New Study Confirms Process Leading To Disorder Causing Male Characteristics In Women
Ovarian stimulation of male steroids is the culprit behind this disorder.
A woman finds herself with excessive facial hair, obesity, menstrual abnormalities, infertility, and enlarged ovaries may have polycystic ovary syndrome (PCOS), an unfortunate condition thought to be caused by excessive secretion by the ovaries of androgen, a hormone associated with male characteristics. Men and women both have hormones expressing male and female characteristics. Yet, the cause of this excessive secretion of a hormone leading to undesired gender traits remains unclear.
Estimates of incidence of this disorder range around the five percent level if both cessation of ovulation and excess hair growth are used in the definition, but they can range over 10 percent in some select populations. Past research emphasized the relative roles of neuroendocrine abnormalities leading to persistent and excessive secretion of luteinizing hormones (LH), one of two glycoprotein hormones that stimulate the final ripening of the follicles and the secretion of progesterone; and the ovarian actions increased insulin in plasma, a consequence of insulin resistance. Additional evidence suggests that unnatural ovarian production of hormonal steroids is a primary abnormality in PCOS.
Human studies of PCOS have found abnormal ovarian steroid responses to administration of gonadial hormones, specifically potent gonadotropin-releasing hormone (GnRH) agonist or a high dose of human chorionic gonadotropin (hCG). The stimuli cause exaggerated secretion of 17-hydroxyprogesterone (17-OHP) and, to a lesser degree, androstenedione, suggesting abnormal ovarian production of steroids. However, these paradigms involve pharmacological ovarian stimulation and do not reproduce physiological LH pulsatility.
Researchers recently hypothesized that near-physiological LH stimuli would effect greater ovarian secretion of androgens and their precursors in women with PCOS compared to controls. To test this supposition, they employed a paradigm of sequential GnRH-receptor antagonist administration to suppress endogenous LH concentrations, and intermittent (pulse-like) infusions of physiological amounts of recombinant human LH (rhLH) to stimulate ovarian steroidogenesis.
A New Study
The authors of “Exaggerated 17-Hydroxyprogesterone Response to Intravenous Infusions of Recombinant Human LH in Women with Polycystic Ovary Syndrome,” are Christopher R. McCartney, Amy B. Bellows, Melissa B. Gingrich, Yun Hu, William S. Evans, John C. Marshall, and Johannes D. Veldhuis, all from the University of Virginia Health System, Charlottesville, VA. Their findings appear in the June, 2004, edition of the American Journal of Physiology – Endocrinology and Metabolism. The journal is one of 14 published each month by the American Physiological Society (APS) (www.the-aps.org).
This study sought to assess ovarian steroid secretion in response to near-physiological gonadotropin stimuli in 12 ovulatory controls and 7 women with PCOS. A gonadotropin-releasing hormone-receptor antagonist (ganirelix, 2 mg subcutaneously) was given to block endogenous LH secretion, followed by dexamethasone (0.75 mg orally) to suppress adrenal androgen secretion. Twelve hours after ganirelix injection, intravenous infusions of recombinant human LH were administered at four-hour intervals with the highest dose last. Plasma LH, 17-hydroxyprogesterone (17-OHP), androstenedione, and testosterone were measured concurrently. LH dose-steroid response relationships (mean sex-steroid concentration versus. mean LH concentration over four post-infusion) were examined for each subject.
The increased 17-OHP responses in PCOS observed in the study may reflect exaggerated acute steroidogenic responses that parallel escalating doses of rhLH. However, an alternative explanation is that the 17-OHP increase in PCOS reflects abrupt (in comparison to normal) rhLH-induced resumption of early steroidogenic steps after temporary removal of physiological LH stimulation.
The findings revealed that leuteinizing hormone dose-ovarian steroid responses were not observed in normal women. Furthermore, acute ovarian steroid responses to rhLH infusions were not commonly apparent when reviewing individual steroid time series. It remains possible that ovarian steroid responses could have occurred after our surveillance had ended. Nonetheless, the observations suggest that ovarian steroidogenesis during the normal follicular phase is influenced by integrated LH stimulation and does not vary acutely to changes in LH pulse mass. This contrasts with acute P responses to endogenous LH pulses during the luteal phase.
The authors conclude that that near-physiological ovarian stimulation via intermittent (pulse-like) rhLH administration produces exaggerated 17-hydroxyprogesterone secretion in patients with PCOS, supporting earlier studies of pharmacological ovarian stimulation. The next step in the key to prevention is to determine the physiological mechanisms leading to this disorder.
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