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Drugs and the Endocrine System
Armario A. Activation of the hypothalamic-pituitary-adrenal axis by addictive drugs: different pathways,
common outcome. Trends Pharmacol Sci. 2010 Jul;31(7):318-25.
Addictive drugs (opiates, ethanol, cannabinoids (CBs), nicotine, cocaine, amphetamines) induce activation of the
hypothalamic-pituitary-adrenal (HPA) axis, with the subsequent release of adrenocorticotropic hormone and
glucocorticoids. The sequence of events leading to HPA activation appears to start within the brain, suggesting that
activation is not secondary to peripheral homeostatic alterations. The precise neurochemical mechanisms and brain
pathways involved are markedly dependent on the particular drug, although it is assumed that information
eventually converges into the hypothalamic paraventricular nucleus (PVN). Whereas some drugs may act on the
hypothalamus or directly within PVN neurons (i.e. ethanol), others exert their primary action outside the PVN (i.e.
CBs, nicotine, cocaine). Corticotropin-releasing hormone (CRH) has a critical role in most cases, but the changes
in c-fos and CRH gene expression in the PVN also reveal differences among drugs. More studies are needed to
understand how addictive drugs act on this important neuroendocrine system and their functional consequences.
PMID: 20537734
Adinoff B, Junghanns K, Kiefer F, Krishnan-Sarin S. Suppression of the HPA axis stress-response:
implications for relapse. Alcohol Clin Exp Res. 2005 Jul;29(7):1351-5.
This article presents the proceedings of a symposium held at the meeting of the International Society for Biomedical
Research on Alcoholism (ISBRA) in Mannheim, Germany, in October 2004. This symposium explored the potential
role of hypothalamic-pituitary-adrenal (HPA) axis dysregulation upon relapse. HPA axis stimulation induces the
release of the glucocorticoid cortisol, a compound with profound effects upon behavior and emotion. Altered stressresponses of the HPA axis in abstinent alcohol-dependent subjects, therefore, may influence their affective and
behavioral regulation, thus impacting their potential for relapse. Bryon Adinoff began the symposium with a review
of HPA axis dysfunction in alcohol-dependent subjects, including recent studies from his lab demonstrating an
attenuated glucocorticoid response to both endogenous and exogenous stimulation in one-month abstinent men.
Klaus Junghanns presented his work demonstrating that a blunted ACTH or cortisol response to subjective stressors
(social stressor or alcohol exposure) is predictive of a return to early drinking. The final two presenters examined
the interaction between naltrexone and HPA responsiveness in alcohol-dependent or at-risk subjects, as
naltrexone induces an increase in ACTH and cortisol. Falk Kiefer discussed the relationship between basal HPA
axis responsivity and clinical outcome following treatment with naltrexone or acamprosate. Plasma ACTH
significantly decreased over the course of the study in the medication groups, but not the placebo group. Lower
basal concentrations of ACTH and cortisol were associated with quicker relapse in the placebo group only.
Suchitra Krishnan-Sarin described her preliminary work, in which family-history positive (FH+) and family history
negative (FH-) subjects were administered naltrexone, followed by an assessment of alcohol-induced craving. The
cortisol response to alcohol was significantly and inversely related to craving in the FH+, but not the FH-, subjects.
Alterations in HPA axis responsivity may therefore have a negative impact upon clinical outcome in alcoholdependent subjects, and disinhibition of the axis with medication may have therapeutic potential.
King AC, Schluger J, Gunduz M, Borg L, Perret G, Ho A, Kreek MJ. Hypothalamic-pituitaryadrenocortical (HPA) axis response and biotransformation of oral naltrexone: preliminary examination of
relationship to family history of alcoholism. Neuropsychopharmacology. 2002 Jun;26(6):778-88.
We examined HPA axis response to 50 mg oral naltrexone compared with placebo in 17 healthy male and female
nonalcoholic subjects, approximately half of whom had a positive family history of alcoholism (FH+) and half of
whom who did not (FH-). Mood response and naltrexone biotransformation were also examined at various
intervals. Subjects participated in two morning test sessions (50 mg naltrexone or identical placebo pill) after an
overnight stay in the Rockefeller University GCRC. For the total sample, ACTH and cortisol significantly
increased after naltrexone compared with placebo (p <.05). Secondary analyses showed the FH+ subgroup had a
different pattern of response over time compared with the FH- subgroup, with heightened ACTH and cortisol, and
decreased vigor ratings, during naltrexone (p <.05). The results demonstrate that orally administered naltrexone
acutely disinhibits the HPA axis, and that individuals with an assumed greater biological vulnerability to addiction,
by virtue of familial alcoholism, had altered regulation of the HPA axis in part under the control of the endogenous
opioid system. 166 words. PMID: 12007748
Leśkiewicz M, Budziszewska B, Lasoń W. [Endocrine effects of antiepileptic drugs]. Przegl Lek.
2008;65(11):795-8.
Both seizures and antiepileptic drugs may induce disturbances in hormonal system. Regarding endocrine effects of
anticonvulsants, an interaction of these drugs with gonadal, thyroid, and adrenal axis deserves attention. Since
majority of antiepileptic drugs block voltage dependent sodium and calcium channels, enhance GABAergic
transmission and/or antagonize glutamate receptors, one may expect that similar neurochemical mechanisms are
engaged in the interaction of these drugs with synthesis of hypothalamic neurohormones such as gonadotropinreleasing hormone (GnRH), thyrotropin-releasing hormone (TRH), corticotropin-releasing hormone (CRH) and
growth hormone releasing hormone (GHRH). Moreover some antiepileptic drugs may affect hormone metabolism
via inhibiting or stimulating cytochrome P-450 iso-enzymes. An influence of antiepileptic drugs on hypothalamicpituitary-gonadal axis appears to be sex-dependent. In males, valproate decreased follicle-stimulating hormone
(FSH) and luteinizing hormone (LH) but elevated dehydroepiandrosterone sulfate (DHEAS) concentrations.
Carbamazepine decreased testosterone/sex-hormone binding globulin (SHBG) ratio, whereas its active metabolite-oxcarbazepine--had no effect on androgens. In females, valproate decreased FSH-stimulated estradiol release and
enhanced testosterone level. On the other hand, carbamazepine decreased testosterone level but enhanced SHBG
concentration. It has been reported that carbamazepine, oxcarbazepine or joined administration of carbamazepine
and valproate decrease thyroxine (T4) level in patients with no effect on thyrotropin (TSH). While valproate itself
has no effect on T4, phenytoin, phenobarbital and primidone, as metabolic enzyme inducers, can decrease the level
of free and bound thyroxine. On the other hand, new antiepileptics such as levetiracetam, tiagabine, vigabatrine or
lamotrigine had no effect on thyroid hormones. With respect to hormonal regulation of metabolic processes,
valproate was reported to enhance leptin and insulin blood level and increased body weight, whereas topiramate
showed an opposite effect. In contrast to thyroid and gonadal hormones, only a few data concern antiepileptic drug
action in HPA axis. To this end, no effect of antiepileptic drugs on adrenocorticotropic hormone (ACTH)/cortisol
circadian rhytmicity was found. Valproate decreased CRH release in rats, whereas lamotrigine stabilized
ACTH/cortisol secretion. Moreover, felbamate was found to inhibit stress-induced corticosterone release in mice.
Interestingly, recent data suggest that felbamat and some other new antiepileptic drugs may inhibit transcriptional
activity of glucocorticoid receptors. Summing up, the above data suggest that traditional antiepileptic drugs may
cause endocrine disturbances, especially in gonadal hormones. PMID: 19205363
Mendelson JH, Mello NK, Cristofaro P, Skupny A, Ellingboe J. Use of naltrexone as a provocative test
for hypothalamic-pituitary hormone function. Pharmacol Biochem Behav. 1986 Feb;24(2):309-13.
Naltrexone (50 mg) administration to normal adult women during the early follicular phase of the menstrual
cycle (day 1 to day 4 following onset of menstruation) induced a significant elevation in plasma LH, prolactin,
ACTH and cortisol levels. Orally administered naltrexone appears to be a safe and effective compound for
assessing function of the hypothalamic-anterior pituitary axis in women. PMID: 3006087
Schluger JH, Ho A, Borg L, Porter M, Maniar S, Gunduz M, Perret G, King A, Kreek MJ. Nalmefene
causes greater hypothalamic-pituitary-adrenal axis activation than naloxone in normal volunteers:
implications for the treatment of alcoholism. Alcohol Clin Exp Res. 1998 Oct;22(7):1430-6.
Among other actions, opioid antagonists modulate the control endogenous opioids exert on the hypothalamicpituitary-adrenal (HPA) axis. Naloxone, nalmefene, and naltrexone are the opioid antagonists approved for use in
man and are primarily mu-opioid selective. Naltrexone and nalmefene have been demonstrated to be useful in the
treatment of alcoholism. Compared with naloxone, nalmefene has a longer half-life, is more potent at the mureceptor, and has a higher affinity for kappa- and delta-opioid receptors. We conducted an inpatient study
comparing the effects of 10 and 30 mg doses of intravenous naloxone and nalmefene in normal, nonsubstance nor
alcohol-abusing, volunteers. Significant increases in ACTH and cortisol were observed after both antagonists,
without an apparent dose-response relationship; however, both doses of nalmefene resulted in greater HPA axis
activation than either dose of naloxone (ACTH: p <0.005). These results indicate that kappa- and delta-opioids
may play important roles in the regulation of the HPA axis; nalmefene may be useful as both a probe to explore the
HPA axis physiology and as a pharmacotherapeutic agent. PMID: 9802524