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To investigate further brain-pituitary-gonadal interrelationships we have generated mice in which the gene encoding the FSH receptor has been disrupted. Female FSH receptor knockout (FSHRKO) mice were infertile. The ovaries were significantly reduced in size, with follicular development arrested at the preantral stage, but there was evidence of stromal hypertrophy. The vagina was imperforate, and the uterus was atrophic. There was no response to administration of PMSG. Inhibins A and B were undetectable in both the serum and gonads. Compared with those in control animals, serum concentrations of FSH and LH were significantly elevated in mutant females. The pituitary content of FSH, but not LH, was also significantly elevated. Estrogen administration in FSHRKO female mice suppressed serum LH levels to those seen in control mice, whereas FSH levels were reduced by only 50%. Male FSHRKO mice were fertile, although testis weight was significantly reduced. However, testicular inhibin A and B concentrations did not differ from those in normal littermates. Serum levels of FSH and LH were elevated in the null mutant male mice, whereas no differences were found in the pituitary content of these hormones. In conclusion, ovarian follicular development cannot progress beyond the preantral stage without FSH. In the absence of mature follicles ovarian estrogen remains low, and consequently accessory sex tissue growth and negative feedback regulation of gonadotropin secretion are severely compromised. In the male, however, inability to respond to FSH does not impair fertility, although testicular weight is reduced, and feedback regulation of pituitary gonadotropins and intratesticular paracrine interactions may be disturbed.

Endometrium collected from 18 normal women at various stages of the menstrual cycle was maintained in organ culture for periods of 6 days. Both prostaglandin F2 alpha (PGF2 alpha) and PGE were detected in medium from late proliferative (days 10-14; n = 13) and late secretory (days 20-26; n = 5) endometria cultured in the absence of exogenous steroids. During the first 48 h in culture, the output of PGF2 alpha by secretory endometrium was significantly greater than that of proliferative tissue. The addition of 17 beta-estradiol to the culture medium at doses ranging from 1.0-100.0 ng/ml induced a significant increase in the output of PGF2 alpha by secretory but not proliferative endometria. The addition of progesterone at doses ranging from 5.0-500.0 ng/ml significantly reduced the output of PGF2 alpha and PGE by both proliferative and secretory endometria and prevented the 17 beta-estradiol-stimulated increase in PGF2 alpha output by secretory tissue.