Endocrine Effects of Marijuana in the Male: Preclinical Studies

2015

The research efforts of many investigators in the recent past have made it abundantly clear that exposure to marijuana has significant effects upon the reproductive system and the effects of cannabinoid treatment are equally significant on both male and female reproductive systems. Among the effects of cannabinoid treatment on the male reproductive system that have been reported arc altered testicular function, in the form of depressed male hormone secretion, and changes in both the quantity and quality of the sperm produced by the seminiferous tubules. There have been changes reported in the weight and in certain of the enzymes associated with the reproductive organs. Much research effort focused on the ability of THC to depress the secretion of the gonadotropins from the pituitary that are responsible for stimulating testosterone production by the Leydig cells of the testis and the action on the hypothalamus to depress gonadotropic releasing hormone (GnRH).

Maintenance and regulation of normal reproductive capacity in the male is a complex and highly integrated phenomenon. It requires proper nutritional and hormonal support, not only by the hormones directly involved in reproduction, hut also by the synergistic action of hormones produced by other endocrine organs throughout the body. The regulation of many endocrine organs in the body is though the hypothalamus, an area which is sensitive to chemical, hormonal, and sensory input from all parts of the body. Thus, it is easy to understand why psychoactive drugs which alter neural function in various parts of the brain have so much of an effect on the output of trophic hormones from the hypothalamus. This review will attempt to summarize the effect that marijuana and its various constituents have on the reproductive system of laborator animals. Although this review emphasizes effects on the male reproductive system, some female data are included for comparative purposes.

The effects of THC on gonadotropins

In 1973 Marks reported that luteinizing hormone levels in ovariectomized rats were reduced sharply by λ9-iltetrahydrocannibinol (THC) (1, 3, and 10 mg/kg I.V.). Marks concluded that the action of THC was not related to activation of muscarinic receptors but that it might be due to the observed ability to increase the uptake and retention of catecholamines by brain tissue, which would in effect produce an inhibition of GnRH release from the hypothalamus. Symons et al. () showed that both acute and chronic treatment of rats with THC (5 mg/kg 2 times a week for 6 weeks i.m.) produced a decrease in both plasma luteinizing hormone (LH) and testosterone levels. They also observed that the effect of an acute dose was more dramatic than the chronic treatment and that THC somehow decreased the pituitary’s response to GnRH.

Collu et al. () reported that injection of prepubertal male rats with 10 mg/kg THC three times a week for 30 days resulted in reduced levels of LH in the plasma while pituitary levels of luteinizing hormone were unmodified. They similarly reported that plasma levels of follicle stimulating hormone (FSH) were not affected by the drug treatment. Dalterio et al. () showed that oral administration of THC (50 mg and 100 mg/kg) to male mice resulted in a reduction of plasma testosterone, LH, and FSH levels, but that single doses of cannabinol (CBN) had no effect on any of these three hormones. They concluded that the reduction in plasma hormone levels was due to inhibition of pituitary LH release, as well as to a direct effect on the testis to alter the responsiveness to LH stimulation.

Smith et al. () injected male Rhesus monkeys with THC (5 mg/kg I.M. acute) and produced a 65% reduction in serum testosterone levels that returned to normal over the next 3-day period. They found a depression in LH levels that was comparable in magnitude and duration to the depression in testosterone levels. Fran these data they postulated that the THC inhibition of male sex hormones was due to its interaction with the central nervous system. Thus it appears that THC affects the hypothalamus and pituitary of males in a similar manner to the way it affects females.

In female ovariectomized monkeys, Snith et al. () compared the effects of various doses of THC on the levels of LH and on the levels of follicle stimulating hormone. Five mg/kg produced a 68% reduction in LH levels and a 56% reduction in FSH levels. The maximum decrease occurred at the same time for both gonadotropins. Smith et al. () have also reported that the decrease in both LH and FSH were equivalent in response to equal doses of THC whether the THC was administered as a pure substance or as the same percent in crude marijuana extract (CME). These data suggest that the inhibitory action of marijuana on gonadotropin levels is produced by THC and that the other cannabis derivatives contained in marijuana do not contribute to the effect, since neither cannabidol (CBD) nor CBN had any significant effect on gonadotropin levels, even up to dosages of 10 mg/kg. Thus they have concluded that the inhibitory effect of cannabis derivatives on gonadotropins is related to their psychoactivity. It should be pointed out, however, that certain non-psychoactive cannabinoids which may not be involved in altering hormonal changes in the hypothalamus, the pituitary, or the testis, may contribute to a direct effect on other reproductive functions such as sperm production by the seminiferous tubules, augmentation of hormonal effects on growth and secretory activity of accessory sex organs (such as prostate and seminal vesicles), interaction with hormones at the target tissue level, or altering receptors for hormones on target tissues.

The effect of marijuana on gonadotropin releasing hormone

Effect of marijuana on the testis and accessory reproductive organs

The effects of THC on prolactin secretion

The reports of research which examined the effect of THC on prolactin secretion in the male are somewhat controversial and contain conflicting reports. Some of the apparent conflict can be attributed to the method of administration of the THC, and perhaps the dosage of THC as well. Collu () administered THC (20µg) intraventricularly for a week to prepubertal and to adult rats. He reported that pituitary levels of prolactin were increased in both prepubertal and adult animals, and noted that there were no changes in brain levels of noradrenaline, dopamine, or serotonin following drug treatment. Kramer and Ben-David () had reported a suppression of prolactin release by acute THC treatment. The administration of the serotonin antagonist, cyprohepatidine, or the dopamine antagonists, perphenazine and chemozine, was able to abolish the THC induced suppression of prolactin. They also questioned whether the ability of THC to decrease TRH, a hormone known to cause prolactin release, might be responsible for the THC-induced suppression of prolactin release.

Bromley et al. () administered a rather high dose of THC (30 mg/kg I.P.) to male rats and showed a marked suppression of prolactin as quickly as 15 minutes after THC injection. They reported that THC blocked the release of prolactin in ether-stressed rats, and also found that THC impaired, but did not prevent, a significant pituitary response to perphenazine.

Dalterio et al. () reported a reduction of plasma prolactin levels in stressed and non-stressed male mice after a single dose of THC (50 mg/kg P.O.). However, chronic treatment had no effect on prolactin under these conditions (3 times/week/3 weeks). Chronic exposure to CBN resulted in reduced plasm prolactin levels in stresssed mice, indicating that perhaps non-psychoactive ingredients in marijuana, at least in the dosages used in this study, can exert effects on endocrine function. Daley et al. (1974) reported that male rats injected with THC (4 and 16 mg/kg I.P.) had heavier pituitary gland weights than controls at both dosage levels and that, although serum prolactin was significantly increased, there was no increase in the total piuitary concentration of prolactin.

Smith et al. () and Asch et al. () have shown that administration of THC (2.5 or 2 mg/kg I.M.) produced a short-lived inhibition of prolactin levels in the serum of male Rhesus monkeys. Administration of thyrotropin releasing hormone (TRH) was able to increase prolactin levels in THC treated monkeys, indicating that the hypothalamus was the site of action in the THC-induced depression of prolactin release fran the pituitary.

Although there are conflicting reports on the ability of THC to either increase or decrease prolactin levels in the pituitary and in the serum, it appears that the effect of THC and perhaps other non-psychoactive ingredients in marijuana is to produce a prompt depression of prolactin secretion from the pituitary gland in the male. The exact mechanism of this inhibition is not known at this time; however, marijuana probably has some action on the hypothalamus to alter secretion of the several neural transmitters which are probably involved in eliciting prolactin release fran the pituitary gland. The ability of THC to inhibit the release of prolactin, LH, and FSH fran the pituitary would appear to be unique, and in apparent contrast to many other psychoactive drugs which stimlate prolactin release while inhibiting the secretion of both LH and FSH. It is also apparent that the male pattern of response to THC with repressed prolactin levels is the same as has been shown to occur in female animals and it is probable that the reduction is caused by the same mechanism that cause the reduction in females.

Effect of marijuana the adrenal gland

The effect of marijuana on thyroid gland

The function of thyrotropin releasing hormone (TRH) is, to elicit thyrotropin (TSH) secretion from the pituitary which in turn stimulates the thyroid gland to concentrate iodide from the blood, and to synthesize and secrete the thyroid hormones. TRH is secreted from the hypothalamus in response to dopamine and norepinephrine stimulation. Grimm and Reichlin () showed that incubation of the hypothalamic tissue from mouse brain with either neurotransmitter, dopamine, or norepinephrine, was effective in causing a release of TRH. However, agents which blocked conversion of dopamine to norepinephrine were unable to elicit this response. They also showed that whereas acetylcholine had no effect on TRH release, serotonin tended to inhibit TRH release

The first indication that thyroid gland function might be affected by marijuana was reported in 1965 by Miras, who showed that cannabis resin administered to rats produced a depression of radioactive iodine accumulation in the thyroid gland. He was, however, unable to show whether the cannabinoids in the extract affected thyroid gland function directly at the site of the thyroid gland or whether the action of the cannabinoids was by alteration of hypothalamic output of TSH. Lomax () injected marijuana distillate extract into rats and found a decreased release of radioactive iodine from the thyroid glands of rats. He showed that the hypothalamus was probably the site of action by injecting TSH during the period when marijuana was maximally depressing the radioactive iodine release and reversed the inhibition of marijuana on radioactive iodine release.

Nazar et al. () reported that acute administration of THC at 2.5 mg/kg, and chronic treatment for 3 days, depressed serum thyroxine concentration in the rat. Single injections depressed thyroxine in the serum for 6 hours following drug treatment. Administration of TSH elevated serum thyroxine, indicating that THC probably had its action on thyroid function at the level of the hypothalamus. Under chronic THC treatment, however, twice daily for 14 days, an apparent tolerance to the thyroid depressant action of THC appeared to develop. They further showed that the presence of the adrenal hormone was not required for the depressant action of THC on thyroid gland function. Esber et al. () administered 2 and 4 mg of THC per day by inhalation to rats and produced a significant lowering of triicdothyronine (T3) in the serum; serum thyroxine was not affected. Oral administration of THC to rats (10 mg/kg/day for 14 days) had a more dramatic effect on serum hormonal levels than administration by inhalation of marijuana smoke. Oral administration significantly depressed both triiodothyronine and thyroxine.

Administering THC or smoking marijuana produced a decrease in body temperature, with a peak response observed between 1 and 2 hours after drug administration, which lasted from 5 to 6 hours. Bhargava () was able to antagonize the hypothermic response to THC in mice by either intracerebral or intraperitoneal administration of TRH prior to the THC injection. Similar effects were produced by histidyl proline diketopiperazine (HPD), postulated as a metabolite of TRH, if given intracerebrally; however, it was completely ineffective if given intraperitoneally. Thus, the antagonism of THC-induced hypothermia by TRH may be mediated by its conversion to HPD in the central nervous system.

Effect of marijuana on growth hormone

There is a body of evidence to indicate that the exposure of animals to marijuana, a marijuana extract, cannabinoids, or the psychoactive ingredient, THC, produced depressed body weights and altered organ sizes. There are a number of reasons to believe that marijuana affects the normal growth processes. Growth of the organism and its organ systems is a complex and highly integrated system affected by many external and internal factors such as nutrition, heredity, and hormonal regulation. Although many hormones interact to affect growth processes, one of the more important hormones is growth hormone; for this reason several research workers have examined the effect that THC has on growth hormone. Collu et al. () injected prepubertal male rats intraperitoneally three times a week for a month with either 1 or 10 mg/kg of THC. Treatment with 10 mg/kg produced rats with smaller tails and prostates than non-treated animals and, in addition, plasma levels of growth hormone and LH were decreased at all drug dosages. While pituitary quantities of GH and LH remain unchanged, they reported no effect on FSH and brain levels of norepinephrine, epinephrine, serotonin, and 5-hydroxyindole acetic acid which were comparable to those of the control group.

Collu () administered THC (20 µg) each day for a week to pre-pubertal and adult rats intraventricularly. Prepubertal rats had lower prostate weight; however, they had increased plasma and pituitary levels of growth hormone. Kokka and Garcia () showed that administration of 5 to 20 µm/kg of THC to adult rats caused an inhibition of growth hormone secretion and a stimulation of ACTH secretion. Dexamethasone, a potent supressor of ACTH secretion, blocked the stimulatory affect of an acute injection of THC on ACTH secretion but did not affect its inhibitory action of GH secretion. Treatment of rats with pentobarbital usually induces a rise of plasma growth hormone; however, THC was able to suppress the pentobarbital induced rise of plasma GH. Dalterio et al. () report that growth hormone levels in the plasma of male mice that received a single dose of THC were reduced only in non-stressed animals, whereas chronic treatment with THC did not affect prolactin or growth hormone levels under either stressed or non-stressed conditions. In apparent contrast to the effects of THC, acute administration of CBD, a non-psychoactive ingredient in marijuana, produced increased plasma GH levels in non-stressed mice, while repeated CBN treatments reduced GH levels in stressed animals.

Endocrine Effects of Marijuana in the Male: Summary

Marijuana affects a variety of hormones that are regulated by hypothalamic function and it appears that the psychoactive ingredient, THC, is the major compound responsible for this action. It is probable that THC affects these hormones through its ability to alter various neural transmitters in the hypothalamus or neural transmitters in the CNS which impinge on the hypothalarms. The dopaminergic and serotonergic fibers seem to be particularly important. The two gonadotropins, LH and FSH, secreted by the pituitary gland are of major importance to reproduction in the male. Both gonadotropins appear to respond to a single releasing factor fran the hypothalmus, GnRH, which is sensitive to catecholamine neurotransmitters. The THC-induced block of GnRH release results in lowered LH and FSH which is responsible for reduced testosterone production by the Leydig cells of the testis. Other hormones that might have a synergistic or antagonistic effect upon reproduction in the male are the adrenal cortical hormones, prolactin, thyroid hormones, and growth hormones. THC appears to depress prolactin, thyroid gland function, and growth hormone while elevating adrenal cortical steriods.

Chronic exposure of laboratory animals, such as rats, mice, and monkeys to marijuana and to the various cannabinoids in marijuana has altered the function of several of the accessory reproductive organs. Reports of reduced prostate and seminal vesicle weights, as well as altered testicular function, have been partially explained by the effect of marijuana in lowering serum testosterone needed for proper function and support. Although some of the change in organ weight may be due to lowered testosterone production by the Leydig cells of the testis, sane of the weight changes may be due to a direct action of THC, and perhaps some of the other nonpsychoactive cannabinoids in marijuana, on the tissue themselves. Also, of concern are the reports that acute cannabinoid treatments affects the quality and quantity of spermatozoa produced by the testis. The question is still unanswered as to whether or not the effects observed on spermatozoa are due to a direct action of the cannabinoids on spermatogenesis, or whether some of the observed effects may be due to altered hormone levels which are necessary for the support of spermatogenesis. Reduced testosterone and FSH may be important in producing the observed changes in sperm production by the seminiferous tubules.

Many of the effects on the endocrine system caused by chronic treatment of animals with THC are completely reversible with time and there is reason to believe that tolerance develops to these effects with acute exposure to THC. Still, many unanswered questions remain regarding the long-term consequence of marijuana use on such important functions of male reproduction as sperm formation and maturation, and the long-term effects on the function of the sexual organs. Until the time that answers to these and other questions are forthcoming, it is questionable whether marijuana should be consumed by adolescent males or those males with marginal fertility problems.

 

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.