Effects of gonadectomy and treatment with gonadal steroids and luteinizing hormone secretion in hypogonadal male and female mice with preoptic area implants.

The ability of male and female hypogonadal (hpg) mice with preoptic area (POA) grafts to show negative feedback was studied. GnRH neurons within POA grafts send axons into the median eminence of the hpg host (HPG/POA), resulting in increased gonadotropin production and gonadal development in the mice that are genetically unable to produce GnRH. The present studies evaluated whether negative feedback, an aspect of normal reproductive function, is present in male and female HPG/POA mice. In normal male mice plasma LH was increased 1 or 5 months after castration and returned to baseline after testosterone propionate treatment. In contrast, no alterations in plasma LH were measured in similarly treated HPG/POA males. HPG/POA female mice were ovariectomized 6 weeks or 3 or 6 months after graft surgery and received sc 17 beta-estradiol (E2) implants 3 months later. Normal mice were studied when 6 weeks old and 8 months old (age-matched to HPG/POA mice ovariectomized 3 months after graft surgery). Further, to determine whether the mice were capable of positive feedback, 1 week after receiving E2 implants, mice in the 6-week and 3-month postgraft surgery groups were challenged with sequential administration of estradiol benzoate and progesterone. The significant increase in plasma LH after ovariectomy or decrease after E2 implant in normal female mice was not present in most HPG/POA female mice. Just 2 of the 24 HPG/POA females studied had increased plasma LH after gonadectomy, and in only 1 of these was plasma LH suppressed by E2 treatment. The ability of an individual HPG/POA mouse to show positive feedback did not predict the ability to show negative feedback, nor did the ability to show negative feedback predict positive feedback capability. Among the mice that failed to respond to ovariectomy with increased LH release were some that had elevated LH in response to steroid challenge or had spontaneously ovulated. On the other hand, neither mouse that had increased LH release after ovariectomy had shown positive feedback to a steroid challenge. Immunocytochemical evaluation revealed GnRH cells within the grafts and GnRH fiber innervation of the host's median eminence, but there was no correlation between numbers of GnRH cells or extent of innervation with the ability to show either negative or positive feedback, nor was the presence of vasoactive intestinal peptide cells within the grafts of predictive value. The failure of negative feedback in most of the HPG/POA mice tested may be due to the failure to establish as yet unidentified but essential afferents to the grafted GnRH cells and/or their axonal processes.