identical to the progesterone your body makes, and the progesterone is 
approved by the Food and Drug Administration (FDA). The FDA-approved progesterone is put into a cherry-
flavored syrup by the research pharmacy at UVA: this formulation is not specifically approved by the FDA, 
although the FDA has given us permission to do this.  
 
You will also take estrogen (i.e., estrogen patches) for a total of 8 days. The doses of estrogen will produce 
estrogen levels that are similar to the levels your ovaries normally produce near the middle part of the 
menstrual cycle (i.e., around the time of ovulation).  
 
You are being asked to be in this study, because you are a healthy woman between the ages of 18 and 35, 
with normal menstrual cycles or because you are a woman with PCOS. 
 
NOTE: All procedures noted in the consent are being done for research purposes only. 
 
Up to 90 people will be in this study at UVA.  
 
How long will this study take? 
Most women will need to come to the Clinical Research Unit (CRU) or alternate UVA clinic for 5 visits over 
approximately 3 or 4 months.  The overnight visits may be done at a hotel. 
 
The first visit is a consent and screening visit and will take approximately two hours. Two visits are for single 
blood draws, and these visits will take approximately 15 minutes each. Two visits are overnight admissions at 
the Clinical Research Unit (CRU), alternate UVA hospital unit, or hotel lasting approximately 26 hours each.  
 
NOTE:  If your lab results are abnormal, we will ask you to come to the CRU to repeat this test.  Therefore, the 
total number of visits may be greater than 5.  Sometimes overnight admissions need to be delayed due to 
scheduling conflicts, menstrual cycle irregularities, or if your blood counts are low.  Thus, the overall time for 
study completion can be greater than 4 months.   
 
 
 


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What will happen if you are in the study? 
 
Visit 1: SCREENING (will take approximately 2 hours to complete): 
 
If you agree to participate, you will sign this consent form before any study related procedures take place.  
Before you can start in the study, there will be a screening period.  You will have tests and procedures during 
this time to make sure you are eligible and it is safe for you to participate.  These include the following:  
 
• A study doctor will record a family and personal medical history 
• You will have a physical exam including a check of your vital signs (blood pressure, heart rate, 
height, weight, waist and hip circumference) 
• Blood (about 3 teaspoons) will be drawn for screening laboratory tests.  You should arrive in a 
fasting state.  If you decide to participate in the study but you have eaten within the previous 8 
hours, you will need to return to have the blood work completed.  When you return you should not 
eat or drink anything except water for 8 hours prior to having your blood drawn.  
• We will measure various types of hormones in your blood (including testosterone and estrogen), 
check your liver and kidney function, blood counts, sugar, insulin, chemistries, and perform a 
pregnancy test.  
• Body Composition Measurements (fat and muscle): 
 Your body fat and muscle will be measured by a device called a BodPod. 
 This requires that you sit down in a fiberglass shell chamber that looks something like a giant 
egg with a window.  
 You will wear a bathing suit provided by the CRU while inside the Bod Pod to increase the 
accuracy of body fat measurement. 
 We will ask you to sit quietly in the BodPod chamber for two separate 1-minute 
measurements. You will simply sit still in the chamber and breathe normally. It is possible that 
we would ask you to do an additional measurement if the results don't match closely 
enough. Then we will ask you to put nose clips on your nose and breathe into a tube while we 
take one final measurement.   
 The entire BodPod procedure takes approximately 15 minutes. 
 
• If you have a low red blood cell count (i.e., low hematocrit and hemoglobin), you have the option to 
take iron supplements for 1-2 months. After the iron treatment, we will recheck your hematocrit and 
hemoglobin prior to study continuation. You will not be allowed to continue with the study if your 
hematocrit and hemoglobin are low after two months of iron treatment.  
 
If the screening tests show that you are eligible to participate in the study, we will work with you to schedule 
your first overnight admission.  
 


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STUDY TREATMENT  
 
VISIT 2: Outpatient visit before first overnight admission (lasting about 15 minutes) 
Clinical Research Unit (CRU) or clinic at the University of Virginia Hospital.  
 
• Four to 5 days before your first overnight admission, you will have a single blood sample (less than 1 
teaspoon) drawn in the CRU or clinic to measure a progesterone level and a pregnancy test. 
• If it has been over 25 days since your most recent blood counts, we will also check blood counts at 
this time.  
• 
If it has been about 3 months since your most recent metabolic tests (i.e., tests that help ensure 
good general health), we will repeat these tests at this time. 
• At this visit, you will obtain estrogen patches, which you will begin to use 3 days before your first 
overnight admission. 
 
*** Estrogen use before the first overnight admission 
• If you are a woman with regular menstrual cycles, you will begin to use estrogen patches on cycle 
day 4-8 (with cycle day 1 being the very first day of menstrual bleeding).  If you are a woman with 
PCOS, you will begin to use estrogen patches no earlier than cycle day 4. 
• You will use 2 estrogen patches at a time, and these patches are applied to the skin of the abdomen.  
• The estrogen patches will produce blood estrogen levels that are normally produced by the body 
during parts of the menstrual cycle. The patches will be changed after 2 days; you will use the 
patches for a total of 4 days.  
 
VISIT 3: First Inpatient Admission 
 
• After being on the estrogen patches for exactly 3 days, you will be admitted to the CRU, hospital 
unit, or hotel for tests that will last approximately 26 hours. (Notably, the estrogen patches will be 
continued throughout this overnight study). You will be asked to report to the CRU, hospital unit or 
hotel by 6 p.m.  
• You will be able to eat a normal diet (three meals per day and snacks) during the overnight 
admission, but we will ask that you eat only what is provided to you during the admission. 
• An intravenous (IV) catheter will be placed into a vein in your arm.  An IV catheter is a small flexible 
tube that is inserted into a vein guided by a needle.  Once the catheter is in place, the needle is 
removed and replaced by a cap that allows blood to be drawn.   
• Blood may be collected for a pregnancy test and laboratory testing. Specifically, a pregnancy test will 
be done only if it was not obtained 4-6 days before your overnight admission; blood counts will be 
checked if they have not been checked in the previous month; and metabolic tests will be checked if 
they have not been checked in the previous 3 months.  


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• Starting at 8 p.m., we will draw a blood sample every 10 minutes, and this will continue for 24 hours 
(that is, until 8 p.m. the following day).  
• You will need to stay awake during typical waking hours (7 a.m. to 10 p.m.).  
• You will be able to sleep from 10 p.m. to 7 a.m.  
• At night, we will monitor your sleep.  
• During your overnight admission, you will wear an actigraph. The actigraph looks like a watch, and it 
is worn on your wrist. The actigraph will help us know when you are awake and when you are asleep. 
• In some cases, we will only use the actigraph (above) to monitor your sleep. However, in some cases, 
we may monitor your sleep in more detail (described below). 
o Around 8 p.m. a sleep technician will place several small button-sized sensors on your head. 
These sensors will tell us if you are awake or asleep. 
o You can go to the bathroom whenever you wish during this time. The sensors will remain 
attached to you, but the sensors will be disconnected from the recorders when you go to 
the restroom.  
• Approximately 205 milliliters (or about 14 tablespoons) will be collected during a single inpatient 
admission.  
• At 6 a.m., you will receive one dose by mouth of either progesterone syrup or “placebo” syrup. The 
placebo syrup is exactly like the progesterone syrup except that it does not contain any 
progesterone.  
o You will be randomly assigned (like the flip of a coin) to receive either progesterone or placebo 
at 6 a.m. Neither you nor your doctor can choose which treatment you are assigned for the first 
admission. Neither you nor your doctor will know which study treatment you will get during the 
first admission until the study is done. But if your doctor needs to know, the people doing this 
study can find out. 
o The progesterone syrup will briefly produce blood progesterone levels that are normally 
produced by the body during parts of the menstrual cycle.  
 
• Blood collection (every 10 minutes) will continue until 8 p.m. The inpatient admission ends at 8 p.m., 
and at this time the estrogen patches will be removed.  
• You will be asked to begin iron tablets to help your body rebuild blood cells. 
 
VISIT 4: Outpatient visit before second overnight admission (lasting about 15 minutes) 
Clinical Research Unit (CRU) or clinic at the University of Virginia Hospital.  
 
• 
Four to 5 days before your second overnight admission, you will have a single blood sample (less 
than 1 teaspoon) drawn to measure a progesterone level and a pregnancy test. 
• 
If it has been over 25 days since your most recent blood counts, we will check blood counts at this 
time.  


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• 
If it has been about 3 months since your most recent metabolic tests (i.e., tests that will help ensure 
good general health), we will repeat these tests at this time. 
• 
At this visit, you will obtain estrogen patches, which you will begin to use 3 days before your second 
admission. 
 
*** Estrogen use before the second overnight admission 
• 
If you are a woman with regular menstrual cycles, you again will begin to use   
 estrogen patches on cycle day 4-8 (with cycle day 1 being the very first day of     
 menstrual bleeding). If you are a woman with PCOS, you will again begin to use estrogen patches 
no earlier than cycle day 4. 
• 
You will use 2 estrogen patches at a time, and these patches are applied to the skin of  
 
the abdomen.  
• 
The estrogen patches will produce blood estrogen levels that are normally produced  
 by the body during parts of the menstrual cycle. The patches will be changed after 2     
 days; you will use the patches for a total of 4 days.   
 
VISIT 5: Second Inpatient Admission 
• 
After being on the estrogen patches for exactly 3 days, you will be admitted to the CRU, hospital 
unit, or hotel for tests that are nearly identical to those of the first study. The only difference is that 
you will receive placebo syrup at 6 a.m. if you had received progesterone syrup during the first 
admission, and you will receive progesterone syrup at 6 a.m. if you had received placebo syrup 
during the first admission.  
• 
The second admission ends at 8 p.m. The estrogen patches will be removed, and you will be asked 
to continue iron tablets for an additional 30 days.   
• 
Your participation in the study is complete at the end of this inpatient admission. 
 
NOTE: For scientific reasons, inpatient admissions should occur when progesterone levels are low, and 
progesterone levels are low during what is called the follicular phase of the cycle. If you have irregular periods, 
it can be difficult to know for sure that you are in the follicular phase of your menstrual cycle at the time of a 
scheduled admission. This is why we check progesterone blood levels shortly before your scheduled admission 
(to make sure the progesterone level is low enough to do the admission). However, in women with irregular 
periods, progesterone levels may rarely increase between the time that progesterone level is checked and 
when the inpatient admission actually occurs. Thus, women with irregular periods may rarely be studied when 
progesterone levels are too high. We would not know that this happened until blood samples from the 
inpatient admission are analyzed, which usually occurs within 1-2 months of the final inpatient admission. If it 
is found that your progesterone level was too high during an inpatient admission, we may ask you to consider 
repeating this overnight admission (along with the outpatient blood draw 1-2 days before the admission) 
approximately 8-12 weeks after your second overnight admission (the exact timing would depend on your 
menstrual cycle). In this situation, you would not be obligated to repeat the study admission, and you would 


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still receive $300 for completing the study (as outlined above). However, if you are asked to repeat one of the 
overnight study admissions, and you do so, you would be compensated an extra $100 for this extra study 
admission.   
 
STUDY TIME CAPSULE: 
 
BEFORE FIRST OVERNIGHT ADMISSION: 
 4-6 days before first overnight admission: single blood sample drawn at the CRU or clinic. 
 3 days before first overnight admission: begin estrogen patches. 
 
FIRST OVERNIGHT ADMISSION (on menstrual cycle day 7-11 for women with regular cycles; no earlier than 
cycle day 7 for women with PCOS): 
 Admit to CRU, hospital unit, or hotel (at 6 p.m.) for 26 hour study. At end of overnight study, estrogen 
patches are discontinued, but iron is started.  
 
 
BEFORE SECOND OVERNIGHT ADMISSION: 
 4-6 days before second overnight admission: single blood sample drawn at the CRU or clinic. 
 3 days before second overnight admission: begin estrogen patches. 
 
SECOND OVERNIGHT ADMISSION (on menstrual cycle day 7-11 for women with regular cycles; no earlier than 
cycle day 7 for women with PCOS): 
Admit to CRU, hospital unit, or hotel (at 6 p.m.) for 26 hour study. At end of overnight study, estrogen patches 
are discontinued, but iron is continued for 30 days. 
 
END OF STUDY: 
At the conclusion of admission #2, your participation in the study is complete.   
 
What are your responsibilities in the study? 
  
You have certain responsibilities to help ensure your safety. These responsibilities are listed below: 
• You must come to each study visit. 
• You must be completely truthful about your health history. 
• Follow all instructions given. 
• You should tell the study doctor or study staff about any changes in your health or the way you feel. 
• Ensure that the study drug is taken as instructed, keep the study drug in a safe place away from other 
children, return any unused study drug at each visit, and report any lost or missed tablets. 
• Ensure that the study drug is taken only by you, the person for whom it has been prescribed. 
• Answer all of the study-related questions completely. 


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• Inform the study doctor or study staff as soon as possible if you have to take any new medications, 
including anything prescribed by a doctor or those that you can buy without a prescription (over-the-
counter), including herbal supplements and vitamins.  The study doctor will let you know if you can 
take these medications. 
 
Study Schedule 
 
 
Screening 
Visit 
(Outpatient 
blood 
draw) 
Study 
medication 
Overnight 
Admit #1  
outpatient 
blood 
draw 
Study 
Medication 
Overnight  
Admit #2 
Study Week 
 
0 
4-6 days 
before 
overnight 
admission 1 
3 days 
before first 
overnight 
admission 
Menstrual 
day 7-11 if 
regularly 
cycling or 
no earlier 
than day 7 
for 
women 
with PCOS 
4-6 days 
before 
overnight 
admission 
2 
3 days 
before first 
overnight 
admission 
Menstrual 
day 7-11 if 
regularly 
cycling or 
no earlier 
than day 7 
for 
women 
with PCOS 
Informed 
Consent 
 
x 
 
 
 
 
 
 
Review study 
eligibility 
x 
x 
 
x 
x 
 
x 
Medical 
History 
x 
 
 
x (brief) 
 
 
x (brief) 
Vital signs 
x 
 
 
x 
 
 
x 
Physical Exam 
x 
 
 
x (brief) 
 
 
x (brief) 
Blood draw 
(for laboratory 
testing) 
x 
x 
 
x 
x 
 
x 
Estrogen 
&Progesterone 
Dispensed 
 
x 
 
x 
x 
 
x 
 
Specimens 
Blood testing  
The total amount of blood we will take will be 29 tablespoons during the course of the entire study.  The blood 
we take will be tested to measure the amount of red blood cells, how well your kidneys and liver work, and a 
variety of hormone levels.  Approximately 29 tablespoons of blood will be drawn during the course of the 
entire study. When these tests are done any blood left over will be thrown away. It will not be stored for any 
future testing. 


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If you want to know about the results before the study is done: 
During the study you are having an investigational procedures done.  The purpose of the procedures is NOT to 
diagnose any disease or abnormality you may have. Because the procedures are investigational there is no 
way for the study leader to understand if the results are “normal” or “abnormal”.    However, if any test 
results are concerning, your study leader will let you know. 
 
In addition, as the research moves forward, your study leader will keep you informed of any new findings 
about the research itself that may be important for your health or may help you decide if you want to 
continue in the study.  The final results of the research will not be known until all the information from 
everyone is combined and reviewed.   At that time you can ask for more information about the study results.  
 
When these tests are done any leftover sample will be thrown away.  It will not be stored for any future 
testing.   
 
What are the risks of being in this study?  
Risks and side effects related to the study procedures and drugs (estrogen, progesterone, iron) include: 
 
Likely 
• Dark bowel movements with iron supplements (temporary and not serious)   
 
 Less Likely   
• The estrogen skin patch can cause local skin irritation. This would be temporary and not 
serious. Mild skin irritation is expected to occur in one out of ten people using the estrogen 
patches. We reduce the possibility of this by changing the patch every 2 days to a new location 
on the abdomen.  
• You may experience mild nausea, swelling or breast tenderness, headache, dizziness, and 
changes in bleeding patterns. These symptoms are usually minor and will disappear after 
stopping the estrogen skin patch. One or more of these symptoms are expected to occur in 
fewer than one out of ten people using the estrogen patches for four days. 
• Withdrawal of the estrogen treatment does not usually produce symptoms, but you may have 
mild hot flashes. This is expected to occur in fewer than one out of ten people using the 
estrogen patches for four days. 
• When taking progesterone, you may experience stomach pain and bloating, skin rash, acne, 
itching, unusual vaginal bleeding or discharge, and muscle or joint pain (these effects would be 
temporary and not serious). However, these symptoms are very unlikely to occur since you will 
take only one dose of progesterone. 


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• Longer-term use of progesterone has been associated with depression, irritability, and 
emotional changes. These symptoms are not expected since only one dose of progesterone is 
given. 
• You may feel tired, particularly when exercising, because of mildly low red blood cell count 
related to blood withdrawal (this would be temporary and not serious). 
• Iron supplements can cause stomach upset or constipation (these effects would be temporary 
and not serious). You should take your iron tablets with food and a full glass of water. You 
should also have 8 glasses of water a day and plenty of whole grains, fruits and vegetables for 
fiber to help prevent these side effects. 
 
Rare but serious 
• There are no long-term risks associated with the doses of estrogen and progesterone given 
during the study. The levels of these hormones in the blood will be similar to those that occur 
during normal menstrual cycles.   
• Higher doses of estrogens can produce or increase hypertension in some women. Long term 
(over months to years) administration of estrogen has been reported to be associated with the 
formation of blood clots in the deep veins of the body, similar to the risk of taking birth control 
pills. 
 
Risks of Sharing the Drug 
Do not share the study drug with anyone. It is prescribed only for you and could hurt someone else. Keep it 
out of reach of children and people not able to read or understand the label. 
 
Blood Donation 
If you participate in this study it may affect your ability to donate blood.  This study involves a drug that is not 
approved by the FDA.  The American Red Cross guidelines state that, if you take a drug that is not approved by 
the FDA, you will not be able to donate blood for one year after you take your last dose of study drug. If you 
have any questions call the organization where you donate blood and talk to one of their nurses. 
 
Risks of having your blood drawn: 
Having blood drawn may cause: 
 pain (common), 
 a bruise (sometimes), 
 fainting or passing out (not very often), and  
 infection (rare). 
 
If the people doing the study are exposed to your blood or body fluids in a way that could give them a disease, 
your blood may be tested. The tests might check for: 
 hepatitis,  


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 HIV (Human Immunodeficiency Virus), or  
 other infections.   
 
You and the person exposed would be told the test results. However, your name would be kept private. If your 
test is positive for hepatitis or HIV or any other infection that may affect your clinical care, we will tell you the 
results and help you understand what the results mean for you.  
 
Risks of taking blood from an IV catheter: 
Risk of Repeated Sticks 
Sometimes the catheter stops working.  In order to get the blood we need, we may have to stick you again 
with another needle. 
 
Risk of Heparin Lock Flush: Heparin works by preventing blood clots from forming in IV catheters when they 
are not in use. Allergic reactions and side effects are rare.  You should not use heparin lock flushes if you are 
allergic to heparin or pork products.  Symptoms of allergic reaction may include, rash, itching or swelling at the 
IV catheter site severe dizziness or trouble breathing.  Side effects though very unlikely may include, unusual 
bleeding or bruising and mild pain at the I.V. site. 
 
Risk of Saline Lock Flush:  Saline works by preventing blood clots from forming in IV catheters when they are 
not in use. Saline is a salt solution.  There are no known risks to saline lock flush other than mild pain at the 
injection site.   
 
A caution about giving too much blood: 
Because of the amount of blood being taken, you should not give blood for other reasons for 3 months. For 
example, avoid giving blood at a blood bank or in another research study. 
 
Risks for women: 
Subjects are not expected to have any decrease in fertility as a result of study medications. Therefore, sexually 
active subjects may get pregnant during this protocol.  If you become pregnant, the study and all study 
medications will be discontinued.  
 
If you are pregnant now, or get pregnant during the study, please tell us. Although the drugs and procedures 
in this study would not be expected to have an adverse effect on a pregnancy or your unborn baby, we cannot 
guarantee this. Also, you should be sure you do not get pregnant for 4 weeks after the study. Use an effective 
method of birth control (that does not involve hormones) during this time. Examples of birth control you may 
use include: 
• Condoms 
• Diaphragm 
• Jellies or foam 
• Rhythm 
• Withdrawal 
• Cervical cap 


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• Sponge 
• Abstinence 
• Copper IUD (intrauterine device) 
 
 
Ask your doctor for more details about the proper birth control method for you. If you become pregnant 
during this study, you must tell your doctor right away. Your doctor will discuss your treatment and the effect 
on the pregnancy. 
 
We will be monitoring for pregnancy throughout the course of the study, and it is important that you avoid 
getting pregnant until the study is completed. If you should become pregnant in spite of taking precautions, 
please immediately contact the investigator whose phone number is listed on this form and he will provide 
you with information and/or resources for your consideration. 
 
Other unexpected risks: 
You may have side effects that we do not expect or know to watch for now.  Call the study leader if you have 
any symptoms or problems. 
 
Could you be helped by being in this study? 
You will not benefit from being in this study.  However the information researchers get from this study may 
help others in the future.  
 
What are your other choices if you do not join this study? 
The only other choice is not to be in this study. 
If you are an employee of UVa your job will not be affected if you decide not to participate in this study.  
If you are a student at UVa, your grades will not be affected if you decide not to participate in this study.   
 
Will you be paid for being in this study? 
You will receive up to $300 for participating in and completing this study. You will receive $100 for each 
completed inpatient admission, and an additional $100 incentive for completing all the admissions and 
outpatient visits in the study. You should expect to receive your payment approximately 2-4 weeks after the 
completion of the study.  If you are asked by the study team to repeat a study admission after you complete 
the main part of the study, you will be compensated an extra $100.   
 
If you do not finish the study, you will be paid $ 100 for completing the first admission.  
 
You may be reimbursed for some of your travel expenses. Specifically, if you must drive 50 miles or more (one-
way trip) to get to UVa, you will be eligible for travel reimbursement at $25 per trip for up to three trips (total 
travel reimbursement for the entire study cannot exceed $75). 
If you are driving to Charlottesville for other reasons as well (e.g., for work), you will not be reimbursed. You 
will also not be reimbursed for the cost of lodging. 


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If you owe money to the University of Virginia or the University of Virginia Medical Center, the money to be 
paid to you in this study can be withheld to pay what you owe.   And if a court has issued a judgment against 
you, the money may also be withheld to pay the judgment creditor for such things as taxes, fines, or child 
support that you owe.  
 
By agreeing to be in this study, you are donating your blood samples for research, and giving up any property 
rights you may have in them.  The results of this research using your donated materials may have commercial 
value.  However, you will not receive any payments.   
 
Will being in this study cost you any money? 
 
The following procedures/tests, which are being done for research purposes, will be provided at no cost to you or 
your health insurance: lab tests, Bod Pod, all study medication (estrogen, progesterone, iron), physician visits. 
 
You and/or your insurance company must pay for any tests or care given beyond what is required in this study.  
In addition, you and/or your health insurance may also have to pay for other drugs or treatments that are 
given to help you control any side effects.  You will have to pay for any costs not covered by your health plan.  
You may be responsible for any co-payments or deductibles.  You may wish to ask your insurance company for an 
estimate of what these costs might be or if pre-approval is required.   
 
Your travel and parking costs will also be reimbursed.  See the “Will you be paid for being in this study?” section of 
this form for more information.   
 
What if you are hurt in this study? 
You do not give up any legal rights, such as seeking compensation for injury, by signing this form.  If you feel 
you have been injured as a result of this study you may contact the Principal Investigator or the IRB (phone 
numbers are located near the end of this form).  If you are hurt as a result of being in this study, there are no 
plans to pay you for medical expenses, lost wages, disability, or discomfort. The charges for any medical 
treatment you receive will be billed to your insurance. You will be responsible for any amount your insurance 
does not cover.    
 
What happens if you leave the study early? 
You can change your mind about being in the study any time. You can agree to be in the study now and 
change your mind later. If you decide to stop, please tell us right away. You do not have to be in this study to 
get services you can normally get at the University of Virginia.  
 
Even if you do not change your mind, the study leader can take you out of the study. Some of the reasons for 
doing so may include  


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a) Your study physician is concerned about your health 
b) The side effects of the investigational procedures are too dangerous for you 
c) You do not follow your doctor’s instructions 
d) The study sponsor closes the study for safety, administrative or other reasons 
 
How will your personal information be shared? 
The UVa researchers are asking for your permission to gather, use and share information about you for this 
study.  If you decide not to give your permission, you cannot be in this study, but you can continue to receive 
regular medical care at UVA.  
 
If you sign this form, we may collect any or all of the following information about you: 
o Personal information such as name, address and  date of birth  
o Social Security number ONLY IF you are being paid to be in this study 
o Your UVA medical records and test results from before and during the study from any of your doctors or 
health care providers (accessing these records is not usually required) 
o NOTE: If we decide that medical records from outside UVA are needed, we will ask your specific 
permission at that time.  
 
Who will see your private information?   
o The researchers to make sure they can conduct the study the right way,  observe the effects of the study 
and understand its results   
o People or groups that oversee the study to make sure it is done correctly   
o People who pay for this study 
o Tax reporting offices (if you are paid for being in the study) 
o People who evaluate study results, which can include government agencies that provide oversight such as 
the Food and Drug Administration (FDA) if the study is regulated by the FDA.  
o If you tell us that someone is hurting you, or that you might hurt yourself or someone else, the law may 
require us to let people in authority know so they can protect you and others.   
 
Some of the people outside of UVa who will see your information may not have to follow the same privacy 
laws that we follow. We ask them to protect your privacy. However, they may release your information to 
others, and it may no longer be protected by those laws. 
 
The information collected from you might be published in a medical journal.  This would be done in a way that 
protects your privacy.  No one will be able to find out from the article that you were in the study. 
 
A description of this clinical trial will be available on http:// www.ClinicalTrials.gov, as required by U.S. Law. 
This Web site will not include information that can identify you. At most, the Web site will include a summary 
of the results. You can search this Web site at any time. 


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What if you sign the form but then decide you don't want your private information shared?  
You can change your mind at any time.  Your permission does not end unless you cancel it.  To cancel it, please 
send a letter to the researchers listed on this form.  Then you will no longer be in the study.  The researchers 
will still use information about you that was collected before you ended your participation. Uva researchers 
will do everything possible to protect your privacy.  
 
A copy of this consent form will be put in your medical record. (This is not the same as the record of this 
research study.) This means that everyone who is allowed to see your medical records will be able to find out 
that you are in this study. This is done so your regular doctors will know what you receive as part of this study.   
If you have other health problems during the study, they will be able to treat you properly. 
 
Please contact the researchers listed below to: 
• Obtain more information about the study 
• Ask a question about the study procedures or treatments 
• Report an illness, injury, or other problem (you may also need to tell your regular doctors) 
• Leave the study before it is finished 
• Express a concern about the study 
 
      Principal Investigator:   
Christopher McCartney, MD 
       
 
 
 
Department of Medicine, School of Medicine 
PO Box 800391 
University of Virginia Health System 
Charlottesville, VA 22908   
Telephone:  (434) 243-6911 
What if you have a concern about this study?  
You may also report a concern about this study or ask questions about your rights as a research subject by 
contacting the Institutional Review Board listed below. 
 
 
University of Virginia Institutional Review Board for Health Sciences Research 
PO Box 800483 
Charlottesville, Virginia 22908 
Telephone: 434-924-9634 
 
When you call or write about a concern, please give as much information as you can. Include the name of the 
study leader, the IRB-HSR Number (at the top of this form), and details about the problem.  This will help 
officials look into your concern. When reporting a concern, you do not have to give your name. 


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Signatures 
What does your signature mean? 
Before you sign this form, please ask questions about any part of this study that is not clear to you.  Your 
signature below means that you have received this information and all your questions have been answered.  If 
you sign the form it means that you agree to join the study.  You will receive a copy of this signed document.   
 
Consent From Adult 
 
______________________ 
PARTICIPANT 
(SIGNATURE) 
 ________________________ 
PARTICIPANT 
(PRINT) 
 _______ 
DATE 
 
 
To be completed by participant if 18 years of age or older.  
 
Person Obtaining Consent 
By signing below you confirm that you have fully explained this study to the potential subject, allowed them 
time to read the consent or have the consent read to them, and have answered all their questions.  
 
_______________________________ 
PERSON OBTAINING CONSENT 
(SIGNATURE) 
 
_____________________________ 
PERSON OBTAINING 
CONSENT 
(PRINT) 
 
________ 
DATE 
 
Consent from Impartial Witness 
If this consent form is read to the subject because the subject is blind or illiterate, an impartial witness not 
affiliated with the research or study doctor must be present for the consenting process and sign the 
following statement.  The subject may place an X on the Participant Signature line above.  
 
I agree the information in this informed consent form was presented orally in my presence to the identified 
individual(s) who has had the opportunity to ask any questions he/she had about the study.   I also agree that 
the identified individual(s) freely gave their informed consent to participate in this trial.  
 
Please indicate with check box the identified individual(s): 
 Subject  
 
_______________________________ 
IMPARTIAL WITNESS 
(SIGNATURE) 
 _____________________________ 
IMPARTIAL WITNESS 
(PRINT) 
 ________ 
DATE