Estrogenic modulation of the gonadotropin-releasing hormone-stimulated secretory activity of the gonadotrope and lactotrope in prepubertal females with Turner's syndrome

The nature of estrogen's modulation of GnRH-stimulated secretion of the female prepubertal gonadotrope and lactotrope was studied in nine girls with primary gonadal failure (Turner's syndrome; mean age, 10.0 ± 0.25 yr). LH, FSH, and PRL release was evaluated by sampling blood every 20 min from 2000-0800 h. Hormone secretion was stimulated by one of two randomized doses of GnRH (50 or 750 ng/kg) delivered at fixed intervals of every 90 min in an attempt to replace the function of the endogenous GnRH pulse generator with an exogenous GnRH clamp. To evaluate the time dependency of estrogen action, studies were conducted at baseline and after 1 and 5 weeks of oral administration of ethinyl estradiol (EE; 100 ng/ kg·day). In vivo gonadotropin secretory dynamics were quantitated by deconvolution mathematical modeling. We found a suppression of total LH secretion in response to repeated fixed doses of GnRH after 1 and 5 weeks of EE exposure, viz. a 10% (1 week) and 60% (5 weeks) reduction in the total mass of LH released after six consecutive GnRH pulses. Before estrogen exposure, patients manifested a decreasing mass of LH secreted per burst (slope of mass/burst vs. GnRH injection number was -3.3 ± 1.44), suggesting down-regulation of the LH secretory response. However, after 5 weeks of EE treatment, the same series of GnRH doses elicited a progressive increase in the mass of LH secreted per burst (slope, 1.06 ± 0.036; P = 0.041). Such serial amplification of LH secretory responses (despite overall suppression of the mean serum LH concentrations by EE) is consistent with the emergence of priming of GnRH actions. This phenomenon was specific, since the half-life of LH and the LH secretory burst duration were not altered. FSH responses to GnRH were significantly suppressed after 5 weeks of EE exposure (mean serum FSH concentrations, 61.9 ± 11.4 IU/L at baseline vs. 14.4 ± 6.9 at week 5; P = 0.003). However, in contrast to the LH responses on a given study day, there was increased FSH responsivity to successive doses of GnRH, suggesting a priming effect of serial GnRH exposure on GnRH-stimulated FSH secretion regardless of the estrogen milieu. PRL secretion was stimulated by GnRH at baseline (16.8 ± 0.88 μg/L), but release was reduced at week 5 on estrogen (11.6 ± 0.4 μg/L). This may represent withdrawal of the paracrine effects of endogenous GnRH and/or increased dopaminergic tone induced by estrogen. We conclude that the GnRH-stimulated secretory behavior of the prepubertal gonadotrope cell can be modulated by estrogen. The differential modulation of GnRH-promoted LH and FSH release by small amounts of estrogen in the prepubertal, functionally agonadal female resembles the physiological model of the effects of estrogen on the human female pituitary gland, in which short term estrogen exposure suppresses LH release with preservation of FSH secretion, followed by a time-dependent escape from this restraint.