GONADOTROPHIN RELEASE IN OVARIECTOMIZED PATIENTS

SUMMARY Administration of clomiphene citrate (150 mg/day) for 5 days to twenty‐four ovariectomized patients and seven normal female patients evoked a significant release of FSH and LH in the normal control group and suppressed the gonadotrophin secretion in the castrated patients. A similar suppressive effect on gonadotrophin secretion was noted in eight ovariectomized patients treated for 10 days with low doses (50 μg/day) of ethinyl oestradiol. It is suggested that in the ovariectomized hypoestrogenic patients, clomiphene acted as an oestrogen, suppressing by a negative feedback action gonadotrophin release in a way similar to ethinyl oestradiol. In the normal control group with an adequate steroid environment, clomiphene acted (probably at the hypothalamic level) as an oestrogen antagonist and stimulated gonadotrophin secretion. In view of our findings, it seems as if the ability of anovulatory patients to respond to clomiphene treatment by increased gonadotrophin secretion depends upon the absolute concentration of the compound in the different organs and by the quantitative relation of clomiphene to the endogenous oestrogens. There is still a considerable degree of uncertainty about the exact mode of action of clomiphene (1‐[p‐β‐diethyl‐aminoethoxyphenyl]‐1,2, dipheny1‐2 chloroethylene citrate) a non‐steroidal oestrogen antagonist. However, it appears increasingly evident that this compound which possesses antioestrogenic properties acts probably in an indirect manner, by competing with oestradiol for the receptor sites at the hypothalamic centres regulating gonadotrophin secretion, thus stimulating gonadotrophin releasing hormone (LHRH) secretion, with a subsequent release of FSH and LH (Igarashi et al ., 1967; Seki et al ., 1970). By contrast, in prepubertal children, a paradoxical suppression of both LH and FSH release was demonstrated following administration of clomiphene (Kelch et al ., 1971). The explanation offered for this phenomenon was that the immature hypothalamic gonadostat is hypersensitive to sex steroids, and as clomiphene has intrinsic oestrogenic properties, it could account for the unexpected gonadotrophin suppression rather than stimulation in the prepubertal child. A similar effect could be obtained in prepubertal children by administration of low doses of oestrogens (Kelch et al ., 1971). In order to gain additional information on the mode of action of clomiphene at the hypothalamic and pituitary levels, we studied the effect of clomiphene and of low doses of oestrogens on LH and FSH release in ovariectomized patients. These patients provide a suitable model for the investigation of the mode of action of clomiphene on a normal hypothalamic‐pituitary system in an environment free of gonadal steroid (Tepperman, 1973).