Gonadotropin-releasing hormone

GnRH neurons and pulsatile release

During embryonic development, GnRH neurons originate in the nasal region and migrate into the brain. In humans, their cell bodies are found in the medial preoptic area and the infundibular nucleus of the hypothalamus.

In mice, the long dendrites of GnRH neurons can form bundles and receive shared synaptic input. This arrangement may help coordinate the activity of these neurons.

GnRH neurons release the hormone in pulses from their terminals at the median eminence. The hypophyseal portal system carries these pulses to the anterior pituitary, where they regulate the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). GnRH is metabolized within minutes in the peripheral circulation, so researchers often use LH pulses as an indirect measure of GnRH secretion in humans.

Regulation of secretion

GnRH neurons receive input from neurons that use norepinephrine, GABA, and glutamate as neurotransmitters. Kisspeptin stimulates GnRH release. In the arcuate nucleus, KNDy neurons produce kisspeptin, neurokinin B, and dynorphin. Synchronized activity in this network leads to episodic kisspeptin release, which helps generate GnRH pulses.

In sheep, some kisspeptin-producing neurons in both the preoptic area and the arcuate nucleus express estrogen receptor alpha, providing a route by which estradiol can influence GnRH secretion.

Estradiol exerts negative feedback on pulsatile GnRH secretion during most of the ovarian cycle. In spontaneously ovulating mammals, sustained high estradiol levels exert positive feedback on the hypothalamic–pituitary–gonadal axis, triggering the preovulatory luteinizing hormone surge. A GnRH surge accompanies this response in several species, but whether a distinct GnRH surge occurs in humans remains uncertain.

Multiple neuronal regions in the limbic system send signals to the hypothalamus to modulate the amount of GnRH production and the frequency of pulses. This provides a possible explanation for why psychic influences typically affect female sexual function.

In the African cichlid Astatotilapia burtoni, males given an opportunity to rise in social rank showed increased expression of one form of GnRH and enlargement of GnRH neuron cell bodies. In convict cichlids, GnRH neuron cell bodies were larger in territorial males than in nonterritorial males and varied in size with breeding state in females.

Changes across the lifespan

In humans, the hypothalamic–pituitary–gonadal axis is active during fetal development and again during early infancy. This postnatal period of activity, known as minipuberty, occurs mainly during the first six months of life. During this period, gonadotropins and sex steroids contribute to the maturation of the reproductive organs. The axis then becomes relatively inactive during childhood and is reactivated at puberty.

Pituitary signaling

GnRH stimulates the synthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by binding to the gonadotropin-releasing hormone receptor (GnRHR) on gonadotropes in the anterior pituitary. GnRHR is a seven-transmembrane G protein-coupled receptor. Its activation stimulates phosphoinositide phospholipase C, which increases intracellular calcium and activates protein kinase C. The frequency and amplitude of GnRH pulses help regulate pituitary LH and FSH output during the reproductive years.

Other organs

GnRH is found in organs outside of the hypothalamus and pituitary, and its role in other life processes is poorly understood. For instance, there is likely to be a role for GnRH1 in the placenta and in the gonads. GnRH and GnRH receptors are also found in cancers of the breast, ovary, prostate, and endometrium.

Reproductive behavior in animals

GnRH activity influences a variety of sexual behaviors. Increased levels of GnRH facilitate sexual displays and behavior in females. GnRH injections enhance copulation solicitation (a type of courtship display) in white-crowned sparrows. In mammals, GnRH injections facilitate sexual behavior of female display behaviors as shown with the musk shrew's (Suncus murinus) reduced latency in displaying rump presents and tail wagging towards males.

An elevation of GnRH raises males' testosterone capacity beyond a male's natural testosterone level. Injections of GnRH in male birds immediately after an aggressive territorial encounter results in higher testosterone levels than is observed naturally during an aggressive territorial encounter.

A compromised GnRH system has adverse effects on reproductive physiology and maternal behavior. In comparison to female mice with a normal GnRH system, female mice with a 30% decrease in GnRH neurons are poor caregivers to their offspring. These mice are more likely to leave their pups scattered rather than grouped together, and will take significantly longer to retrieve their pups.