ENDOCRINE EFFECTS OF MARIJUANA.pdf

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NOVEMBER EFFECTS

ENDOCRINE SUPPLEMENT

BROWN AND DOBS OF MARIJUANA

Endocrine Effects of Marijuana

Todd T. Brown, MD, and Adrian S. Dobs, MD, MHS

In the 35 years since the active compound of marijuana,

-tetrahydrocannabinol, was isolated, the psychological

and physiological impact of marijuana use has been actively

investigated. Animal models have demonstrated that

cannabinoid administration acutely alters multiple hor-

monal systems, including the suppression of the gonadal ste-

roids, growth hormone, prolactin, and thyroid hormone and

the activation of the hypothalamic-pituitary-adrenal axis.

These effects are mediated by binding to the endogenous

cannabinoid receptor in or near the hypothalamus. Despite

these findings in animals, the effects in humans have been in-

consistent, and discrepancies are likely due in part to the de-

velopment of tolerance. The long-term consequences of mari-

juana use in humans on endocrine systems remain unclear.

Journal of Clinical Pharmacology, 2002;42:90S-96S

n the late 1960s, the dramatic increase in the casual

use of marijuana raised questions about its potential

adverse effects on health. In 1972, Harmon and

Aliapoulios

provided the first report of marijuana’s

clinical impact on the endocrine system with the initial

description of marijuana-associated gynecomastia.

Further investigation has demonstrated that marijuana

and its active component,

∆

-tetrahydrocannabinol

(THC), have widespread effects on multiple hormonal

systems, including gonadal, adrenal, prolactin, growth

hormone, and thyroid hormone regulation in experi-

mental models. In addition, the effects on the

neuroendocrine mechanism of feeding are being delin-

eated. Many of these acute effects, however, are tran-

sient as tolerance likely develops, and the long-term

impact of marijuana smoking on the endocrine systems

in humans remains unclear. This review will outline

the effects of cannabinoids on the various hormonal

systems both in animals and in man and evaluate the

evidence of possible clinical consequences on the en-

docrine system with marijuana use.

HYPOTHALAMIC-

PITUITARY-GONADAL AXIS

In both males and females, the secretion of sex hor-

mones is directly controlled by the pituitary and in-

directly influenced by the hypothalamus. From cells

in the medial basal hypothalamus, gonadotropin-

From the Division of Endocrinology and Metabolism, Johns Hopkins Uni-

versity, Baltimore, Maryland. Address for reprints: Adrian S. Dobs, MD,

MHS, Division of Endocrinology and Metabolism, Johns Hopkins Univer-

sity, 1830 E. Monument St. Suite 333, Baltimore, MD 21287.

DOI: 10.1177/0091270002238799

releasing hormone (GnRH) is secreted in a pulsatile

fashion under the influence of a variety of other factors,

including endogenous opiates, catecholamines,

prolactin, corticotropin-releasing hormone (CRH), and

neuropeptide Y. GnRH stimulates the production of

follicle-stimulating hormone (FSH) and luteinizing

hormone (LH) in the anterior pituitary gonadotrophs.

In both males and females, FSH and LH act on the go-

nads, leading to the secretion of testosterone in males

and estradiol and progesterone in females. These hor-

mones feed back to the hypothalamus and anterior pi-

tuitary to modulate GnRH and gonadotropin release.

Marijuana,

∆

-THC, and other cannabinoids acutely

alter hypothalamic-pituitary-gonadal (HPG) integrity

and affect reproductive function by acting at the hypo-

thalamus either directly through GnRH or indirectly

through other modulators (Figure 1). These effects are

likely mediated by central cannabinoid (CB1) receptors

in the hypothalamus.

CB1 receptors have also been

found in the testes

and the ovaries

of experimen-

tal animals, suggesting a possible direct effect of

cannabinoids on the gonads. In addition, marijuana

condensate and

∆

-THC inhibit binding of dihydrotes-

tosterone (DHT) to the androgen receptor,

and

noncannabinoid components of marijuana extract

have been shown to bind to the estrogen receptor.

The

extent to which these non-CB1-mediated pathways

contribute to marijuana’s effects on the HPG axis has

not been clarified.

HPG AXIS EFFECTS IN MALES

LH stimulates the Leydig cells in the testes to produce

testosterone, while FSH primarily acts on the Sertoli

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J Clin Pharmacol 2002;42:90S-96S

ENDOCRINE EFFECTS OF MARIJUANA

EFFECTS ON REPRODUCTIVE

HORMONES IN MALES

Studies in male rodents have shown significant de-

creases in both testosterone and gonadotropins

with

acute administration of

∆

-THC due to inhibition of the

GnRH pulse generator

in the hypothalamus. Similar

effects have been demonstrated in primates. In the rhe-

sus monkey, THC reduced testosterone levels by 65%,

which lasted 1 hour.

Chronic effects of cannabinoid ad-

ministration are less clear. Although dose-dependent

decreases in LH have been observed with chronic ad-

ministration of

∆

- THC,

the effect of chronic exposure

is less dramatic than that of acute administration

and

may be related to the development of tolerance.

Human studies investigating the effects of

cannabinoids on reproductive hormones have been

conflicting. Lower testosterone levels have been re-

ported in chronic marijuana users compared to nonus-

ers,

and acute decreases in both LH and testosterone

have been observed after marijuana smoking,

but

multiple subsequent studies have not confirmed these

findings.

14-17

In one study, heavy chronic users were

found to have similar testosterone levels compared to

casual users at baseline and did not experience any sig-

nificant alterations in testosterone after a 21-day period

of intense marijuana smoking in a controlled research

setting.

A subsequent study of similar design by the

same investigators showed no significant changes in

integrated LH levels over the study period.

These in-

consistent observations may be due to differences in

study design but also may reflect the development of

tolerance, as suggested by the animal studies.

Down-regulation and desensitization of CB1 receptors

in the hypothalamus may underlie the weakening of ef-

fect observed with chronic cannabinoid administra-

tion.

18,19

EFFECTS ON

TESTICULAR FUNCTION

Marijuana and

∆

-THC can have direct effects on the

testes. Reductions in testicular size have been observed

in rodents

and dogs

with administration of cannabis

extract. Degeneration of the seminiferous tubules may

provide an explanation for this observation

and is

dose dependent, with lower doses showing no appre-

ciable effect.

Abnormal sperm morphology has been

characterized in rodents exposed to marijuana smoke

∆

-THC

for a 5-day period. In vitro studies have

demonstrated that cannabinoids directly inhibit

Figure 1. Effects of marijuana and

∆

-THC on male hypothalamic-

pituitary-gonadal (HPG) function. Animal models demonstrate inhi-

bition of the HPG axis by indirect suppression of LHRH (GHRH) se-

cretion. In addition, direct effects on Leydig and Sertoli cells have

been observed. Inconsistent results in human studies may be due to

the development of tolerance. LH, luteinizing hormone; LHRH,

luteinizing hormone-releasing hormone; GHRH, growth hormone-

releasing hormone; FSH, follicle-stimulating hormone; C, choles-

terol; T, testosterone. Adapted from Griffin JE, Wilson JD: Disorders of

the testes, in: Isselbacher KJ, et al (eds.),

Harrison’s Principles of Inter-

nal Medicine.

13th ed. New York: McGraw-Hill, 1994.

cells to regulate spermatogenesis. In the adult human

male, testosterone has a variety of actions throughout

the body, including the maintenance of secondary sex

characteristics, the facilitation of Sertoli cell function,

and the promotion of sexual function. Hypogonadism

results in decreased quality of life marked by fatigue,

decreased libido, diminished sense of well-being, im-

paired fertility, and changes in body composition, in-

cluding reduced bone mineral density and lean body

mass. In experimental animals, acute administration of

cannabinoids has been shown to both decrease testos-

terone levels and disrupt normal spermatogenesis.

Findings in humans have not been consistent.

NOVEMBER SUPPLEMENT

BROWN AND DOBS

Leydig cell function.

The observed effects of

cannabinoids on the testes notwithstanding, the im-

pact on fertility is not clear. While

∆

-THC administra-

tion to mice 4 weeks prior to and during mating had no

effect on fertility,

impregnation rates for mates of

THC-treated mice were significantly lower than un-

treated controls.

This observation may be due in part

to reduction in copulatory behavior.

In humans, effects on sperm production and mor-

phology have also been observed. Dose-related

oligospermia has been observed in chronic users.

Similarly, a 58% decrease in sperm concentration was

reported in chronic users after intensive marijuana

smoking without a significant change in LH or testos-

terone.

Reversible reductions in sperm concentration

were seen 5 to 6 weeks after the initiation of intensive

smoking, suggesting an effect on sperm production.

In addition, abnormal sperm morphology has been

noted in chronic smokers.

Although these findings

imply a significant effect on gonadal function in hu-

mans, the true impact of marijuana on fertility is not

known. However, discontinuation of casual marijuana

use is recommended for infertile men.

GYNECOMASTIA

Gynecomastia is defined as the accumulation of breast

tissue in men and results from increases in the circulat-

ing estrogen/androgen ratio.

Marijuana has been asso-

ciated with the development of gynecomastia in an

early case series,

but a case control study showed no

association.

Given the effects of marijuana on the HPG

axis in males and the possibility that noncannabinoid

components of marijuana smoke have affinity to the es-

trogen receptor,

an association with gynecomastia is

plausible but has not been convincingly demonstrated.

HPG AXIS EFFECTS IN FEMALES

The secretion of estrogen from the ovary and the regula-

tion of the ovulatory cycle are tightly controlled by the

secretion of gonadotropins from the anterior pituitary.

With waning levels of estrogen and progesterone at the

end of menses, FSH levels increase, stimulating the

growth and development of an ovarian follicle and thus

the production of estrogen. Estrogen reduces FSH and

LH secretion by negative feedback, but when estrogen

levels peak, a LH surge is provoked by positive feed-

back, causing ovulation. LH then stimulates the pro-

duction of estrogen and progesterone by the corpus

luteum. Marijuana and

∆

-THC have been shown to

disrupt the normal ovulatory cycle and hormonal se-

cretion in both animals and humans. However, similar

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J Clin Pharmacol 2002;42:90S-96S

to the findings in males, tolerance may develop over

time, and the consequences of chronic use have not

been firmly established.

As seen in male rodents, studies in female ro-

dents have shown that the acute administration of

cannabinoids markedly decreases LH levels

35,36

by sup-

pressing LH pulsatile secretion. Direct and indirect ef-

fects on GnRH secretion have been implicated.

The in-

hibition of gonadotropin secretion underlies the

disruption of the ovulatory cycle. Administration of

cannabinoids to rats blocked the LH surge normally

leading to ovulation

and abolished the ovulatory cy-

cle in rats

38,39

and rabbits.

Studies in monkeys have demonstrated similar

acute effects of cannabinoids on female reproductive

function.

∆

-THC decreased LH levels by 50% to 80%

in monkeys

and has been shown to suppress the LH

surge, resulting in anovulation.

After 3 to 4 months of

chronic administration, however, normal menstrual

cycles spontaneously returned in treated monkeys,

which is thought to be related to the development of

tolerance.

Evidence for tolerance with long-term ad-

ministration also comes from a study of rhesus mon-

keys given oral THC that showed no difficulties with

conception.

The impact of marijuana and THC on humans has

been less clear than in female animals. Some studies re-

port a suppressive effect on LH secretion,

while oth-

ers show a stimulatory effect.

These inconsistencies

may be due to the timing of cannabinoid administra-

tion in relation to the ovulatory cycle. Mendelson et al

showed a 30% decrease in LH in women compared to

controls 1 hour after administration of a marijuana cig-

arette (1 g 1.8% THC) when in the luteal phase but re-

ported no effect in the follicular phase. In another

study, a marijuana cigarette given in periovulatory

stages increased LH levels,

while no acute change in

LH was seen in menopausal women.

Studies of the effects of marijuana on ovulation have

also been inconsistent. While female chronic smokers

have been shown to have normal menses after inten-

sive smoking,

some reports demonstrate increased

anovulatory cycles and decreased length of the luteal

phase.

Women who smoke marijuana may have a

slightly increased risk of infertility due to an ovulatory

abnormality, which was shown in a case control study of

female recreation drug users with primary infertility.

EFFECTS ON PROLACTIN

Prolactin is synthesized in the anterior pituitary and is

important in the stimulation of milk production and

maintenance of lactation in mammals. Its release is un-

ENDOCRINE EFFECTS OF MARIJUANA

der tonic inhibition by dopamine secretion from

tuberoinfundibular neurons in the hypothalamus.

Cannabinoids, including components of marijuana,

modulate the activity of dopaminergic neurons,

thereby altering prolactin secretion. Animal studies

have demonstrated an acute reduction of prolactin lev-

els after THC administration in both rodents

and pri-

mates.

Smith et al

showed that prolactin was re-

duced by a maximum of 84% in ovariectomized female

monkeys and 74% in males at 30 to 90 minutes by a sin-

gle injection of THC.

Not all findings in animals have

been consistent, however, and may be dependent on

the stage of the ovulatory cycle

or the timing of

prolactin measurement in relation to cannabinoid ad-

ministration.

Initial increases in prolactin after acute

administration followed by significant decrements be-

low baseline have been reported and may be due to a

direct effect on the anterior pituitary.

Findings in humans reflect the inconsistencies seen

in animal studies. Some studies have shown an acute

prolactin decrease with administration,

while others

have found no changes.

Similar to the observations in

animals, changes in prolactin may be dependent on the

menstrual cycle stage as an acute decrease in prolactin

in females was reported after smoking a marijuana ciga-

rette in the luteal phase but not in the follicular phase.

It is unknown whether changes in prolactin are seen

with chronic marijuana use. Block et al

found no dif-

ferences in prolactin levels in both men and women in

the largest cross-sectional study of chronic marijuana

users.

EFFECTS ON THE

HYPOTHALAMIC-

PITUITARY-ADRENAL AXIS

Glucocorticoids (GC) are secreted by the adrenal gland

in a diurnal pattern and play an essential role in carbo-

hydrate, protein, and lipid metabolism; immunologic

action; and renal and cardiac function. Physiological

and psychological stresses provoke increased release of

glucocorticoid, which is essential for the survival of the

organism. The secretion of glucocorticoids is regulated

by adrenocorticotropic hormone (ACTH) released by

the anterior pituitary. Corticotropin-releasing hormone

(CRH) synthesized in the hypothalamus regulates

ACTH secretion and is affected by multiple hypotha-

lamic neurotransmitters, including serotonin, dopa-

mine, and catecholamines. Cannabinoids alter HPA

axis function by modulating CRH release either di-

rectly through CB1-mediated effects on CRH neurons

in the paraventricular nucleus

or indirectly through

other hypothalamic pathways.

NOVEMBER SUPPLEMENT

In multiple animal studies, acute administration of

cannabinoids increased both ACTH and GC in a

dose-related fashion,

60-62

an effect that is likely medi-

ated by an increase in CRH.

Rodents administered po-

tent CB1 agonist HU-210 had marked activation of the

HPA axis, but at the highest doses, ACTH decreased

while GC increased, suggestive of rapid negative feed-

back by GC.

However, tolerance to these effects devel-

ops quickly with chronic administration.

Human studies have shown variable effects of mari-

juana and component cannabinoids on the HPA axis.

Similar to the effects in animals, increased cortisol lev-

els have been reported after acute administration of

marijuana.

However, in contrast to these findings, no

change in the diurnal rhythm of cortisol secretion was

observed during THC ingestion in chronic smokers.

Marijuana may also impair cortisol response to a stress-

ful stimulus. Benowitz et al

reported an impaired re-

sponse to insulin-induced hypoglycemia after 4 days

of oral THC ingestion.

It is possible that prolonged

activation of the HPA axis led to a reduction in

adrenocortical reserve. It should be noted, however,

that despite these statistically significant differences,

clinical significance is unlikely in that all subjects had

a cortisol response in the normal range (mean cortisol

at maximum stimulation = 31.7

3.2 mcg/dl).

EFFECTS ON

GROWTH HORMONE

Growth hormone (GH) is secreted by the anterior pitu-

itary, stimulated by the hypothalamic release of growth

hormone-releasing hormone (GHRH), and inhibited by

somatostatin. Serotonin from the limbic system, dopa-

mine in the arcuate nucleus, and catecholamines in the

ventromedial nucleus influence GH secretion by in-

creasing GHRH release. In the adult, GH has wide-

spread effects on many aspects of metabolism. Adult

onset growth hormone deficiency is characterized by

changes in body composition (increased fat mass and

decreased muscle mass), impaired sense of well-being,

reduced bone mineral density, and reduced cardiac

performance.

Cannabinoids have been shown to inhibit GH secre-

tion due to stimulation of somatostatin release.

Acute

decreases in GH have been observed with THC

HU-210 (a synthetic CB1 agonist) administration in

rats.

There are few studies investigating the effect of

marijuana and other cannabinoids on GH secretion in

humans. Benowitz et al

showed that 4 days of oral THC

blunted the normal GH response to insulin-induced

hypoglycemia, the “gold standard” test of GH axis in-

BROWN AND DOBS

tegrity. Long-term effects on GH dynamics in chronic

marijuana users are unknown.

THYROID HORMONE AXIS

Thyroid hormones have widespread effects on cellular

metabolism. Their synthesis and secretion are regu-

lated by thyroid-stimulating hormone (TSH) from the

anterior pituitary, which in turn is controlled by

thyrotropin-releasing hormone (TRH). Cannabinoid ef-

fect on thyroid function was first noted in 1965, when

marijuana extract was shown to reduce iodine accumu-

lation in the rat thyroid.

Acute administration of THC

in rodents

70,71

reduces levels of thyroxine and TSH by

as much as 90% for up to 6 hours. In addition, mari-

juana extract has been shown to decrease the release of

radioactive iodine from the thyroid.

These effects are

reversed by administration of exogenous TSH, suggest-

ing a hypothalamic site of action.

71,72

With chronic ad-

ministration of THC, however, the thyroid depressant

effect of cannabinoids is lost, which may indicate the

development of tolerance.

There are no data regard-

ing the effect of cannabinoids on thyroid function in

humans.

EFFECTS ON THE NEUROENDOCRINE

REGULATION OF FEEDING

The neuroendocrine mechanisms underlying appetite

and feeding behavior are being clarified. Hunger and

satiety signals from the GI tract, adipose tissue, and var-

ious endocrine systems regulate a vast array of hypo-

thalamic hormones that modulate feeding behavior.

Leptin, a polypeptide hormone secreted by adipose tis-

sue, is thought to be a major satiety factor and central

regulator on hypothalamic feeding centers. Leptin may

cause appetite suppression by down-regulating endog-

enous cannabinoids, such as anandamide and

2-arachidonyl glycerol and other appetite-stimulating

peptides.

Exogenous cannabinoids (i.e., marijuana

and THC) also stimulate appetite,

likely through the

activation of CB1 receptors in hypothalamic feeding

centers. This effect provides the rationale for the use of

oral THC in AIDS wasting.

SUMMARY AND CONCLUSIONS

Marijuana and its active component THC affect multi-

ple endocrine systems. A suppressive effect is seen on

the reproductive hormones, prolactin, growth hor-

mone, and the thyroid axis, while the HPA axis is acti-

vated. These effects are mediated through CB1 receptor

activation in the hypothalamus, which directly or indi-

rectly modulates anterior pituitary function. Many of

the responses observed, however, are lost with chronic

administration, which is likely due to the development

of tolerance. Studies in humans have had inconsistent

results that may reflect differences in study design, the

hormonal milieu (e.g., stage in menstrual cycle), or the

development of tolerance. Long-term effects on the var-

ious endocrine systems have not been clearly demon-

strated, and clinical consequences, if present, are likely

to be subtle.

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