Human Chorionic Gonadotropin (hCG): the pregnancy hormone used in fertility treatment

What this is

Human chorionic gonadotropin (hCG) is a hormone the placenta makes during pregnancy — and the molecule that every home pregnancy test is designed to detect. It is produced by placental cells from the moment of implantation and signals to the ovaries that pregnancy has begun. Clinically, hCG has two well-established uses in medicine: as an ovulation trigger in IVF and assisted reproduction, and as an LH-mimetic drug in men with hypogonadotropic hypogonadism to stimulate testosterone production and preserve fertility. It is FDA-approved for both indications under several brand names (Ovidrel for recombinant choriogonadotropin alfa; Pregnyl and Novarel for urinary-derived preparations). The stored sequence for this card (SKEPLRPRCRPINATLAVEKEGCPVCITVNTTICAGYCPTMMRVLQGVLPALPQVVCTYR) represents the first 60 residues of the 145-amino acid hCGβ subunit; the biologically active molecule is an α+β heterodimer weighing approximately 36–40 kDa with extensive glycosylation — the full β subunit and its glycan modifications are described throughout this card.

hCG is also one of the most persistently mythologized hormones in consumer health: the so-called "hCG diet" — combining injections with a 500 kcal/day diet — has been tested in placebo-controlled trials and a meta-analysis, all finding hCG adds nothing beyond the calorie restriction itself. The FDA and FTC declared over-the-counter "homeopathic hCG" weight-loss products illegal and fraudulent in 2011.

History

The existence of a pregnancy-specific humoral substance was demonstrated in 1927 by Selmar Aschheim and Bernhard Zondek at the Charité in Berlin. Their "A–Z test" — injecting pregnant urine into immature mice and observing ovarian stimulation — was the first reliable pregnancy test. The heterodimeric α/β subunit structure was elucidated by Canfield and colleagues in the 1970s, establishing hCG as part of the glycoprotein hormone superfamily alongside LH, FSH, and TSH, all sharing a common α subunit. The CGB gene cluster on chromosome 19q13.3 — comprising multiple β-hCG gene copies — was characterized in the 1980s as a primate-specific expansion from a common LHβ-like ancestor, explaining why chorionic gonadotropin exists only in primates and equids.

Urinary-derived hCG preparations (Pregnyl) became available in the mid-20th century for ovulation induction and male hypogonadism. Recombinant choriogonadotropin alfa (Ovidrel) was FDA-approved in September 2000, providing a defined product free of the batch variation inherent to urinary extracts. The Simeons "hCG diet" emerged in 1954 when British endocrinologist Albert T. W. Simeons proposed daily hCG injections combined with a 500 kcal/day diet for obesity; his claims were tested in placebo-controlled trials over the following decades and consistently failed to separate from placebo. A criteria-based meta-analysis by Lijesen and colleagues (British Journal of Clinical Pharmacology, 1995) concluded there was no scientific evidence that hCG produced weight loss beyond caloric restriction. In December 2011, the FDA and FTC took joint action against over-the-counter homeopathic hCG weight-loss products, declaring them illegal and fraudulent. The molecular finding that LH and hCG — despite sharing a receptor — activate meaningfully distinct downstream signaling cascades has been clarified through studies reviewed by Casarini and colleagues (2018), challenging the long-held assumption that the two hormones are clinically interchangeable.

What it does

hCG acts as a surrogate for LH (luteinizing hormone) by binding the LH/CG receptor (LHCGR) expressed on Leydig cells in the testes, and on theca, granulosa, and luteinized follicular cells in the ovaries. In women undergoing IVF or ovulation induction, a bolus of hCG — given approximately 36 hours before planned egg retrieval — mimics the endogenous LH surge, triggering resumption of meiosis in the oocyte and final follicular maturation. During early pregnancy, endogenously rising hCG maintains the corpus luteum, sustaining progesterone production until the placenta takes over at around 8–10 weeks. In men, hCG drives Leydig cell testosterone synthesis via the cAMP/PKA steroidogenic cascade, maintaining intratesticular testosterone concentrations required for spermatogenesis — an effect useful when pituitary LH is absent (hypogonadotropic hypogonadism) or suppressed by exogenous testosterone or anabolic steroid use. In prepubertal boys with cryptorchidism, hCG can stimulate testosterone-mediated testicular descent in some cases, though surgery remains the standard for non-responders.

A critical distinction from LH: although both hormones bind LHCGR, hCG preferentially drives the cAMP/PKA steroidogenic pathway, while LH more strongly activates ERK1/2 and AKT pathways associated with cell proliferation and gametogenesis support. This differential signaling has direct ART implications — hCG is associated with a higher number of retrieved oocytes while LH has been associated with better pregnancy rates per oocyte, as detailed by Casarini and colleagues (Endocrine Reviews, 2018).

Evidence

• Human: Extensive. hCG as an IVF ovulation trigger is supported by decades of randomized trial data. In men, hCG monotherapy restores testosterone in hypogonadotropic hypogonadism and can partially restore spermatogenesis; full sperm output typically requires FSH co-administration, as reviewed by Choi and Smitz (Gynecological Endocrinology, 2014). For the hCG diet, multiple placebo-controlled trials and the 1995 Lijesen meta-analysis are uniformly negative — hCG shows no benefit over saline when caloric intake is matched (Choi and Smitz, 2014).
• Animal: Comprehensive. hCG's effects on LHCGR, steroidogenesis, and gonadal function are thoroughly characterized in rodents and large mammals, and it has been used in livestock reproductive biology for decades.
• In vitro: Very strong. In granulosa and Leydig cell systems, hCG activates cAMP/PKA preferentially over ERK1/2 and AKT; LH activates ERK1/2 and AKT preferentially over cAMP/PKA. These differential signaling profiles are quantitatively documented and translate to measurably different biological outcomes in ART datasets (Casarini et al., Endocrine Reviews, 2018).

Myths and misconceptions

• "The hCG diet produces weight loss because hCG suppresses appetite or burns abnormal fat" — This claim originates from Simeons' 1954 protocol and has been repeatedly tested and disproven. Placebo-controlled trials gave both groups identical very-low-calorie diets and found no difference in weight loss, fat distribution, or hunger. The Lijesen criteria-based meta-analysis (British Journal of Clinical Pharmacology, 1995) concluded there was no scientific evidence for any hCG-specific effect on weight beyond caloric restriction. The FDA explicitly states hCG is not approved for weight loss and considers OTC hCG weight-loss products fraudulent.

• "hCG and LH are the same hormone" — They bind the same receptor and produce similar end effects, but they are structurally and pharmacologically distinct. hCG has a 24-amino acid C-terminal peptide (CTP) on its β subunit that LH lacks; the CTP carries four O-linked glycans that dramatically slow renal clearance, giving hCG a half-life of ~24–36 hours versus LH's ~90 minutes. They also activate different downstream signaling ratios at LHCGR: hCG is cAMP/PKA-dominant (steroidogenic), while LH is relatively more ERK1/2/AKT-dominant (proliferative). These differences have measurable clinical consequences in ART (Casarini et al., 2018).

• "hCG causes testicular atrophy" — The reverse is true. It is exogenous testosterone that suppresses pituitary LH and thereby causes testicular atrophy. hCG mimics LH and actively maintains Leydig cell activity and testicular volume, which is precisely why it is used as a TRT adjunct to counteract testosterone-induced testicular atrophy.

• "Homeopathic hCG drops are a safer, needle-free alternative" — Homeopathic hCG products either contain essentially no measurable hCG (by the definition of homeopathic dilution) or unregulated amounts. None have demonstrated efficacy beyond their accompanying very-low-calorie diet. The FDA and FTC declared them illegal in 2011. Legitimate hCG is an injectable prescription drug.

Common questions

How is hCG different from LH if they bind the same receptor? hCG has a 24-amino acid C-terminal peptide (CTP) on its β subunit that LH lacks. The CTP carries O-linked glycans that protect hCG from renal clearance and substantially slow its dissociation from LHCGR — giving it a plasma half-life of ~24–36 hours versus pituitary LH's ~90 minutes. Beyond pharmacokinetics, the two hormones also differ in how they weight the downstream signaling cascades they activate after binding: hCG drives the cAMP/PKA steroidogenic arm more strongly; LH drives ERK1/2 and AKT proliferative pathways more strongly. As a result, they are not clinically interchangeable in all settings.

Why is hCG used instead of LH to trigger ovulation in IVF? Two practical reasons: hCG has been available in large quantities from pregnant urine since the mid-20th century, and its long half-life provides a sustained LHCGR signal that reliably completes oocyte maturation within the 36-hour retrieval window. The trade-off is that hCG's prolonged receptor stimulation of multiple large follicles also drives more VEGF release from luteinized granulosa cells, contributing to ovarian hyperstimulation syndrome (OHSS) risk — a risk that can be largely avoided by substituting a GnRH agonist trigger in antagonist-protocol cycles.

How does hCG restore fertility in hypogonadotropic hypogonadism? In hypogonadotropic hypogonadism, the pituitary fails to secrete LH and FSH. Exogenous hCG provides the missing LH-like stimulus to Leydig cells, driving intratesticular testosterone and supporting spermatid maturation. However, FSH is required for full Sertoli cell function and sperm production. In practice, hCG monotherapy normalizes testosterone and can achieve fertility in some patients; adding recombinant FSH after several months of hCG priming restores sperm output in most cases, as reviewed by Choi and Smitz (2014).

Known effects

• Ovulation triggering in ART — established; hCG bolus 36 hours before oocyte retrieval is standard of care globally
• Corpus luteum maintenance — endogenous hCG prevents luteolysis in early pregnancy; exogenous hCG used for luteal phase support in ART
• Testosterone stimulation in males (hypogonadotropic hypogonadism) — established; Leydig cell cAMP/PKA/StAR cascade drives intratesticular testosterone
• Spermatogenesis support in hypogonadotropic hypogonadism — partial; hCG alone is insufficient for full sperm output; FSH co-administration required for most patients (Choi and Smitz, 2014)
• Testicular descent in cryptorchidism — partial; approximately 15–25% of undescended testes respond; surgery remains standard for non-responders
• Ovarian hyperstimulation syndrome (OHSS) — a principal iatrogenic risk; hCG's prolonged LHCGR stimulation across multiple stimulated follicles drives VEGF-mediated vascular permeability; severity ranges from mild bloating to hospitalization
• Preservation of testicular volume and spermatogenesis during TRT — Moderate evidence; low-dose hCG alongside testosterone has been shown to preserve intratesticular testosterone and sperm production
• No meaningful weight loss in eugonadal individuals — multiple placebo-controlled trials and the Lijesen meta-analysis uniformly negative

Safety signals

Ovarian hyperstimulation syndrome (OHSS): The primary serious risk of hCG in ART. hCG provides a sustained LHCGR stimulus to multiple large follicles developed during gonadotropin stimulation, driving VEGF release from luteinized granulosa cells. This causes vascular hyperpermeability, fluid shift, ascites, pleural effusion, hemoconcentration, and thromboembolism risk in severe cases. Mild OHSS occurs in roughly 30% of ART cycles; severe OHSS requiring hospitalization in approximately 0.5–2%. Risk mitigation strategies include using a GnRH agonist trigger instead of hCG in antagonist-protocol cycles, and freeze-all embryo strategies with delayed transfer.

Multiple gestation: hCG trigger in multi-follicular stimulation cycles contributes to the risk of multiple ovulation and multiple pregnancy.

In males — estradiol elevation: hCG-stimulated testosterone aromatizes to estradiol; aggressive dosing can raise estradiol sufficiently to cause gynecomastia or require aromatase inhibitor management.

In males — Sertoli cell imbalance with prolonged high-dose use: Prolonged hCG without FSH co-administration can result in preferential Leydig cell stimulation with inadequate Sertoli cell support, paradoxically impairing sperm production despite normalized testosterone.

Anti-hCG antibodies: Can develop with repeated urinary-derived hCG exposure; generally clinically insignificant with short-term therapeutic use.

Thromboembolism: OHSS-associated hemoconcentration and elevated estrogen-driven coagulation activation increase DVT/PE risk in severe OHSS.

Regulatory status

• US: Prescription-only. FDA-approved: Ovidrel (recombinant choriogonadotropin alfa, EMD Serono) for final follicular maturation in IVF; Pregnyl and Novarel (urinary-derived hCG) for ovulation induction, male hypogonadotropic hypogonadism, and prepubertal cryptorchidism. hCG is explicitly not approved for weight loss; OTC homeopathic hCG weight-loss products were declared illegal by the FDA and FTC in 2011.
• EU: EMA-approved; Ovitrelle (EU trade name for recombinant choriogonadotropin alfa) and urinary-derived preparations are authorized for the same indications.
• WADA: Prohibited under S2 (Peptide Hormones, Growth Factors, Related Substances and Mimetics) for male athletes at all times, both in and out of competition, because hCG stimulates endogenous testosterone. The prohibition does not apply to female athletes.
• Tumor marker: Serum β-hCG is a standard clinical marker for gestational trophoblastic neoplasia, testicular germ cell tumors, and certain other malignancies. This diagnostic application is distinct from the therapeutic uses described on this card.

Related peptides

See also: Kisspeptin-10, Sermorelin, Gonadorelin (GnRH)

Mechanism

hCG is a cystine-knot glycoprotein hormone consisting of two non-covalently associated subunits: the α subunit (92 aa, shared with LH, FSH, and TSH) and the β subunit (145 aa, hCG-specific, plus a primate-unique 24-aa C-terminal peptide). The α subunit carries two N-linked glycans; the β subunit carries two N-linked and four O-linked glycans, three of which are on the C-terminal peptide. The extensive glycosylation accounts for roughly 30% of the heterodimer's ~36–40 kDa molecular weight. The O-linked glycans on the CTP — absent from LH — are the primary structural basis for hCG's dramatically extended plasma half-life (~24–36 hours for hCG versus ~90 minutes for pituitary LH), because they protect the C-terminus from proteolytic cleavage and slow renal clearance.

LHCGR binding: LHCGR is a leucine-rich repeat G protein–coupled receptor expressed on Leydig cells, ovarian theca and granulosa cells, and luteinized follicular cells. hCG binds LHCGR with approximately 5–10-fold higher affinity than LH, largely because the CTP and higher sialylation reduce the dissociation rate. Upon binding, the transmembrane domain undergoes conformational change and activates the Gs protein.

cAMP/PKA pathway (steroidogenesis — hCG-preferred): Gs activation drives adenylyl cyclase, elevating intracellular cAMP and activating protein kinase A (PKA). PKA phosphorylates StAR (steroidogenic acute regulatory protein), driving cholesterol into the inner mitochondrial membrane for conversion by CYP11A1 (P450scc) to pregnenolone. Downstream steroidogenic enzymes (CYP17A1, HSD3B, CYP19A1) complete the synthesis of testosterone (Leydig cells) or estrogens and progesterone (ovary). hCG's prolonged receptor occupancy sustains cAMP generation and steroidogenic output more durably than LH's brief pulse (Casarini et al., Endocrine Reviews, 2018).

ERK1/2 and AKT pathways (proliferative — LH-preferred): LHCGR also couples to Gi, βγ subunits, and β-arrestin scaffolds, which activate PI3K→AKT and Ras→Raf→MEK→ERK1/2. In granulosa cells, LH activates these pathways more strongly than hCG at comparable receptor occupancies, providing proliferative and anti-apoptotic support for follicular development and gametogenesis. In Leydig cells, both LH and hCG activate cAMP/PKA and ERK1/2 comparably, producing equivalent testosterone synthesis — the basis for hCG's clinical role as an LH surrogate in male hypogonadism (Casarini et al., 2018).

Oocyte maturation trigger: In the dominant pre-ovulatory follicle, hCG binding to LHCGR on granulosa cells raises cAMP, activating phosphodiesterase 3A and the cyclin B1/CDK1 pathway, triggering resumption of meiosis I in the arrested oocyte. The 36-hour interval between hCG administration and ovulation is the clinical basis for timing oocyte retrieval.

Corpus luteum rescue: After ovulation, syncytiotrophoblasts begin secreting hCG at implantation (~7–8 days post-ovulation), binding LHCGR on luteal cells and sustaining corpus luteum progesterone production. Without this hCG signal, luteolysis would occur and progesterone would fall, ending the pregnancy. The corpus luteum is maintained until the placenta assumes progesterone synthesis at approximately 8–10 weeks (the luteoplacental shift).

LH and hCG mutations and their clinical consequences — including LHβ null mutations causing azoospermia in males and anovulation in females, and LHCGR gain-of-function mutations causing familial male-limited precocious puberty — confirm the essential and distinct roles of each ligand and the receptor in reproductive physiology, as systematically reviewed by Choi and Smitz (Gynecological Endocrinology, 2014).

Open questions

• Whether the distinct intracellular signaling biases of LH versus hCG at LHCGR (ERK/AKT versus cAMP/PKA) have exploitable clinical consequences in ART — specifically, whether replacing hCG with recombinant LH for final oocyte maturation improves embryo quality or implantation rates in specific patient populations — remains under investigation
• The full physiological roles of LHCGR in extra-gonadal tissues (endometrium, thyroid, kidney, brain) and the contributions of LH versus hCG signaling in those tissues are incompletely characterized
• Whether hyperglycosylated hCG (the "invasive trophoblast antigen" isoform produced early in pregnancy and by some tumors) acts differently at LHCGR or via distinct receptors, and what consequences that may have for invasion and angiogenesis, is not fully resolved
• Long-term safety of chronic low-dose hCG as a TRT adjunct over years rather than months is not well characterized in controlled trials