Premature Response to Luteinizing Hormone of Granulosa Cells from Anovulatory Women with Polycystic Ovary Syndrome: Relevance to Mechanism of Anovulation

Abstract

Polycystic ovary syndrome is the most common cause of anovulatory infertility. Anovulation in polycystic ovary syndrome is characterized by the failure of selection of a dominant follicle with arrest of follicle development at the 5-10 mm stage. In an attempt to elucidate the mechanism of anovulation associated with this disorder we have investigated at what follicle size human granulosa cells from normal and polycystic ovaries respond to LH. Granulosa cells were isolated from individual follicles from unstimulated human ovaries and cultured in vitro in serum-free medium 199 in the presence of LH or FSH. At the end of a 48-h incubation period, estradiol (E2) and progesterone (P) were determined in the granulosa cell-conditioned medium by RIA. In ovulatory subjects (with either normal ovaries or polycystic ovaries), granulosa cells responded to LH once follicles reached 9.5/10 mm. In contrast, granulosa cells from anovulatory women with polycystic ovaries responded to LH in smaller follicles of 4 mm. Granulosa cells from anovulatory women with polycystic ovaries were significantly more responsive to LH than granulosa cells from ovulatory women with normal ovaries or polycystic ovaries (E2, P < 0.0003; P, P < 0.03). The median (and range) fold increase in estradiol and progesterone production in response to LH in granulosa cell cultures from size-matched follicles 8 mm or smaller were E2, 1.0 (0.5-3.9) and P, 1.0 (0.3-2.5) in ovulatory women and E2, 1.4 (0.7-25.4) and P, 1.3 (0.3-7.0) in anovulatory women. Granulosa cells from anovulatory (but not ovulatory) women with polycystic ovaries prematurely respond to LH; this may be important in the mechanism of anovulation in this common endocrinopathy.

Luteal-phase inhibin A and follicular-phase inhibin B levels are not characteristic of patients with an elevated LH-to-FSH ratio

“…As opposed to normal women, where inhibin B production by granulosa cells in the early follicular phase is under the control of FSH but not LH, theca interstitial cells around small antral follicles in PCOS patients might respond with an increased α-subunit expression to elevated LH levels, supplying granulosa cells with an increased amount of this subunit, which would result in an elevated secretion of inhibin B by granulosa cells. Furthermore, premature sensitivity of granulosa cells from small antral follicles to LH has been reported in PCOS [31], thus LH might also stimulate inhibin B production directly in granulosa cells. In contrast to these findings and theories, several studies demonstrated reduced expression of the α-subunit in PCOS granulosa cells, which, possibly regulated by elevated LH levels, might be responsible for decreased inhibin A and B concentrations in follicular fluid [32,33].…”

Luteinizing hormone/chorionic gonadotrophin receptor overexpressed in granulosa cells from polycystic ovary syndrome ovaries is functionally active

“…We provide evidence here that overexpression of functional LHCGR in GCs of PCOS is likely to be part of the mechanism of OHSS. Moreover, previous studies suggested that LHCGR may be expressed prematurely in women with PCOS (Jakimiuk et al, 2001, Willis et al, 1998. Interestingly, a number of genes involved in gonadotrophic response, steroidogenesis and water permeability e.g.…”

“…Moreover, previous studies have suggested that LHCGR, which is critical for ovulation, may be induced prematurely in women with PCOS (Jakimiuk et al, 2001, Willis et al, 1998. Despite a plethora of studies on clinical, metabolic, genetic and evolutionary factors in PCOS (Gorry et al, 2006, BenShlomo and Younis, 2014, Corbett and Morin-Papunen, 2013, Williams et al, 2013, only few studies have advanced our understanding of the physiopathology of this disorder.…”

LH receptor gene expression in cumulus cells in women entering an ART program

“…during the mid follicular phase [13]. Interestingly, it has been shown that in ovulatory women with or without polycystic ovaries, granulosa cells responded to LH once follicles reached 9.5-10 mm, whereas in anovulatory patients with polycystic ovaries they responded to LH in follicles smaller than 4 mm [39]. LHR expression is further induced by FSH stimulation before oocyte maturation [10].…”