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The physiologic role of corticotropin-releasing hormone (CRH) was examined in the ovary. We investigated the effects of CRH on steroidogenesis in rat and human granulosa cells in vitro as well as the direct effects of CRH on the ovary in vivo. We further examined the gene expression of CRH in human granulosa cells. CRH significantly inhibited the production of estradiol (E2) and progesterone (P4) in rat and human granulosa cells in vitro. These inhibitory effects were completely abolished by alpha-helical CRH, a CRH receptor antagonist. Forskolin-induced increase in E2 and P4 production was attenuated by CRH. On the other hand, CRH significantly increased serum concentrations of E2 and corticosterone in vivo in hypophysectomized rats, but this increase was completely blocked by adrenalectomy. It is probable that these effects did not result from a direct action on the ovary but were an indirect effect via the adrenal gland. Finally, by reverse transcriptase polymerase chain reaction we demonstrated that CRH mRNA was expressed in human granulosa cells. Our findings indicate that CRH exerts inhibitory effects on steroidogenesis in rat and human granulosa cells, acting through the CRH receptor. These effects are attributed to cellular events downstream of cyclic adenosine monophosphate generation. CRH seems to modulate steroidogenesis via autocrine or paracrine actions in the ovary.

The objective of this study was to compare, in infertile women suffering from severe hypogonadotropic amenorrhea, the therapeutic utility and the incidence of complications arising from fertility treatment by the conventional human menopausal gonadotropin/human chorionic gonadotropin (hMG-hCG) method, the hMG step-down method, the sequential hMG/gonadotropin-releasing hormone (GnRH) method and a new, modified hMG-GnRH method that has been developed by us. In the step-down method, the daily dose of hMG was decreased from 150 IU to 75 IU when the follicle diameter reached 11-13 mm. In the sequential hMG-GnRH, hMG injection was switched to pulsatile GnRH administration (20 microg/120 min SC), when the follicle diameter reached 11-13 mm. In our new modified hMG-GnRH, pulsatile GnRH was injected together with hMG. Daily hMG was stopped and the GnRH dosage was changed from 10 microg to 20 microg when the follicle diameter reached 11-13 mm. Initially, the three established methods were applied randomly to treat 34 cycles in 20 women; and subsequently, five patients who failed to conceive following treatment by sequential hMG-GnRH were then treated by the modified hMG-GnRH method. More than eight growing follicles and multiple pregnancies were observed during treatment by the conventional method. The incidence of ovarian hyperstimulation syndrome (OHSS) was 25.7% with the conventional method, 20.0% with the step-down method and 0% with the sequential hMG-GnRH method; however, the rate of ovulation was only 50% with the sequential hMG-GnRH method. By contrast, with the modified hMG-GnRH method, less than three growing follicles occurred in 81.8% of patients, there was a 100% rate of ovulation, and neither OHSS nor multiple pregnancies were observed. Moreover, the modified hMG-GnRH method induced pregnancy in 3 out of 5 patients. These data indicate that this new method is favorable for the treatment of severe hypogonadotropic amenorrhea.

The pathogenesis of hypothalamic progestin-nonresponsive amenorrhea is unclear and this disease often fails to respond to treatment. The pulsatile patterns of diurnal and nocturnal secretion of serum LH as well as serum levels of melatonin were examined to improve the understanding of the pathogenesis and to develop strategies for the management of a severe type of hypothalamic amenorrhea. Four types of LH pulsatile patterns were observed: a) no pulse during the day or night (Group 1); b) more than 1 pulse only at night (Group 2); c) only 1 pulse during the day and more than 2 pulses at night (Group 3); and d) more than 2 pulses during the day and at night (Group 4). Serum estradiol was less than 30 pg/mL, and the serum PRL and PRL response to TRH did not differ among the four groups. The basal level and the pulse amplitude of LH increased successively from Group 1 to Group 4. The serum level of melatonin at night was noticeably increased in Group 1 and correlated negatively with the LH pulse frequency at night. After 6-month hormone replacement therapy with estrogen and progesterone, the rate of improvement in ovarian function were 0%, 33.3%, 57.1% and 67.0% in Groups 1, 2, 3, and 4, respectively. In 5 patients, the LH pulse pattern was re-examined at 6 months, the LH pulsatile pattern was changed from that of Group 1 to that of Group 4, with a decrease in serum concentrations of nocturnal melatonin, indicating improved ovarian function. In conclusion, classification of patients according to the LH secretion pattern is useful in establishing the severity of hypothalamic disturbance in hypothalamic progestin-nonresponsive amenorrhea and in predicting its prognosis; in addition nocturnal melatonin can be used as a marker for severer cases of hypothalamic amenorrhea.