The effect of marijuana on gonadotropin releasing hormone


The hypothalamus contains neurosecretory neurons which are responsible for the synthesis and secretion of factors that regulate the release of the hormones elaborated by the anterior lobe of the pituitary gland. A single hypothalamic factor seems to be responsible for the release of both LH and FSH and this factor is gonadotropin releasing hormone. The secretion of GnRH is affected by a variety of factors including neural, chemical, sensory, hormonal, and various drug treatments of the animal. Normally, release of GnRH is regulated by the neural transmitters of the hypothalamus. Thus, factors which alter dopamine and norepinephrine concentrations also alter GnRH release. As a general rule, things which enhance the release of adrenergic or dopaminergic substances in the hypothalamus should stimulate the release of GnRH, and those substances, such as drugs, which antagonize adrenergic and dopaminergic release should inhibit the release of GnRH.

Several studies have indicated that the pharmacological effect of THC on gonadotropin levels involves the alteration of gonadotropin releasing hormone. Smith et al. () using the overiectomized monkey, showed that administration of GnRH to monkeys that had received THC 6 hours before (2.5 mg/kg I.M.), was able to reverse THC-induced reduction in LH and FSH within 30 minutes after GnRH administration. Tyrey () similarly showed that administration of GnRH to ovariectomized rats previously treated with THC reversed the effects of THC induced depression of LH and FSH. Nir et al. () had shown earlier that GnRH might be involved, in a study that examined the effect; of THC-induced suppression of ovulation in rats by the administration of GnRH; and Asch et al. () also reported that GnRH could reverse the THC-induced suppression of ovulation in rabbits.

Thus it appears that THC blocks GnRH release by the hypothalamus. Since the pituitary remains capable of responding to exogenous GnRH in the presence of THC, it seems likely that the observed THC-induced suppression of gonadotropin output arises indirectly from an action of THC upon the hypothalamus and not through a direct effect upon the pituitary.

In contrast to the acute studies reported above, Rosenkranz and Esber () reported that prolonged oral administration of THC to young rats (2, 10, or 50 mg/kg for 14 to 180 days) tended to increase gonadotropins, indicating that tolerance to the effects of THC may develop in males. They also reported that cannabidiol treated male monkeys had increased follicle stimulating hormones (CBD, 20, 100, and 300 mg/kg oral), but that the steroid hormones were essentially unchanged.

It is not surprising that the psychoactive ingredient in marijuana, THC, has as a major effect the depressing of gonadal hormone levels by acting through the hypothalamus to suppress GnRH release. In view of the psychoactive nature of THC, it is possible that it alters neural transmitter substances throughout the brain, but especially in that region of the central nervous system that is important in regulating GnRH release from the hypothalmus. Very few studies have examined whether hypothalamic neural transmitters are in fact affected by marijuana smoke or THC treatment. There are, however, some studies which have shown that THC affects neural transmitter substances in other areas of the brain. Kramer and Ben-David () have shown that both serotonin and dopamine are probably responsible for the inhibitory effect of THC on prolactin, and Marks () indicated that hypothalamic cholinergic mechanisms are probably not involved in the THC depression of LH release. Several early studies (), reported that biogenic amines in the CNS are altered by THC treatment. Others () showed that THC prevents reuptake of dopamine, norepinephrine, and serotonin into the respective nerve endings throughout the brain. Other authors () have shown that THC depressed cholinergic activity in the rat hippocampus.

These reports indicate that serotonin levels in certain areas of the brain may increase with concomittant decrease in catecholamines in other areas of the brain. Thus it appears that future studies, which address themselves to clarifying the effect of marijuana or THC on neurotransmitters in the hypothalamic area and their sub sequent effect on GnRH and other factors involved in regulating pituitary function, would be quite important.

There are other possible mechanisms to partially explain the observed effects of THC on pituitary horn-one output other than through altering hypothalamic regulation of GnRH. Jakubovic and McGeer () showed that THC (but not nonpsychoactive cannabinoids) decreased the synthesis of protein and nucleic acid in the infant rat brain. Cannabinoids also may affect the cell membranes of nerves, for Greenberg et al. () have shown an inhibition of LPC acyltransferase, a plasma membrane bound enzyme, which may be involved in neurotransmitter uptake mechanisms in the synpatosomes of mouse brain. Also, marijuana may produce morphological changes, at the ultrastructural level in the neural tissue, such as synaptic cleft widening and clumping of synaptic vesicles in the synaptic cleft ().


Selections from the book: “Marijuana Effects on the Endocrine and Reproductive Systems”. Monique C. Braude, Ph.D., and Jacqueline P. Ludford, M.S., eds. A RAUS Review Report of animal studies and preclinical and clinical studies of effects of cannabinoids on human endocrine and reproductive functions. National Institute on Drug Abuse Research Monograph 44, 1984.