Hormone Receptor Signaling in Reproductive Physiology

Hormone receptor signalling underpins every aspect of reproductive physiology, orchestrating the synthesis of gametes, steroidogenesis and reproductive behaviour. Central to this network are the glycoprotein hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which bind to their cognate G protein-coupled receptors (FSHR and LHCGR) on ovarian granulosa cells and testicular Leydig and Sertoli cells. Ligand binding induces conformational changes in the receptor transmembrane domain, activating heterotrimeric G proteins and triggering second-messenger cascades such as cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA), mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT pathways. These pathways converge to regulate gene transcription, cell proliferation, survival and steroid hormone production. Beyond the classical cascade, receptor recruitment of β-arrestins and receptor oligomerisation modulate signalling kinetics, receptor desensitisation and trafficking. Allosteric modulators and natural biased agonists further reshape signalling output, opening avenues for selective therapeutic interventions. Steroid hormone receptors for oestrogens, androgens and progestogens add an additional layer of feedback control at the hypothalamic–pituitary–gonadal axis. Dysregulation of any component in these pathways can lead to infertility, ovarian hyperstimulation, polycystic ovary syndrome or subfertility. Emerging research explores structural and functional nuances of receptor activation, the impact of environmental disruptors on G protein coupling, and the design of small-molecule modulators to fine-tune reproductive outcomes.

Research from Nature Portfolio

High-resolution cryo-electron microscopy has delineated both inactive and active structures of the FSH receptor bound to its natural hormone and to a synthetic allosteric agonist. These structures revealed conserved molecular switches and a unique receptor residue that dictates selectivity for small-molecule activation, offering a blueprint for drug design in fertility treatments and controlled ovarian stimulation. Complementing structural insights, work on benzo[a]pyrene exposure has demonstrated that low-nanomolar concentrations of this environmental contaminant selectively impair LH/hCG-mediated Gαs activation in mouse Leydig tumour cells, reducing cAMP production and downstream steroidogenesis without affecting human granulosa-lutein cells. This highlights the specificity of receptor–G protein interfaces in mediating toxicant effects and underlines the need to assess short-term endocrine disruption. Earlier foundational studies also established that LH and hCG, despite sharing a receptor, act as natural biased agonists, differentially engaging cAMP, β-arrestin recruitment and MAPK pathways, thus informing personalised approaches to assisted reproduction.

Hormone Receptor Signaling in Reproductive Physiology publication trend

The graph below shows the total number of articles in hormone receptor signaling in reproductive physiology across all publications each year (not limited to Nature Index journals).

Technical terms

G protein-coupled receptor (GPCR): A membrane protein that transduces extracellular signals into intracellular responses via heterotrimeric G proteins.

Cyclic adenosine monophosphate (cAMP): A second messenger generated by adenylyl cyclase that activates protein kinase A and regulates gene expression.

Allosteric modulator: A compound that binds to a site distinct from the primary ligand-binding pocket to enhance or inhibit receptor activity.

Biased agonism: The ability of different ligands to stabilise distinct receptor conformations, selectively engaging specific downstream pathways.

β-arrestin: A multifunctional adaptor protein that terminates G protein signalling, mediates receptor internalisation and activates alternative pathways.

Gonadotropin: A pituitary-derived glycoprotein hormone (FSH or LH) that regulates gonadal function and gametogenesis.

References

1. Mechanism of hormone and allosteric agonist mediated activation of follicle stimulating hormone receptor. Nature Communications (2023).
2. Benzo[a]pyrene disrupts LH/hCG-dependent mouse Leydig cell steroidogenesis through receptor/Gαs protein targeting. Scientific Reports (2024).
3. LH and hCG Action on the Same Receptor Results in Quantitatively and Qualitatively Different Intracellular Signalling. PLOS ONE (2012).
4. Highly-Sensitive In Vitro Bioassays for FSH, TSH, PTH, Kp, and OT in Addition to LH in Mouse Leydig Tumor Cell. International Journal of Molecular Sciences (2023).
5. Allosteric modulation of gonadotropin receptors. Frontiers in Endocrinology (2023).
6. Tracking conformational transitions of the gonadotropin hormone receptors in a bilayer of (SDPC) poly-unsaturated lipids from all-atom molecular dynamics simulations. PLOS Computational Biology (2024).