Gonadotropin-releasing hormone (GNRH), also known as Luteinizing-hormone releasing hormone (LHRH), is a tropic peptide hormone responsible for the release of FSH and LH from the anterior pituitary. GNRH is synthesized and released from neurons within the hypothalamus.

Production

The gene, GNRH1, for the GNRH precursor is located on chromosome 8. In mammals, the linear decapeptide end product is synthesized from a 92 amino acid preprohormone in the preoptic anterior hypothalamus.

Structure

The identity of GNRH was clarified by the 1977 Nobel Laureates Roger Guillemin and Andrew V. Schally:

pyroGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly CONH2.

GNRH as a neurohormone

GNRH is considered a neurohormone, a hormone produced in a specific neural cell and released at its neural terminal. A key area for production of GNRH is the preoptic area of the hypothalamus, that contains most of the GNRH-secreting neurons. GNRH is secreted in the hypophysial portal bloodstream at the median eminence. The portal blood carries the GNRH to the pituitary gland, which contains the gonadotrope cells, where GNRH activates its own receptor, gonadotropin-releasing hormone receptor (GNRHR), a seven transmembrane G-protein coupled receptor that stimulates the beta isoform of Phosphoinositide phospholipase C, which goes on to mobilize calcium and protein kinase C. This results in the activation of proteins involved in the synthesis and secretion of the gonadotropins, LH and FSH. GNRH is degraded by proteolysis within a few minutes.

Control of FSH and LH

At the pituitary, GNRH stimulates the synthesis and secretion of the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). These processes are controlled by the size and frequency of GNRH pulses, as well as by feedback from androgens and estrogens. Low frequency GNRH pulses lead to FSH release, whereas high frequency GNRH pulses stimulate LH release.

There are differences in GNRH secretion between females and males. In males, GNRH is secreted in pulses at a constant frequency, but in females the frequency of the pulses varies during the menstrual cycle and there is a large surge of GNRH just before ovulation.

GNRH secretion is pulsatile in all vertebrates, and is necessary for correct reproductive function. Thus, a single hormone, GNRH1, controls a complex process of follicular growth, ovulation, and corpus luteum maintenance in the female, and spermatogenesis in the male.

Activity

GNRH activity is very low during childhood, and is activated at puberty. During the reproductive years, pulse activity is critical for successful reproductive function as controlled by feedback loops. However, once a pregnancy is established, GNRH activity is not required. Pulsatile activity can be disrupted by hypothalamic-pituitary disease, either dysfunction (i.e., hypothalamic suppression) or organic lesions (trauma, tumor). Elevated prolactin levels decrease GNRH activity. In contrast, hyperinsulinemia increases pulse activity leading to disorderly LH and FSH activity, as seen in Polycystic ovary syndrome (PCOS). GNRH formation is congenitally absent in Kallmann syndrome.

The GNRH neurons are regulated by many different afferent neurons, using several different transmitters (including norepinephrine, GABA, glutamate). For instance, dopamine appears to stimulate LH release (through GnRH) in estrogen-progesterone primed females; dopamine may inhibit LH release in ovariectomized females. Kisspeptin appears to be an important regulator of GNRH release. GNRH release can also be regulated by estrogen. It has been reported that there are kisspeptin-producing neurons that also express estrogen receptor alpha.

GNRH in 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.

Medication

GNRH is available as gonadorelin hydrochloride (Factrel) for injectable use. Studies have described it being used via an infusion pump system to induce ovulation in patients with hypothalamic hypogonadism.

Agonists and antagonists

While GNRH has been synthesized and become available, its short half-life requires infusion pumps for its clinical use. Modifications of the decapeptide structure of GNRH have led to GNRH1 analog medications that either stimulate (GNRH1 agonists) or suppress (GNRH antagonists) the gonadotropins. It is important to note that, through downregulation, agonists are also able to exert a prolonged suppression effect.

References

Further reading