Endocrine Effects Of Marijuana

[Jacob Bell]

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

In the 35 years since the active compound of marijuana,
9-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 hormonal
systems, including the suppression of the gonadal steroids,
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 inconsistent,
and discrepancies are likely due in part to the development
of tolerance. The long-term consequences of marijuana
use in humans on endocrine systems remain unclear.
Journal of Clinical Pharmacology, 2002;42:90S-96S

In 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
Aliapoulios1 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, Δ9-tetrahydrocannabinol
(THC), have widespread effects on multiple hormonal
systems, including gonadal, adrenal, prolactin, growth
hormone, and thyroid hormone regulation in experimental
models. In addition, the effects on the
neuroendocrine mechanism of feeding are being delineated.
Many of these acute effects, however, are transient
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 endocrine
system with marijuana use.
HYPOTHALAMICPITUITARY-
GONADAL AXIS
In both males and females, the secretion of sex hormones
is directly controlled by the pituitary and indirectly
influenced by the hypothalamus. From cells
in the medial basal hypothalamus, gonadotropinreleasing
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 gonads,
leading to the secretion of testosterone in males
and estradiol and progesterone in females. These hormones
feed back to the hypothalamus and anterior pituitary
to modulate GnRH and gonadotropin release.
Marijuana, Δ9-THC, and other cannabinoids acutely
alter hypothalamic-pituitary-gonadal (HPG) integrity
and affect reproductive function by acting at the hypothalamus
either directly through GnRH or indirectly
through other modulators (Figure 1). These effects are
likely mediated by central cannabinoid (CB1) receptors
in the hypothalamus.2 CB1 receptors have also been
found in the testes3 and the ovaries4 of experimental
animals, suggesting a possible direct effect of
cannabinoids on the gonads. In addition, marijuana
condensate and Δ9-THC inhibit binding of dihydrotestosterone
(DHT) to the androgen receptor,5 and
noncannabinoid components of marijuana extract
have been shown to bind to the estrogen receptor.6 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
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, impaired
fertility, and changes in body composition, including
reduced bone mineral density and lean body
mass. In experimental animals, acute administration of
cannabinoids has been shown to both decrease testosterone
levels and disrupt normal spermatogenesis.
Findings in humans have not been consistent
EFFECTS ON REPRODUCTIVE
HORMONES IN MALES
Studies in male rodents have shown significant decreases
in both testosterone and gonadotropins7 with
acute administration of Δ9-THC due to inhibition of the
GnRH pulse generator8 in the hypothalamus. Similar
effects have been demonstrated in primates. In the rhesus
monkey, THC reduced testosterone levels by 65%,
which lasted 1 hour.9 Chronic effects of cannabinoid administration
are less clear. Although dose-dependent
decreases in LH have been observed with chronic administration
of Δ9- THC,10 the effect of chronic exposure
is less dramatic than that of acute administration7 and
may be related to the development of tolerance.11
Human studies investigating the effects of
cannabinoids on reproductive hormones have been
conflicting. Lower testosterone levels have been reported
in chronic marijuana users compared to nonusers,
12 and acute decreases in both LH and testosterone
have been observed after marijuana smoking,13 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 significant
alterations in testosterone after a 21-day period
of intense marijuana smoking in a controlled research
setting.14 A subsequent study of similar design by the
same investigators showed no significant changes in
integrated LH levels over the study period.16 These inconsistent
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 effect
observed with chronic cannabinoid administration.
18,19
EFFECTS ON
TESTICULAR FUNCTION
Marijuana and Δ9-THC can have direct effects on the
testes. Reductions in testicular size have been observed
in rodents20 and dogs21 with administration of cannabis
extract. Degeneration of the seminiferous tubules may
provide an explanation for this observation21 and is
dose dependent, with lower doses showing no appreciable
effect.22 Abnormal sperm morphology has been
characterized in rodents exposed to marijuana smoke23
or Δ9-THC24 for a 5-day period. In vitro studies have
demonstrated that cannabinoids directly inhibit
Leydig cell function.25 The observed effects of
cannabinoids on the testes notwithstanding, the impact
on fertility is not clear. While Δ9-THC administration
to mice 4 weeks prior to and during mating had no
effect on fertility,26 impregnation rates for mates of
THC-treated mice were significantly lower than untreated
controls.27 This observation may be due in part
to reduction in copulatory behavior.28
In humans, effects on sperm production and morphology
have also been observed. Dose-related
oligospermia has been observed in chronic users.12
Similarly, a 58% decrease in sperm concentration was
reported in chronic users after intensive marijuana
smoking without a significant change in LH or testosterone.
29 Reversible reductions in sperm concentration
were seen 5 to 6 weeks after the initiation of intensive
smoking, suggesting an effect on sperm production.30
In addition, abnormal sperm morphology has been
noted in chronic smokers.31 Although these findings
imply a significant effect on gonadal function in humans,
the true impact of marijuana on fertility is not
known. However, discontinuation of casual marijuana
use is recommended for infertile men.32
GYNECOMASTIA
Gynecomastia is defined as the accumulation of breast
tissue in men and results from increases in the circulating
estrogen/androgen ratio.33 Marijuana has been associated
with the development of gynecomastia in an
early case series,1 but a case control study showed no
association.34 Given the effects of marijuana on the HPG
axis in males and the possibility that noncannabinoid
components of marijuana smoke have affinity to the estrogen
receptor,6 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 regulation
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 feedback,
causing ovulation. LH then stimulates the production
of estrogen and progesterone by the corpus
luteum. Marijuana and Δ9-THC have been shown to
disrupt the normal ovulatory cycle and hormonal secretion
in both animals and humans. However, similar
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 rodents
have shown that the acute administration of
cannabinoids markedly decreases LH levels35,36 by suppressing
LH pulsatile secretion. Direct and indirect effects
on GnRH secretion have been implicated.2 The inhibition
of gonadotropin secretion underlies the
disruption of the ovulatory cycle. Administration of
cannabinoids to rats blocked the LH surge normally
leading to ovulation37 and abolished the ovulatory cycle
in rats38,39 and rabbits.40
Studies in monkeys have demonstrated similar
acute effects of cannabinoids on female reproductive
function. Δ9-THC decreased LH levels by 50% to 80%
in monkeys41 and has been shown to suppress the LH
surge, resulting in anovulation.42 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.43 Evidence for tolerance with long-term administration
also comes from a study of rhesus monkeys
given oral THC that showed no difficulties with
conception.44
The impact of marijuana and THC on humans has
been less clear than in female animals. Some studies report
a suppressive effect on LH secretion,45 while others
show a stimulatory effect.46 These inconsistencies
may be due to the timing of cannabinoid administration
in relation to the ovulatory cycle. Mendelson et al45
showed a 30% decrease in LH in women compared to
controls 1 hour after administration of a marijuana cigarette
(1 g 1.8% THC) when in the luteal phase but reported
no effect in the follicular phase. In another
study, a marijuana cigarette given in periovulatory
stages increased LH levels,46 while no acute change in
LH was seen in menopausal women.47
Studies of the effects of marijuana on ovulation have
also been inconsistent. While female chronic smokers
have been shown to have normal menses after intensive
smoking,48 some reports demonstrate increased
anovulatory cycles and decreased length of the luteal
phase.49 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.50
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-
der tonic inhibition by dopamine secretion from
tuberoinfundibular neurons in the hypothalamus.
Cannabinoids, including components of marijuana,
modulate the activity of dopaminergic neurons,51
thereby altering prolactin secretion. Animal studies
have demonstrated an acute reduction of prolactin levels
after THC administration in both rodents52 and primates.
53 Smith et al53 showed that prolactin was reduced
by a maximum of84%in ovariectomized female
monkeys and74%in males at 30 to 90 minutes by a single
injection of THC.53 Not all findings in animals have
been consistent, however, and may be dependent on
the stage of the ovulatory cycle54 or the timing of
prolactin measurement in relation to cannabinoid administration.
55 Initial increases in prolactin after acute
administration followed by significant decrements below
baseline have been reported and may be due to a
direct effect on the anterior pituitary.56
Findings in humans reflect the inconsistencies seen
in animal studies. Some studies have shown an acute
prolactin decrease with administration,49 while others
have found no changes.57 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 cigarette
in the luteal phase but not in the follicular phase.58
It is unknown whether changes in prolactin are seen
with chronic marijuana use. Block et al17 found no differences
in prolactin levels in both men and women in
the largest cross-sectional study of chronic marijuana
users.
EFFECTS ON THE
HYPOTHALAMICPITUITARY-
ADRENAL AXIS
Glucocorticoids (GC) are secreted by the adrenal gland
in a diurnal pattern and play an essential role in carbohydrate,
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 hypothalamic
neurotransmitters, including serotonin, dopamine,
and catecholamines. Cannabinoids alter HPA
axis function by modulating CRH release either directly
through CB1-mediated effects on CRH neurons
in the paraventricular nucleus59 or indirectly through
other hypothalamic pathways.2
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 mediated
by an increase in CRH.63 Rodents administered potent
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 feedback
by GC.64 However, tolerance to these effects develops
quickly with chronic administration.62
Human studies have shown variable effects of marijuana
and component cannabinoids on the HPA axis.
Similar to the effects in animals, increased cortisol levels
have been reported after acute administration of
marijuana.65 However, in contrast to these findings, no
change in the diurnal rhythm of cortisol secretion was
observed during THC ingestion in chronic smokers.57
Marijuana may also impair cortisol response to a stressful
stimulus. Benowitz et al66 reported an impaired response
to insulin-induced hypoglycemia after 4 days
of oral THC ingestion.66 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 pituitary,
stimulated by the hypothalamic release of growth
hormone-releasing hormone (GHRH), and inhibited by
somatostatin. Serotonin from the limbic system, dopamine
in the arcuate nucleus, and catecholamines in the
ventromedial nucleus influence GH secretion by increasing
GHRH release. In the adult, GH has widespread
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 secretion
due to stimulation of somatostatin release.67 Acute
decreases in GH have been observed with THC68 or
HU-210 (a synthetic CB1 agonist) administration in
rats.64 There are few studies investigating the effect of
marijuana and other cannabinoids on GH secretion in
humans. Benowitz et al66 showed that 4 days of oralTHC
blunted the normal GH response to insulin-induced
hypoglycemia, the "gold standard" test of GH axis in-
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 regulated
by thyroid-stimulating hormone (TSH) from the
anterior pituitary, which in turn is controlled by
thyrotropin-releasing hormone (TRH). Cannabinoid effect
on thyroid function was first noted in 1965, when
marijuana extract was shown to reduce iodine accumulation
in the rat thyroid.69 Acute administration of THC
in rodents70,71 reduces levels of thyroxine and TSH by
as much as 90% for up to 6 hours. In addition, marijuana
extract has been shown to decrease the release of
radioactive iodine from the thyroid.72 These effects are
reversed by administration of exogenous TSH, suggesting
a hypothalamic site of action.71,72 With chronic administration
of THC, however, the thyroid depressant
effect of cannabinoids is lost, which may indicate the
development of tolerance.71 There are no data regarding
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 various
endocrine systems regulate a vast array of hypothalamic
hormones that modulate feeding behavior.
Leptin, a polypeptide hormone secreted by adipose tissue,
is thought to be a major satiety factor and central
regulator on hypothalamic feeding centers. Leptin may
cause appetite suppression by down-regulating endogenous
cannabinoids, such as anandamide and
2-arachidonyl glycerol and other appetite-stimulating
peptides.73 Exogenous cannabinoids (i.e., marijuana
and THC) also stimulate appetite,74 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 multiple
endocrine systems. A suppressive effect is seen on
the reproductive hormones, prolactin, growth hormone,
and the thyroid axis, while the HPA axis is activated.
These effects are mediated through CB1 receptor
activation in the hypothalamus, which directly or indirectly
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 various
endocrine systems have not been clearly demonstrated,
and clinical consequences, if present, are likely
to be subtle.
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Source: Endocrine Effects Of Marijuana