Prolonged Negative Feedback Suppression after Estradiol Administration: Proposed Mechanism of Eugonadal Secondary Amenorrhea*

Abstract

The finding of normal gonadotropin and estradiol levels in eugonadal women with secondary amenorrhea suggests a disordered feedback relationship of the hypothalamic-pituitary-ovarian axis. To identify possible defects in negative and positive feedback, we compared the effects of five daily injections of 17β- estradiol (E₂) in 13 normal women and 11 eugonadal patients with absent cyclic menses. The suppression phase of negative feedback was normal, as LH and FSH were similarly lowered in both groups on day 3. Continued LH (P < 0.01) and FSH (P < 0.02) inhibition on day 10 of the protocol, 5 days after the last E₂ injection, indicated a defect in the recovery phase of negative feedback in the 11 amenorrheic women. In the 4 patients studied, gonadotropin suppression persisted for 3 weeks. E₂ did not blunt pituitary responsiveness to GnRH in the amenorrheic women, suggesting a central nervous system site for prolonged gonadotropin inhibition. Nine normal but only 3 amenorrheic women (X² = 4.15; P < 0.05) exhibited a positive feedback increase in LH on days 4–6. We propose that a defect in the recovery phase of negative feedback to E₂ rather than absent positive feedback may be the dominant physiological abnormality which causes secondary amenorrhea by preventing early follicular phase gonadotropin increments and follicular maturation.