Mid-follicular phase pulses of inhibin B are absent in polycystic ovarian syndrome and are initiated by successful laparoscopic ovarian diathermy: a possible mechanism regulating emergence of the dominant follicle

Abstract

The hypothalamic pulse generator of GnRH is recognized to be central to ovulatory function as evidenced by the anovulation of women with hypogonadotrophic hypogonadism due to Kallmann's syndrome or severe anorexia nervosa. LH is released from the anterior pituitary in pulses, the frequency of which is closely entrained with those of GnRH. In contrast, secretion of FSH is influenced by a number of regulatory molecules, including GnRH, estradiol, inhibin, and activin. The close temporal relationship between changes in levels of inhibin B and FSH in the mid-follicular phase suggests that the release of inhibin B by the preovulatory follicle critically regulates pituitary FSH secretion. Polycystic ovarian syndrome (PCOS) is one of the most common endocrine disorders affecting ovulation, and abnormal ovarian morphology as detected by ultrasonography remains the most sensitive diagnostic marker for this disorder. The etiology of PCOS is unclear, but its effective treatment by both anti-estrogens and by exogenous FSH suggests that a primary disorder of FSH regulation may be central. To investigate the possible role of inhibin B in the pathology of PCOS, serum inhibin B levels were measured in 10 women with PCOS on cycle day 5 of a spontaneous or progestrogen-provoked bleed and compared with levels on cycle day 5 of 10 women with regular ovulatory cycles. The mean serum inhibin B levels in the PCOS patients were significantly higher at 248 (+/- 43.4) pg/mL compared with normal controls, 126 (+/- 18.6) pg/mL (P < 0.01). Ten women with clomiphene resistant PCOS and 5 normal controls consented to undergo serial blood sampling on cycle day 5. Time Series Analysis using a Fourier Transformation to analyze the power spectrum of the data revealed that in normal women there is a distinct periodicity in inhibin B levels with a clear peak detectable every 60-70 min (P < 0.05), whereas in women with ovulatory dysfunction due to PCOS, no such pattern of regular pulsatility was seen. Four women with PCOS whose anovulation was successfully treated with laparoscopic ovarian diathermy (LOD) underwent repeat venous sampling following LOD. Their serum inhibin B levels fell to the upper limit of the normal range (160 +/- 38.5) pg/mL, and pulsatility was initiated. It is possible that inhibin B pulses are being generated directly by the ovary in response to pulses of GnRH in the peripheral circulation, or indirectly in response to FSH pulses arising in the pituitary. The function of inhibin B pulses in the mid-follicular phase of the normal cycle remains to be elucidated, but the absence of the normal pulsatile pattern in women with PCOS, in conjunction with high basal levels of inhibin B arising from the multiple small follicles characteristic of the PCOS ovary, appears to reinforce the development of a large cohort of small, developmentally arrested, and ultimately atretic follicles in these patients. Initiation of normal inhibin B pulsatility by LOD in patients with polycystic ovaries appears to correlate with the post-operative onset of ovular cycles.