HCG

Dosing from the Literature

Published for testosterone support: 500 IU every other day on TRT (Coviello 2005), and the label's doses for its approved uses. Not published: a large randomized trial of hCG alongside TRT.

The labels say the regimen depends on the indication, the patient's age and weight and the physician's preference, and list regimens "advocated by various authorities" (Pregnyl label). Each row below names its source.

What It Is

Human chorionic gonadotropin (hCG) is a heterodimeric glycoprotein hormone produced naturally by the syncytiotrophoblast cells of the placenta during pregnancy. Its primary physiologic role in pregnancy is to rescue the corpus luteum from programmed regression, maintaining progesterone production in early gestation until the placenta takes over as the dominant progesterone source. hCG is the hormone detected by pregnancy tests — serum levels rise detectably within days of implantation and peak near the end of the first trimester.

Structurally, hCG is composed of two subunits: the α-subunit (92 amino acids), which is shared with LH, FSH, and TSH, and the β-subunit (145 amino acids), which confers receptor specificity. Both subunits are heavily glycosylated, and the unique hCG β-subunit C-terminal extension (a 28-amino-acid sequence not found in LH-β) is responsible for the compound's substantially longer circulating half-life — approximately 24–36 hours of biological activity versus 20 minutes for native LH.

Therapeutic hCG is available in two major formats. Urinary-derived hCG (Pregnyl by Organon, Novarel by Ferring) is purified from the urine of pregnant women and has been in clinical use since the 1930s. Recombinant choriogonadotropin alfa (Ovidrel by EMD Serono, ovitrelle in Europe) is made by genetically modified Chinese hamster ovary (CHO) cells; its label calls it comparable to urinary hCG, with the same α-chain, a very similar β-chain and sugar chains that differ mainly in branching and sialylation, made to a high level of purity with consistent product characteristics (Ovidrel label). Both bind the same LH/CG receptor and drive the same downstream signaling; the clinical choice is usually driven by indication, formulation convenience, and payer coverage.

In men's health, hCG's primary role is as an adjunct to testosterone replacement therapy (TRT). Exogenous testosterone suppresses the hypothalamic-pituitary-gonadal (HPG) axis via negative feedback on the hypothalamus and pituitary, causing endogenous LH and FSH production to drop — which leads to reduced Leydig cell stimulation, testicular atrophy, cessation of intratesticular testosterone production, and spermatogenic arrest. Because hCG is an LH-receptor agonist, it replaces the missing LH signal at the testicular level, maintaining Leydig cell function, intratesticular testosterone (ITT) — which runs approximately 50–100-fold higher than serum testosterone and is essential for spermatogenesis — and testicular volume during TRT. Coviello et al. (J Clin Endocrinol Metab 2005; PMID 15713727) measured the dose-response in 29 healthy men given testosterone enanthate 200 mg weekly for 3 weeks: with placebo, ITT fell 94%; with hCG every other day it ended 25% below baseline at 125 IU, 7% below at 250 IU and 26% above at 500 IU.

Mechanism of Action

The labels describe hCG's action as virtually identical to that of LH, the pituitary hormone, with a small degree of FSH activity as well (Pregnyl label); its half-life is about 36 hours, against about 30 minutes for LH, by one review (Lee & Ramasamy, 2018; PMID 30159241), and 29 hours after an injection of Ovidrel under the skin (Ovidrel label). It stimulates the testes' Leydig cells to make androgens and the corpus luteum of the ovary to make progesterone (Pregnyl label).

• LH/CG receptor (LHCGR) agonism — hCG binds the receptor it shares with LH, the LH/hCG receptor (Ovidrel label; Lee & Ramasamy, 2018; PMID 30159241). In men it acts on the testes' Leydig cells; in women, on the granulosa and theca cells of the ovary and on the corpus luteum (Pregnyl label; Ovidrel label).
• Steroidogenesis — Leydig cell — hCG stimulates the Leydig cells to make testosterone (Mulhall et al., 2018; PMID 29601923). The labels add that the androgens drive secondary sex characteristics and may bring down an undescended testis when nothing blocks it anatomically (Pregnyl label).
• Intratesticular testosterone (ITT) maintenance — In 29 healthy men, ITT was about 80 times the serum level (1,174 vs 14.1 nmol/L), and testosterone enanthate 200 mg weekly cut LH to 5% of baseline and ITT by 94% within 3 weeks; with hCG every other day, ITT ended 25% below baseline at 125 IU, 7% below at 250 IU and 26% above at 500 IU. The authors note that high ITT is thought necessary for sperm production, but the level required is not known (Coviello et al., 2005; PMID 15713727). A review puts ITT at 100 to 1,000 times the blood level (Shiraishi & Matsuyama, 2017; PMID 28100869).
• Testicular aromatase — intratesticular estradiol — Aromatase, the enzyme that turns testosterone into estradiol, is found in the testis as well as the liver, brain and fat (Crosnoe et al., 2013; PMID 26813847). In the record review of 26 men on testosterone plus hCG, mean serum estradiol was higher during treatment than before, but not significantly (Hsieh et al., 2013; PMID 23260550).
• Testicular volume preservation — Testicular shrinkage is not uncommon on testosterone and usually reflects lost sperm production and Leydig-cell function (Ramasamy et al., 2015; PMID 25337850). An algorithm its authors base on historical evidence adds hCG 1,500 IU weekly to keep testicular size in men on testosterone who are not seeking fertility (Ramasamy et al., 2015; PMID 25337850; Lee & Ramasamy, 2018; PMID 30159241).
• Ovulation induction — female use — In reproductive medicine, hCG is the "trigger shot": it stands in for the mid-cycle LH surge that triggers ovulation (Pregnyl label). The labels give a single dose of 5,000–10,000 IU of urinary hCG intramuscularly, or 250 mcg of Ovidrel under the skin, one day after the last dose of the follicle-stimulating drug (Pregnyl label; Ovidrel label).
• Cryptorchidism (pediatric) — In prepubertal boys whose undescended testes are not blocked anatomically, the labels say the androgens hCG stimulates may bring the testes down; their four regimens range from 500 to 5,000 IU per injection, given over about 1 to 6 weeks. Descent is temporary in most cases, and hCG may help predict whether orchiopexy will be needed (Pregnyl label).
• Little FSH activity — hCG acts like LH, with only a small degree of FSH activity (Pregnyl label). In men with hypogonadotropic hypogonadism, FSH is added when hCG alone has not started sperm production within 4–6 months (Lee & Ramasamy, 2018; PMID 30159241).

What the Research Shows

The hCG evidence base spans multiple FDA-approved indications and decades of post-marketing data. The men's-health TRT-adjunct use case has smaller but mechanistically clean evidence.

• Intratesticular testosterone preservation (Coviello et al., J Clin Endocrinol Metab 2005; PMID 15713727) — 29 healthy men were randomized to testosterone enanthate 200 mg weekly with placebo or hCG 125, 250 or 500 IU every other day for 3 weeks; ITT was measured in testicular fluid drawn by fine-needle aspiration. Testosterone alone: ITT fell 94% (1,234 to 72 nmol/L). With hCG it ended 25% below baseline at 125 IU, 7% below at 250 IU and 26% above at 500 IU, rising linearly with dose. The AUA guideline cites this trial for its 250 or 500 IU every-other-day figure (Mulhall et al., 2018; PMID 29601923).
• Spermatogenesis preservation on TRT (Hsieh et al., J Urol 2013; PMID 23260550) — A retrospective review of 26 hypogonadal men (mean age 35.9) on daily testosterone gel or weekly testosterone injections plus hCG 500 IU intramuscularly every other day, followed for a mean of 6.2 months: semen parameters did not change, no man became azoospermic, and 9 of the 26 contributed to a pregnancy. The AUA guideline calls it the only study of this combination's effect on semen (Mulhall et al., 2018; PMID 29601923).
• Hypogonadotropic hypogonadism (HH) fertility induction — Gonadotropins are the main treatment for infertility in men with HH: hCG first, with FSH added if sperm have not appeared in 4–6 months; maximum sperm production can take up to 2 years (Lee & Ramasamy, 2018; PMID 30159241). A meta-analysis of 44 studies found sperm appeared in 75% of men overall, in 68% of men in studies limited to HH that began before puberty against 84% in studies of mixed groups, and more often when hCG and FSH were combined (Rastrelli et al., 2014; PMID 25271205).
• Men's-health translational review (Lee & Ramasamy, Transl Androl Urol 2018; PMID 30159241) — Clinical review of hCG indications in male infertility and hypogonadism management; synthesizes the indication matrix for urology and reproductive endocrinology practice.
• Adolescent cryptorchidism (Ehrlich et al., older studies) — Multiple mid-20th-century studies established efficacy of hCG in stimulating testicular descent in prepubertal boys with non-anatomic cryptorchidism. Modern guidelines favor surgical orchiopexy as first-line, with hCG reserved for select cases.
• Ovulation induction — assisted reproduction — In the three controlled trials on Ovidrel's label, 250 mcg under the skin matched 5,000 or 10,000 IU of urinary hCG: for eggs retrieved in two IVF trials (297 and 205 women) and for ovulation in 242 anovulatory women (91.9% of those on Ovidrel ovulated) (Ovidrel label).
• Anabolic-steroid PCT context — In a case series of 26 men with recent anabolic-steroid use, hCG 3,000 units intramuscularly every other day for at least 3 months restored sperm production in all but two, in an average of 3.1 months after injected testosterone and 7.4 months after transdermal testosterone (Crosnoe et al., 2013; PMID 26813847). One group gives 3,000 IU every other day with anastrozole, tamoxifen or clomiphene, with sperm returning in 4–6 months (Ramasamy et al., 2015; PMID 25337850). The AUA guideline reports that hCG alone or with a SERM has helped such men recover, though sperm can take up to two years to return and some men never recover (Mulhall et al., 2018; PMID 29601923). The evidence is case series and clinical experience, not randomized trials.
• Obesity (Simeons diet — discredited) — The historical "HCG diet" claim that low-dose hCG enhances fat loss on a 500-kcal diet has been repeatedly disproven in controlled trials. The FDA issued a warning letter in 2011 against the homeopathic "HCG for weight loss" products. This use is not supported.

Human Data

hCG has been studied in humans for more than 80 years. The following are representative pivotal references across its major uses:

• Coviello et al., 2005 (PMID 15713727) — Quantitative dose-response of hCG 0–500 IU EOD on ITT during testosterone-induced gonadotropin suppression in healthy men. The foundational modern TRT-adjunct paper.
• Hsieh et al., 2013 (PMID 23260550) — Retrospective record review of 26 hypogonadal men on TRT + concomitant IM hCG; no patient became azoospermic, and nine of the 26 contributed to a pregnancy during follow-up.
• Lee & Ramasamy, 2018 (PMID 30159241) — Indications review: hypogonadism, male infertility, fertility preservation.
• Ovulation-induction RCTs — The three randomized trials on Ovidrel's label, two in IVF (297 and 205 women) and one in ovulation induction (242 women), found 250 mcg of recombinant choriogonadotropin alfa equivalent to 5,000 or 10,000 IU of urinary hCG (Ovidrel label). FDA approved Ovidrel in 2000.
• Hypogonadotropic hypogonadism fertility-induction trials — A 2014 meta-analysis pooled 44 studies of gonadotropin therapy in men with HH and no sperm: sperm appeared in 75% overall, more often when hCG and FSH were combined, and earlier testosterone therapy did not change the result (Rastrelli et al., 2014; PMID 25271205).
• Kim et al., BJU Int 2016 (PMID 26496621) — Two phase III randomised, double-blind trials of oral enclomiphene citrate against topical testosterone gel in overweight men aged 18–60 with secondary hypogonadism: enclomiphene raised total testosterone while sperm counts were preserved, unlike the gel — an adjacent mechanism (SERM-based axis restoration) relevant to the hCG-vs-SERM decision point in men wanting to preserve fertility without direct testicular stimulation.
• The March 2020 transition — On March 23, 2020, under the Biologics Price Competition and Innovation Act (BPCIA), the approved hCG products (Novarel, Pregnyl, chorionic gonadotropin) became licensed biologics by statute, moving from the drug pathway to section 351 of the Public Health Service Act. FDA’s position is that biologics fall outside the compounding exemptions in sections 503A and 503B, which ended the compounding of hCG that had been common in men’s-health protocols.
• Safety databases — Decades of FDA Adverse Event Reporting System (FAERS) data for Pregnyl and Novarel; well-characterized side-effect profile dominated by local injection reactions and dose-dependent estradiol-mediated effects.

Reconstitution & Storage

Pregnyl and Novarel come as a freeze-dried powder in a multiple-dose vial with a 10 mL vial of diluent: water for injection with 0.56% sodium chloride and 0.9% benzyl alcohol for Pregnyl, bacteriostatic water with 0.9% benzyl alcohol for Novarel. Pregnyl's directions add 1 to 10 mL of it to the powder; Novarel's give 1 mL or 10 mL (Pregnyl label; Novarel label). Ovidrel comes as a prefilled syringe of 250 mcg in 0.5 mL for subcutaneous injection (Ovidrel label).

• Reconstitution — The labels describe adding the diluent to the powder and agitating gently until it dissolves, without shaking (Pregnyl label); online reconstitution guides add running the diluent slowly down the vial wall. Pregnyl's powder is white and its solvent clear and colorless (Pregnyl label).
• Storage — before mixing — The urinary products are stored at room temperature: 15–25°C for Pregnyl, 20–25°C for Novarel (Pregnyl label; Novarel label). Ovidrel syringes are kept refrigerated at 2–8°C until the expiry date, or for up to 30 days at room temperature up to 25°C, protected from light (Ovidrel label).
• Storage — reconstituted — Refrigerated at 2–8°C and not frozen: used within 60 days for Pregnyl and 30 days for Novarel (Pregnyl label; Novarel label). Both supplied diluents are preserved with 0.9% benzyl alcohol, which Pregnyl's label says is not for use in newborns (Pregnyl label).
• Injection route — The urinary products are labeled for intramuscular use only and Ovidrel for subcutaneous use (Pregnyl label; Novarel label; Ovidrel label). The AUA guideline's table lists hCG subcutaneously or intramuscularly for men (Mulhall et al., 2018); the record review of hCG with testosterone used intramuscular injections (Hsieh et al., 2013).
• Inspection — The labels call for checking the solution for particles and discoloration before injection; Pregnyl's says not to use it if either is present (Pregnyl label; Novarel label).

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Side Effects & Risks

• Estradiol elevation — In a record review of 26 men on testosterone plus hCG, mean serum estradiol was higher during treatment than before, but not significantly (Hsieh et al., 2013). The labels list gynecomastia and edema among hCG's adverse reactions (Novarel label).
• Gynecomastia — The labels say hCG may occasionally cause breast enlargement in men (Pregnyl label). In men on testosterone therapy who develop breast symptoms, the AUA guideline measures estradiol and notes that the symptoms sometimes settle on their own (Mulhall et al., 2018).
• Injection-site reactions — The labels list bruising, pain, redness, swelling and itching at the injection site (Pregnyl label). In the Ovidrel trials, injection-site problems affected 14.6% of women on Ovidrel and 28% on urinary hCG (Ovidrel label).
• Headache — Listed among the adverse reactions on the labels (Pregnyl label; Novarel label).
• Mood changes — The labels list irritability, restlessness and depression (Pregnyl label; Novarel label).
• Fluid retention — The labels report water and sodium retention occasionally after high doses, regarded as a result of excess androgen production, and advise caution in heart or kidney disease, high blood pressure, epilepsy, migraine or asthma (Pregnyl label).
• OHSS (ovarian hyperstimulation syndrome) — female ovulation-induction context — A label warning: severe OHSS may be life-threatening (Pregnyl label). In the Ovidrel trials it occurred in 4 of 236 women in assisted reproduction (1.7%) and 3 of 99 in ovulation induction (3.0%) (Ovidrel label). The labels call for monitoring ovarian response and following women for at least two weeks after hCG (Pregnyl label).
• Multiple gestation — female fertility context — Multiple births have been reported with all gonadotropin therapy, hCG included (Pregnyl label); in the Ovidrel trials, 30.9% of live deliveries after assisted reproduction and 13.3% after ovulation induction were multiple births. The labels use ultrasound and serum estradiol monitoring to limit the risk (Ovidrel label).
• Prostate concerns — The labels contraindicate hCG in men with prostate cancer or another androgen-dependent tumor (Novarel label). For men on testosterone therapy, the AUA guideline measures PSA before treatment in men over 40 and then follows its prostate cancer screening guideline (Mulhall et al., 2018).
• Thromboembolic risk (rare) — In women, the labels report rare thromboembolism with FSH/hCG therapy, usually with severe OHSS but also apart from it (Pregnyl label).
• Cardiovascular (indirect) — When hCG is taken with testosterone, the testosterone carries a higher risk of polycythemia; the AUA guideline checks hematocrit before treatment and every 6–12 months, keeping it below 54% (Mulhall et al., 2018).
• Hypersensitivity — The labels report local and systemic allergic reactions, including anaphylaxis with urinary-derived hCG (Pregnyl label); Novarel's label says it is unclear whether they come from the hormone or the benzyl-alcohol diluent (Novarel label). Allergic reactions, including anaphylaxis, have also been reported with recombinant Ovidrel since it was marketed (Ovidrel label).
• WADA status — males — hCG is specifically prohibited in male athletes at all times under WADA code S2 (peptide hormones, growth factors, related substances and mimetics). Females may use hCG for obstetric or reproductive indications per their sport's medical certification.

Bloodwork & Monitoring

The AUA guideline's follow-up for men treated for low testosterone, with hCG among the treatments it covers, is summarized below (Mulhall et al., 2018); no label or trial sets a separate schedule for hCG taken with testosterone. In women, the labels set the monitoring for fertility treatment (Pregnyl label).

• Total testosterone — Measured every 6–12 months once treatment is stable; in men on hCG, the first follow-up test comes no sooner than four weeks after starting (Mulhall et al., 2018).
• Estradiol — Measured in men who develop breast symptoms or gynecomastia on treatment and in all men on an aromatase inhibitor; the guideline notes that immunoassays are less accurate than LC-MS/MS at low estradiol levels (Mulhall et al., 2018).
• LH and FSH — The AUA guideline measures LH in men with low testosterone, and FSH at baseline in men who want to keep their fertility, before hCG, a SERM or an aromatase inhibitor is started (Mulhall et al., 2018). In the 2005 trial, testosterone enanthate 200 mg weekly cut LH and FSH to 5% and 3% of baseline (Coviello et al., 2005). hCG can cross-react in gonadotropin assays, especially for LH (Pregnyl label).
• Semen analysis — The published algorithm starts with a baseline semen analysis in men who want to keep their fertility on testosterone, repeated every 2 months when pregnancy is sought within 6 months (Lee & Ramasamy, 2018); the AUA guideline orders one when FSH is elevated (Mulhall et al., 2018).
• Hematocrit — Measured before treatment (below 50% to start) and every 6–12 months, keeping it below 54% (Mulhall et al., 2018); the Endocrine Society also measures hematocrit in men on testosterone (Bhasin et al., 2018).
• PSA (men >40) — Measured before treatment; after that, the AUA guideline follows its prostate cancer screening guideline, by shared decision (Mulhall et al., 2018). The Endocrine Society evaluates prostate cancer risk during the first year of testosterone therapy (Bhasin et al., 2018).
• Women in fertility treatment — The labels monitor ovarian response with serum estradiol and transvaginal ultrasound, follow women for OHSS for at least two weeks after hCG and exclude pregnancy before treatment; hCG can interfere with pregnancy test results (Pregnyl label; Ovidrel label).

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Legal Status

Related Compounds

Compounds that work upstream, downstream, or alongside hCG in the HPG axis.

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References

1. Coviello AD, Matsumoto AM, Bremner WJ, Herbst KL, Amory JK, Anawalt BD, Sutton PR, Wright WW, Brown TR, Yan X, Zirkin BR, Jarow JP. Low-dose human chorionic gonadotropin maintains intratesticular testosterone in normal men with testosterone-induced gonadotropin suppression. J Clin Endocrinol Metab. 2005;90(5):2595-2602. PMID: 15713727.
2. Hsieh TC, Pastuszak AW, Hwang K, Lipshultz LI. Concomitant intramuscular human chorionic gonadotropin preserves spermatogenesis in men undergoing testosterone replacement therapy. J Urol. 2013;189(2):647-650. PMID: 23260550.
3. Lee JA, Ramasamy R. Indications for the use of human chorionic gonadotropic hormone for the management of infertility in hypogonadal men. Transl Androl Urol. 2018;7(Suppl 3):S348-S352. PMID: 30159241.
4. Kaminetsky J, Werner M, Fontenot G, Wiehle RD. Oral enclomiphene citrate stimulates the endogenous production of testosterone and sperm counts in men with low testosterone: comparison with testosterone gel. J Sex Med. 2013;10(6):1628-1635. PMID: 23530575. (Adjacent SERM-based axis-restoration evidence; informs the hCG-vs-SERM decision in men preserving fertility.)
5. Rastrelli G, Corona G, Mannucci E, Maggi M. Factors affecting spermatogenesis upon gonadotropin-replacement therapy: a meta-analytic study. Andrology. 2014;2(6):794-808. PMID: 25271205. (Meta-analysis of spermatogenesis response to gonadotropin replacement — relevant to hCG/FSH combined fertility induction.)
6. U.S. Food and Drug Administration. Pregnyl (chorionic gonadotropin) Prescribing Information. Organon USA Inc.
7. U.S. Food and Drug Administration. Novarel (chorionic gonadotropin) Prescribing Information. Ferring Pharmaceuticals.
8. U.S. Food and Drug Administration. Ovidrel (choriogonadotropin alfa) Prescribing Information. EMD Serono. First approved 2000.
9. U.S. Food and Drug Administration. Notice to compounders: changes that affect compounding as of March 23, 2020. fda.gov. (Names human chorionic gonadotropin among the transitioning biological products.)
10. U.S. Food and Drug Administration. Mixing, Diluting, or Repackaging Biological Products Outside the Scope of an Approved Biologics License Application. Guidance for industry, January 2018. fda.gov/media/90986.
11. Ramasamy R, Armstrong JM, Lipshultz LI. Preserving fertility in the hypogonadal patient: an update. Asian J Androl. 2015;17(2):197-200. PMID: 25337850.
12. Bhasin S, Brito JP, Cunningham GR, Hayes FJ, Hodis HN, Matsumoto AM, Snyder PJ, Swerdloff RS, Wu FC, Yialamas MA. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(5):1715-1744. PMID: 29562364. (Society practice guideline framing TRT adjuncts including hCG.)
13. Crosnoe LE, Grober E, Ohl D, Kim ED. Exogenous testosterone: a preventable cause of male infertility. Transl Androl Urol. 2013;2(2):106-113. PMID: 26813847. (Mechanism and clinical framing of TRT-induced infertility and hCG-based prevention.)
14. WADA. 2026 World Anti-Doping Code Prohibited List. Section S2 — Peptide hormones, growth factors, related substances, and mimetics. World Anti-Doping Agency. (hCG specifically prohibited in males.)
15. Shiraishi K, Matsuyama H. Gonadotoropin actions on spermatogenesis and hormonal therapies for spermatogenic disorders. Endocr J. 2017;64(2):123-131. PMID: 28100869.
16. Dubey A, Jalali M, Fauzdar A, Hargreave TB. The efficacy of different protocols of hCG administration in hypogonadotrophic hypogonadism. Clin Endocrinol (Oxf). 2007;67(3):389-395. (Dual-gonadotropin fertility-induction protocol evidence.)
17. Swerdloff RS, Wang C. The testis and male hypogonadism, infertility, and sexual dysfunction. In: Goldman-Cecil Medicine. 26th ed. Elsevier. (Standard clinical reference for HPG-axis pharmacology and hCG use.)
18. Kim ED, McCullough A, Kaminetsky J. Oral enclomiphene citrate raises testosterone and preserves sperm counts in obese hypogonadal men, unlike topical testosterone: restoration instead of replacement. BJU Int. 2016;117(4):677-685. PMID: 26496621.
19. Mulhall JP, Trost LW, Brannigan RE, Kurtz EG, Redmon JB, Chiles KA, Lightner DJ, Miner MM, Murad MH, Nelson CJ, Platz EA, Ramanathan LV, Lewis RW. Evaluation and Management of Testosterone Deficiency: AUA Guideline. J Urol. 2018;200(2):423-432. PMID: 29601923.

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