The Effects of Daily Administration of Single and Multiple Injections of Gonadotropin-Releasing Hormone on Pituitary and Gonadal Function in the Hypogonadal (hpg) Mouse*

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Abstract
Hypogonadal (hpg) mice have a deficiency of hypothalamic GnRH [gonadotropin releasing hormone] with an associated reduction in pituitary and plasma gonadotropins and a failure of postnatal gonadal development. GnRH is naturally delivered to the pituitary in a pulsatile manner. The main aim was to investigate the effect of daily single compared with daily multiple GnRH injections on pituitary and gonadal function of the hpg mouse. In male hpg mice, single daily s.c. injections of GnRH at dosages from 50 ng-20 .mu.g for 20 days increased the pituitary FSH content from .apprx. 500 ng to 17,800-32,200 ng/pituitary, the content in normal mice being .apprx. 20,000 ng/pituitary. The injections only slightly increased pituitary LH [luteinizing hormone] content. The weight of the testes was increased to about a third of those in normal adult mice and, by 60 days of injection, all stages of spermatogenesis were present in the seminiferous tubules. However, in none of the animals was there any growth of the seminal vesicles. By contrast, GnRH given as 12 injections each day for 15 days produced an increase in pituitary LH (although not to normal adult levels) as well as pituitary FSH content, and stimulated a significant increase in the weights of the seminal vesicles as well as the testes. Injection of 60 ng GnRH 12 times daily for 15 days produced increases in pituitary LH content, daily for 15 days produced increases in pituitary LH content, plasma FSH concentration, and seminal vesicle weights which were much greater than those produced by 1 .mu.g GnRH given once daily; pituitary FSH contents were similar in the 2 groups of animals. Castration, castration plus adrenalectomy, or the implantation of silastic capsules that contained testosterone propionate did not inhibit the increase in pituitary FSH content produced by GnRH injections. In female hpg mice single daily s.c. injections of GnRH for 10-15 days increased pituitary FSH content to a level 4 times that in normal adult female mice, but there was no increase in uterine weight. Multiple injections of GnRH, either 4 or 12 each day for 10-15 days, increased pituitary FSH content to the level in normal adult female mice and also increased significantly the uterine weights. Pituitary LH content was increased to nearly normal values by 12 injections of 60 ng GnRH/day but remained low in animals given single daily injections of GnRH even at doses as high as 1 .mu.g. Treatment with estrogen significantly reduced, whereas ovariectomy significantly enhanced, the increase in pituitary FSH content produced by multiple GnRH injections. Compared with the effects of single daily injections of GnRH, multiple daily injections of GnRH produce a more normal function of the pituitary-gonadal-accessory sex organ system in hpg mice of either sex. A major site of negative feedback of estrogen appears to be at the pituitary in the female, whereas in the male testosterone appears to exert its inhibitory effect at the hypothalamus or above. With every injection regimen used, GnRH is considerably more potent at stimulating FSH compared with LH synthesis in the hpg mouse.

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