The control of endocannabinoids on GnRH release
Hypothalamic Hormones

Author: silvia mingozzi
Date: 21/02/2012

di Silvia Mingozzi, Alessandra Macchi, Valentina Tomasone

GnRH release is under the control of stimulatory and inhibitory neurotransmitters such as norepinephrine and GABA.
It has been demonstrated that ANA (anandamide) increase the release of GABA, a neurotransmitter involved in the inhibition of GnRH release.


In an experiment conduced by Gammon et al. ("Regulation of Gonadotropin-Releasing Hormone Secretion by Cannabinoids. 2005") using immortalized hypothalamic GnRH neurons, it has been found that these cells produce and secrete ANA (anandamide) and 2-AMG (2-arachidonyl monoacylglycerol) that are two endocannabinoids.
ANA and 2-AMG are transported into GnRH neurons and are degraded to other lipids by fatty-acid amide hydrolase (FAAH).

The immortalized GnRH neurons also possess CB1 and CB2 receptors that are coupled to Gi/Go proteins whose activation leads to inhibition of GnRH secretion.

In this experiment they also found that:

  • immortalized GnRH neurons synthesize endocannabinoids and that NE (norepinephrine) and other agents that increase entry of Ca2+ into cells can stimulate the release and accumulation of 2-AMG in the medium
  • immortalized GnRH neurons synthesize ANA and can rapidly remove it from the medium
  • immortalized GnRH neurons contain an enzyme for degrading endocannabinoids: FAAH. FAAH degrades endocannabinoids in many different cells
  • immortalized GnRH neurons contain CB1 and CB2 receptor transcripts albeit at low levels
  • a CB receptor agonist can perturb pulsatile GnRH secretion from the immortalized GnRH neurons
  • if the CB1 receptor is expressed in GnRH neurons, it is at a very low level and most CB1 receptors are localized in neighboring cells.

These neurons contain a complete and functional CB system, that suggests that endocannabinoids may play an important role in GnRH physiology and reproduction.
Since GnRH can inhibit its own secretion from the immortalized neurons and because an ultra-short feedback system resides on GnRH neurons in vitro and in vivo, endocannabinoids may play a role in this process by autocrine, paracrine or, more likely, juxtacrine interactions with cells in close ap-position to GnRH neurons (juxtacrine signalling requires physical contact between the two cells in-volved).

FAAH has two different inhibitors, oleylethanolamide and arachidonyl trifluoromethyl ketone, that enhance 2-AMG and ANA accumulation. Interestingly, in some systems ANA is taken-up and rap-idly converted to other eicosanoids, or is degraded by FAAH to AA (arachidonic acid) and ethano-lamine. AA can be converted into eicosanoids such as thromboxanes and prostaglandins . This suggests that CBs may be intimately linked with various eicosanoid signaling pathways to modulate GnRH release. (Eicosanoids)


The CB1 receptor is expressed primarily in the central nervous system, whereas the CB2 receptor is found in the periphery and in immune cells. (Cannabinoids Receptors ) ("Alcohol inhibits luteinizing hormone-releasing hormone release by activating the endocannabinoid system. 2004")

Endocannabinoids such as ANA could bind to CB receptors on neighboring cells and perhaps on GnRH neurons, to exert feedback control over GnRH function. This network could serve as a novel mechanism for regulating GnRH secretion.
CBs exert potent negative effects on rodent, primate, and human reproduction.

Chronic administration of CBs to male rodents and humans reduces sperm counts, depresses serum testosterone concentrations, and may suppress levels of LH in serum.

In females, chronic CBs exposure delays sexual maturation, disrupts menstrual or estrous cycles, depresses follicular maturation of the ovary, alters uterine and vaginal cytology, and may reduce contents of LH and sex steroids in blood.

While some of these influences may be mediated at the levels of the pituitary and gonads, the primary effects have been ascribed to hypothalamic action.

Although CBs influence reproduction through hypothalamic mechanisms, it has not been clear whether these lipids exert their effects directly on GnRH neurons or on neighboring cells that control GnRH release. Importantly, CB1 receptors are localized in the preoptic area and hypothalamus brain areas where the GnRH neurons reside. (For further informations: "Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. 1991" and "Localization of cannabinoid receptor mRNA in rat brain. 1993")


The endogenous ligands are lipids and include anandamide (ANA), 2-arachidonyl monoacylglycerol (2-AMG), noladin ether, virodhamine, and N-arachidonyldopamine.
Anandamide structure: (Anandamide)

Anandamide structure


Endocannabinoids decrease adenylyl cyclase activity, that induces a reduction of cAMP levels in the cell. The result is an inhibition of PKA that normally inactivates the GABA transporters.
So the GABA release is increased and LHRH release is decreased.

(Cannabinoids Receptors)

Diagram of the postulated mechanism of action of alcohol and ANA to suppress LHRH release acting through CB1-r.


Ethanol (EtOH) acts through the endocannabinoid system to inhibit GnRH release. In this study ("Alcohol inhibits luteinizing hormone-releasing hormone release by activating the endocannabinoid system. 2004") it is hypothesized that both EtOH and ANA affect the adenylate cyclase activity, acting through the same GTP-coupled receptors (CB1-r).
EtOH, as well as ANA, stimulates GABA release by acting through CB1-r inhibiting the activity of adenylyl cyclase, preventing the inhibition of basal GABA release by cAMP.

In other studies ("Chronic ethanol administration down-regulates cannabinoid receptors in mouse brain synaptic plasma membrane. 1998") has been found that both cannabinoids and alcohol cause the release of dopamine in the nucleus accumbens of CB1-r + / + mice.

Interference with dopamine-mediated neurotrasmission could underlie some of the effects of ANA on the hypothalamic-pituitary axis.

These effects consist mainly of the enhancement or inhibition of hypothalamic hormones, which leads to an increase in ACTH release and the inhibition of GH, LH and PRL release.

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