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  • Title: Effect of mifepristone (RU486) on the pituitary response to gonadotrophin releasing hormone in women.
    Author: Kazem R, Messinis LE, Fowler P, Groome NP, Knight PG, Templeton AA.
    Journal: Hum Reprod; 1996 Dec; 11(12):2585-90. PubMed ID: 9021355.
    Abstract:
    Mifepristone interrupts folliculogenesis in women but the mechanism is not clear. Previous studies have investigated the effect of this compound on gonadotrophin secretion and have provided conflicting results. To study further the effect of mifepristone on basal and gonadotrophin-releasing hormone (GnRH)-induced gonadotrophin secretion, 12 normally ovulating women were investigated during two consecutive menstrual cycles, comprising an untreated cycle (control) and a cycle treated with mifepristone. All women were treated with mifepristone on days 2-8 at the dose of 100 mg (group 1, eight women) or 10 mg per day (group 2, six women). Two women were treated with both regimens in two different cycles. On day 8 of both cycles, the women received two GnRH pulses of 10 micrograms each 2 h apart. Blood samples in relation to the first GnRH pulse were taken at-15, 0, 30, 60, 120, 150, 180 and 240 min. In group 1, the increase in luteinizing hormone (delta LH) in response to GnRH was significantly attenuated from 30 to 180 min, while the increase in follicle stimulating hormone (delta FSH) was attenuated only in response to the second GnRH pulse. No significant decrease in delta LH and delta FSH response to GnRH was seen during treatment with the 10 mg dose (group 2). In group 1, serum oestradiol and inhibin-A concentrations after day 8 were lower than in the control cycles and the LH peak was postponed by 7 days on average. Basal LH values increased significantly on day 8 in both groups, while FSH values did not change significantly compared with the control cycles. A significant increase in serum progesterone and cortisol values occurred during the treatment only in group 1. Mid-luteal values of inhibin-A were significantly lower in cycles treated with 100 mg mifepristone than in the control cycles. We conclude that the disruption of folliculogenesis by mifepristone cannot be explained by a decrease in basal FSH concentrations during the critical period of follicle recruitment and selection. It is possible that mifepristone exerts its effect at the level of the ovary. It is also suggested that progesterone during the follicular phase of the cycle may participate in the control of the self-priming action of GnRH on the pituitary. In the UK and Greece, clinical researchers investigated 12 normally ovulating women during two consecutive menstrual cycles (control) and a cycle treated with oral mifepristone (case) on days 2-8 to determine the role of progesterone during the follicular phase of the menstrual cycle and the possible mechanism through which mifepristone interrupts folliculogenesis in women. 7 women received 100 mg mifepristone, and the other 5 women received 10 mg mifepristone. Treatment with 100 mg mifepristone/day during the first half of the follicular phase yielded a significant increase in the timing of the luteinizing hormone (LH) response to gonadotropin releasing hormone (GnRH) from 30 to 180 minutes. In fact, the weakened LH response occurred in both GnRH pulses, suggesting that mifepristone influenced both the releasable and reserve pool of LH in the pituitary gland. Mifepristone (100 mg) also weakened the response of follicle stimulating hormone (FSH) to the second GnRH pulse. 10 mg mifepristone did not have similar effects on the LH and FSH responses to GnRH, however. 100 mg mifepristone caused a reduction in serum estradiol and inhibin-A concentrations after day 8 (p 0.05) and postponed the LH peak by 7 days on average. Mid-luteal inhibin-A concentrations were lower in cycles treated with 100 mg mifepristone than in the control cycles. Both mifepristone doses increased basal LH secretion on day 8 (p 0.05). Basal FSH concentrations throughout the treatment periods were similar to those in controls, however. This suggests that the inhibitory effect of mifepristone on either the selection or further growth of the dominant follicle occurs within the ovary. These findings suggest that progesterone during the follicular phase may contribute to the control of the self-priming action of GnRH on the pituitary.
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