Human Chorionic Gonadotropin (hCG) in Men’s Health: A Comprehensive Review

Introduction

Human chorionic gonadotropin (hCG) is a glycoprotein hormone primarily known for its role in female pregnancy; however, its clinical utility in men's health is both significant and underappreciated. Structurally analogous to luteinizing hormone (LH), hCG is employed in the treatment of male hypogonadism, for the preservation of fertility during testosterone replacement therapy (TRT), and for maintaining testicular volume. Furthermore, emerging evidence suggests hCG’s potential role in supporting neurosteroidogenesis through activation of LH receptors in extragonadal tissues, including the central nervous system. Understanding the biochemical, physiological, and clinical underpinnings of hCG use in men’s health is critical for functional and regenerative medicine practitioners seeking to optimize male hormonal health while preserving fertility and broader endocrine function.

Structure and Molecular Biology

hCG is a heterodimeric glycoprotein composed of two subunits: a common α-subunit identical to that of LH, follicle-stimulating hormone (FSH), and thyroid-stimulating hormone (TSH), and a unique β-subunit that differentiates hCG from other glycoprotein hormones. Despite this β-subunit difference, hCG retains sufficient homology with LH to bind and activate LH receptors (LHCGR) with high affinity. One key structural distinction is hCG’s enhanced glycosylation compared to LH, which substantially extends its biological half-life. This prolonged receptor interaction permits sustained physiological stimulation of target tissues with less frequent administration.

Mechanism of Action

hCG exerts its biological effects primarily by acting as an LH receptor agonist. LH receptors are G-protein-coupled receptors (GPCRs) predominantly expressed on Leydig cells within the testes. Upon binding to the LH receptor, hCG initiates a cascade of intracellular signaling events via the Gαs subunit, leading to activation of adenylate cyclase and subsequent increase in cyclic adenosine monophosphate (cAMP) levels. Elevated cAMP activates protein kinase A (PKA), which phosphorylates and activates several downstream targets critical to steroidogenesis, including:

• Steroidogenic Acute Regulatory Protein (StAR): Facilitates cholesterol transport into mitochondria, a rate-limiting step in steroid hormone synthesis.

• Cytochrome P450 side-chain cleavage enzyme (CYP11A1): Converts cholesterol into pregnenolone within the mitochondria.

• 3β-Hydroxysteroid dehydrogenase (3β-HSD), 17α-hydroxylase (CYP17A1), and 17β-Hydroxysteroid dehydrogenase (17β-HSD): Sequentially catalyze the conversion of pregnenolone to testosterone.

The end result of this pathway is the production of testosterone within the Leydig cells, supporting both systemic androgen levels and localized intratesticular testosterone concentrations essential for spermatogenesis.

Clinical Applications in Men’s Health

Restoration of Endogenous Testosterone Production

In men with secondary hypogonadism—where dysfunction at the hypothalamic or pituitary level impairs endogenous LH secretion—hCG can effectively bypass the central deficit by directly stimulating LH receptors in the testes. This restores the physiological process of testosterone synthesis without the need for exogenous testosterone administration. By preserving endogenous steroidogenic pathways, hCG therapy maintains the normal paracrine signaling required for spermatogenesis and Sertoli cell function, which are typically disrupted by exogenous testosterone.

Preservation of Fertility and Testicular Volume During TRT

Exogenous testosterone suppresses the hypothalamic-pituitary-gonadal (HPG) axis via negative feedback inhibition of gonadotropin-releasing hormone (GnRH) and downstream LH and FSH secretion. This central suppression leads to decreased intratesticular testosterone levels, impaired spermatogenesis, and testicular atrophy. Incorporating hCG into TRT protocols can help mitigate these effects by providing peripheral stimulation of LH receptors, thus maintaining intratesticular testosterone production despite systemic suppression.

Clinically, this approach has several benefits:

• Preservation of spermatogenesis: hCG maintains the testicular microenvironment required for sperm production by preserving high intratesticular testosterone concentrations.

• Maintenance of testicular volume: By preventing atrophy of Leydig and Sertoli cells, hCG preserves testicular architecture and function.

• Hormonal homeostasis: By engaging endogenous steroidogenic pathways, hCG maintains a more physiological hormonal milieu compared to exogenous testosterone monotherapy.

This makes hCG a critical adjunctive therapy for men undergoing TRT who wish to preserve fertility or avoid testicular atrophy.

Limitations and Considerations in Fertility Preservation

It is important to emphasize that while hCG therapy can support the maintenance of intratesticular testosterone and promote spermatogenesis during testosterone replacement therapy, its use does not guarantee the preservation of fertility in all patients. Response to hCG varies based on individual factors such as baseline testicular function, duration of TRT, and degree of suppression of the hypothalamic-pituitary-gonadal axis. In many cases, hCG alone is sufficient to maintain normal or near-normal semen parameters; however, some patients may require the addition of recombinant FSH (rFSH) to adequately stimulate Sertoli cell activity and support full spermatogenic maturation. In select cases, concurrent use of hCG and rFSH while on TRT may allow patients to maintain active fertility without needing to discontinue testosterone therapy. Alternatively, for patients seeking to restore fertility, hCG-based protocols can often facilitate earlier discontinuation of TRT and recovery of endogenous reproductive function. Proper management requires individualized assessment, ongoing laboratory monitoring, and tailored adjustments to therapy based on both hormonal and semen analysis data.

Activation of Extragonadal LH Receptors and Neurosteroidogenesis

While LH receptors are most densely expressed in Leydig cells, they are also present in extragonadal tissues, including the adrenal glands, skin, and central nervous system. Within the brain, LH receptors have been identified in regions such as the hippocampus and cerebral cortex, suggesting a role in modulating neurosteroidogenesis—the local synthesis of steroid hormones like pregnenolone, allopregnanolone, and dehydroepiandrosterone (DHEA) within neural tissue.

Neurosteroids play essential roles in regulating:

• GABAergic and glutamatergic neurotransmission

• Cognitive function and memory

• Mood regulation and stress resilience

• Neuroprotection and neural repair mechanisms

By stimulating peripheral LH receptors, hCG may contribute to the preservation of neurosteroid production in men undergoing TRT, helping to mitigate central nervous system side effects associated with long-term HPG axis suppression, such as mood disturbances, cognitive decline, or reduced stress tolerance. While clinical data specifically validating this application remain limited, the mechanistic rationale supports consideration of hCG for maintaining broader endocrine function beyond reproductive health.

Pharmacological Considerations

The pharmacokinetic properties of hCG, particularly its extended half-life due to enhanced glycosylation, facilitate sustained receptor stimulation relative to native LH. This prolonged action enables consistent activation of the steroidogenic machinery within Leydig cells while reducing the frequency of administration necessary for clinical efficacy.

Pharmacodynamically, hCG’s action is highly specific for LH receptors, leading directly to testosterone biosynthesis via cholesterol transport and conversion pathways within the mitochondria and smooth endoplasmic reticulum of Leydig cells. Unlike FSH, which predominantly stimulates Sertoli cells and promotes spermatogenesis directly, hCG acts upstream by providing the androgenic environment necessary for FSH-mediated sperm maturation.

Clinical Safety and Monitoring

hCG is generally well tolerated when used under medical supervision; however, its potent stimulation of testosterone biosynthesis warrants appropriate monitoring for androgen-related adverse effects, including:

• Elevated estradiol levels due to increased aromatization of testosterone, which may require concurrent management.

• Polycythemia, given testosterone’s erythropoietic stimulation.

• Gynecomastia, as a secondary effect of estradiol elevation.

• Testicular discomfort in rare cases, typically associated with rapid restoration of testicular volume.

Patients undergoing therapy with hCG, whether as monotherapy or adjunctive treatment, should have serum testosterone, estradiol, hematocrit, and fertility markers (when applicable) monitored regularly to ensure treatment efficacy and mitigate risks.

Conclusion

Human chorionic gonadotropin (hCG) serves as a clinically indispensable tool in men’s health for restoring or maintaining endogenous testosterone production, preserving fertility, and preventing testicular atrophy. Its role as an LH receptor agonist enables practitioners to support physiological steroidogenesis even during exogenous testosterone therapy, aligning with a functional and regenerative medicine approach that prioritizes hormonal balance and system-wide optimization.

By engaging both gonadal and extragonadal LH receptors, hCG not only supports reproductive health but may also contribute to broader endocrine and neurosteroidal functions. When integrated thoughtfully into individualized treatment protocols, hCG offers a critical means of safeguarding fertility, maintaining testicular integrity, and potentially supporting neurological health in men undergoing testosterone optimization therapies.

Disclaimer:
This information is intended for educational purposes only and does not constitute medical advice, diagnosis, or treatment. Therapies such as hCG and testosterone replacement require individualized assessment and must be prescribed and monitored by a qualified healthcare provider. Do not initiate, modify, or discontinue any medical treatment based on the content of this website without consulting a licensed medical professional.