Ovarian Morphology and Theca Cell Androgen Production in Women With Polycystic Ovary Syndrome (PCOS)
Condition: Polycystic Ovary Syndrome
MeSH terms: Polycystic Ovary Syndrome; Syndrome
Study type: Interventional

Summary: 
      Women with PCOS suffer from excess male hormone (androgen) production by the ovary. Androgen
      is made by cells that surround follicles that contain eggs. As the follicles (and eggs) grow
      and mature, there are more androgen producing cells. Women with PCOS have more follicles than
      normal women and therefore more androgen producing cells. While androgen production has been
      associated with the number of follicles, the relationship to the individual size of follicles
      in PCOS or normal women. This study intends to determine whether the size and number of
      ovarian follicles are correlated to androgen production in PCOS and normal women.
    

Detailed description: 
      In women with polycystic ovary syndrome (PCOS), the major 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 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 androgen. Stimulatory agents have included GnRH agonist,
      Lupron, at a dose of 10 microgram per kilogram, or hCG at a dose of 10,000 IU.

      The investigators recently showed that hCG administered intravenously in a dose-response
      fashion revealed gradual increases of 17P and a non-dose dependent increase of serum T and A.
      The pattern of steroid hormone production revealed the predominant pathway by which androgens
      are generated in women with PCOS. Extending these studies, the investigators selected the
      mid-maximal dose of hCG to stimulate ovarian androgens and included morphometric measures of
      the ovary, such as ovarian follicle number (as determined by ultrasound) and related
      hormones, such as anti-mullerian hormone and inhibin B, both products of the ovarian
      follicle. The results showed that increased androgen and 17P responses in PCOS women were
      associated with increased antral follicle number and greater AMH levels compared to normal
      women. Inhibin B levels were similar between groups.

      Based on responses observed in normal women, the PCOS women were divided into two groups.
      Those with 17P responses that did not exceed the normal mean plus 2 standard deviations
      (normal responder PCOS; NR-PCOS) and those that did exceed the normal response (high
      responder PCOS; HR-PCOS). This separation occurred at a rate of 50%. Notably, serum AMH
      levels were 2-fold higher in NR-PCOS compared to HR-PCOS. This finding was puzzling as serum
      AMH levels have been shown to correlate to the number of small follicles present in ovaries
      suggesting that AMH may be a surrogate for small follicle number. However, both PCOS
      subgroups had equivalent follicle numbers. The investigators hypothesize that the NR-PCOS
      have greater number of small follicles compared to HR-PCOS. To address this issue the
      investigators propose to assess the number of small follicles in NR- and HR-PCOS women and
      normal controls.

      In a secondary consideration the HR-PCOS group was heavier than the NR-PCOS. This implies
      that the HR-PCOS women may have had greater insulin resistance and hyperinsulinemia that may
      have contributed to the significantly higher 17P responses to hCG. As a result, the
      investigators will also perform an oral glucose tolerance test in all subjects.

      Power Analysis Results of the investigators' pilot study have shown that approximately 50% of
      PCOS women will exhibit 17OHP responses to hCG stimulation similar to those of normal women.
      Consequently, a sample size of 20 subjects in each group has an 80% power to detect a
      difference in the means of 0.820 ng/ml (the difference between the average 17OHP expression
      level in high responder PCOS women (HR-PCOS), 2.840 ng/ml, and that of normal responder PCOS
      (NR-PCOS) women, 2.02 ng/ml), which is a 33% increase. In the proposed study, the
      investigators believe that HR-PCOS (n=20) will show significantly greater (33% more) 17OHP
      production in response to hCG stimulation than NR-PCOS (n=20) at a power of 0.8 and a type I
      error rate of 0.05. The investigators will recruit 25 subjects in each group to allow for
      subject drop out. A secondary analysis will be performed between women with PCOS and normal
      controls (n=20).
    

Intervention name(s): hCG
Intervention type(s): Drug
Intervention description(s): 3. On study day one, recombinant-hCG (r-hCG) will be administered intravenously at a dose of 25 micrograms.
4. Blood samples will be obtained at T = -0.5, 0, and +24 hours.
Other intervention name(s): Re-combinant human choriogonadotropin
Intervention MeSH terms: Chorionic Gonadotropin
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic