GnRH: Physiological and pharmacological overview

[madman]

Gonadotropin-Releasing Hormone (GnRH) is a peptide controlling reproductive functions. It binds to GNRHR receptors and has diverse effects. GnRH plays a role in infertility, reproductive disorders, assisted reproduction technology, endometrium, ovary, prostate physiology, tumor transformation, neurogenesis, and neuroprotection. This review provides an overview of GnRH physiology and the pharmacological use of synthetic analogs in managing reproductive and non-reproductive diseases.

• GnRH-I neurons in humans begin migration around gestational weeks 5-6 and approach the hypothalamic region by weeks 11-12
• Humans have a significantly higher number of GnRH immunoreactive neurons compared to rodents
• In the human fetal brain, there are about 10,000 GnRH neurons, with 2,000 located in the hypothalamus and 8,000 distributed in other brain areas
• GnRH-I neurons establish specific contacts with capillaries and form synaptic connections with various neuronal networks
• The activity of GnRH-I neurons is regulated by neurotransmitters, glial-derived growth factors, neuropeptides, genetic and/or epigenetic factors, and the hormonal milieu

Key takeaways:

• GnRH is released in a pulsatile manner to synchronize gonadotropin secretion
• The GnRH neuronal network is active during late fetal maturation, early neonatal period, and puberty
• The release of GnRH is controlled by a complex neuronal network and peripheral signals
• Various factors, such as kisspeptin, norepinephrine, neuropeptide Y, estrogens, opioids, interleukin-1, progesterone, and androgens, modulate GnRH secretion
• GnRH may regulate its own secretion through a feedback loop on hypothalamic neurons
• In humans, GnRH cannot be accurately measured in peripheral blood but can be inferred through plasma LH or FAS measurement
• GnRH pulses occur approximately every 120 minutes in adult males
• The pattern of pulsatile GnRH release in women varies during reproductive stages and the ovulatory cycle

Key takeaways:

• GnRH regulates LH and FSH differently based on pituitary gonadotrope cells' decoding capacity
• Pulsatile GnRH release is necessary for the efficient activation of gonadotrope cells
• Continuous GnRH infusion suppresses LH and FSH release, causing a reversible shutdown of the reproductive axis
• GnRH receptor modulation plays a role in the dual effect of GnRH on gonadotrope cells
• Different G protein subunits are activated by rhythmic stimulation of pituitary GnRH receptors
• Intracellular signal cascades and transcription factors drive LH and FSH gene expression
• LH expression is induced by high-frequency GnRH pulses, while FSH expression is induced by low-frequency pulses
• Efficient therapeutic application of GnRH requires intermittent delivery, while continuous administration leads to "medical castration"
• Continuous GnRH exposure alters the fine-tuning control of gonadotropin synthesis and release

GnRH analogs (agonists and antagonists) are widely used in therapeutic protocols to restore GnRH deficiency and suppress fertility. They are effective not only in reproductive disorders but also in treating cancer and neurological conditions. While new non-peptide analogs are being developed for improved patient compliance, further studies and characterization of these drugs will enhance their efficacy and delivery protocols.

 

[madman]

Fig. 1. Schematic representation of the hypothalami-pituitary-gonadal (HPG) axis. The decapeptide GnRH produced by hypothalamic neurons exerts direct control on gonadotropin (LH and FSH) synthesis and secretion. These, in turn, stimulate the gonads to carry out their reproductive and endocrine functions. Short and long feedback effects regulate the secretion of GnRH itself.

 

[madman]

Fig. 2. Schematic representation of the GnRH gene (A) and GnRH peptide (B). A) The gene encodes for a 92- amino acid (AA) proGnRH mainly organized into a 23- AA signal peptide (signal), the GnRH decapeptide (GnRH), and a secreted 56-AA peptide (GnRH-associated peptide, GAP). B) The amino acid sequences of mature GnRH; the A residues involved in receptor binding and activation as well as the major bonds cleaved by peptidase are indicated.

 

[madman]

Table 1 Amino acid sequences of natural GnRH isoforms.

 

[madman]

Fig. 3. Schematic representation of the response, in terms of gonadotropin serum levels, to different regimens of GnRH and GnRH-a administration. A) Pulsatile i.v. ads stration is able to induce efficient episodic releases of FSH and LH; B) continuous (i.m. or s.c., daily or depot) administration induces an intense reduction of serum gonadotropin levels and a reproductive axis shutdown. The administration of GnRH superagonists may produce an initial intense stimulation of the pituitary GnRH receptor and the characteristic transient serum gonadotropin burst (flare effect).

 

[madman]

Table 2 Amino acid sequences of GnRH agonists and antagonists.

 

[madman]

TABLE 3 Pharmacokinetic data of some GnRH agonists.

 

[madman]

Table 4 Pharmacokinetic data of some GnRH antagonists.

 

[madman]

Fig. 4. Non-peptide GnRH modulators. A) Structure of non-peptide antagonists; the region involved in molecule activity (arm2) is indicated; B) structure of the first reported non-peptide GnRH agonist.

 

[madman]

Table 5 Pharmacokinetic data of non-peptide GnRH antagonists.

 

[madman]

The function of gonadotropin-releasing hormone and inhibin

https://www.sciencedirect.com/book/9780128216767/human-gonadotropins#book-description Function of gonadotropin releasing hormone and inhibin (2022) Marja Brolinson, Ariel Dunn, Joshua Morris, and Micah Hill Gonadotropin-releasing hormone Neuroanatomy The hypothalamus is located at the...

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