What are hCG, enclomiphene and the other drugs used with or instead of testosterone?

What they are

Human chorionic gonadotropin (hCG), enclomiphene, clomiphene, gonadorelin and anastrozole are prescription drugs that act on the hormones linking the brain and testicles. Some men take hCG with testosterone to try to keep making sperm; gonadorelin has been proposed for this too. Anastrozole has been tested with testosterone, to lower estrogen. Others take hCG, enclomiphene, clomiphene or anastrozole instead of testosterone, to try to raise their own.^{1,2,3,4,5,6,7,8,9,10,11,12,13}

Testosterone taken as a drug makes the pituitary gland, at the base of the brain, release less luteinizing hormone (LH) and follicle-stimulating hormone (FSH), the signals that drive the testicles. They then make less testosterone, and sperm production can fall. Testosterone labels warn that the effect on fertility may be irreversible.^6,14,15

The Endocrine Society’s 2018 guideline recommends against starting testosterone in men planning to father a child in the near term. It says men unsure about future children may want to bank sperm first, if their semen contains sperm.¹⁶

Prescribing clomiphene or anastrozole to men, or hCG with testosterone, is off-label: using an FDA-approved drug for a purpose the FDA has not approved. Clinicians may do this when they judge it medically appropriate, but the FDA has not found that the benefits outweigh the risks for these uses.¹⁷

How they work

The hypothalamus, a brain region, releases gonadotropin-releasing hormone (GnRH) in pulses, prompting the pituitary to release LH and FSH. Sperm production depends on FSH and on testosterone inside the testicles, which is normally far higher than in blood. Estrogen, made partly from testosterone, acts as a brake on this chain.^{2,3,8,18,19,20,21}

hCG, a hormone the placenta makes in pregnancy, acts almost exactly like LH. Given with testosterone, it can keep the testicles making testosterone while the body’s own LH is suppressed.^8,19,22

Clomiphene and enclomiphene are selective estrogen receptor modulators (SERMs), drugs with mixed estrogen-blocking and estrogen-like effects. They block estrogen’s brake on the hypothalamus and pituitary, so LH and FSH rise. Clomiphene mixes two forms of one molecule (isomers): enclomiphene, at least half of it, and zuclomiphene. Its label says zuclomiphene may act more like estrogen and stayed detectable for over a month after one dose. As a drug, enclomiphene is that first form alone.^6,9,13,21

Gonadorelin is a lab-made copy of GnRH, a chain of 10 amino acids, and prompts the pituitary to release LH and FSH. Pulses like the body’s own stimulate the pituitary, while steady exposure suppresses it.^2,18

Anastrozole blocks aromatase, the enzyme that turns testosterone into estradiol, a form of estrogen. With less estrogen braking the pituitary, LH and FSH rise and the testicles make more testosterone.^10,23,24

How they are taken

What the research in people shows

For hCG added to testosterone, the evidence is two small, short randomized studies in healthy men and a records review. In 2005, 29 men got testosterone injections for 3 weeks; testosterone inside the testicles fell sharply with a placebo but stayed normal with hCG. In 2006, 18 men took testosterone and a progestin, a progesterone-like hormone, for 6 weeks; the 6 also given hCG kept most types of sperm-forming cells at normal levels. A 2013 review of 26 men’s records found semen quality held steady on testosterone and hCG, and some partners became pregnant, but it had no comparison group.^1,19,20

A 2018 randomized trial in 282 men not taking testosterone found testosterone rose similarly on clomiphene, hCG or both over 3 months. Symptom scores improved most with both; there was no placebo group.⁵

hCG’s other large trials are in women: three randomized fertility trials of 205 to 297 women each, which found lab-made hCG worked about as well as urine-derived hCG. A 2025 analysis of 41 studies covered 1,673 men with low testosterone from weak pituitary signals (hypogonadotropic hypogonadism). Treatment with hCG, alone or with FSH, produced sperm in most, more often with FSH added, but fewer reached the counts usually needed for pregnancy without fertility treatment.^25,27

Enclomiphene’s main published evidence is two randomized late-stage (phase 3) trials its developer ran, reported in 2016, in 256 overweight men with low testosterone from weak pituitary signals. Over 16 weeks, it raised testosterone, LH and FSH and kept sperm counts normal, while testosterone gel lowered LH, FSH and sperm counts. The FDA’s 2022 review found the trials had not shown it improves symptoms; neither used symptom questionnaires tested for reliability.^6,13

Two other phase 3 trials, with 332 men, posted results on ClinicalTrials.gov in 2015 but were not published in a journal. A third, of 194 men, finished in 2007 and has posted no results. A 2026 British Society for Sexual Medicine statement, a 4-page editorial, saw enclomiphene as an option for men wanting to preserve fertility. Noting that the evidence comes from small, short-term studies, it did not recommend routine use outside specialist settings. Three of its five authors list a UK online health company as an affiliation.^{13,21,28,29,30,31}

The Endocrine Society’s 2018 guideline says randomized trials had not shown clomiphene effective or safe for men with low testosterone from weak pituitary signals. A 2025 review pooled 10 randomized trials of clomiphene or enclomiphene, with 819 men followed for 2 to 30 weeks, mostly measuring hormones rather than symptoms. The drugs raised testosterone, LH and FSH more than placebo. Against testosterone gel, testosterone was similar and sperm concentration held up better.^16,32

In a 2018 placebo-controlled trial of 78 obese men with low testosterone, those taking clomiphene for 12 weeks reported improvement in one sexual complaint, weaker erections. Their overall symptom scores improved no more than on placebo.^32,33

For male infertility, a 1992 World Health Organization trial in 190 couples with unexplained poor semen quality found 6 months of clomiphene no better than placebo for pregnancies or semen quality. In 2013, an analysis of 11 randomized trials found more pregnancies with clomiphene or tamoxifen, a similar drug, than with controls. In 2025, a review of 10 trials found no clear difference in pregnancies between clomiphene and placebo; too few tamoxifen trials reported pregnancies to pool.^34,35,36

Clomiphene’s largest trials are in women. In a 2007 trial of 626 women with polycystic ovary syndrome, clomiphene led to more live births than metformin, a diabetes drug. In a 2014 trial of 750 such women, it led to fewer than letrozole, a drug like anastrozole.^57,37

No published study has tested whether gonadorelin keeps sperm production going in men taking testosterone. Its largest randomized trial, reported in 1986, in 252 boys with undescended testicles, found a gonadorelin nasal spray little better than placebo. A 1995 analysis of randomized trials found gonadorelin brought testicles down more often than placebo, but in a minority of cases.^2,38,39

In a year-long placebo-controlled trial of 88 men aged 60 or older with low or borderline-low testosterone, reported in 2009, anastrozole raised testosterone but did not change fat, muscle or strength. A second report, on the 69 men who finished, found spine bone density fell compared with placebo. The largest trial on its label, ATAC, in 9,366 women with breast cancer after menopause, found longer survival without the cancer returning than with tamoxifen.^10,24,40

In a 2015 trial, 26 infertile men with low testosterone were randomly assigned clomiphene or anastrozole for 12 weeks. Both raised testosterone, clomiphene more, and neither changed semen quality or symptoms.⁷

Two trials gave anastrozole with testosterone. In a 3-month trial of 40 men with epilepsy and low testosterone, reported in 2010, sexual function returned to normal in more men given anastrozole than placebo, possibly by chance. In a 2013 trial of 400 healthy men whose own hormones were suppressed, about half also took anastrozole. Low estrogen mainly explained gains in body fat and contributed to declines in sexual function.^3,4

Side effects and risks

For enclomiphene, the FDA’s 2022 review listed heart and clotting events in trials. They included a fast heart rhythm problem (atrial flutter), deep vein clots, a lung clot and a stroke from a blocked artery. It also noted rises in estradiol, PSA (a prostate blood test) and red blood cells. The European Medicines Agency counted four clotting events, one fatal, on enclomiphene and none on testosterone or placebo. Blurred vision was among the most common reasons people stopped. Cataracts appeared in animal studies but were not clearly linked in people.^13,41

Clomiphene’s label warns of blurred vision, spots or flashes, which usually clear but have sometimes lasted after stopping and may be irreversible, especially with higher doses or longer use. People with visual symptoms should stop it and have an eye exam. It also reports high triglycerides, a blood fat, sometimes with pancreatitis, an inflamed pancreas.⁹

The label says clomiphene must not be used with liver disease or a past liver problem, uncontrolled thyroid or adrenal disease, or a growth inside the skull such as a pituitary tumor. Reports after approval include lung clots, stroke, liver inflammation (hepatitis), mood changes and psychosis. In men, it notes reports of breast enlargement and of testicular tumors; whether clomiphene caused the tumors is not known.⁹

In the 2018 trial in obese men, clomiphene lowered HDL, the cholesterol linked to lower heart risk. A 2021 review gathered 11 studies, with 384 men, that reported sperm counts falling on clomiphene; in some men they did not recover after stopping.^33,42

Anastrozole’s label warns of bone loss, higher cholesterol and, in women with existing heart disease, more heart events than with tamoxifen. Serious reactions seen in fewer than 1 in 10,000 patients include severe skin reactions, allergic swelling of the face and throat, and liver inflammation. Reports after approval also include anaphylaxis, a severe allergic reaction. Tendon problems, including rupture, were added to those reports in December 2024.^10,43

hCG’s labels list headache, irritability, restlessness, depression, tiredness, fluid retention, breast enlargement and injection-site pain, and urge caution with heart or kidney disease, epilepsy, migraine or asthma. Men with prostate cancer or other tumors driven by male hormones, and anyone who has had an allergic reaction to hCG, must not use it; anaphylaxis has been reported. One label also rules out men with breast cancer, a pituitary or hypothalamus tumor, or uncontrolled thyroid, adrenal or pituitary disease. Another notes sporadic reports of testicular tumors in young men given hCG for infertility, with no causal link established.^8,22,44

Gonadorelin’s safety in men taking testosterone has not been studied. In pump studies of men born with GnRH deficiency, allergic skin reactions were more common than with hormone injections, and mostly mild or moderate.²⁶

Unlike hCG, the other four can reach patients as compounded products. The FDA warns that poor compounding can cause contamination or the wrong amount of active ingredient, which can lead to serious injury and death.^{45,46,47,48,49}

No current FDA-approved label for people lists risks for enclomiphene or gonadorelin. The labels for hCG, clomiphene and anastrozole carry no boxed warning, the FDA’s most serious kind.^{8,9,10,11,12,13,22,44}

FDA status

hCG is FDA-approved for undescended testicles in boys, selected men with low testosterone from a pituitary deficiency, and inducing ovulation in some women. Since March 23, 2020, hCG has been regulated as a biologic, a medicine made from living sources. So it cannot be compounded under section 503A, for state-licensed pharmacies, or 503B, for outsourcing facilities.^{8,22,44,45,47}

Enclomiphene is not FDA-approved. In December 2015 its developer announced an FDA letter declining approval, which said its phase 3 design was no longer adequate to show clinical benefit. The European Medicines Agency recommended refusal in January 2018, finding safety and effectiveness not sufficiently shown.^13,41

Enclomiphene has no United States Pharmacopeia (USP) quality standard, and the FDA does not count it as an ingredient of an FDA-approved drug. So a 503A pharmacy may use it only if the FDA adds it to the 503A bulks list, its list of other ingredients pharmacies may compound with. In 2022 the FDA recommended against that, and its advisers agreed, 8 votes to 4. Pending a final decision, the FDA’s May 14, 2026 list keeps it in Category 1, where the FDA says it does not intend to act against compounders that meet its conditions.^13,46,47,50

Clomiphene is FDA-approved only for ovulation problems in women who want to become pregnant; its label says no adequate or well-controlled studies demonstrate it works for male infertility. Anastrozole is approved only for breast cancer in women after menopause. Both are ingredients of FDA-approved drugs, so, unlike enclomiphene, they do not depend on the 503A bulks list. Compounded versions are not FDA-approved: the FDA does not check their safety, effectiveness or quality before sale.^{9,10,13,47,48,49}

Gonadorelin has no FDA-approved product marketed for people: the FDA’s drug database lists both human injections, approved in 1982 and 1989, as discontinued. Versions approved for cattle are labeled not for human use. The FDA’s 2025 list for outsourcing facilities marks gonadorelin acetate as an ingredient of an FDA-approved drug, so it does not depend on the 503A bulks list.^{11,12,18,47,48}

On October 30, 2026 the Department of Health and Human Services (HHS), the FDA’s parent department, published a draft policy covering six other peptides, not gonadorelin. For those six, HHS says it does not intend to take enforcement action against state-licensed pharmacies, federal facilities and licensed physicians that compound them under section 503A and meet set conditions.^51,52

Controlled substance and sport rules

Testosterone is a federally controlled substance; none of these five drugs is. The World Anti-Doping Agency’s 2026 and 2027 Prohibited Lists ban all five for male athletes at all times.^53,54,55

What isn’t known

No randomized trial has tested whether any of the five preserves fertility in men taking testosterone. The two randomized studies of hCG with testosterone in healthy men treated them for 3 to 6 weeks and measured hormones or sperm-forming cells, not pregnancies.^19,20

Most trials in men not taking testosterone measured hormone levels or sperm counts, not pregnancies. The clomiphene and enclomiphene trials pooled in 2025 lasted at most 30 weeks. Longer data come from studies without a comparison group: a 2019 review of 400 men’s records, 120 of whom took clomiphene for over 3 years, reported few side effects.^6,32,56

For anastrozole in men, the longest trial ran 1 year and measured bone density, not fractures.⁴⁰

Questions to ask a clinician