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46, XX Disorders of Sex Development

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Flutamide

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Hormone Antagonists

Antineoplastic Agents, Hormonal

Flutamide 125 mg orally daily for six 28-day cycles.

Flutamide 125 mg orally each 28 day cycle for 6 cycles

Placebo orally each 28 day cycle for 6 cycles

Placebo

Daniel Dumesic, MD

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.

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).

Androgen Excess as a Cause for Adipogenic Dysfunction in PCOS Women

This study carefully considers the safety of low-dose flutamide in examining how hyperandrogenism in PCOS affects ovarian function, subcutaneous fat storage and glucose metabolism. The 125 mg oral dose of flutamide has been specifically chosen because it has not been associated with liver enzyme abnormalities (0%, 62.5-125 mg/day), while being as effective as high dose flutamide in improving androgenic symptoms. Furthermore, in the rare event mild elevation of hepatic enzymes occurs with low-dose flutamide despite its dose-dependency, it is easily detected and reversible.

Women with PCOS exhibit impaired glucose tolerance that correlates with abnormal subcutaneous (SC) abdominal adipocytes. Since a common denominator to these abnormalities is hyperandrogenism, we hypothesize that 6-month flutamide (antiandrogen) administration to lean PCOS women will improve glucose tolerance by glucose tolerance testing and normalize subcutaneous (SC) abdominal adipocytes, as determined by SC abdominal fat biopsy.

Oregon Health and Science University

University of California, Los Angeles

Professor, Division of Reproductive Endocrinology and Infertility

During the initial visit, a transvaginal or transabdominal pelvic ultrasonography will be performed in all participants, based on the sexual history and consent form by trained gynecologists who are part of study investigators. A transvaginal ultrasound is the accepted and validated method to assess the ovarian morphology in the study of patients with PCOS.

Diagnostic Ultrasound

After an overnight fast of at least 6 hours (ideally), a 18 ml sample of venous blood will be collected from each study participant (i.e., the basal fasting sample). About 12 ml of the venous blood will be collected in plain tubes for serum cryopreservation and subsequent analysis, and the remainder in plain tubes for immediate glucose estimation in serum.

Venous puncture

Walter E Osorio, M.D

Maria N Posada, M.D

Diana Bedoya, M.D.

Ricardo Azziz, M.D.

The goal of this observational study is to know the prevalence of PCOS among economically productive and reproductive age women from Medellín and the Valle de Aburrá, Colombia. The main questions it aims to answer are:

1. What is the phenotypic distribution of PCOS detected in women seeking medical attention as a requirement for employment in Medellín and the Valle de Aburrá, Colombia?
2. What is the effect of environmental factors, such as geographical location and diet, and biological factors (such as obesity and ethnicity/race) on the prevalence and phenotype of PCOS in this populatión?

Participants will undergo anthropometric measurements and physical examination for hirsutism, acne, alopecia, acanthosis nigricans, and thyroid enlargement. During the initial visit, a transvaginal or transabdominal pelvic ultrasonography will be performed. A sample of venous blood will be collected in plain tubes for serum cryopreservation and for immediate glucose estimation. Some participants will be rescheduled for a second evaluation visit for additional assessment when they have a possible PCOs.

During the first visit, potential study participants, scheduled for routine occupational pre-admission medical examination at Colmédicos Medical Centre, will be invited to participate in the study. Eligible study participants will be counselled on the objectives of the study and the study protocol and a copy of the consent form will be handed to them. A confidential study register containing details of potential study participants (name, age, height, weight, and contact) will be start on the first visit day. Informed written consent will be obtained from each study participant before recruitment for the study in the evaluation visit number one. All study participants personal data will be protected according to the law (ley 1581de Colombia).

1. Evaluation Visit #1:

   After obtaining an informed consent, data will be collected from each study participant using a standard format in a clinical report form (CRF) for uniform data collection from all participants. Each CRF will bear a unique serial identification number and will be written in the local language. The CRF will be filled by a trained researcher (including the PI, co-investigators and medically trained research assistants). All CRF will be checked for missing data within 24 hours of completion, and any missing data will be detected and collected immediately. At no time, will the study personnel have access to the participant´s medical occupational records, following the restrictions defined in the colombian legislation (resolution 2346 de 2007, R 1918 de 2011).

   Each participant will undergo anthropometric measurements (weight, height, waist circumference and hip circumference) and physical examination for hirsutism, acne, alopecia, acanthosis nigricans, and thyroid enlargement. Participants with an initial hirsutism (mFG) score of 4 or more (≥ 4) will be re-assessed by a physician. During the initial visit at Colmédicos, a transvaginal or transabdominal pelvic ultrasonography will be performed in all participants, based on the sexual history and consent form by trained gynecologists who are part of study investigators. A transvaginal ultrasound is the accepted and validated method to assess the ovarian morphology in the study of patients with PCOS.

   After an overnight fast of at least 6 hours (ideally), a 18 ml sample of venous blood will be collected from each study participant (i.e., the basal fasting sample). About 12 ml of the venous blood will be collected in plain tubes for serum cryopreservation and subsequent analysis, and the remainder in plain tubes for immediate glucose estimation in serum.
2. Sample Processing:

   The initial blood specimens will be labeled with the participant´s unique ID number, time and date of blood collection and date of last menstrual period (LMP). The samples will be obtained by trained laboratory personnel from Colmédicos medical center during the morning hours (08:00 to 10:00 hours), regardless of the participant's menstrual cycle. Participants with oligomenorrhoea or amenorrhoea will have a urine pregnancy done test prior to blood sampling.

   At Colmédicos laboratory, the blood samples will be separated into serum, plasma and whole blood by centrifugation for 20 minutes at 3000 rpm. The biological specimens will be stored, in small aliquots (of 1,25 ml), in 1.5 to 2.0 ml plastic containers (about 4 cryovials) able to withstand temperatures of -80 degrees centigrade. The aliquoted samples will be sent to the ABAD Zona 2 SUR laboratory (Carrera 32 No. 2 Sur 47 local 9701) in dry ice containers by the laboratory's courier staff where they will be stored at -20 degrees centigrade for a maximum of 3 months for processing. If necessary, for longer storage, the samples will be transferred to the Inser Medellin laboratory and stored at -80 degrees centigrade where they will remain in custody until their use or final disposal according to the established institutional waste management protocol.
3. Hormonal \& chemical analyses:

   Samples for hormonal assay and the initial evaluation will be batched at regular intervals for the analysis every week to provide the study participants with timely results, allow classification of participants and minimize the impact of inter-assay variability. In addition, this will allow us to timely contact participants who require additional studies.

   All participants will be evaluated in a uniform manner regardless of the phase of the cycle in which they are.
4. Evaluating subjects with "Possible PCOS":

   The cohort of participants who initially meet clinical features suggestive of PCOS (i.e., HA, OA or PCOM, will be designated as "Possible PCOS", and will undergo the following measurements in their samples:
   1. In all "Possible PCOS" subjects TSH, prolactin (PRL), and 17-HP will be measured in the basal serum samples as well as fasting glucose.

      Note: All subjects diagnosed with PCOS should have a normal TSH, PRL, and 17-HP (basally or after acute ACTH stimulation).
   2. In women presenting clinically with HA+OA, if the TV-U/S performed demonstrates PCOM the subject is classified as having PCOS phenotype A (HA+OA+PCOM); if not the subject is classified as having PCOS phenotype B (HA+OA).
   3. Subjects presenting clinically with HA only will return during the luteal phase (days 21-24) of their menstrual cycle for a serum progesterone (P4) level. Subjects with HA who demonstrate OA (i.e., luteal P4 \< 3 ng/mL) will be classified as having PCOS phenotype A if they have PCOM by TV-U/S (HA+OA+PCOM) or PCOS phenotype B (HA+OA) if they do not exhibit PCOM. HA subjects who also demonstrate PCOM, but no OA (i.e., luteal P4 ≥3 ng/mL) will be classified as PCOS phenotype C. Participants with HA, but no PCOM or OA will be classified as having isolated HA.
   4. Subjects presenting clinically with OA only, their basal serum samples will be assayed for androgen levels (total \[TT\] and free testosterone \[FT\], dehydroepiandrosterone sulphate \[DHEAS\], and androstenedione \[A4\]). Subjects with OA who demonstrate HA (i.e., elevated androgen levels) will be classified as having PCOS phenotype A if they have PCOM by TV-U/S (HA+OA+PCOM) or PCOS phenotype B (HA+OA) if they do not exhibit PCOM. OA subjects who also demonstrate PCOM, but no HA (i.e., normal androgen levels) will be classified as PCOS phenotype D. Participants with OA, but no PCOM or HA will be classified as having isolated OA.
   5. Subjects presenting with PCOM by TV-U/S will return during the luteal phase (days 22-24) of their menstrual cycle for a serum progesterone (P4) level and their basal serum samples will be assayed for androgen levels (total \[TT\] and free testosterone \[FT\], dehydroepiandrosterone sulphate \[DHEAS\], and androstenedione \[A4\]). Subjects with PCOM who demonstrate OA (i.e., luteal P4 \< 3 ng/mL) will be classified as having PCOS phenotype D. If they also demonstrate HA (i.e., elevated androgen levels) (HA+OA+PCOM) will be classified as having PCOS phenotype A. PCOM subjects who also demonstrate HA, but no OA (i.e., luteal P4 ≥3 ng/mL) will be classified as PCOS phenotype C. Participants with PCOM, but no HA or OA will be classified as having isolated PCOM.
5. Diagnosing PCOS:

   Related or mimicking disorders will be excluded using history, physical examination, and serum TSH, PRL and 17-OHP. Study participants with a basal 17-OHP \>2 ng/ml (or 200 ng/dl) will undergo a repeat 17-OHP measurement in the follicular phase and if the 17-OHP is still \> 2ng/mL an acute adrenocorticotrophic hormone (ACTH) stimulation test will be performed to exclude non-classical congenital adrenal hyperplasia (NCAH). We estimate, considering our previous data, that approximately 6% of subjects screened will require an acute ACTH stimulation test.

   Overall, PCOS will be diagnosed when subjects present with either HA+OA+PCOM (phenotype A), HA+OA (phenotype B), HA+PCOM (phenotype C) and OA+PCOM (phenotype D) and demonstrate normal levels of TSH (0,37 to 4,7 mUI/L), PRL (\<25 ng/mL) and 17-OHP, per our diagnostic algorithm.
6. Evaluation visit #2:

   In the following cases subjects will be rescheduled for a second evaluation visit (evaluation visit #2) for additional assessment:
   1. All subjects with PCOS will be scheduled for a return visit to undergo a 2-hour 75g oral glucose tolerance test (OGTT) with 3 ml of venous blood collected in serum tubes at 0 minutes and at 120 minutes post-glucose load. Glucose and insulin (from serum tubes) levels will be assessed at 0 and 120 min.
   2. Participants will be reevaluated during the follicular phase of the menstrual cycle (between day 1 and 5):

   i. With a repeat ultrasound in case there is a dominant follicle (≥ 10 mm) or an ovarian cyst at the initial ultrasound evaluation.

   ii. A repeat 17-hydroxyprogesterone (17-OHP) measurement in the event the initial 17-OHP is \>2 ng/mL and was obtained during the luteal phase according to menstrual history. Approximately 50% of Participants evaluated in luteal phase are expected to have a 17-OHP \>2 ng/mL.

   iii. An acute intravenous (iv) ACTH-1-24 (0.25 mg) stimulation test, if the initial and repeat 17-OHP obtained during the follicular phase, according to menstrual history, is \> 2 ng/mL.
7. Reassessing hormonal levels:

At the completion of the study, a repeat analysis of the samples for androgen levels in all PCOS subjects and a group of 'super-controls' (30 controls) will be performed at a reference laboratory. A fasting glucose level also be analyzed in a group of super controls (100 controls). Genetic analysis could be performed depending on the availability of financial support in a reference laboratory.

Phenotype and Epidemiology of the Polycystic Ovary Syndrome (PCOS) in Colombia (PEP - Colombia) Study.

Prevalence of PCOS among a medically unselected population-based sample representing the Latino population. In addition, Percentage of participants with phenotype A, B, C or D, among participants diagnosed with PCOS.

Percentage of participants with obesity, endocrine disorders, metabolic syndrome, hyperandrogenism, hirsutism, oligomenorrhea, anovulation and irregular menses among the study population, which will also have a detailed description of their demographic characteristics

University of Alabama at Birmingham

Colmédicos S.A.S.

ABAD Laboratorio

Instituto de fertilidad humana, InSer

Anti-Inflammatory Agents

Antiemetics

Gastrointestinal Agents

Reproductive Control Agents

Dexamethasone

Dexamethasone acetate

Testosterone

Chorionic Gonadotropin

Glucocorticoids

Intervention: Each subject in the PCOS group will receive 1 mg of oral dexamethasone in the evening and return in the morning for an injection of 25ug of IV recombinant human chorionic gonadotropin. Subjects will also have blood drawn at times -0.5, 0, 0.5, and 24 hours after the injection of r-hCG for measurement of steroid hormones.

Intervention: Each subject in the Normal group will receive dexamethasone 1 mg orally in the evening and return the next morning for an injection of 25ug of IV recombinant human chorionic gonadotropin. Subjects will the have blood drawn at -0.5, 0, 0.5, and 24 hours after hCG injection for steroid hormone measurements.

Intervention: Each subject in the Oligomenorrhea group will receive dexamethasone 1 mg orally in the evening and return the next morning for an injection of 25ug of IV recombinant human chorionic gonadotropin. Subjects will the have blood drawn at -0.5, 0, 0.5, and 24 hours after hCG injection for steroid hormone measurements.

Each subject in each group will receive 1 mg of oral dexamethasone in the evening and return in the morning for an injection of 25ug of IV recombinant human chorionic gonadotropin. Subjects will also have blood drawn at times -0.5, 0, 0.5, and 24 hours after the injection of r-hCG for measurement of steroid hormones.

Each subject in each group will receive 1 mg of oral dexamethasone in the evening and return in the morning for an injection of 25ug of IV recombinant human chorionic gonadotropin (r-hCG). Subjects will also have blood drawn at times -0.5, 0, 0.5, and 24 hours after the injection of r-hCG for measurement of steroid hormones.

recombinant human chorionic gonadotropin (r-hCG)

R. Jeffery Chang, M.D.

In women with polycystic ovary syndrome (PCOS), the cardinal physiological abnormality is excessive ovarian androgen production marked by increased serum testosterone (T) and androstenedione (A) levels. Studies to determine the alteration in ovarian steroidogenesis that lead to abnormal production of ovarian androgens have revealed increased CYP17 gene expression with accentuated 17-hydroxylase activity leading to exaggerated 17-hydroxyprogesterone (17P) responses to luteinizing hormone (LH) stimulation. In contrast, T and A responses did not distinguish between PCOS and normal women, although these androgens were clearly greater in the former compared to the latter group. As a result, 17P responsiveness has been employed to determine the functional capacity of the ovary to produce androgens. The stimulatory agents that have been used included GnRH agonist, Lupron, at a dose of 10 microgram per kilogram, or hCG at a dose of 10,000 IU. The investigators propose to conduct a study that will determine the pattern of androgen responsiveness to 25ucg of hCG after 24 hours in adolescents with PCOS, those with oligomenorrhea, and in normal controls. This will allow for a comparison of these adolescents' ovarian functional capacity to produce androgens.

In women with polycystic ovary syndrome (PCOS), the cardinal physiological abnormality is excessive ovarian androgen production marked by increased serum testosterone (T) and androstenedione (A) levels. Studies to determine the alteration in ovarian steroidogenesis that lead to abnormal production of ovarian androgens have revealed increased CYP17 gene expression with accentuated 17-hydroxylase activity leading to exaggerated 17-hydroxyprogesterone (17P) responses to luteinizing hormone (LH) stimulation. In contrast, T and A responses did not distinguish between PCOS and normal women, although these androgens were clearly greater in the former compared to the latter group. As a result, 17P responsiveness has been employed to determine the functional capacity of the ovary to produce androgens. The stimulatory agents that have been used included GnRH agonist, Lupron, at a dose of 10 microgram per kilogram, or hCG at a dose of 10,000 IU.We propose to conduct a study that will determine the pattern of androgen responsiveness to 25ucg of hCG after 24 hours in adolescents with PCOS, those with oligomenorrhea, and in normal controls. This will allow for a comparison of these adolescents' ovarian functional capacity to produce androgens.

Theca Cell Function in Adolescents With Polycystic Ovary Syndrome (PCOS)

Assess serum levels of 17OHP after stimulation with recombinant hCG

Assess seruim levels of testosterone after stimulation with recombinant hCG

Assess serum levels of androstenedione after stimaultion with recombinant hCG

Assess serum levels of DHEA after stimulation with recombinant hCG

University of Virginia

University of California, San Diego

Principal Investigator

The number of participants at risk for Other Adverse Events, All-Cause Mortality, and Serious Adverse Events should be 24

PCOS Group

Normal Group

Oligomenorrhea Group

Total

Age, Continuous

Sex: Female, Male

Race and Ethnicity were not collected from any participant.

Race and Ethnicity Not Collected

Oligpomenorrhea subjects not part of study

Dr. R. Jeffrey Chang

17OHP Levels After hCG

Intervention: Each subject in the Normal group will receive dexamethasone 1 mg orally in the evening and return the next morning for an injection of 25ug of IV recombinant human chorionic gonadotropin. Subjects will the have blood drawn at -0.5, 0, 0.5, and 24 hours after hCG injection for steroid hormone measurements.

.

Oligpmenrreha group not included in study

Oligomenorreha group not inlcuded in study

Androstenedione

Oligomenrrhea group not included in study

DHEA

Intervention: Each subject in the PCOS group will receive dexamethasone 1 mg orally in the evening and return the next morning for an injection of 25ug of IV recombinant human chorionic gonadotropin. Subjects will the have blood drawn at -0.5, 0, 0.5, and 24 hours after hCG injection for steroid hormone measurements.

Dexamethasone: Each subject in each group will receive 1 mg of oral dexamethasone in the evening and return in the morning for an injection of 25ug of IV recombinant human chorionic gonadotropin. Subjects will also have blood drawn at times -0.5, 0, 0.5, and 24 hours after the injection of r-hCG for measurement of steroid hormones.

recombinant human chorionic gonadotropin (r-hCG): Each subject in each group will receive 1 mg of oral dexamethasone in the evening and return in the morning for an injection of 25ug of IV recombinant human chorionic gonadotropin (r-hCG). Subjects will also have blood drawn at times -0.5, 0, 0.5, and 24 hours after the injection

Intervention: Each subject in the Normal group will receive dexamethasone 1 mg orally in the evening and return the next morning for an injection of 25ug of IV recombinant human chorionic gonadotropin. Subjects will the have blood drawn at -0.5, 0, 0.5, and 24 hours after hCG injection for steroid hormone measurements.

Dexamethasone

There Were Only 2 Groups: PCOS and Normal Subjects

Overall Study

Menstruation Disturbances

Adult women will be assigned to this category if they report a history of regular menstrual cycles.

Adult women will be assigned to this category if they report a history of irregular menstrual cycles, including women with a pre-existing diagnosis of PCOS.

Marla E. Lujan, PhD

In women with regular menstrual cycles, antral follicles have been shown to grow in synchronous cohorts, called waves, 2-3 times in a menstrual cycle. It is unknown whether these waves of follicle growth also occur in women with amenorrhea or if there is abnormal/absent follicle growth. Further, oligo- or amenorrhea has been associated with metabolic disturbances, such as over- or under-nutrition, central obesity and insulin resistance. Yet, mechanisms whereby metabolic factors influence folliculogenesis in women are poorly understood. To understand potential mechanisms, the investigators plan to characterize follicle growth dynamics in women with or without regular menstrual cycles and identifying key metabolic differences in these women which may be important in normal follicle development and fertility.

In the ovaries, eggs rest in fluid filled sacs called follicles. When follicles grow they form small fluid-filled cysts that can be easily seen when we use ultrasound to view the ovaries. In women with regular menstrual cycles, groups of 10 to 20 follicles grow and regress at 2 or 3 different times during their cycle (usually over a 28- day period). Several of these follicles grow to a stage where they begin to develop the potential to ovulate - but in general only one follicle is chosen to ovulate. Thus, at any given time during the menstrual cycle, numerous fluid-filled follicles can be visualized in a woman's ovaries at various stages of development using transvaginal ultrasonography. In women with absent or infrequent menstrual cycles, very little is known about the growth patterns of their follicles and how factors such as metabolic hormones, might play a role in the failure to ovulate. Being underweight or overweight increases your chances of having irregular or absent menstrual cycles and that a history of abnormal reproductive function compounds a woman's risk for chronic diseases such as infertility, diabetes, hypertension, atherosclerosis and certain cancers. This is particularly the case for women with polycystic ovary syndrome (PCOS) that have menstrual cycles that appear to worsen or improve depending on their body weight and metabolic status. PCOS is an endocrine disorder that affects 6-12% of reproductive-aged women within the general population. The hallmark features of PCOS are menstrual irregularity, increased levels of androgens, and polycystic ovaries. The current diagnostic criteria require 2 out of 3 of these features to be present for the diagnosis, therefore a number of phenotypes of PCOS exist. However, the metabolic and reproductive differences across the phenotypic spectrum of PCOS are not well understood. Women with PCOS characteristically have polycystic ovaries, where up to 10 times more follicles are present in the ovary at any given time. Further, the follicle-size populations and overall distribution throughout the ovary varies in women - follicles may be situated around the periphery of the ovary or may be distributed throughout the ovary. Presumably these small follicles are arrested in development - but emerging data from the Lujan laboratory suggest that this is not the case. It is assumed that ovulation does not occur and that follicles do not grow in a normal wave pattern. In truth, no study has ever looked to see whether follicles are actually growing, regressing or are arrested in women with irregular/absent menstrual cycles. By comparing follicle wave dynamics, reproductive hormones and markers of metabolism in women with regular and irregular menstrual cycles, the researchers plan to identify what factors might explain why fertility potential and long-term health are compromised in some women but not in others. Further, we will determine if any of these metabolic factors are unique to PCOS representing specific metabolic risks or follicle growth impairment. The ultimate goal of this research is to understand how body composition, nutrition and metabolism regulate follicle development in women so we can better develop lifestyle and drug therapies to help women preserve their fertility and long-term health. Since obesity has recently become the leading cause of infertility in North America, these studies are especially important.

To accomplish our objective, the investigators plan to recruit up to 40 women with regular menstrual cycles and up to 40 women with irregular/absent menstrual cycles. Our goal is to recruit an equal number of women in each group such that they are matched for age (18 - 35 years old) and body mass index (BMI; Normal weight = 18 - 24 kg/m2; Overweight = 25 - 29 kg/m2; Obese = 30kg/m2). Women will undergo serial ultrasonographic of their ovaries every other day from ovulation to ovulation in women with regular menstrual cycles or for 5 weeks in women with cycle irregularity. Blood samples will be collected at each visit. Ultrasound scans of the ovaries will be assessed for the total number, size, and distribution of follicles using ultrasound imaging techniques. Blood samples collected will be assayed to determine serum concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol, progesterone, anti-müllerian hormone (AMH), and inhibin B. During day 3-5 in women with regular menstrual cycles or at a time where no dominant follicle or corpus luteum is present, an early morning visit will be conducted to assess the following metabolic parameters : (1) 75-gram oral glucose tolerance test to characterize glucose and insulin dynamics at 0, 30, 60, 90, and 120 minutes post-glucose ingestion; (2) dual X-ray absorptiometry (DXA) scan to quantify body fat and lean muscle distribution; (3) vitals and anthropometry assessment to measure waist and hip circumference, height, weight, blood pressure, and heart rate, and (4) fasting blood tests to detect serum concentrations of androgens (i.e., total testosterone, androstenedione, free androgen index) and serum markers of metabolic syndrome (i.e., lipids and hemoglobin A1C); (5) optional subcutaneous fat biopsy to analyze fat cells, which represent a site of reproductive hormone synthesis.

Ultrasound Characterization of Ovarian Follicle Dynamics in Women With Amenorrhea

The number of all antral follicles in each ovary will be determined using ultrasonography for each participant. Changes in follicle number over time will be compared between groups.

The diameter of all follicles \>2mm will be determined using ultrasonography for each participant. Changes in follicle diameter over time will be compared between groups.

The size of each ovary will be determined using ultrasonography for each participant during study participation and compared between groups.

The serum AMH concentration will be determined during study participation and assessed in association with the change in follicle number, diameter and between groups.

The serum FSH concentration will be determined during study participation and assessed in association with the change in follicle number, diameter and between groups.

The serum progesterone concentration will be determined during study participation, assessed in association with luteal dynamics and compared between groups.

The ratio of circulating LH to FSH concentrations will be determined for each participant and compared between groups.

Insulin sensitivity will be determined by administration of an oral glucose tolerance test and compared between groups.

Total testosterone, androstenedione and free androgen index concentrations in serum will be determined and compared between groups.

Average menstrual cycle length as determined by self-reported history and the menstrual cycle length during study participation will be determined and compared between groups.

Degree of hirsutism as judged by the Ferriman-Gallwey scale will be determined and compared between groups.

Lipids, glucose and HbA1C concentrations will be determined and compared between groups.

Blood pressure will be determined and compared between groups.

The ratio of weight to height will be determined and compared between groups.

The ratio of waist circumference to hip circumference will be determined and compared between groups.

Percentage and distribution of fat and lean mass as assessed using DXA technology will be compared between groups.

Fat cells, representing an important site of reproductive hormone production, will be compared between groups.

Cornell University

Central Nervous System Depressants

Other Dietary Supplements

Benzocaine

Tannic Acid

Subjects in experimental group will receive a standardized acupuncture treatment, 10 times per 4 weeks for 16 weeks with a total of 40 sessions in addition to usual care.

Subjects in control group will receive usual care only.

Acupuncture intervention Disposable, sterilized needles (0.25×40 mm and 0.30×50 mm) will be used and selected acupoints will include GV20, CV4, and bilateral BL32, ST25, ST29, EX-CA1, LI4, LR3, SP6, SP9. Subject will be prone position first and BL32 will be inserted with an angle of 30-45° in an inferomedial direction and a depth of 30-50 mm. Once the subject has a needle sensation ('De-qi'), the needle will be removed immediately. Then the subject will be supine position, and GV20, CV4, ST25, ST29, EX-CA1, LI4, LR3, SP6, SP9 will be needled with a depth of 10-40mm. After subject feel 'De-qi', the needles will be placed for 20 min to maintain the stimulation.

Usual care intervention The subjects will receive the health advice including diet with regular meal, enough sleep, and appropriate exercise.

Behavioral: Usual care Usual care intervention The subjects will receive the health advice including diet with regular meal, enough sleep, and appropriate exercise.

Acupuncture+Usual care

Usual care intervention The subjects will receive the health advice

Usual care

Chunlan Jin, MD

Jiping Zhao, MD

Jin-Moo Lee, KMD, PhD.

This study is an international multicenter, pilot randomized, assessor-blind, controlled trial, which is aimed to preliminarily investigate the efficacy and safety of acupuncture on oligomenorrhea due to polycystic ovary syndrome (PCOS).

A total of 60 subjects will be recruited and randomly allocated into experimental or control group with 30 subjects respectively. The subjects in experimental group will receive a standardized acupuncture treatment plus usual care, whereas the ones in control group will be managed only with usual care.

Acupuncture for Oligomenorrhea Due to Polycystic Ovary Syndrome

Efficacy and Safety of Acupuncture on Oligomenorrhea Due to Polycystic Ovary Syndrome: an International Multicenter, Pilot Randomized Controlled Trial

The agreement for sharing IPD is not designed to be signed in informed consent form.

Menstrual cycle improvement will be assessed by menstrual frequency (cycle/month).

Menstrual period is assessed in days from the 1st day of menstruation cycle to 1st day of the next menstruation cycle.

Change in the level of serum estradiol in pg/mL

Change in the level of serum luteinizing hormone (LH) in mIU/mL

Change in the level of serum follicle stimulating hormone (FSH) in mIU/mL

Change in the level of serum free testosterone (T) in ng/mL

The ratio is calculated based on the value of LH and FSH.

Change in the number of antral follicles of the ovary and ovarian volume by ultrasound imaging.

Body Mass Index (BMI) is defined as the body weight divided by the square of height, and expressed in kg/m2.

The ratio is calculated based on the length of waist and hip.

Acne severity is assessed by Pillsbury acne grading system. The grade of Pillsbury acne grading system ranges from 0 to 4. The high-scored grade means the more severe acne (i.e., grade 0 is considered to be normal, and grade 4 is considered severe).

SF-36 is a 36-item, patient-reported survey of patient health, which consists of eight sections. The score of SF36 ranges from 0 to 100. The higher the score, the less disability, i.e., a score of 0 is equivalent to maximum disability and a score of 100 is equivalent to no disability.

All expected or unexpected adverse events in both groups will be measured at every study visit.

* Assessment of severity: mild, moderate, severe
* Assessment of relation: definitely related, probably related, possibly related, probably not related, definitely not related, unknown.

The incidence of patients with abnormal complete blood count which includes the white blood cells count in ×10\^9/L, the red blood cells count in ×10\^12/L, platelets count in number ×10\^9/L, and hemoglobin in g/L, and hematocrit in %.

Incidence of patients with abnormal erythrocyte sedimentation rate in mm/h.

Incidence of abnormal lactate dehydrogenase and creatine phosphokinase. Incidence of patients with abnormal lactate dehydrogenase in U/L, and creatinine phosphokinase in U/L.

Incidence of patients with abnormal liver function evaluated by serum aspartate aminotransferase in U/L, alanine aminotransferase in U/L, and γ-glutamyl-transpeptidase in U/L, alkaline phosphatase U/L, total protein in g/L, and albumin in g/L.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Androgen Excess as a Cause for Adipogenic Dysfunction in PCOS Women	NCT01889199	Polycystic Ovar...	Flutamide Placebo	18 Years - 35 Years	University of California, Los Angeles
Phenotype and Epidemiology of the Polycystic Ovary Syndrome (PCOS) in Colombia (PEP - Colombia) Study.	NCT05926115	Polycystic Ovar... Hyperandrogenis... Endocrine Syste...	Diagnostic Ultr... Venous puncture	18 Years - 45 Years	Instituto de fertilidad humana, InSer
Phenotype and Epidemiology of the Polycystic Ovary Syndrome (PCOS) in Colombia (PEP - Colombia) Study.	NCT05926115	Polycystic Ovar... Hyperandrogenis... Endocrine Syste...	Diagnostic Ultr... Venous puncture	18 Years - 45 Years	Instituto de fertilidad humana, InSer
Theca Cell Function in Adolescents With Polycystic Ovary Syndrome (PCOS)	NCT01154192	PCOS	Dexamethasone recombinant hum...	12 Years - 18 Years	University of California, San Diego
Ultrasound Characterization of Ovarian Follicle Dynamics in Women With Amenorrhea	NCT01927432	Oligomenorrhea Amenorrhea Polycystic Ovar...		18 Years - 35 Years	Cornell University
Acupuncture for Oligomenorrhea Due to Polycystic Ovary Syndrome	NCT04509817	Polycystic Ovar... Oligomenorrhea	Acupuncture+Usu... Usual care	20 Years - 40 Years	China Academy of Chinese Medical Sciences
Acupuncture for Oligomenorrhea Due to Polycystic Ovary Syndrome	NCT04509817	Polycystic Ovar... Oligomenorrhea	Acupuncture+Usu... Usual care	20 Years - 40 Years	China Academy of Chinese Medical Sciences

Spots Global Cancer Trial Database for oligomenorrhea