Relative Contributions of Predictors of Hyperandrogenism in Older vs. Young Women With PCOS

Inclusion Criteria:

• Women with PCOS aged 20-30 years and 40-49 years. Subject is considered to have PCOSif she has current or verifiable history of: a) clinical and/or biochemical evidenceof hyperandrogenism plus b) oligomenorrhea (average menstrual cycle length >45 days orfewer than 9 menses/year) or irregular menstruation (substantially inconsistentmenstrual cycle length). Note: For subjects aged 40-49 years, they will be allowed toparticipate if they have fewer than 10 menses/year (average menstrual cycle length >35days) as long as they have a compelling past history of oligomenorrhea or irregularmenstruation.
• Screening safety labs within normal reference ranges although mild abnormalities thatare common in obesity and/or hyperandrogenism will not be grounds for exclusion (seeexclusion criteria).
• Subjects must be willing and able to provide written informed consent.
• Willingness to strictly avoid pregnancy (using non-hormonal methods) during the timeof the study
• Willingness and ability to comply with scheduled visits and study procedures

Exclusion Criteria:

• Postmenopausal status (i.e., absence of periods for previous year plus elevatedfollicle stimulating hormone [FSH] level)
• Biochemical evidence for perimenopause as defined by an anti-Mullerian hormone <0.5ng/mL. As an alternative, cycle day 3 FSH > 9 IU/L (with concomitant estradiol level >80 pg/mL), if this testing is available, will serve as evidence of perimenopausestatus. NOTE: If FSH >9 IU/L on screening (but it is not cycle day 3), FSH andestradiol will be repeated on cycle day 3.
• History of hysterectomy and/or bilateral oophorectomy
• BMI ≥ 40 kg/m2
• Inability to comprehend what will be done during the study or why it will be done.
• Being a study of older women with PCOS, children and men will be excluded.
• Pregnancy or lactation within the past 6 months. Subjects with a positive pregnancytest will be informed of the result by the screening physician.
• Prisoners.
• History of (or clinical evidence for) Cushing's syndrome or adrenal insufficiency.
• History of congenital adrenal hyperplasia or 17-hydroxyprogesterone (17-OHP) >200ng/dL, which suggest the possibility of congenital adrenal hyperplasia. 17-OHP will becollected during follicular phase. NOTE: if a 17-OHP >200 ng/dL and is confirmed onrepeat testing, an ACTH-stimulated 17-OHP <1000 ng/dL will be required for studyparticipation.
• Total testosterone >150 ng/dL, which suggests the possibility of virilizing neoplasm.
• DHEA-S greater than 1.5 times the upper limit of normal range (mild elevations may beseen in PCOS, so elevations < 1.5 times the upper limit of normal will be accepted inthese groups).
• Virilization
• Diagnosis of diabetes mellitus (DM), fasting glucose ≥ 126 mg/dL, or a hemoglobin A1cof ≥ 6.5%.
• Abnormal thyroid stimulating hormone (TSH). Subjects with stable andadequately-treated hypothyroidism, reflected by normal TSH values, will not beexcluded.
• Moderate to severe hyperprolactinemia. Mild prolactin elevations may be seen in PCOS,and elevations < 1.5 times the upper limit of normal will be accepted in this group.
• Persistent liver abnormalities, with the exception that mild bilirubin elevations willbe accepted in the setting of known Gilbert's syndrome. Mild transaminase elevationsmay be seen in women with obesity, so elevations <1.5 times the upper limit of normalwill be accepted in this group.
• Hemoglobin level is less than 11 g/dL.
• Persistent hematocrit <36% and hemoglobin <12 g/dL.
• Subjects who remain anemic after two sequential months of ferrous gluconate (325 mgtwice daily) will be excluded from study participation.
• Abnormal sodium, potassium, or bicarbonate concentrations or elevated creatinineconcentration.
• Significant history of pulmonary dysfunction (e.g., asthma or COPD requiringintermittent systemic corticosteroid, pulmonary hypertension, etc.).
• History of known or suspected congestive heart failure.
• History of known or suspected ischemic heart disease or cerebrovascular disease.
• History of moderate to severe hypertriglyceridemia (triglyceride level > 500 mg/dL).Subjects with stable and adequately treated hypertriglyceridemia reflected by normaltriglyceride values will not be excluded.
• History of breast, ovarian, or endometrial cancer.
• The cut off threshold for estimated dominant ovarian cyst size on the day of r-hCGinjection will be 18 mm. Since the ultrasound will be assessed 3-4 days prior to r-hCGadministration, we will estimate the size of the dominant follicle (at the time ofr-hCG administration) using the typical rate of ovarian follicle growth of 1.4 mm perday. If the dominant follicle size exceeds the cut off threshold, the subject will beasked to repeat the transvaginal ultrasound: if menses begin within 3 weeks of theprior ultrasound, the ultrasound would be repeated during the new menstrual cycle. Ifmenses do not occur within 3 weeks of the prior ultrasound, the ultrasound will thenbe scheduled at the subject's earliest convenience.
• Ovarian enlargement, defined by ovarian volume greater than 15 mm on transvaginalultrasound. If the ovarian volume exceeds the cut off threshold, the participant willbe given an option to repeat the transvaginal ultrasound in 2-3 months.
• History of venous thromboembolism (e.g. deep venous thrombosis (DVT), pulmonaryembolism (PE)).
• History of blood clotting disorders (e.g., protein C, protein S, positiveantiphospholipid antibodies).
• First-degree relative history of blood clotting disorder, unless the same disorder hasbeen formally excluded for the study subject. Note: any abnormal labs may be repeatedto exclude a lab error.
• No medications known to affect the reproductive system can be taken in the 2 monthsprior to screening and 3 months prior to the study. Such medications include oralcontraceptive pills, metformin, progestins, glucocorticoids, anti-psychotics and/ormood stabilizers that are known to cause hormone abnormalities.