Clinical trial NCT01889199
Conditions: Polycystic Ovary Syndrome (PCOS)
Keywords: polycystic ovary syndrome hirsutism anovulation oligomenorrhea amenorrhea hyperandrogenism antiandrogen effect
Sponsor: University of California, Los Angeles
Start date: 2013-04-01; Completion date: 2023-07-06
Enrollment: 23 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this research study is to collect specimen samples and study medical information from women with Polycystic Ovary Syndrome (PCOS) and women without PCOS. The goal is to learn more about the changes that take place in the body that result in PCOS.

We anticipate that 32 women will take part in this study (16 without PCOS and 16 with PCOS). All patients will undergo a physical exam, blood tests, and ultrasound of their ovaries. If they meet the criteria for this study, they will then undergo additional blood tests, removal of a small amount of subcutaneous abdominal fat, measurement of regional body fat (i.e., DXA scan) and a modified frequently-sampled intravenous glucose tolerance test (FSIGTT). The women without PCOS will complete the study at this point.

The women with PCOS will be randomized to receive the drug flutamide 125 mg/day or placebo. They will take the drug every day for six 28-day cycles. They will be asked to collect and store a urine sample once a week. They will also be asked to complete a pill diary and menstrual diary. Once a month while they are taking the flutamide/placebo, they will return to the clinic and bring their frozen urine samples. At that time they will undergo a physical exam, toxicity assessment, and blood draw.

Quality of Life assessments will be done at the beginning of the study for all participants. Women with PCOS who are taking the flutamide or placebo will be asked to repeat the Quality of Life assessments during the study and at the end of the study.

After the six 28-day cycles are completed they will then undergo additional blood tests, removal of a small amount of subcutaneous abdominal fat, measurement of regional body fat (i.e., DXA scan) and a modified frequently-sampled intravenous glucose tolerance test (FSIGTT).

Six months following the completion of all study protocol procedures, participants who received flutamide/placebo will be contacted by phone to check on the status of their health. They will be asked if they have experienced any health problems or have become pregnant since they completed the study procedures.

Detailed description:
Aim 1. Examine mechanisms of subcutaneous abdominal adipose (fat) development in normal-weight PCOS women vs. BMI- and age-matched normal (control) women.

Subjects and clinical assessment: We will recruit 16 lean (18.5-25 kg/M2) PCOS subjects and 16 age- and BMI-matched controls. Subjects will complete a standardized questionnaire emphasizing menstrual dating, abnormal hair growth and acne. The questionnaire also will annotate age, smoking status, medications, surgical history and family histories of excess hair growth in female relatives and of diabetes in parents or siblings for exclusion criteria and for inclusion of some basic traits as covariates. Subjects also will undergo a physical examination; hirsutism will be scored by the modified Ferriman-Gallwey (mFG) method. Transvaginal sonography (TVUS) will be performed to determine the presence or absence of polycystic ovaries. A screening blood sample will be obtained for determinations of steroid hormones, SHBG, TSH, and prolactin.

Women of any ethnicity between the ages of 18 and 35 years will be recruited. PCOS patients will be diagnosed by 1990 NIH criteria. Controls will have regular menstrual cycles at 21 to 35 day intervals, a luteal phase progesterone (P4) level \> 3 ng/mL, and no evidence of hirsutism, acne, alopecia, polycystic ovaries or endocrine dysfunction. Exclusion criteria are: present/past history (\<1 year) of smoking, cancer, alcohol abuse, drug addiction, severe depression, or post traumatic stress; diabetes; uncontrolled hypertension (≥ 165/100); clinically significant hepatic or renal disease, or other major medical illness; signs or symptoms of infection; recent (within 30 days) use of an experimental device; recent (within 3 months) use of androgens, anabolic steroids or non-steroidal anti-inflammatory drugs; recent (within 3 months) use of hormonal agents (including birth control pills or insulin sensitizers); use of the drug warfarin.

Studies will be conducted in the follicular phase in controls and during amenorrhea in PCOS women. All subjects will undergo a modified frequently-sampled intravenous glucose tolerance test (FSIGTT). Glucose in the form of a 50% solution (0.3 g/kg) and regular human insulin (0.03 units/kg) will be injected through an intravenous line at 0 and 20 min, respectively. Blood will be collected at -20, -15, -5, 0, 2, 4, 8, 19, 22, 30, 40, 50, 70, 90, and 180 min for glucose and insulin determinations. Mathematical modeling of serial glucose and insulin determinations will calculate: insulin sensitivity index (SI, i.e. the action of insulin to accelerate glucose uptake and suppress glucose production), glucose effectiveness index (SG, i.e. the combined effect of glucose to enhance glucose uptake and suppress endogenous glucose production at basal insulin levels) and the acute response to glucose (AIRG).

Adipocytes isolation and culture: Approximately 1-2 gms of fat will be obtained from the lower SC abdomen using standard procedures under local anesthesia. Adipocytes (fat cells) and surrounding fat tissue will be isolated to measure adipocyte cell number and diameter, lipid accumulation and function, adiponectin, and stem cell development.

Procedures: All procedures will be performed in normal and PCOS women at the start of study.

i). Venipuncture: Fasting blood will be collected for blood count, chemistry panel, LH, FSH, total/free T, DHT, A4, DHEAS, E1, E2, anti-mullerian hormone (AMH), SHBG, adiponectin, leptin, IL-6, lipid profile and free fatty acids (FFAs).

ii ). Body composition: Body composition will be assessed by BMI, waist-to-hip circumference and DEXA scanning. Girths will be measured at the waist (narrowest section of the torso between ribs and umbilicus) and hips (largest protrusion of the hip region, above the gluteal fold). For total body fat and regional fat distribution, whole body scans will be performed, utilizing DEXA imaging.

iii). Body fat distribution: Total body DEXA will measure abdominal fat (i.e., the area between the dome of the diaphragm and the top of the hip. Total body DEXA images also will determine % body fat; fat-free body mass; total body, abdominal, and leg fat; and abdomen/leg fat mass ratio. The leg region is that area below the top of the hip bone (greater trochanter).

iv). Ovarian testing: Transvaginal ultrasound will be performed in the follicular phase in controls and during amenorrhea in PCOS women. Ovarian volume will be calculated. Antral follicle number, defined as the total follicle number (2-9 mm in diameter) of both ovaries, will be determined by 1 investigator (D.A.D.). Polycystic ovaries will be identified, with one such ovary sufficient to define PCO

Aim 2. Determine the role of androgen in SC abdominal ASC dysfunction and its relation to metabolism in normal-weight PCOS women through androgen. antagonism by clinical use of flutamide vs. placebo.

Modified FSIGTT and Adipogenic studies: The modified FSIGTT and all adipogenic studies performed at study initiation will be repeated at the end of the 6-month flutamide vs. placebo intervention in PCOS women.

Procedures: All procedures performed at study initiation also will be repeated at the end of the six 28-day cycles of flutamide vs. placebo intervention in PCOS women. In addition, monthly liver function studies will be performed to detect possible elevations of serum transaminase levels above the normal range during flutamide vs. placebo therapy.

Menstrual records: Ovulatory frequency will be determined by having subjects keep a daily menstrual record and collect weekly first morning urine samples for possible progesterone and creatinine determinations. Urine samples will be frozen for later analysis to determine evidence of ovulation, as necessary.

Aim 3. Identify epigenetic changes that underlie SC abdominal ASC dysfunction in normal-weight PCOS women vs. BMI- and age-matched controls.

Subcutaneous abdominal adipose stem cells from PCOS and control women will be grown into newly-formed fat cells (adipocytes) in the laboratory. Cells will be studied before and after 6-month treatment with placebo vs flutamide for changes in the cell epigenome (methylation, RNA sequences and histone modification).

Arms: arm 1: Placebo intervention arm 2: Flutamide 125 mg orally daily for six 28-day cycles.
Interventions: intervention 1: Flutamide intervention 2: Placebo
Intervention descriptions: intervention 1: Flutamide 125 mg orally each 28 day cycle for 6 cycles intervention 2: Placebo orally each 28 day cycle for 6 cycles

Protocol documents:
Prot_SAP_000.pdf: 
Revised 3-7-18 
UCLA IRB #12-001780 
Page 1 of 27
Protocol 
March 7, 2018 
Androgen Excess as a Cause for Adipogenic Dysfunction in PCOS Women 
NIH Prime Award No 1U54HDO71836-01A1, Subaward #9009028 UCLA 
NCT01889199 
UCLA IRB #12-001780 
Principal Investigator 
Daniel Dumesic, MD 
Chief, Division of Reproductive Endocrinology and Infertility 
UCLA Department of Obstetrics and Gynecology 
Co-Principal Investigator 
Gregorio Chazenbalk, PhD 
Division of Reproductive Endocrinology and Infertility 
UCLA Department of Obstetrics and Gynecology 
Co-Investigators 
Reza Jarrahy, MD 
UCLA Department of Plastic Surgery 
Daniel Margolis, MD 
UCLA Department of Radiological Sciences 
Michael Albert Thomas, PhD 
UCLA Department of Radiological Sciences 
Collaborating Investigator 
David Abbott, PhD 
Department of Obstetrics and Gynecology 
University of Wisconsin, Madison 


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LAY SUMMARY 
 
The purpose of this research study is to collect specimen samples and study medical 
information from women with Polycystic Ovary Syndrome (PCOS) and women without 
PCOS. The goal is to learn more about the changes that take place in the body that 
result in PCOS. 
 
We anticipate that 70 women will be enrolled  in this study (20 without PCOS and 50 
with PCOS). All patients will undergo a physical exam, blood tests, and transvaginal 
ultrasound of their ovaries. If they meet the criteria for this study, they will then undergo 
additional blood tests, removal of abdominal fat, transvaginal ovarian ultrasound, MRI, 
DXA scan, frequently-sampled intravenous glucose tolerance test (FSIGT), follicle 
stimulating hormone stimulation test, and Quality of Life surveys. The women without 
PCOS will be complete the study at this point.  
 
The women with PCOS will be stratified according to whether they are insulin resistant 
or non insulin resistant based upon the results of their glucose tolerance test. Both 
groups will be randomized to receive the drug flutamide 125 mg/day or placebo. 
Subjects will take the drug/placebo every day for 6 - 28 day cycles and will continue to 
take the drug/placebo until all post treatment assessments are completed. Subjects will 
be asked to collect and store a urine sample once a week during the 6 - 28 day cycles. 
Subjects will also be asked to complete diaries. Once a month while they are taking the 
flutamide/placebo, they will return to the clinic and bring their urine samples. At that time 
they will undergo a physical exam, toxicity assessment, and blood draw. Quality of Life 
surveys will be performed at baseline, midpoint, and end of study for PCOS participants. 
Non-PCOS participants will complete Quality of Life surveys at baseline only. 
 
After the 6 - 28 day cycles are completed the PCOS participants will continue to take 
study drug/placebo until they have completed end of treatment evaluations which 
include physical exam, additional blood tests, removal of abdominal fat, trasvaginal 
ovarian ultrasound, MRI, DXA scan, frequently-sampled intravenous glucose tolerance 
test (FSIGT), and follicle stimulating hormone stimulation test.  
 
Per amendment #11 submitted 11-25-13, subjects who previously underwent an OGTT 
will be asked to undergo an FSIGT. Women enrolled on the PCOS arm may choose to 
decline the FSIGT and will undergo an OGTT post treatment. 
 
Per Amendment #24 submitted 6/10/15, we requested permission to add a Family 
History Questionnaire to this study.  Subjects who have been enrolled in the past as 
well as future participants will be asked to complete the questionnaire.  Active study 
participants will be asked to complete the questionnaire at their next regularly scheduled 
study visit.  Those who have completed all of their study visits will be contacted by 
phone or email to ask if they will complete the questionnaire.  If they agree, it will be 
sent to the participant by US mail with a stamped return envelope or the questionnaire 
will be completed over the phone.  New study participants will be asked to complete the 
questionnaire at their eligibility visit.  If any participant(s) decline, their participation in 


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this study will not be affected nor will their future healthcare at UCLA. 
 
BACKGROUND AND SIGNIFICANCE 
 
Polycystic ovary syndrome (PCOS): PCOS, a common endocrinopathy affecting 6–10% 
of women, manifests by hyperandrogenism, ovulatory dysfunction and polycystic 
ovaries (PCO) in its complete phenotype. Abdominal adiposity occurs frequently in 
PCOS women vs. controls, including some, but not all, nonobese individuals. 
Consequently, the estimated prevalence of MBS in PCOS is 33-47%, about 2-3 times 
higher than that of age-matched controls.  
 
Interplay between adipose function and androgen excess: In PCOS, intrinsic defects 
combine with endocrine factors to impair insulin sensitivity and induce adipocyte insulin 
resistance (IR). Conversely, physiological androgen administration to women induces 
IR. In PCOS women, therefore, androgen excess could decrease numbers of SC 
abdominal adipocytes and reduce capacity of this adipose to safely store fat. Thus, if 
energy intake exceeds this capacity, SC abdominal adipocytes would likely overfill with 
lipid to promote ectopic lipid deposition. We hypothesize that PCOS-related 
hyperandrogenism decreases adipogenic differentiation and increases adipocyte lipid 
content in a constrained SC abdominal adipose, inducing lipotoxicity, IR and ovulatory 
dysfunction. 
 
Therefore, reducing PCOS-related androgen excess could improve SC abdominal 
adipogenic function and ovarian folliculogenesis, reducing use of ovulation-inducing 
agents in PCOS women wishing to conceive, and risks of multiple pregnancy. 
 
Effect of flutamide on PCOS: Administration of flutamide, a nonsteroidal anti-androgen, 
to PCOS women lowers circulating androgen and triglycerides levels. Flutamide also 
restores ovulation in some, but not all, PCOS women. We will systematically compare 
SC abdominal adipogenesis, circulating adipogenic markers and SC abdominal as well 
as visceral (omental plus mesenteric) adipose content of lean PCOS women 
randomized to 6-month low-dose flutamide vs. placebo to determine how differences in 
key variables affect ovarian function and morphology, as well as in vivo E2 
responsiveness to FSH. 
 
We also are able to quantify SC abdominal and visceral adipose content by magnetic 
resonance imaging (MRI), as performed by Dr. Margolis. Finally low-dose flutamide vs, 
placebo administration to lean PCOS women will discover novel molecular and 
biochemical markers that predict efficacy of androgen blockade in restoring adipogenic 
and ovarian function. 
AIMS AND OBJECTIVES 
 
The purpose of this research study is to collect specimen samples and study medical 
information from women with PCOS and women without PCOS. The goal is to learn 
more about the changes that take place in the body that result in PCOS. 


Revised 3-7-18 
UCLA IRB #12-001780 
Page 4 of 27 
 
 
Our Aims are to:  
 
Aim 1: Compare differences in SC abdominal adipose structure-function and regional 
abdominal adipose content in lean PCOS women vs. age- and BMI-matched controls. 
Hypothesis: SC abdominal adipose storage is constrained in lean PCOS women. 
• Analyze adipocyte size, lipid accumulation, function and secretion of adipokines. 
• Analyze same parameters indicated above and signaling pathways in new adipocytes 
originated from isolated adipose stem cells.  
• Use cell culture to examine interactions between adipose stromal-vascular cells and 
adipocytes in the control of adipose development. 
• Correlate key factors with insulin action in vivo; regional and percent body fat; 
circulating lipids, free fatty acids (FFAs), sex steroids, and adipokines; and ovarian 
volume, antral follicle number and serum AMH as well as serum E2 response to 
recombinant human (rh)FSH per antral follicle. 
 
Aim 2. Examine effect of flutamide on SC abdominal adipose structure-function, 
regional abdominal adipose content and ovarian folliculogenesis in lean PCOS women. 
Hypothesis: SC abdominal adipose storage is normalized in lean PCOS women 
receiving flutamide. 
• Examine in vitro effects of sex steroids on adipogenesis. 
• Determine changes in SC abdominal adipogenesis, circulating lipids, FFAs, sex 
steroids, and adipokines. 
• Determine changes in SC abdominal and visceral adipose content, fat free mass as 
well as percent body fat. 
• Determine changes in ovarian morphology and function as well as ovulatory 
frequency, as measured by weekly urinary pregnanediol glucuronide (UPDG). 
• Determine key factors that predict ovulation by serial urinary UPDG measurements. 
RESEARCH DESIGN AND METHODS 
 
Aim 1. Compare differences in SC abdominal adipogenesis of lean PCOS women vs. 
age- and BMI-matched controls  
 
Subjects and clinical assessment: We will recruit subjects with the intention of enrolling 
90 women - 70 lean (18.5-25 kg/M2) PCOS subjects and 20 age- and BMI-matched 
controls with the assumption that there will be dropouts such that 36 women with PCOS 
and 12 controls will complete the study. Subjects will complete a standardized 
questionnaire emphasizing menstrual dating, abnormal hair growth and acne. The 
questionnaire also will annotate age, smoking status, medications, surgical history and 
family histories of excess hair growth in female relatives and of diabetes in parents or 
siblings for exclusion criteria and for inclusion of some basic traits as covariates. 
Subjects also will undergo a physical examination; hirsutism will be scored by the 
modified Ferriman-Gallwey (mFG) method. Transvaginal sonography (TVUS) will be 
performed to determine the presence or absence of polycystic ovaries by Rotterdam 


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criterion. A screening blood sample will be obtained for determinations of steroid 
hormones, TSH, and prolactin; biochemical hyperandrogenism will be defined as an 
elevated serum total or free T > 2 SD above the mean value.  
Non-Hispanic Caucasian women between the ages of 18 and 35 years will be recruited 
to avoid confounding differences as a function of race. PCOS patients will be diagnosed 
by 1990 NIH criteria. Controls will have regular menstrual cycles at 21 to 35 day 
intervals, a luteal phase progesterone (P4) level > 3 ng/mL, and no evidence of 
hirsutism, acne, alopecia, polycystic ovaries or endocrine dysfunction. Exclusion criteria 
are: present/past history of smoking during the past year, cancer, alcohol abuse, drug 
addiction, severe depression, or post traumatic stress; diabetes; uncontrolled 
hypertension (≥ 165/100); clinically significant hepatic or renal disease, or other major 
medical illness; signs or symptoms of infection; recent (within 30 days) use of an 
experimental device; recent (within 6 months) use of androgens, anabolic steroids or 
non-steroidal anti-inflammatory drugs; recent (within 3 months) use of hormonal agents 
(including birth control pills, Plan B, Mirena IUD, or insulin sensitizers); use of the drug 
warfarin; beta blockers; CYP active medications or herbs. 
 
Frequently sampled intravenous glucose tolerance test (FSIGT): All studies will be 
conducted in the follicular phase in controls and during amenorrhea in PCOS women. 
Each subject will be instructed to drink only water during the 12-hour fasting period 
before the FSIGT, and to avoid caffeinated fluid intake. Glucose in the form of a 50% 
solution (0.3 g/kg) and regular human insulin (0.03 units/kg) will be injected through an 
intravenous line at 0 and 20 min, respectively. Blood will be collected at -20, -15, −5, 0, 
2, 4, 8, 19, 22, 30, 40, 50, 70, 90, and 180 min for glucose and insulin determinations. 
Approximately 2-3 tablespoons (28-42 ml) will be drawn for the FSIGT test. 
Adipocytes isolation and culture: Approximately 1.0 gm of fat will be obtained from the 
lower SC abdomen using standard procedures under local anesthesia. Adipocytes and 
the stromal vascular fraction will be isolated to measure adipocyte cell number and 
diameter, lipid accumulation and function, adiponectin, and stem cell development.  
 
Procedures: All procedures will be performed in normal and PCOS women at the start 
of study. 
 
i). Venipuncture: Fasting blood will be collected for blood count, chemistry panel, LH, 
FSH, total/free T, DHT, A4, DHEAS, E1, E2, anti-mullerian hormone (AMH), SHBG, 
adiponectin, IL-6,lipid profile, C-reactive protein, glucagon, leptin, C-peptide, and FFAs.  
Blood samples for all participants will be shipped to Oregon State Health University 
(OHSU) for analysis of AMH, IL-6, adiponectin,  glucagon, leptin, and C-peptide levels.  
The University of Michigan will perform a comprehensive hormone analysis by LC-
MS/MS, including traditional (T, AD, DHEA, DHEAS) and emerging androgen 
biomarkers (11-oxygenated C19 steroids, 11 OHA, 11KA, 11OHT, 11KT).  There will be 
no personal identifiers on the samples that sent to OHSU or University of Michigan.  


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Study numbers will be used. 
 
ii ). Body composition: Body composition will be assessed by BMI, waist-to-hip 
circumference and DXA scanning. Girths will be measured at the waist (narrowest 
section of the torso between ribs and umbilicus) and hips (largest protrusion of the hip 
region, above the gluteal fold). For total body fat and regional fat distribution (central vs. 
appendicular), whole body scans will be performed, utilizing DXA imaging (Hologics 
QDR 1500). A portable BIA will calculate lean body mass changes by computerized 
methods to measure resistance and reactance. 
 
iii). Body fat distribution: Total body DXA will measure abdominal fat (i.e., the area 
between the dome of the diaphragm [cephalad limit] and the top of the greater 
trochanter [caudal limit]). Total body DEXA images also will determine % body fat; fat-
free body mass; total body, abdominal, and leg fat; and abdomen/leg fat mass ratio. The 
leg region is that area below the top of the greater trochanter. 
Multiple axial abdominal and pelvic MRI slices from the diaphragm to the pelvis will 
assess cross-sectional areas of SC abdominal and visceral fat.  
 
iv). Ovarian testing:  
 
a). Ovarian morphology: TVUS using a 4- to 8-mHz vaginal probe will be performed in 
the follicular phase in controls and during amenorrhea in PCOS women. Summed 
ovarian volume will be calculated. Antral follicle number, defined as the total follicle 
number (2-9 mm in diameter) of both ovaries, will be determined by 1 investigator 
(D.A.D.). Polycystic ovaries will be defined by 12 or more follicles in each ovary 
measuring 2-9 mm in diameter, and/or increased ovarian volume (> 10 ml), with one 
such ovary sufficient to define PCO. 
 
b). E2 response to recombinant human (rh)FSH. Blood samples will be drawn through 
an indwelling iv catheter at -90, -60, -30 minutes and time 0 as well as 0.5, 1, 1.5, 2, 3, 
4, 6, 8, 10, 12, 16, 20, and 24 h after 150 U rhFSH injection (112). The E2 response to 
rhFSH will be assessed before and after adjusting for numbers of TVUS-detected 
ovarian antral follicles. 
 
Aim 2. Examine effect of flutamide in lean PCOS women on SC abdominal 
adipogenesis, visceral adipose content and ovarian folliculogenesis. 
 
 
Per amendment #29, we are requesting permission to change the randomization 
strategy since all PCOS subjects enrolled thus far have been non-insulin resistant 


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Page 7 of 27 
 
based upon the results of the Frequently Sampled Intravenous Glucose Tolerance Test.  
Therefore, the need to stratify the PCOS subjects into two groups (i.e. insulin resistant 
versus non-insulin resistant) is unnecessary.  All PCOS subjects recruited will now be 
randomized to study drug versus placebo based upon non-insulin resistant status.  Of 
note, the control subjects are not randomized since they do not receive study drug or 
placebo. 
 
Adipogenic studies: All adipogenic studies performed at study initiation will be repeated 
at the end of the 6 - 28 day cycles of flutamide vs. placebo intervention in PCOS 
women. 
 
Procedures: All procedures performed at study initiation also will be repeated at the end 
of the 6 - 28 day cycles of flutamide vs. placebo intervention in PCOS women. The end 
of treatment fat biopsy will be performed of the opposite side of the lower abdomen than 
where the first biopsy was taken.  In addition, monthly liver function studies will be 
performed to detect possible elevations of serum transaminase levels above the normal 
range during flutamide vs. placebo therapy. 
 
Menstrual records and urinary pregnanediol glucuronide (UPDG): Ovulatory frequency 
will be determined by having subjects keep a daily menstrual record and collect weekly 
first morning urine samples for UPDG and creatinine assay. Urine samples will be 
stored for later analysis.  Urine samples will be analyzed at the University of Wisconsin-
Wisconsin National Primate Research Center for the urinary metabolite of progesterone 
(urinary pregnanediol glucuronide [UDPG]) and creatinine testing. 
 
Six months following the completion of protocol procedures, participants who received 
flutamide/placebo will be contacted by phone to check on the status of their health. 
Subjects will be asked if they have experienced any health problems or have become 
pregnant since they completed the study procedures. 
 
Daily diaries will include self reporting on taking pills, menstrual flow, symptoms, 
concomitant medications, exercise patterns, and diet habits.  
 
Quality of life assessments and ovarian size measurements will be conducted at 
baseline, and at the end of 3 and 6 months of treatment.  The PHQ, Beck's Anxiety, 
Beck's Depression questionnaires will be completed at baseline.  The Beck's 
Depression and Beck's Anxiety will be completed at 3 and 6 month visits.  Scoring of the 
Quality of Life surveys (Beck’s anxiety and Beck’s depression questionnaires) will be at 
the time the subject is present for their study visit.  If any areas of concern are identified, 
they will be addressed with the subject before they leave and the appropriate referrals 


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will be made. 
 
In order to conduct quality control testing on the urine samples, we are requesting 
approval to utilize urine specimens from IRB #11-001454, "A Study to Collect 
Specimens and Medical Information for Use in Research" - PI - Joshua Cohen, MD and 
UCLA IRB #13-000430 "A study to learn more about the optimal conditions for storing 
and shipping urine samples for research purposes" - PI - Daniel Dumesic, MD.    We will 
also utilize blood and tissue samples from participants in IRB #11-001454 in order to 
conduct further laboratory tests including  immunohistological assessments which will 
allow us to integrate adipose/hormonal data to more fully investigate the 
pathophysiology processes of diseases under study.  Specimens may be analyzed in 
Dr. Dumesic's lab at UCLA and/or shipped for analysis to David H. Abbott, Ph.D.; 
Wisconsin National Primate Research Center, 1223 Capitol Court, Madison, WI, 53715.   
Participants will be given the opportunity to sign a minimal risk consent form if they wish 
to communicate by e-mail during their participation in this study. 
 
In December, 2013 an amendment was submitted for this study requesting a change 
from using the OGTT test to an FSIGT test. Subjects in the control arm who have 
already undergone an OGTT test and do not wish to undergo an FSIGT test will not be 
affected and the data from their OGTT test will be used. Subjects in the PCOS arm who 
have undergone an OGTT test at baseline may choose to repeat a baseline FSIGT test 
and have an FSIGT test at the end of study. If they do not wish to have an FSIGT test, 
an OGTT test will be performed at the end of study. 
 
Per amendment #34:  To date, our preliminary data have shown as expected that serum 
levels of Anti-Mullerian Hormone (AMH), as a marker of ovarian follicle number, are 
greater in PCOS than control subjects. However, one PCOS subject has serum AMH 
levels that cannot be detected by the routine AMH assays performed at Oregon Health 
Sciences University (OHSU). Re-analysis of her serum AMH levels at ANSH 
Laboratories, Texas (per IRB approved amendment #33) using antibodies directed 
towards different regions of the AMH protein suggest that this PCOS subject has an 
AMH protein that  is not biologically active. This exciting discovery offers an important 
scientific opportunity to identify the type of AMH abnormality in this PCOS subject, 
particularly because serum AMH measurement as a clinical marker of ovarian follicle 
number may be misleading in some PCOS women. Therefore, ANSH Laboratories and 
the University Medical Center Rotterdam, Netherlands have agreed to conduct tests to 
identify the gene mutation and protein structure/function abnormality of AMH in this 
PCOS subject. These findings will be compared with 5-10 PCOS and 5-10 control 
subjects who are either new subjects, currently participating or have previously 
participated in this study. For the analysis, frozen monocytes, frozen serum, and/or 
fresh whole blood samples are needed.  As part of our current study design, we already 
have frozen monocytes and serum aliquots from all subjects on hand that can be 
analyzed immediately.  However, an additional 20 mL of plasma collected in EDTA 


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plasma tubes for the newly proposed studies are needed. The additional blood will be 
drawn at the initial Frequently-Sampled Intravenous Glucose Tolerance Test (FSIGT) 
visit for new subject and at the convenience of the subjects who sign the addendum 
consent form. All collected specimens analyzed at ANSH Laboratories or University 
Medical Center Rotterdam will be de-identified and ANSH Laboratories will forward the 
specimens to the University Medical Center Rotterdam on our behalf.  Any additional 
specimens remaining after analysis by AHSH Laboratories or University Medical Center 
Rotterdam will be destroyed. 
The findings of these additional tests will be conveyed only to the subject with the 
anomaly since it could impact her future clinical care.  We anticipate that there will be no 
impact from the findings on the PCOS or control subjects who have measurable AMH 
levels.   
Per amendment #42, epigenetic studies (RNA sequencing, DNA Methylation, and 
Assay for Transposase Accessible Chromatin Sequencing) on existing fat cell samples 
will be conducted at UCLA. 
INCLUSION CRITERIA 
Caucasian and Non-Hispanic women between the ages of 18 to 35 years.  
 
Groups will be: 12 lean controls (Aim 1); 36 age- and BMI-matched PCOS women 
randomized to flutamide vs. placebo for 6 months (Aims 1 and 2). 
 
i) Lean patients with PCOS: 36 subjects with PCOS (defined by 1990 NIH criteria [all 
Aims]), BMI 18.5-25 kg/m2. This BMI range is defined as normal and has been chosen 
to examine underlying mechanisms of PCOS-related androgen excess in the genesis of 
adipogenic and ovarian dysfunction, independent of obesity. Excessive course hair on 
upper lip, chin, chest, upper back, lower back, upper abdomen, lower abdomen, arm 
and/or thigh. 
 
ii) Lean control women: 12 healthy subjects, BMI 18.5-25 kg/m2. Controls will have 
regular menstrual cycles, and no evidence of hirsutism, acne, alopecia, polycystic 
ovaries, and/or endocrine dysfunction. This BMI range has been chosen to match that 
of the PCOS group. 
 
Up to 70 lean PCOS patients and 20 lean controls will be recruited, for a total of 90 
study participants over a 5-year interval, accounting for a 20% rate of patient drop-out or 
insufficient adipose procurement. Participants must be fluent in English. 
 
EXCLUSION CRITERIA 
 
Exclusion criteria for study participation are: present or past history of smoking within 
past 1 year, cancer, alcohol abuse within past 5 years, drug addiction within past 5 
years, severe depression within past 5 years, or post traumatic stress disorder within 


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past 5 years; diabetes; uncontrolled hypertension (≥ 165/100); clinically significant 
hepatic or renal disease, or other major medical illness; recent (within 3 months) use of 
androgens, anabolic steroids or hormonal agents (including birth control pills or insulin 
sensitizers), Mirena IUD, or Plan B contraception. These exclusion criteria are chosen 
to avoid effects from medical conditions, environmental factors or exogenous agents. 
Women taking the drug warfarin, beta blockers, CYP active medications, or herbs will 
be excluded.  
 
Since this study involves MRI testing, women with pacemakers, metal implants, or 
claustrophobia will be excluded.  
 
The screener will assess the participants response to establish if depression or drug 
use exclude participation in this study. 
 
If a woman becomes pregnant while participating in this study she will be excluded from 
further participation. 
 
Non-English speaking individuals will be excluded from this study. The eligibility criteria 
includes non-Hispanic Caucasians only so it is assumed that the vast majority of 
participants will be English speaking. Since PCOS phenotype varies by ethnicity, 
eligibility was restricted to only one ethnic group in order to control for ethnic variability. 
 
SUBJECT IDENTIFICATION AND RECRUITMENT 
 
Initial contact may be made at the time the patient visits the clinic for non-research 
related indications. The treating physician, colleague physician, nurse, medical assistant 
or study coordinator will interface with the potential subject to obtain their consent to be 
contacted regarding the study. In addition, IRB approved scripts for contact recruitment, 
responding by e-mail, in person contact or referral contact will be used. 
 
Additionally, patients will be recruited by obtaining a list of possibly eligible patients by 
extraction of electronic medical records as described in the "Review of Medical 
Records" section below. After reviewing their charts, verifying eligibility, and obtaining 
approval from their PCP or GYN provider, patients will be directly contacted by a 
member of the study team using the IRB approved screening script. 
 
Since potential subjects may contact us directly in response to flyers, ads, etc., we will 
respond to all inquiries via phone or email as they prefer. If a potential participant 
contacts us directly by email and wishes more information without phone contact, the 
consent form will be sent to them via email for their consideration. If they are interested 
in the study, they will have the option to respond by phone for further screening. The 
study team will utilize the recruitment script/screening script. The recruitment 
script/screening script will not be sent via email to potential subjects. 
 
Subjects who have already undergone an OGTT test will be contacted at their next 


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study visit or by phone to be given the opportunity to undergo FSIGT testing.  
 
Per amendment #15 we will not include identifiers on the screening script worksheet.  A 
screening code number will be assigned to each interested potential participant.  A 
separate database on a password protected computer in a locked office will include the 
link between the personal identifiers and the code number so that we can contact the 
potential participant.  In order to minimize the amount of time spent by potential 
participants as well as the study staff on potential participants who are not eligible for 
the study, we have added additional screening questions. 
 
Flyers will be available in 100, 200, and 300 Med Plaza, West Medical, UCLA Clinics, 
Community Clinics, UCLA and other college campuses, off campus student groups, 
offices of community physicians, student health centers, and community locations. 
Information regarding study design and eligibility also will be available on the UCLA 
OB/GYN Departmental website and Craigslist as well as other internet postings. 
Newspaper ads that contain information from the IRB approved flyers will be used. 
Announcements of the study and flyers will be sent to UCLA and community physicians, 
UCLA and community clinics, hospitals, student health centers, college campuses, 
community health centers, Craigslist and internet postings. 
 
Potential patients will be assured that their health care will not be affected by their 
decision whether or not to participate in this study. 
 
The source of referrals will be the health care providers of patients seen in the OB/GYN 
Clinics at 200 Med Plaza, West Medical, Simms Mann, the office of Dr. Heaps in 100 
Med Plaza, community clinics and private practices, student health centers, and any 
additional individual interested in and eligible for participating in clinical research. A 
member of the health care team (i.e. treating physician, colleague physician, nurse, 
medical assistant, or study coordinator) will give the patient a brief overview of the study 
and ask their permission for the study physician to contact them. Please be assured that 
referring physicians will request and document patients' permission to provide us with 
their contact information. 
 
PROCEDURES 
 
The following information, as stated in the consent form, outlines the events that will 
take place at each visit and the anticipated length of time required by the subject. The 
sequence of the procedures may vary. 
 
The study procedures will take place at UCLA Westwood Campus in the 200 and 300 
Medical Plaza Buildings, the Clinical Translational Research Center, Ronald Reagan 
Medical Center, and/or Room 22-265 in the Center for Health Sciences. 
 
Before subjects begin the study: 
 
Before they begin the study, subjects will need to agree to use a non-hormone type of 


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birth control for the duration of their participation in this study. If subjects have not 
undergone permanent sterilization, examples of acceptable types of birth control are an 
IUD (without hormones) or spermicidal jelly in combination with a diaphragm or 
condoms. 
 
During the study: 
 
If subjects take part in this study, the researcher(s) will ask them to do the following: 
 
All Study Participants 
 
 
Initial Visit 
 
• The consent form will be reviewed with the subject and anyone they wish to have 
present. If they choose to participate, they will sign the consent form and HIPAA 
Authorization form. Subjects will be given a copy for their records. 
• The doctor will ask questions regarding their past medical history, family medical 
history, and lifestyle to determine if they are eligible to participate in this study.  
• If subjects are not eligible to participate in this study, no further study related office 
visits or procedures will be performed and they will receive $10 for their time 
• If subjects are eligible to participate, they will undergo the following: 
o Physical Exam 
o An assessment of their skin 
o Height, weight, waist and hip measurements 
o Transvaginal ultrasound of their ovaries 
o Blood tests - approximately 1 teaspoon (6 ml) of blood will be drawn from their 
vein. All of the blood samples in this study will be used to detect any abnormal 
hormone levels.  A pregnancy test will also be performed. 
o Complete questionnaires regarding their feelings about various areas of their 
health, quality their life, and family history of PCOS and/or diabetes. Subjects 
have the right to refuse to answer any questions that they do not wish to answer. 
o Whether subjects are eligible or not, they will be paid $20 for completing this visit.  
o  It is estimated that this visit will take approximately 2 hours. 
 
Women with and without PCOS 
 
If subjects are eligible and choose to continue participation, they will undergo the 
following tests and procedures. Subjects will be given separate instructions on how to 
prepare for the tests.  Subjects will complete a contact information sheet with the name 
of someone to contact in the event of an emergency. 


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Frequently-Sampled Intravenous Glucose Tolerance Test (FSIGT) and Blood Tests 
• Approximately 5 tablespoons (64 ml) of blood will be drawn from their vein for research 
purposes. 
• The first blood draw will be sent to the laboratory for an immediate test of their 
progesterone level, which indicates whether or not they are ovulating. If the 
progesterone test indicates that they are ovulating, the Frequently-Sampled Intravenous 
Glucose Tolerance Test will not be able to be performed that day and will need to be 
rescheduled. • A Frequently-Sampled Intravenous Glucose Tolerance Test (FSIGT) will 
be performed. Subjects will be given instructions on how to prepare for the test, which 
include not eating or drinking anything except water after midnight on the day of the 
test. A small amount of glucose will be injected into their vein. Shortly thereafter, a small 
amount of insulin will also be injected in their vein so that researchers can learn more 
about how their body reacts to glucose and insulin. Two small catheters will be attached 
to their veins in order to remove the blood samples so that they will not have to be stuck 
with a needle at each time interval. A total of approximately 2-3 tablespoons (28-42 
ml's) will be removed from their vein for the FSIGT test. Their blood will be drawn 20, 
15, and 5 minutes and at time 0 immediately before infusion of the glucose.  Insulin will 
be injected 20 minutes after the glucose injection.    Your blood will be drawn at 2, 4, 8, 
19, 22, 30, 40, 50, 70, 90, and 180 minutes after the glucose injection.  
• It is estimated that this visit will take approximately 5-6 hours. 
 
 
MRI and DXA Scan 
In order to be sure that participants are not ovulating, approximately ½ teaspoon (2 
ml’s) of blood may be drawn and sent to the laboratory for an immediate test of their  
progesterone level before their MRI and/or DXA scan.  If the progesterone test indicates 
that they are ovulating, the test(s) may not be able to be performed that day and may 
need to be rescheduled. 
• Subjects will undergo a Magnetic Resonance Imaging (MRI) of their abdomen and 
pelvis. They will NOT be injected with a dye before the MRI.  
• Subjects will be asked to ingest only a clear liquid diet beginning at midnight on the 
day of the MRI and DXA scan. 
• Their bone density and body fat composition will be assessed by a test called a DXA 
Scan. 
• It is estimated that this visit will take approximately 2 hours. 
• The medical images will be performed at UCLA.  The imaging studies are 
performed as part of this research study and will not be reviewed or interpreted by a 
UCLA radiologist.  Any information regarding the imaging findings should be directed to 
the study PI 
 


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Removal of Abdominal Fat  
 
• In order to be sure that participants are not ovulating, approximately ½ teaspoon 
(2 ml’s) of blood may be drawn and sent to the laboratory for an immediate test 
of your progesterone level before the removal of fat.  If the progesterone test 
indicates that you are ovulating, the fat removal may not be able to be performed 
that day and may need to be rescheduled. 
• Subjects will be asked to ingest only a clear liquid diet beginning at midnight on 
the day of the procedure to remove abdominal fat. 
 
• Subjects will be given local anesthetic and a small amount of fat approximately the 
size of a quarter will be removed from under the skin in their lower abdomen.  
• Subjects will be asked to ingest only a clear liquid diet beginning at midnight on the 
day of the procedure to remove abdominal fat. 
• It is estimated that this visit will take approximately 2 hours. 
 
Follicle Stimulating Hormone (FSH) Stimulation Test and Ultrasound of the Ovaries 
 
• Subjects will undergo a transvaginal ultrasound. 
o Subjects will undergo a Follicle Stimulating Hormone (FSH) stimulation test. FSH is 
the hormone that normally induces the ovary to develop a follicle and a single injection 
of FSH predicts how sensitive the ovary is to FSH. Their blood will be drawn at -90, -60, 
-30 minutes and time 0 as well as at 1/2, 1, 1 1/2, 2, 3, 4, 6, 8, 10, 12, 16, 20, and 24 
hours after the injection. In order to prevent multiple needle sticks for the blood draws, a 
catheter will be placed in a vein in their arm before the first blood draw. Their blood will 
be drawn at the intervals described above through the catheter.  
• The first blood draw will be sent to the laboratory for an immediate test of their 
progesterone level which indicates whether or not they are ovulating. If the 
progesterone test indicates that they are ovulating, the FSH test will not be able to be 
performed that day and will need to be rescheduled. If the test cannot be performed, 
they will be paid $10 for this visit and another appointment will be scheduled. 
• It will be necessary for them to stay at UCLA Medical Center in the Clinical 
Translational Research Center, which is located in the Center for Health Sciences 
building for approximately 26 hours in order to complete this test. Food will be provided 
to them during the testing. 
• Approximately 1-2 tablespoons (21 mL) of blood will be drawn from their vein. 
 
If subjects have PCOS, an additional 4 mL (approximately 1 teaspoon) of blood will be 
drawn for a complete blood count and comprehensive metabolic panel in order to 
assure that there are no abnormalities in these blood values before they begin taking 
flutamide or placebo.  
 
Since some of the blood tests to confirm hormonal levels are timed around different 
phases of the menstrual cycle and menstrual cycles vary, it is possible some of the 
blood tests described above will need to be repeated. The Frequently Sampled 


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Intravenous Glucose Tolerance Test and the Follicle Stimulating Hormone Test will only 
be performed as described above. 
 
Subjects will be paid $280 once they have completed the FSIGT, DXA, MRI, Fat 
Removal, and FSH stimulation visits.  If they report to UCLA for a study visit and their 
blood tests indicate that they are not in the desired part of their menstrual cycle for a 
particular test, they will be compensated an additional $10 and the visit will be 
rescheduled. Participants will be asked to complete a form so that a check can be 
mailed to them within 2 months.   
Women who do not have PCOS will conclude their participation in this study at this 
point. No further procedures for this study will be conducted. 
 
Women with PCOS will continue participation as described below. 
 
Women with PCOS will be asked to do the following: 
 
• Take one pill (either placebo or flutamide) each morning before breakfast for 6 
complete 28 day cycles. The drug flutamide has not been approved by the FDA for use 
in women or for the treatment of PCOS. 
• Complete a diary regarding what time they took the pill, whether they had any 
menstrual bleeding, any changes in their health, any medications they took, if they 
exercised that day, and a brief summary of their diet. 
• Collect a sample of their first morning urine once a week and store it until their next 
clinic visit. Subjects will be given instructions on the collection and storage of the 
samples.  
 
• Return to the UCLA Clinic once a month for the following: 
 
o A brief physical exam including a measurement of their height, weight, waist, 
and hips.  Review any symptoms subjects may have experienced during the 
past month. 
o Bring their prescription bottles so that the pills can be counted. 
o Bring their weekly urine samples.  
o Bring their completed diaries.  
o Have blood tests (serum pregnancy test, complete blood count, and 
comprehensive metabolic panel)  – approximately 1 teaspoon (5 ml) of blood 
will be drawn. 
o After the third and sixth cycle, subjects will be asked to complete 
questionnaires regarding their feelings about various areas of their health and 
the quality of their life. Subjects have the right to refuse to answer any 
questions that they do not wish to answer.  


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• After the third and sixth cycle, subjects will also have an assessment of their skin, and 
a transvaginal ultrasound of their ovaries.  
• It is estimated that each of these visits will take approximately 1 hour 
• Subjects will receive be reimbursed for their parking expenses  and receive $240after 
all 6 visits have been completed.  
• Subjects will be asked to continue taking the flutamide or placebo until the procedures 
listed below are completed.  Every effort will be made to complete all study visits as 
soon as possible. 
 
After Completing Flutamide/Placebo 
 
The FSIGT, MRI, DXA, Removal of Abdominal Fat, and FSH tests will be repeated as 
described above.  Please note that a testosterone blood test, complete blood count, and 
comprehensive metabolic panel will be performed at the post-treatment FSH test. 
 
30 Days after Last Pill 
 
o Physical Exam 
o Blood tests (pregnancy test, complete blood count, and comprehensive 
metabolic panel) - approximately 1 teaspoon (6 ml) of blood will be drawn 
from their vein. 
 
Participants will be paid $300 once you have completed the FSIGT, DXA, MRI, Fat 
Removal, FSH stimulation, and 30 day after last pill visits.  If they report to UCLA for a 
study visit and their blood tests indicate that they are not in the desired part of their 
menstrual cycle for a particular test, they will be compensated an additional $10 and the 
visit will be rescheduled.  
 
6 months after completion of the study procedures 
 
Participants who have received the flutamide or placebo will be contacted by 
phone 6 months after the study procedures have been completed. Subjects 
will be asked if they have experienced any health problems or become 
pregnant since they completed the study procedures. There will be no 
compensation for the phone call. 
 
 
 
 


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PRIVACY AND CONFIDENTIALITY 
 
Subjects will be recruited with the clear understanding that they are participating in 
research. All information obtained from these studies will be maintained in charts 
separate from the hospital medical records. Only Dr. Dumesic and the study team will 
be privy to the study charts and the names of those individuals participating. All blood, 
urine and fat samples will be obtained and stored with careful attention to current HIPAA 
privacy regulations, and all study subjects will be assigned a unique identifier number. 
All data sent for analysis will be coded, in order to remove unique identifiers from the 
data. Nevertheless, the likelihood that the data generated in the study will be of a 
sensitive nature is minimal.  
 
Regarding confidentiality, all information obtained from this study will be maintained in 
charts separate from the hospital medical records. Data will be maintained in locked file 
cabinets and in password protected files on computer systems. Data will be coded and 
all analyses performed using coded data only. Identifying information needed for cohort 
follow-up and retention will be kept separate from data analysis files. Only a limited 
number of individuals of the clinical team will be able to re-link the study codes to the 
identity of specific study participants. In the event that participants no longer want their 
blood samples to be included in the study, we will document this in the central database 
and destroy their samples if they have not already been used. 
Study information will be kept in locked offices and password protected computers. Only 
members of the study team will have access to identifiable data. 
POTENTIAL RISKS 
Postmarketing data report the need for hospitalization and rare death events from liver 
failure in patients receiving flutamide. The flutamide dose chosen for this study is lower 
than the flutamide dose previously reported to harm the liver, with long-term (>1 year 
duration) flutamide studies showing no harmful liver effects at a dose of flutamide of 125 
mg orally daily. Therefore, we do not anticipate that study participants with PCOS who 
receive flutamide (125 mg orally daily) in our study are at significant risk for harmful liver 
toxicity. 
 
Study participants with PCOS who receive flutamide or placebo (125 mg orally daily) will 
be monitored with monthly blood tests. We will utilize the National Cancer Institute 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Should a 
patient experience any hematologic or non-hematologic toxicity at grade 3 or higher, 
flutamide/placebo will discontinued and weekly blood tests will be performed until values 
return to normal. 
 
If a patient experiences an acute life threatening adverse event, we will immediately 
contact the Investigational Drug Pharmacist and the blind will be broken. 
 
As stated in the consent form, the risks include: 


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UCLA IRB #12-001780 
Page 18 of 27 
 
 
The possible risks and/or discomforts associated with the procedures described in this 
consent form include:  
 
Flutamide: 
 
Symptoms of liver injury, including loss of appetite, nausea and vomiting, fatigue, 
stomach or abdominal pain, flu-like symptoms and jaundice (yellowing of the skin or 
whiteness of the eyes), have occasionally been reported with the use of flutamide. Such 
liver injury, however, is related to the dose of flutamide and is reversible following 
discontinuation of the drug. For this reason, the flutamide dose chosen for this study is 
below the dose previously reported to harm the liver, with long-term (>1 year) flutamide 
studies showing no harmful liver effects at 125 mg orally on a daily basis. Additional 
risks of flutamide therapy include anemia, photosensitivity, breast tenderness, retention 
of fluid, discharge of fluid from your nipples, rash, hypertension, hot flashes, central 
nervous system reactions, decreased interest in having sexual relations, diarrhea, and 
anorexia. For these reasons, monthly blood tests will be done to monitor the safety of 
flutamide and this medication will be discontinued if there are any temporary changes in 
blood or liver function. Brownish urine also can occur and is due to a metabolite of 
flutamide. 
 
Placebo Pills 
 
There are no known risks from taking a placebo pill. 
 
Risks of an Ultrasound: 
Participants may experience some discomfort from having the ultrasound probe placed 
in their vagina and moved during the exam. 
 
Ultrasound imaging has been used for over 20 years and has an excellent safety 
record. It is non-ionizing radiation, so it does not have the same risks as x-rays or other 
types of ionizing radiation. 
Even though there are no known risks of ultrasound imaging, it can produce effects on 
the body. When ultrasound enters the body, it heats the tissues slightly. In some cases, 
it can also produce small pockets of gas in body fluids or tissues (cavitation), although 
this is extremely rare. The long-term effects of tissue heating and cavitation are not 
known. 
 
Risks of Blood Draw: 
 
Drawing blood may cause temporary pain from the needle stick, bruising or swelling at 
the site, and rarely, infection or fainting.  
 


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Risks of Procedure to Remove Fat from Under the Skin: 
 
Potential problems during the collection of the subcutaneous abdominal fat specimens 
include a temporary discomfort from the local injection of anesthetic and/or pain, 
bleeding, and infection at the site of the lower abdominal incision. In very rare 
circumstances, local injection of anesthetic and/or the removal of abdominal fat may be 
associated with fainting with or without convulsions.  Only experienced surgeons will 
perform the procedure to remove the small amount of fat, which should not significantly 
distort the contour of the abdominal skin.  
 
 
Risks of Frequently-Sampled Intravenous Glucose Tolerance Test: 
 
Insulin (introduced into your body during the intravenous glucose tolerance test) is the 
1body’s natural hormone for lowering blood sugars. If your blood sugars fall rapidly, you 
may experience mild dizziness, nausea, vomiting, shortness of breath, increased heart 
rate or sweating. If these effects occur, they are easily detected and treated with 
administration of supplemental sugar through the indwelling catheter, thereby raising 
the blood sugar. This condition is only temporary and has no known long-term health 
impact. The glucose (commonly called sugar) infused through the catheter as part of the 
intravenous glucose tolerance test may cause an initial feeling of warmth and flushing of 
the face, which are both transient symptoms that rapidly resolve. You will be asked to 
arrive for your testing after having fasted from midnight the night before. In light of the 
prolonged fast, you may feel hungry during the testing. 
 
Risks of Follicle Stimulating Hormone (FSH) Stimulation Test.   
Participants may experience lower abdominal bloating and/or vaginal spotting from this 
test. 
 
Risks of DXA Scan:  
 
Since the radiation procedures are all standard of care, the amount of radiation Subjects 
will receive is the same as that for similar patients who are not participating in this study. 
Therefore, they will not be exposed to any additional radiation by participating in this 
study. 
 
Risks of Magnetic Resonance Imaging (MRI): 
 
The MRI procedure uses a powerful magnetic field to generate detailed images of the 
body. The magnet could move objects within their body that contain metal, such as 
implants, clips and pacemakers. Subjects will be asked to tell the doctor if they have 
any metal items within their body.  
 
MRI scanning is painless but they might experience discomfort in the machine. In 
particular, loud beeping and hammering noises occur during the study when the 


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scanner is collecting measurements. Subjects also may be bothered by feelings of 
claustrophobia when placed inside the MRI, or by lying in one position for a long time. 
Subjects might also experience stimulation of the nerves in their body, which feels like a 
gentle tap or sensation of mild electric shock.  
 
Because the risks to a fetus from MRI are unknown, subjects cannot participate in this 
study if they are pregnant.  
 
Known Reproductive Risks:  
 
Subjects should not become pregnant while on this study because the drugs in this 
study and the DXA scan can affect an unborn baby. Women should not breastfeed a 
baby while on this study. Therefore, subjects will need to use effective birth control while 
on this study. Examples of acceptable types of birth control are a diaphragm with 
spermicidal jelly, condoms, or an IUD (without hormones).  Subjects should use birth 
control starting at the beginning of their participation in this study. 
 
Unknown Risks to Women of Child Bearing Potential and Pregnant Women:  
 
Flutamide can occasionally induce ovulation in a woman with PCOS who does not 
ovulate. This is important because this medication blocks androgen action and can 
impair the ability of androgen to normally induce development of the external genitalia in 
the male fetus. For this reason, if subjects believe that they are pregnant or have a 
chance of becoming pregnant they should not participate in this study. A serum 
pregnancy test will be performed before the start of study procedures and monthly 
throughout their participation in this study. If they are pregnant, the will not be allowed to 
participate in the study. If women do participate in this study, they must use a medically 
effective form of birth control before entering the study, while participating in the study, 
and for at least one month after stopping the study. If they become pregnant during the 
study, they will be asked to tell the researchers right away.  
 
Unknown Risks to Infants:  
 
The side effects of Flutamide on infants are not known, therefore if women are currently 
breastfeeding they cannot participate in this study. 
 
Loss of Confidentiality:  
 
As this study involves the use of identifiable, personal information, there is a chance 
that a loss of confidentiality will occur. The researchers have procedures in place to 
lessen the possibility of this happening. 
Unknown Risks and Discomforts: 
 
The experimental treatments may have side effects that no one knows about yet. The 
researchers will inform subjects if they learn anything that might make them change 


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their mind about participating in the study.  
 
POTENTIAL BENEFITS 
Society will benefit from the knowlege gained by this study. 
 
PCOS affects at least 7% of the general female population, and these women have an 
increased risk of diabetes, hypertension and dyslipidemia, infertility, dysfunctional 
uterine bleeding and endometrial carcinoma. The proposed studies will have the 
potential benefit of improving our understanding of how altered adipogenesis in PCOS 
adversely affects metabolic and reproductive function, allowing for the development of 
newer, and more targeted, therapies. Specifically, clinically relevant knowledge gained 
by these studies will be a decisive step in improving reproduction in PCOS women and 
the safety of ovulation-inducing agents when necessary by diminishing the risks of 
ovarian hyperstimulation syndrome and multiple pregnancy. 
DATA AND SAFETY MONITORING PLAN 
 
A physician member of the OB/GYN Department (Dr. Brian Koos), who is not affiliated 
with the study, will monitor the study on a regular basis. In addition, Dr. Dumesic will 
review on a monthly basis the status of recruitment and the occurrence of any adverse 
events. If any untoward events occur, necessary systems changes will be promptly 
instituted.  
STOPPING RULES 
All Grade 3 toxicities will be immediately evaluated by Dr. Dumesic and Dr. Koos. The 
study will be terminated if two patients experience Grade 3 NCI-defined adverse hepatic 
events (i.e., serum alkaline phosphatase > 5-20 ULN, alanine aminotransferase > 5-20 
ULN, aspartate aminotransferase > 5-20 ULN, total bilirubin > 3-10 ULN) or if one 
patient experiences a single Grade 4 NCI-defined adverse hepatic event (i.e., serum 
alkaline phosphatase > 20 ULN, alanine aminotransferase > 20 ULN, aspartate 
aminotransferase > 20 ULN, total bilirubin > 10 ULN). 
RULES FOR WITHDRAWING PARTICIPANTS FROM STUDY INTERVENTIONS 
Reasons participants may be withdrawn from the study include but are not limited to the 
following: 
 
1) Participant chooses for any reason to discontinue her participation in the study. 
 
2) It is deemed by the Principal Investigator that continued participation is not in the best 
interests of the participant. 
 
3) Blood samples cannot be obtained by a health care provider licensed to perform 


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phlebotomy.. 
 
4) The subject has a persistent adverse reaction to blood sampling, such as dizziness, 
anxiety or pain. 
 
5) During the frequently sampled glucose tolerance test (FSIGT), the subject 
experiences nervousness, irritability, headache, pale and clammy skin or excessive 
sweating, which are not promptly reversed according to the protocol stated on the 
signed physician’s orders. 
 
6) During the entire duration of procedures involving blood draws, nursing staff will be 
present to monitor for any of the above adverse symptoms. If significant symptoms of 
hypoglycemia develop, oral or intravenous glucose will be administered. 
 
7) The surgeon performing the removal of the fat deems the fat acquisition procedure 
unsafe due to pre-existing anatomic distortion of the abdomen, or to unrelated 
complications arising during the procedure. Because a low yield of adipocytes may 
result from small adipose sampling, and poor sample handling or cellular fragility, only 
an experienced surgeon (Drs. Dumesic or Jarrahy) will perform the subcutaneous fat 
biopsy procedure. 
 
8) Elevation in liver function studies above the normal range. 
 
9) If the participant becomes pregnant. 
 
10) Noncompliance  
11)  Subjects will be monitored for hypertension.  If a subject has persistent increase in 
diastolic blood pressure of 20 mm Hg or more, or if a previously normotensive subject 
experiences persistent increase in blood pressure to > 150/100, flutamide/placebo will 
be discontinued and the subject will be withdrawn from study treatment. 
  
FINANCIAL OBLIGATIONS 
Neither the subject nor their insurance carrier will be charged for their participation in 
this study. 
Control participants may receive up to $300 for their participation in this study and 
PCOS participants may receive up to $840.  
Participants will be reimbursed for their parking expenses.  Meal vouchers will be 
provided during the FSH visit. 
 
STATISTICAL CONSIDERATIONS 
 


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We will use one-way factorial analysis of variance (ANOVA) methods to compare 
continuous outcomes including hormone levels; adipocyte size, lipid content and 
glycerol release; numbers of ASCs and preadipocytes; mRNA levels. If data are not 
normally distributed on any scale, we will carry out nonparametric ANOVA. 
 
Our previous comparison of cFOS gene expression in PCOS women vs. controls 
showed an increase in ΔCt (6.0 ± 1.4). Based on this, we hypothesize that the mean 
difference between controls and IR PCOS is 1.7 SD units. Assuming this, a sample size 
of 8/group (IR vs. non-IR PCOS) provides over 80% power using the usual two-sided p 
< 0.05. 
 
We also will compare all outcomes before vs. after 6 months of placebo or flutamide 
treatment controlling for IR status, using either the parametric paired t test or non-
parametric Wilcoxon signed rank test. Insulin action and sensitivity will be assessed by 
calculating a Matsuda Index from blood glucose and insulin levels during the oral 
glucose tolerance test. Ovarian estradiol sensitivity to FSH will be calculated from the 
24-hr area-under-the-curve (AUC) serum estradiol response to FSH infusion.  
 
Based on our in vitro data, we observed a mean 0.17 log scale change in ΔCt PPARγ 
(SD=0.26 log units) after treatment with T + Flutamide vs. T alone. A sample size of 14 
(7 non-IR, 7 IR) provides more than 80% power for the IR adjusted mean change. 
 
 
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1. Wild RA, Carmina E, Diamanti-Kandarakis E, Dokras A, Escobar-Morreale HF, 
Futterweit W, Lobo R, Norman RJ, Talbott E, Dumesic DA 2010. Assessment of 
cardiovascular risk and prevention of cardiovascular disease in women with the 
polycystic ovary syndrome: a consensus statement by the Androgen Excess and 
Polycystic Ovary Syndrome (AE-PCOS) Society. J Clin Endocrinol Metab 95(5):2038-
49. 
2. Dunaif A, Segal KR, Shelley DR, Green G, Dobrjansky A, Licholai T 1992. Evidence 
for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome. 
Diabetes 41(10):1257-66. 
3. 2004. Revised 2003 consensus on diagnostic criteria and long-term health risks 
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4. Azziz R, Marin C, Hoq L, Badamgarav E, Song P 2005. Health care-related economic 
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83(5):1454-60. 
6. Toprak S, Yonem A, Cakir B, Guler S, Azal O, Ozata M, Corakci A 2001. Insulin 
resistance in nonobese patients with polycystic ovary syndrome. Horm Res 55(2):65-70. 


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7. Dunaif A, Segal KR, Futterweit W, Dobrjansky A 1989. Profound peripheral insulin 
resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 38(9):1165-
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8. Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan MK, Imperial J 1999. Prevalence 
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23. Apridonidze T, Essah PA, Iuorno MJ, Nestler JE 2005. Prevalence and 
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Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the 
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30. Rosenbaum D, Haber RS, Dunaif A 1993. Insulin resistance in polycystic ovary 
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Abnormal Expression of Genes Involved in Inflammation, Lipid Metabolism, and Wnt 
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Hellstrom M, Lonn L, Olivecrona G, Stener-Victorin E, Lonn M 2010. Adipose tissue has 
aberrant morphology and function in PCOS: enlarged adipocytes and low serum 
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ICF_001.pdf: 
 
 
 
Androgen Excess as a Cause for Adipogenic Dysfunction in 
PCOS Women 
NCT01889199 
Informed Consent 
2-26-2020 
 


Revised 02-26-20 
Page 1 of 20 
 
 
 
 
 
 
 
 
 
Study Title: 
Androgen Excess Causes Adipogenic Dysfunction in PCOS 
Women 
 
Lay Title: 
A Study to Learn More about Polycystic Ovarian Syndrome (PCOS) 
 
 
INTRODUCTION 
 
Daniel Dumesic, MD and his associates from the Department of Obstetrics 
and Gynecology at the University of California, Los Angeles are conducting 
a research study. 
 
The researchers will explain this study to you. Research studies are 
voluntary and include only people who choose to take part. Please take 
your time about deciding  whether to participate in this study. Before 
deciding: 
 
• You can discuss this study with friends and family. 
• You can also discuss it with your health care doctor or request a second 
opinion. 
• If you have any questions, you can ask the researchers for more 
information before deciding to participate. 
 
The research team is asking you to be in this study because you are a lean 
woman between the ages of 18 and 35 years. For this study, women with 
Polycystic Ovarian Syndrome (PCOS) and women without PCOS are eligible 
to participate. 
 
WHY IS THIS STUDY BEING DONE? 
 
The purpose of this research study is to collect specimen samples and study 
medical information from women with PCOS and women without PCOS. The 
goal is to learn more about the changes that take place in the body that result 
in PCOS. Flutamide is a Food and Drug Administration (FDA)-approved 
medication used to treat prostate cancer in men, which acts by blocking the 
action of male hormones. The investigator of this study wants to know if 
flutamide will help block the male hormones found in women that may cause 
PCOS. 
UNIVERSITY OF CALIFORNIA LOS ANGELES 
CONSENT TO PARTICIPATE IN RESEARCH 


Revised 02-26-20 
Page 2 of 20 
 
 
 
 
Both groups of women will undergo the same evaluations and procedures 
during the first 2 months. After the first 2 months, women without PCOS will 
have completed their participation in this study. Women with PCOS will be 
asked to take a pill once a day for 6 complete 28-day cycles and then 
continue to take the medication until all the post 
treatment assessments have been completed. Participants will be asked to 
return to the office once a month for an exam and blood tests. The pill will 
either be a drug called flutamide or an inactive substance known as a 
placebo. Flutamide is not approved by the FDA for use in women or for the 
treatment of PCOS. Neither you nor your doctor will know if you are 
receiving the drug or placebo. At the end of the 6 complete 28-day cycles 
the same evaluations and tests that were performed in the first 2 months will 
be repeated. 
 
The following definitions may help you understand how this research study is 
designed: Randomized: 
assigned to a group by chance (similar to 
flipping a coin) 
Double Blind: 
neither you nor your doctor will know if you are receiving 
the study drug Flutatmide or a placebo 
Placebo: 
a pill that does not contain a medication (i.e. 
sugar pill) Glucose 
Tolerance 
Test: 
glucose is the sugar the body uses for energy. This test 
is done to learn how your body processes glucose. 
 
 
This study is being funded by the National Institute of Child Health and 
Human Development. 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
We anticipate that 150 women will be enrolled in this study at UCLA 
(40 without PCOS and 110 with PCOS). 
 
WHAT WILL HAPPEN IF I TAKE PART IN THIS STUDY? 
 
The study procedures will take place at UCLA Westwood Campus in the 200 
Medical Plaza Building, 100 Medical Plaza Building, the Clinical Translational 
Research Center, Ronald Reagan Medical Center, and/or Room 22-265 in 
the Center for Health Sciences. 


Revised 02-26-20 
Page 3 of 20 
 
 
 
 
Before you begin the study: 
 
Before you begin the study, you will need to agree to use a non-hormone 
type of birth control for the duration of your participation in this study. If you 
have not undergone permanent sterilization, examples of acceptable types 
of birth control are an IUD (without hormones) or spermicidal jelly in 
combination with a diaphragm or condoms. 
 
You will be asked to provide the name, phone number(s), and email address 
for someone we can contact in the event of an emergency or if we are 
unable to communicate directly with you. 
 
During the study: 
 
If you take part in this study, the researcher(s) will ask you to do the following: 
 
All Study Participants 
 
Appendix I at the end of this consent form provides a flow sheet of the study 
procedures. The order in which the procedures are performed may vary (i.e. 
you may have DXA before the Frequently-Sampled Intravenous Glucose 
Tolerance Test, etc). If you would like a copy of any of the results of the 
study tests or procedures, they will be provided to you free of charge. 
 
Initial Visit 
 
• This consent form will be reviewed with you and anyone you wish to 
have present. If you choose to participate, you will sign the consent 
form and HIPAA Authorization form. You will be given a copy for 
your records. 
• The doctor will ask you questions regarding your past medical 
history, family medical history, and lifestyle to determine if you are 
eligible to participate in this study. 
• If you are not eligible to participate in this study, no further study 
related office visits or procedures will be performed. 
• If you are eligible to participate, you will undergo the following: 
o Physical Exam 
o An assessment of your skin 
o Height, weight, waist and hip measurements 
o Transvaginal (Appendix II)" or abdominal ultrasound of your 
ovaries (if the investigator thinks the transvaginal ultrasound 
might be too painful for you) Blood tests - approximately 1 
teaspoon (6 ml) of blood will be drawn from your vein. All of the 
blood samples in this study will be used to detect any abnormal 
hormone levels. 
o A pregnancy test will be performed. 
o Complete questionnaires regarding your feelings about various 
areas of your health, quality of your life, and your family history 


Revised 02-26-20 
Page 4 of 20 
 
 
 
 
of PCOS and/or diabetes. You have the right to refuse to 
answer any questions that you do not wish to answer. If your 
responses to the questionnaires suggest that you may be 
suffering from severe depression or that you may pose a 
risk to yourself or others, you will be referred for the appropriate 
follow-up care. 
• It is estimated that this visit will take approximately 2 hours. 
 
Women with and without PCOS 
 
If you are eligible and choose to continue participation, you will undergo the 
following tests and procedures. You will be given separate instructions on 
how to prepare for the tests. 
 
Frequently-Sampled Intravenous Glucose Tolerance Test (FSIGT) and 
Blood Tests 
• Approximately 5 tablespoons (64 ml) of blood will be drawn from your 
vein for research purposes. 
• The first blood draw will be sent to the laboratory f or an immediate 
test of your progesterone level, which indicates whether or not you 
are ovulating. If the progesterone test indicates that you are 
ovulating, the Frequently-Sampled Intravenous Glucose Tolerance 
Test will not be able to be performed that day and will need to be 
rescheduled. 
• A Frequently-Sampled Intravenous Glucose Tolerance Test (FSIGT) 
will be performed. You will be given instructions on how to prepare for 
the test, which  include not eating or drinking anything except water 
after midnight on the day of the test. A small amount of glucose will be 
injected into your vein. Shortly thereafter, a small amount of insulin will 
also be injected in your vein so that researchers can learn more about 
how your body reacts to glucose and insulin.  Two small catheters will 
be attached to your veins in order to remove the blood samples so that 
you will not have to be stuck with a needle at each time interval. Your 
blood will be drawn 20, 15, and 5 minutes and at time 0 immediately 
before infusion of the glucose. Insulin will be injected 20 minutes after 
the glucose  injection. Your blood will be drawn at 2, 4, 8, 19, 22, 30, 
40, 50, 70, 90, and 180 minutes after the glucose injection. A total of 
approximately 2-3 tablespoons (28-42 ml’s) will be removed from your 
vein for the FSIGT test. 
• If subjects have PCOS, an additional 4Ml (approximately 1 teaspoon) 
of blood will be drawn for a complete blood count and comprehensive 
metabolic panel in order to assure that there are no abnormalities in 
these blood values before they begin taking flutamide or placebo. 
• It is estimated that this visit will take approximately 5-6 hours. 


Revised 02-26-20 
Page 5 of 20 
 
 
 
 
 
DEXA Scan 
 
• In order to be sure that you are not ovulating, approximately ½ 
teaspoon (2 ml’s) of blood may be drawn and sent to the laboratory 
for an immediate test of your progesterone level before your DEXA 
scan. If the progesterone test indicates that you are ovulating, the 
test(s) may not be able to be performed that day and may need to be 
rescheduled. 
• You will be asked to ingest only a clear liquid diet beginning 
at midnight on the day of the DEXA scan. 
• Your bone density and body fat composition will be assessed by a 
test called a  DEXA Scan. 
• It is estimated that this visit will take approximately 2 hours. 
• Your medical images will be performed at UCLA. The imaging studies 
are performed as part of this research study and will not be reviewed 
or interpreted by a UCLA radiologist. Any information regarding the 
imaging findings should be directed to the study PI. 
 
Removal of Abdominal Fat 
 
• In order to be sure that you are not ovulating, approximately ½ 
teaspoon (2 ml’s)  of blood may be drawn and sent to the laboratory 
for an immediate test of your progesterone level before the removal of 
fat. If the progesterone test indicates that you are ovulating, the fat 
removal may not be able to be performed that day and may need to 
be rescheduled. 
• You will be asked to ingest only a clear liquid diet beginning at 
midnight on the day of the procedure to remove abdominal fat. 
• You will be given local anesthetic and a small amount of fat 
approximately the size of a quarter will be removed from under the 
skin in your lower abdomen. 
• It is estimated that this visit will take approximately 2 hours. 
 
Women who do not have PCOS will conclude their participation in this study 
at this point.  No further procedures for this study will be conducted. 
 
Women with PCOS will continue participation as described below. 
 
Women with PCOS will be asked to do the following: 
 
• Take one pill (either placebo or flutamide) each morning before 
breakfast for 6 complete 28-day cycles. The drug flutamide has not 


Revised 02-26-20 
Page 6 of 20 
 
 
 
 
been approved by the FDA for use in women or for the treatment of 
PCOS. 
• Complete a short diary of 7-8 questions regarding what time you 
took the pill,  whether you had any menstrual bleeding, any 
changes in your health, any medications you took, if you exercised 
that day, and a brief summary of your diet. 
• Collect a sample of your first morning urine once a week and store 
it until your next clinic visit. You will be given instructions regarding 
the collection and storage of the samples. 
• Return to the UCLA Clinic once a month for the following: 
o A brief physical exam including a measurement of your 
height, weight, waist, and hips. Review any symptoms you 
may have experienced during the past month. 
o Bring your prescription bottles so that the pills can be counted. 
o Bring your weekly urine samples. 
o Bring your completed diaries. 
o Have blood tests (pregnancy test, complete blood count, 
comprehensive metabolic panel) – approximately 1 
teaspoon (5 ml) of blood will be drawn. 
o After the third and sixth cycle, you will be asked to complete 
questionnaires regarding your feelings about various areas of 
your health and the quality of your life. You have the right to 
refuse to answer any questions that you do not wish to answer. 
If your responses to the  questionnaires suggest that you may 
be suffering from severe depression  or that you may pose a 
risk to yourself or others, you will be referred for the 
appropriate follow-up care. 
• After the third and sixth cycle, you will also have an assessment of 
your skin, and a transvaginal ultrasound of your ovaries. 
• At the sixth cycle, approximately 1 teaspoon (5 ml) of blood will be 
drawn. This will be used to test for levels of testosterone, a complete blood 
count, and a comprehensive metabolic panel.It is estimated that each of 
these visits will take approximately 1 hour 
• You will be asked to continue taking the flutamide or placebo until 
the procedures listed below are completed. Every effort will be 
made to complete these procedures as quickly as possible. 
 
After completing flutamide/placebo 
 
Frequently-Sampled Intravenous Glucose Tolerance Test and Blood Tests 
 
• Approximately 6-7 tablespoons (90-105 ml) of blood will be drawn 
from your vein for research purposes. 
• The first blood draw will be sent to the laboratory for an immediate 
test of your progesterone level, which indicates whether or not you 
are ovulating. If the progesterone test indicates that you are 
ovulating, the Frequently-Sampled Intravenous Glucose Tolerance 
Test will not be able to be performed that day and will need to be 


Revised 02-26-20 
Page 7 of 20 
 
 
 
 
rescheduled. 
• A Frequently-Sampled Intravenous Glucose Tolerance Test (FSIGT) 
will be performed. You will be given instructions on how to prepare for 
the test, which include not eating or drinking anything except water 
after midnight on the day of  the test.  A small amount of glucose will 
be injected into your vein. Shortly thereafter, a small amount of insulin 
will also be injected in your vein so that researchers can learn more 
about how your body reacts to glucose and insulin. Two small 
catheters will be attached to your veins in order to remove the blood 
samples so that you will not have to be stuck with a needle at each 
time interval. Your blood will be drawn 20, 15, and 5 minutes and at 
time 0 immediately before infusion of the glucose. Insulin will be 
injected 20 minutes after the glucose injection. Your blood will be 
drawn at 2, 4, 8, 19, 22, 30, 40, 50, 70, 90, and 180 minutes after the 
glucose injection. Two small catheters will be attached to your veins in 
order to remove the blood samples so that you will not have to be 
stuck with a needle at each time interval. A total of approximately 3 
tablespoons (45 ml’s) will be removed from your vein for the FSIGT 
test. 
• It is estimated that this visit will take approximately 5-6 hours. 
 
DEXA Scan 
 
• In order to be sure that you are not ovulating, approximately ½ 
teaspoon (2 ml’s)  of blood may be drawn and sent to the laboratory 
for an immediate test of your progesterone level before your DEXA 
scan. If the progesterone test indicates that you are ovulating, the 
test(s) may not be able to be performed that day and may need to be 
rescheduled. 
 
• You will be asked to ingest only a clear liquid diet beginning at 
midnight on the day of your  DEXA scan. 
• Your bone density and body fat composition will be assessed by a 
test called a  DEXA Scan. 
• It is estimated that this visit will take approximately 2 hours. 
• Your medical images will be performed at UCLA. The imaging studies 
are performed as part of this research study and will not be reviewed 
or interpreted by a UCLA radiologist. Any information regarding the 
imaging findings should be directed to the study PI. 
 
Removal of Abdominal Fat 
 
• In order to be sure that you are not ovulating, approximately ½ 
teaspoon (2 ml’s) of blood may be drawn and sent to the laboratory 
for an immediate test of your progesterone level before the removal 


Revised 02-26-20 
Page 8 of 20 
 
 
 
 
of fat. If the progesterone test indicates that you are ovulating, the fat 
removal may not be able to be performed that day and may need to 
be rescheduled 
• You will be given local anesthesia and a small amount of fat 
approximately the size of a quarter will be removed from under the 
skin in your lower abdomen on the opposite side from where the first 
biopsy was taken. 
• You will be asked to ingest only a clear liquid diet beginning at 
midnight on the day of the procedure to remove abdominal fat. 
• It is estimated that this visit will take approximately 2 hours. 
 
30 days after last pill 
 
o Physical Exam 
o Blood tests (pregnancy test, complete blood count, 
comprehensive metabolic panel) - approximately 1 teaspoon 
(6 ml) of blood will be drawn  from your vein. 
o It is estimated that this visit will take approximately ½ - 1 hour. 
 
6 months after completion of the study procedures 
 
Participants who have received the flutamide or placebo will be contacted by 
phone 6 months after the study procedures have been completed.  You will 
be asked if you have experienced any health problems or become pregnant 
since you completed the study procedures. There will be no compensation 
for the phone call. It is estimated that this phone call will take approximately 
¼ - ½ hour. 
HOW LONG WILL I BE IN THIS STUDY? 
 
If you have PCOS, this study will last approximately 10 months with a follow- 
up phone call 6 months after completion of the study procedures. If you do 
not have PCOS, your participation will last approximately two months. There 
will be no long-term follow-up review of medical records, telephone follow-up 
or physical exam. 
 
WHAT KINDS OF RISKS OR DISCOMFORTS COULD I EXPECT? 
 
Known risks and discomforts: 
 
The possible risks and/or discomforts associated with the procedures 
described in this  consent form include: 


Revised 02-26-20 
Page 9 of 20 
 
 
 
 
Flutamide: 
 
Symptoms of liver injury, including loss of appetite, nausea and vomiting, 
fatigue,  stomach or abdominal pain, flu-like symptoms and jaundice 
(yellowing of the skin or whiteness of the eyes), have occasionally been 
reported with the use of flutamide. Such liver injury, however, is related to the 
dose of flutamide and is reversible following discontinuation of the drug. For 
this reason, the flutamide dose chosen for this study is below the dose 
previously reported to harm the liver, with long-term (>1 year) flutamide 
studies showing no harmful liver effects at 125 mg orally on a daily basis. 
Additional risks of flutamide therapy include anemia, photosensitivity, breast 
tenderness, retention of fluid, discharge of fluid from your nipples, rash, 
hypertension, hot flashes, central nervous system reactions, decreased 
interest in having sexual relations, diarrhea, and anorexia. For these 
reasons, monthly blood tests will be done to monitor the safety of 
flutamide and this medication will be discontinued if there are any temporary 
changes in blood or liver function. Brownish urine also can occur and is due 
to a metabolite of flutamide. Call the study doctor immediately if you notice 
any yellowing of skin or eyes. 
 
Placebo Pills 
 
There are no known risks from taking a placebo pill. 
 
Risks of a Transvaginal Ultrasound: 
 
You may experience some discomfort from having the ultrasound probe 
placed in your vagina and moved during the exam. 
 
Ultrasound imaging has been used for over 20 years and has an excellent 
safety record. It is non-ionizing radiation, so it does not have the same risks 
as x-rays or other  types of ionizing radiation. 
 
Even though there are no known risks of ultrasound imaging, it can produce 
effects on the body. When ultrasound enters the body, it heats the tissues 
slightly. In some cases, it can also produce small pockets of gas in body 
fluids or tissues (cavitation), although this is extremely rare. The long-term 
effects of tissue heating and cavitation are not known. 
 
Risks of Blood Draw: 
 
Drawing blood may cause temporary pain from the needle stick, bruising or 
swelling at  the site, and rarely, infection or fainting. 
 
Risks of Procedure to Remove Fat from Under the Skin: 
 
Potential problems during the collection of the subcutaneous abdominal fat 
specimens include a temporary discomfort from the local injection of anesthetic 


 
Revised July 27, 2018 
Page 10 of 20 
 
 
 
and/or pain, bleeding, and infection at the site of the lower abdominal incision. 
In very rare circumstances, local injection of anesthetic and/or the removal of 
abdominal fat may be associated with fainting with or without convulsions. 
Only experienced surgeons will perform the procedure 
to remove the 
small amount of fat, which should not significantly distort the  
contour of 
the abdominal skin. 
 
Risks of Frequently-Sampled Intravenous Glucose Tolerance Test: 
 
Insulin (introduced into your body during the intravenous glucose tolerance 
test) is the body’s natural hormone for lowering blood sugars. If your blood 
sugars fall rapidly, you may experience mild dizziness, nausea, vomiting, 
shortness of breath, increased heart rate or sweating. If these effects occur, 
they are easily detected and treated with administration of supplemental 
sugar through the indwelling catheter, thereby raising the blood sugar. This 
condition is only temporary and has no known long-term health impact. The 
glucose (commonly called sugar) infused through the catheter as part of the 
intravenous glucose tolerance test may cause an initial feeling of warmth and 
flushing of the face, which are both transient symptoms that rapidly resolve. 
You will be asked to arrive for your testing after having fasted from midnight 
the night before. In light of the prolonged fast, you may feel hungry during the 
testing. 
 
Risks of Radiation from DEXA Scans: 
 
Since the radiation procedures are all standard of care, the amount of 
radiation you will receive is the same as that for similar patients who are not 
participating in this study. 
Therefore, you will not be exposed to any additional radiation by participating 
in this study. 
 
Known Reproductive Risks: 
 
You should not become pregnant while on this study because the drugs in this 
study and the DEXA testing can affect an unborn baby. Women should not 
breastfeed a baby while on this study. Therefore, you need to use effective 
birth control while on this study. If you have not undergone permanent 
sterilization, examples of acceptable types of birth control are an IUD (without 
hormones) or spermicidal jelly in combination with a diaphragm or condoms. 
You must use birth control starting at the beginning of your participation in this 
study and for one month after. 
 
Unknown Risks to Women of Child Bearing Potential and Pregnant Women: 
 
Women formerly thought to be infertile may ovulate and become pregnant 
when taking flutamide.  This drug may cause abnormalities in a fetus. For 


 
Revised July 27, 2018 
Page 11 of 20 
 
 
 
this reason, if you believe 
that you are pregnant or have a chance of becoming pregnant you should not 
participate in this study. A serum pregnancy test will be performed before the 
start of study procedures and monthly throughout your participation in this 
study. If you are pregnant, you will not be allowed to participate in the study. 
If you do participate in this study, you must use a medically effective form of 
birth control before entering the study,  while participating in the study, and 
for at least one month after stopping the study. If  you become pregnant 
during the study, tell the researchers right away. 
 
 
Unknown Risks to Infants: 
 
The side effects of flutamide on infants are not known, therefore if you are 
currently breastfeeding you cannot participate in this study. 
Loss of Confidentiality: 
 
As this study involves the use of your identifiable, personal information, there 
is a chance that a loss of confidentiality will occur. The researchers have 
procedures in place to lessen the possibility of this happening (see “How will 
my information about me and my participation be kept confidential?” section 
below). 
 
Unknown Risks and Discomforts: 
 
The experimental treatments may have side effects that no one knows about 
yet. The researchers will let you know if they learn anything that might make 
you change your mind about participating in the study. 
 
ARE THERE ANY BENEFITS IF I PARTICIPATE? 
 
Possible benefits to me or others in society: 
There will be no direct benefit to you from participating in this study. However, 
this study will help the researchers learn more about the differences between 
women with and without PCOS and the role of the drug flutamide in patients 
with PCOS. Hopefully this information will help in the treatment of future 
patients PCOS. 
 
The possible benefits you may experience from being in this study include the 
additional knowledge about your health from undergoing the exams, blood 
tests and procedures. If you would like a copy of any of the results of the 
study tests or procedures, they will be provided to you free of charge. 


 
Revised July 27, 2018 
Page 12 of 20 
 
 
 
 
WHAT OTHER CHOICES DO I HAVE IF I DON’T WANT TO PARTICIPATE? 
 
If you decide not to take part in this study, or if you withdraw from this study 
before it is completed, the following alternative procedures or courses of 
treatment are available: 
 
• Standard care for women with and without PCOS 
 
CAN THE RESEARCHERS REMOVE ME FROM THIS STUDY? 
 
The researchers may end your participation in this study for a number of 
reasons, such as if your safety and welfare are at risk, if you do not follow 
instructions or if you miss scheduled visits. If you become pregnant, you will 
be removed from the study. The  researchers or the study sponsor might 
also decide to stop the study at any time. 
 
If you decide to stop being in the study, or are removed from the study, or 
the study is stopped the researcher will ask you to return for a final close-out 
visit or evaluation and return unused study medication. 
 
HOW WILL INFORMATION ABOUT ME AND MY PARTICIPATION BE 
KEPT CONFIDENTIAL? 
 
The researchers will do their best to make sure that your private information is 
kept confidential. Information about you will be handled as confidentially as 
possible, but participating in research may involve a loss of privacy and the 
potential for a breach in confidentiality. Study data will be physically and 
electronically secured. As with any use  of electronic means to store data, 
there is a risk of breach of data security. 
 
Use of personal information that can identify you: 
 
You will be assigned a study code number that will be linked to your 
personal information. 
 
How information about you will be stored: 
 
Information about you will be stored in password-protected computers and 
locked offices. 
 
People and agencies that will have access to your information: 
 
Dr. Dumesic and the research team will have access to the research 


 
Revised July 27, 2018 
Page 13 of 20 
 
 
 
data/records/specimens and will share information through secured electronic 
files and/or or study charts that are kept in locked offices. 
 
The research team, authorized UCLA personnel, and regulatory agencies 
such as the Food and Drug Administration (FDA), may have access to study 
data and records to monitor the study. Research records provided to 
authorized, non-UCLA personnel will not contain identifiable information 
about you. Publications and/or presentations that result from this study will 
not identify you by name. 
 
To help us protect your privacy, we have received a Certificate of 
Confidentiality from the National Institutes of Health. The researchers can 
use this Certificate to legally 
refuse to disclose information that may identify you in any federal, state, or 
local civil, criminal, administrative, legislative, or other proceedings, for 
example, if there is a court subpoena. The researchers will use the 
Certificate to resist any demands for information that would identify you, 
except as explained below. 
The Certificate cannot be used to resist a demand for information from 
personnel of the United States Government that is used for auditing or 
evaluation of Federally funded projects or for information that must be 
disclosed in order to meet the requirements of the federal Food and Drug 
Administration (FDA). 
You should understand that a Certificate of Confidentiality does not prevent 
you or a member of your family from voluntarily releasing information about 
yourself or your involvement in this research. If an insurer, employer, or 
other person obtains your written consent to receive research information, 
then the researchers may not use the Certificate to withhold that 
information. 
The Certificate of Confidentiality will not be used to prevent disclosure to 
state or local authorities if there are concerns about harm to you or others. 
You should understand that a Certificate of Confidentiality does not prevent 
you or a member of your family from voluntarily releasing information about 
yourself or your involvement in this research. If an insurer, employer, or 
other person obtains your written consent to receive research information, 
then the researchers may not use the Certificate to withhold that 
information. 
 
How long information from the study will be kept: 
 
Information will be kept for an indefinite period of time. 
 
ARE THERE ANY COSTS FOR TAKING PART IN THIS STUDY? 
 
The study sponsor will supply and pay for the cost of supplying and 


 
Revised July 27, 2018 
Page 14 of 20 
 
 
 
administering the study drug and the extra-related laboratory tests. However, 
you and your insurer will be billed for the costs of all other study procedures 
as these are considered standard of care. 
 
You or your insurer will be billed for the costs of any standard medical care 
you receive during your participation in the study and you will be responsible 
for any associated co- payments and deductibles. There is a possibility that 
your medical insurance company may not cover these costs because you are 
in a research study. If this happens you might have unexpected expenses 
from being in this study, such as the costs associated with treating side 
effects. Financial counseling and itemized cost estimates are available upon 
request. 
 
WILL I BE PAID FOR MY PARTICIPATION? 
 
Personal information about you, including your name, address, and social 
security number will be released to the UCLA Accounting Office for the 
purpose of payment. 
Women who are found to be not eligible after completing the history and 
questionnaires will receive $15. Women who are found to be not eligible 
after completing the history, questionnaires, physical exam and blood tests 
will be paid $20. 
 
Women without PCOS may receive up to $200 for their participation in this 
study.  If you are in this group, you will receive 2 payments as follows: 
 
1) $20 after the eligibility visit is completed 
2) $165 after the FSIGT, DXA, and Fat Removal, visits are completed. 
 
Women with PCOS may receive up to $605 for their participation in this 
study.  If you are in this group, you will receive 4 payments as follows: 
 
1) $20 after the eligibility visit is completed 
2) $165 after the FSIGT, DXA and Fat Removal, visits are completed. 
3) $255 after completion of all 6 of the 28 day cycles when you will 
be taking flutamide or a placebo 
4) $165 after the repeat FSIGT, DXA, Fat Removal and the 30 day after 
last pill visits are completed. 
 
Women who are found to be ovulating on the day of the study procedure will be 
paid 
$15 and the procedure will be rescheduled. 
 
You will be asked to complete a form so that a check can be mailed to you 
within 2 months of completing the intervals described above. If you are paid 
$600 or more for participation in this study, your payment will be reported to 


 
Revised July 27, 2018 
Page 15 of 20 
 
 
 
the IRS. 
 
You will be be reimbursed for your parking expenses for each study visit. 
You will not be reimbursed for any other out of pocket expenses, such as 
transportation fees. 
 
WHAT OTHER THINGS SHOULD I CONSIDER BEFORE PARTICIPATION? 
 
Use of my specimens: 
 
Any specimens (e.g., tissue, blood, urine) obtained for the purposes of this 
study will become the property of the University of California. Once you 
provide the specimens you will not have access to them. The University may 
share your specimens in the future with other researchers or outside 
institutions. Information that identifies you will not be shared with anyone 
outside of UCLA. The specimens will be used for research  and such use 
may result in inventions or discoveries that could become the basis for new 
products or diagnostic or therapeutic agents. In some instances, these 
inventions  and discoveries may be of potential commercial value and may 
be patented and  licensed by the University. You will not receive any money 
or other benefits derived from any commercial or other products that may be 
developed from use of the specimens. 
MAKING YOUR CHOICES ABOUT FUTURE RESEARCH 
 
UCLA researchers may contact me in the future to ask me to take part in 
other research studies.   Please circle your answer in the boxes below. 
 
 
UCLA researchers may share my coded specimens and medical record 
information with other researchers who are studying conditions including but 
not limited to PCOS. 
These researchers will not have access to my personal identity. 
 
 
YES 
NO 
YES 
NO 


 
Revised July 27, 2018 
Page 16 of 20 
 
 
 
 
 
  
 
Signature of Participant 
Date/Time 
 
 
 
Signature of Investigator 
Date/Time 
 
 
Researcher Financial Interests in this Study 
 
The study team has no personal financial interest in any outside entity funding 
this study or other personal financial interests in entities that might reasonably 
be affected by the research. 
 
WHO CAN I CONTACT IF I HAVE QUESTIONS ABOUT THIS STUDY? 
 
The Research Team: 
 
You may contact Dr. Daniel Dumesic at (310) 794-5542 with any questions or 
concerns about the research or your participation in this study. You can also 
call the UCLA Page Operator at (310) 825-6301 to reach Dr. Dumesic 24 
hours a day, 7 days week. 
UCLA Office of the Human Research Protection Program (OHRPP): 
 
If you have questions about your rights while taking part in this study, or you 
have concerns or suggestions and you want to talk to someone other than 
the researchers about the study, you may contact the UCLA OHRPP by 
phone: (310) 825-5344; by email: mirb@research.ucla.edu or U.S. mail: 
UCLA OHRPP, 11000 Kinross Ave., Suite 211, Box 951694, Los Angeles, 
CA 90095-1694. 
 
Public Information about this Study: 
 
ClinicalTrials.gov is a website that provides information about federally and 
privately supported clinical trials. A description of this clinical trial will be 
available on http://www.ClinicalTrials.gov, as required by U.S. Law. This 
website will not include information that can identify you. At most, the 
website will include a summary of the results. You can search this website 
at any time. 
 
WHAT HAPPENS IF I BELIEVE I AM INJURED BECAUSE I TOOK PART 
IN THIS STUDY? 
 
It is important that you promptly tell the researchers if you believe that you 
have been injured because of taking part in this study. You can tell the 


 
Revised July 27, 2018 
Page 17 of 20 
 
 
 
researcher in person or call him/her at the number listed above. 
 
If you are injured as a result of being in this study, UCLA will provide 
necessary medical treatment. The costs of the treatment may be covered by 
the University of California or billed to you or your insurer just like other 
medical costs, depending on a number of factors. The University and the 
study sponsor do not normally provide any other form of compensation for 
injury. For more information about this, you may call the UCLA Office of the 
Human Research Protection Program at 310-825-5344 or send an email to 
mirb@research.ucla.edu. 
 
 
WHAT ARE MY RIGHTS IF I TAKE PART IN THIS STUDY? 
 
Taking part in this study is your choice. You can choose whether or not you 
want to participate. Whatever decision you make, there will be no penalty to 
you and you will not lose any of your regular benefits. 
• You have a right to have all of your questions answered before deciding 
whether to  take part. 
• Your decision will not affect the medical care you receive from UCLA. 
• If you decide to take part, you can leave the study at anytime. 
• If you decide to stop being in this study you should notify the research 
team right away. The researchers may ask you to complete some 
procedures in order to protect your safety. 
• If you decide not to take part, you can still get medical care from UCLA. 


 
Revised July 27, 2018 
Page 18 of 20 
 
 
 
HOW DO I INDICATE MY AGREEMENT TO PARTICIPATE? 
 
If you agree to participate in this study you should sign and date below. You 
have been given a copy of this consent form and the Research Participant’s 
Bill of Rights to keep. You will be asked to sign a separate form authorizing 
access, use, creation, or disclosure of health information about you. 
 
SIGNATURE OF THE PARTICIPANT 
 
 
Name of Participant 
 
 
 
Signature of Participant 
Date/Time 
 
 
SIGNATURE OF PERSON OBTAINING CONSENT 
 
 
Name of Person Obtaining Consent 
Contact Number 
 
 
 
Signature of Person Obtaining Consent 
Date/Time 


 
Revised July 27, 2018 
Page 19 of 20 
 
 
 
 
 
 
Appendix I - Study Flow Sheet 
 
Enroll women with PCOS and without PCOS 
Screening Visit (Informed Consent, Questionnaires) 
If eligible and wish to continue participation 
Physical Exam, Transvaginal or Abdominal Ultrasound of the Ovaries, 
Blood tests If eligible and wish to continue participation 
 
• 
Frequently-Sampled Intravenous Glucose Tolerance Test and Blood 
Tests 
• 
DEXA scan 
• 
Removal of a small amount of fat from the lower abdomen 
• 
Quality of Life Questionnaires 
Women with PCOS 
 
Women without PCOS 
Randomization to 
Study Participation is Complete 
receive flutamide or placebo 
daily for 6 complete 28-day cycles 
and until completion of all tests and evaluations 
• Take pill every morning 
• Complete daily diaries 
• Collect and store weekly urine samples 
• Monthly visit to clinic for exam and blood tests 
• Ultrasound and Quality of Life Questionnaires after cycles 3 and 6 
Post Treatment Evaluations 
• Physical Exam 
• Transvaginal of Abdominal Ultrasound of the ovaries 
• Frequently-Sampled Intravenous Glucose Tolerance Test and Blood Tests 
• DEXA scan 
• Removal of a small amount of fat from the lower abdomen 
• Final visit 30 days after the last dose of flutamide or placebo 
• Follow-up phone call 6 months after completion of study procedures 


 
Revised July 27, 2018 
Page 29 of 20 
 
 
 
 
Appendix II 
Transvaginal Ultrasound