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The ability of cannabinoids to affect anterior pituitary luteinizing hormone (LH) secretion has been largely attributed to a central nervous system site of action, however, the mechanism(s) by which cannabinoids alter LH release remains unclear. In the present study, the acute administration of delta-9-tetrahydrocannabinol (THC) produced a dose-related suppression of plasma LH and stimulation of adrenocorticotropin (ACTH) levels in ovariectomized female rats. To determine if activation of the hypothalamic-pituitary-adrenal axis was involved in the ability of THC to inhibit LH release, female rats were either pretreated with the corticotropin-releasing hormone (CRH) receptor antagonist, alpha-helical CRH, or were adrenalectomized prior to acute THC administration, in order to assess the roles of CRH and corticosterone in the ability of THC to suppress LH secretion. A low dose of THC (0.5 mg/kg b.w., iv) produced a decrease in plasma LH levels at 20 and 40 min posttreatment in ovariectomized, sham adrenalectomized rats. However, in adrenalectomized animals, plasma LH levels were suppressed at 40 min and remained decreased at 80 min following THC administration. Thus, the duration of LH suppression following THC treatment was significantly increased in adrenalectomized versus sham adrenalectomized rats (p < 0.05). Furthermore, pretreatment with the CRH receptor antagonist, alpha-helical CRH (100 micrograms/5 microliters, icv), 30 min before THC administration, attenuated the ability of a high THC dose (1.0 mg/kg) to inhibit LH release in ovariectomized rats. Together, these results demonstrate that THC has significant effects on LH and ACTH secretion in ovariectomized rats and suggest that THC-induced CRH activation, but not corticosterone release, plays a role in the suppression of LH release by cannabinoids.

The acute dose-response effects of delta-9-tetrahydrocannabinol (THC), cannabinol (CBN) and cannabidiol (CBD) on gonadotropin and testosterone (T) secretion and on hypothalamic norepinephrine (NE) metabolism were tested in adult male rats. THC and CBN both produced an acute suppression of plasma-luteinizing hormone (LH) and T levels and median eminence NE turnover although a dose-response relationship could not be demonstrated. CBD had no significant effect on any of these parameters and none of these cannabinoids had any effect on plasma follicle-stimulating hormone levels or median eminence LH-releasing hormone (LHRH) content. Except for the highest dose of CBN, none of the in vivo cannabinoid treatments significantly altered in vitro LH secretion although there was a trend towards decreased LH secretion. These results suggest that the decrease in LH secretion in THC- or CBN-treated rats is due to reductions in NE stimulation of LHRH release rather than to changes in LHRH synthesis or pituitary LHRH response.

The effect of 5 alpha-dihydroprogesterone (5 alpha-DHP) on gonadotropin release was examined in the immature acutely ovariectomized (OVX) rat primed with a low dose of estradiol (E2). Treatment with various doses of 5 alpha-DHP given in combination with E2 increased levels of follicle-stimulating hormone (FSH) but had no effect on serum luteinizing hormone (LH). A single injection of a maximally stimulating dose of 5 alpha-DHP (0.4 mg/kg) stimulated increases in serum FSH at 1200 h and, 6 h later, at 1800 h. Pituitary LH and FSH content was dramatically enhanced by 1600 h and levels remained elevated at 1800 h. The administration of pentobarbital at 1200 h, versus 1400 h or 1600 h, prevented the increase in basal serum FSH levels at 1800 h, implying that the release of hypothalamic LH releasing hormone (LHRH) is modulated by 5 alpha-DHP. In addition, changes in pituitary sensitivity to LHRH as a result of 5 alpha-DHP were measured and a significant increase in the magnitude of FSH release was observed at 1200 h and 1800 h. Although the LH response to LHRH in 5 alpha-DHP-treated rats was not different from controls, the duration of LH release was lengthened. These results suggest that 5 alpha-DHP may stimulate FSH release by a direct action at the pituitary level. Together, these observations support the theory that 5 alpha-DHP mediates the facilitative effect of progesterone on FSH secretion and further suggests an action of 5 alpha-DHP in this phenomenon at both pituitary and hypothalamic sites.

Significant divergence between the pattern of FSH and LH secretion has been observed in the ovulatory cycle, after ovariectomy and during puberty. The presence of an FSH-releasing factor, gonadal FSH inhibiting and releasing peptides and changes in the pulsatile pattern of LHRH secretion are among the postulates used to explain the divergent secretion of FSH and LH. Experiments in our laboratory have shown considerable evidence of differential regulation of FSH and LH secretion by steroids in the absence of gonadal regulatory peptides. Natural and synthetic estrogens show significant differences in the suppression of FSH and LH in the ovariectomized rat using a standard uterine response to the estrogen as the end point. In the immature ovariectomized rat treated with a low dose of estradiol that is sufficient for the synthesis of progesterone receptors to ensure progesterone sensitivity, but not large enough to induce estrogen triggered LH surges, progesterone administration resulted in a pattern of LH and FSH secretion similar to that observed on the day of proestrus in the cycling rat. Selective secretion of FSH was induced in the estrogen primed immature rat model by the administration of progesterone metabolite 5 alpha-dihydroporgesterone (5 alpha-DHP) while selective LH secretion was induced by 3 alpha, 5 alpha-tetrahydroprogesterone (3 alpha,5 alpha-THP). The selective secretion of FSH and LH induced by progesterone metabolites was confirmed in the immature female rat primed with PMSG and maintained in constant light. 5 alpha-DHP was also able to induce a greater release of FSH when administered to the adult cycling rat on proestrus. The priming of the pituitary gonadotrope in secreting a high baseline level of FSH or responding to LHRH in releasing a greater amount of FSH appeared to be an important factor in selective FSH release and such priming can be brought about by 5 alpha-DHP in the absence of gonadal regulatory peptides.