Relative Contributions of Predictors of Hyperandrogenism in Older vs. Young Women With PCOS
Relative Contributions of Predictors of Hyperandrogenism in Older vs. Young Women With PCOS
The objective of the study is to determine the relative contributions of four established
 predictors of hyperandrogenism (luteinizing hormone [LH] secretion, ovarian response to
 recombinant human chorionic gonadotropin [r-hCG] administration, adrenal response to
 adrenocorticotropic hormone [ACTH] administration, and hyperinsulinemia) in older vs. young
 women with Polycystic Ovary Syndrome (PCOS) in a cross-sectional, physiological study. The
 investigators hypothesize that hyperinsulinemia is a stronger independent predictor of free
 testosterone (T) in older reproductive aged (vs. young) women with PCOS.
PCOS is a highly prevalent reproductive disorder characterized by hyperandrogenism (HA) and
 oligo/anovulation. PCOS is also associated with metabolic syndrome, obesity and insulin
 resistance. In young women with PCOS, several factors contribute to HA: a) excess LH
 secretion, b) abnormal ovarian steroidogenesis, c) abnormal adrenal steroidogenesis, and d)
 hyperinsulinemia/ insulin resistance. Of interest, HA (and menstrual function) improves with
 age in PCOS. However, the relative contributions of the aforementioned HA-related factors in
 young adult vs. late reproductive-aged women with PCOS are not known. Identifying the most
 important predictor(s) of HA in older women with PCOS will be critically important for
 devising the most relevant therapeutic strategies for older women with PCOS. The
 investigators propose to determine the relative contributions of four established predictors
 of HA (LH secretion, ovarian response to r-hCG administration, adrenal response to ACTH
 administration, and hyperinsulinemia) in older vs. young women with PCOS in a physiological
 study. The investigators hypothesize that hyperinsulinemia is a stronger independent
 predictor of free testosterone (T) in older reproductive aged (vs. young) women with PCOS. In
 addition, the investigators hypothesize that, in older vs. young women with PCOS: a) ovarian
 response to r-hCG will be a weaker independent predictor of free T; b) mean LH will be a
 stronger independent predictor of free T; and c) the predictive ability of adrenal response
 to ACTH will be similar. This will be a cross-sectional physiological study. Ordinary Least
 Square (OLS) regression will be utilized to determine the relative contributions of 4
 established predictors of HA in older vs. young women with PCOS. Statistical plans include
 intra-age group hypothesis testing, inter-age group hypothesis testing, and a ranking of the
 importance of predictors in each age group.
Inclusion Criteria:

 -  Women with PCOS aged 20-30 years and 40-49 years. Subject is considered to have PCOS
 if she has current or verifiable history of: a) clinical and/or biochemical evidence
 of hyperandrogenism plus b) oligomenorrhea (average menstrual cycle length >45 days or
 fewer than 9 menses/year) or irregular menstruation (substantially inconsistent
 menstrual cycle length). Note: For subjects aged 40-49 years, they will be allowed to
 participate if they have fewer than 10 menses/year (average menstrual cycle length >35
 days) as long as they have a compelling past history of oligomenorrhea or irregular
 menstruation.

 -  Screening safety labs within normal reference ranges although mild abnormalities that
 are common in obesity and/or hyperandrogenism will not be grounds for exclusion (see
 exclusion criteria).

 -  Subjects must be willing and able to provide written informed consent.

 -  Willingness to strictly avoid pregnancy (using non-hormonal methods) during the time
 of 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 elevated
 follicle stimulating hormone [FSH] level)

 -  Biochemical evidence for perimenopause as defined by an anti-Mullerian hormone <0.5
 ng/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 perimenopause
 status. NOTE: If FSH >9 IU/L on screening (but it is not cycle day 3), FSH and
 estradiol 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 pregnancy
 test 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) >200
 ng/dL, which suggest the possibility of congenital adrenal hyperplasia. 17-OHP will be
 collected during follicular phase. NOTE: if a 17-OHP >200 ng/dL and is confirmed on
 repeat testing, an ACTH-stimulated 17-OHP <1000 ng/dL will be required for study
 participation.

 -  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 be
 seen in PCOS, so elevations < 1.5 times the upper limit of normal will be accepted in
 these groups).

 -  Virilization

 -  Diagnosis of diabetes mellitus (DM), fasting glucose ≥ 126 mg/dL, or a hemoglobin A1c
 of ≥ 6.5%.

 -  Abnormal thyroid stimulating hormone (TSH). Subjects with stable and
 adequately-treated hypothyroidism, reflected by normal TSH values, will not be
 excluded.

 -  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 will
 be accepted in the setting of known Gilbert's syndrome. Mild transaminase elevations
 may be seen in women with obesity, so elevations <1.5 times the upper limit of normal
 will 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 mg
 twice daily) will be excluded from study participation.

 -  Abnormal sodium, potassium, or bicarbonate concentrations or elevated creatinine
 concentration.

 -  Significant history of pulmonary dysfunction (e.g., asthma or COPD requiring
 intermittent 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 normal
 triglyceride 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-hCG
 injection will be 18 mm. Since the ultrasound will be assessed 3-4 days prior to r-hCG
 administration, we will estimate the size of the dominant follicle (at the time of
 r-hCG administration) using the typical rate of ovarian follicle growth of 1.4 mm per
 day. If the dominant follicle size exceeds the cut off threshold, the subject will be
 asked to repeat the transvaginal ultrasound: if menses begin within 3 weeks of the
 prior ultrasound, the ultrasound would be repeated during the new menstrual cycle. If
 menses do not occur within 3 weeks of the prior ultrasound, the ultrasound will then
 be scheduled at the subject's earliest convenience.

 -  Ovarian enlargement, defined by ovarian volume greater than 15 mm on transvaginal
 ultrasound. If the ovarian volume exceeds the cut off threshold, the participant will
 be given an option to repeat the transvaginal ultrasound in 2-3 months.

 -  History of venous thromboembolism (e.g. deep venous thrombosis (DVT), pulmonary
 embolism (PE)).

 -  History of blood clotting disorders (e.g., protein C, protein S, positive
 antiphospholipid antibodies).

 -  First-degree relative history of blood clotting disorder, unless the same disorder has
 been formally excluded for the study subject. Note: any abnormal labs may be repeated
 to exclude a lab error.

 -  No medications known to affect the reproductive system can be taken in the 2 months
 prior to screening and 3 months prior to the study. Such medications include oral
 contraceptive pills, metformin, progestins, glucocorticoids, anti-psychotics and/or
 mood stabilizers that are known to cause hormone abnormalities.