Androgen Adjuncts
hCG, selective estrogen receptor modulators (SERMs) and aromatase inhibitors can raise endogenous testosterone in selected men. A higher serum testosterone or sperm concentration is not proof of improved pregnancy or live-birth outcomes. Treatment should follow the cause of the endocrine disorder and the patient's reproductive goals.[1]
The AUA/ASRM 2024 guideline conditionally allows hCG, SERMs, aromatase inhibitors or combinations for infertile men with low testosterone (Grade C). It advises against prescribing exogenous testosterone when current or future fertility is a priority. Adding hCG to testosterone has insufficient evidence to guarantee preserved fertility or support routine use as a workaround.[1]
For diagnosis, indications and monitoring of conventional treatment, see testosterone replacement. Confirm symptoms and repeated appropriate testosterone measurements; assess LH/FSH and the cause of deficiency before selecting an adjunct. Markedly elevated LH from testicular failure predicts limited response to stimulation; primary pituitary dysfunction can also prevent a SERM response. Neither situation should be reduced to “testosterone is the only option” when fertility evaluation may still be needed.[1][2]
Regulatory and mechanism overview
| Agent | Mechanism | US status for the use discussed here |
|---|---|---|
| Urinary-derived hCG (e.g., Pregnyl) | LH-receptor agonism directly stimulates Leydig cells | Approved for selected male hypogonadotropic hypogonadism (HH). The reviewed Pregnyl label specifies intramuscular administration; specialist subcutaneous use is a route change outside that label. |
| Recombinant hCG (Ovidrel) | LH-receptor agonism | Its US approval is for female ovulation/ART indications. Male use is off-label; do not assume interchangeable units or dosing with urinary hCG. |
| Clomiphene | Estrogen-feedback antagonism increases pituitary LH/FSH when that axis can respond | Approved for female ovulatory dysfunction; male hypogonadism/fertility use is off-label. |
| Enclomiphene | The trans isomer of clomiphene; increases LH/FSH | Not FDA-approved. A compounded preparation is not an FDA-approved alternative formulation. |
| Anastrozole | Aromatase inhibition lowers estradiol and can increase endogenous LH/testosterone | Approved for specified postmenopausal breast-cancer indications; male endocrine use is off-label. |
| Tamoxifen / raloxifene | SERMs with tissue-specific estrogen effects | Hypogonadism/fertility use is off-label. Tamoxifen does have a separate male metastatic breast-cancer indication, so “only hCG is approved for any male use” is incorrect. |
Sources: product labels and the 2026 specialist position statement.[3][4][5][6][7][8]
hCG and gonadotropin treatment
hCG can support intratesticular testosterone through direct LH-receptor stimulation. It does not preserve normal hypothalamic-pituitary feedback: rising testosterone/estradiol can suppress endogenous gonadotropins. Spermatogenesis also depends on Sertoli-cell stimulation by FSH; serum testosterone alone is an inadequate fertility-monitoring endpoint.[1][3]
Dosing and response
The Pregnyl US label lists two regimens for selected male HH: 500–1,000 units IM three times weekly for three weeks, then the same dose twice weekly for three weeks; or 4,000 units IM three times weekly for 6–9 months, then 2,000 units three times weekly for another three months. These are label examples, not one universal modern induction protocol. Specialist regimens are individualized to testosterone, adverse effects, testicular development and serial semen results; FSH may be added or used in a combined induction strategy.[1][3]
The label retains a cryptorchidism indication, but this should not be read as a recommendation for routine hormonal induction of descent: AUA guidance favors timely surgical management and recommends against hormones for that purpose.[3][9]
Fertility evidence
Muir 2025 pooled 41 studies/1,673 men with pathological gonadotropin deficiency. After median 18 months of treatment, 78% achieved some sperm in the ejaculate, but only 36% exceeded 5 million/mL and 15% exceeded 20 million/mL. Combined hCG/FSH was associated with better sperm outcomes than hCG alone. These heterogeneous treatment cohorts do not establish an 80% natural-conception rate or a universal 50% pregnancy expectation.[10]
Response depends on etiology, testicular development and prior cryptorchidism; some patients need prolonged treatment or assisted reproduction. Following testosterone-induced suppression, recovery can take many months or longer and may be incomplete. Do not promise recovery by six months or two years.[1]
The often-cited Hsieh series involved only 26 men receiving testosterone plus hCG 500 units every other day. It reported no azoospermia and nine partner pregnancies, but was retrospective without a control group. It supports further study, not a guarantee that concomitant hCG protects a patient who continues testosterone.[11][1]
Safety and access
Monitor gynecomastia/breast symptoms, edema, headache, mood symptoms and injection reactions; anaphylaxis is possible. The reviewed label lists hormone-sensitive tumors, including male breast/prostate tumors, and uncontrolled endocrine disease among relevant contraindications. A rise in estradiol alone does not mandate adding an aromatase inhibitor.[3]
Urinary and recombinant products are not automatically interchangeable. A small 2024 pharmacology study found similar testosterone responses at the tested doses, despite lack of formal pharmacokinetic bioequivalence; it does not establish a universal conversion or equivalence of every dispensing device.[12]
Following the March 2020 biologic transition, hCG products are not eligible for the usual 503A/503B compounded-drug exemptions. Confirm the specific authorized product and pharmacy supply; old published dollar estimates are not current price guidance.[13]
Clomiphene citrate
Clomiphene contains enclomiphene and zuclomiphene, with different estrogenic effects and persistence. Male use is off-label. The AUA testosterone-deficiency table describes 25–50 mg orally every one to two days; titration requires reassessment of symptoms, testosterone and the endocrine response rather than chasing a high laboratory value. This is not the female ovulation-induction schedule.[2][5]
What the studies can and cannot tell us
- Habous 2018 compared clomiphene, hCG and their combination over three months. Testosterone rose in all groups; the combination had greater questionnaire improvement. It did not demonstrate equivalent pregnancy/live-birth outcomes or establish a universal percentage testosterone rise.[14]
- Krzastek 2019 was a retrospective series of 400 men with mean treatment 25.5 months, range up to 84 months. Only 120 received treatment beyond three years; the reported 88% eugonadism, 77% symptom improvement and 8% side effects refer to this subgroup. It is not seven years of follow-up in all 400, and cannot exclude rare or delayed harms.[15]
- Testosterone responses do not ensure sexual-symptom or fertility improvement. The small randomized clomiphene/anastrozole comparison found biochemical differences but no significant improvement in semen or patient-reported outcomes over 12 weeks.[16]
Visual warning and other precautions
Stop clomiphene and obtain prompt ophthalmic assessment for new blurred vision, flashes, spots or other visual symptoms. The label warns that symptoms can persist and can be irreversible, particularly with greater dose or duration; “usually reversible” is not sufficient counseling. Avoid driving when affected.[5]
Check liver disease/history of liver dysfunction, uncontrolled thyroid/adrenal disease and organic intracranial lesions such as pituitary tumors against the label contraindications. Breast symptoms, increased estradiol and mood changes can occur. Consider the patient's thrombotic risk and the SERM class's reported thromboembolic complications; small male cohorts do not establish their incidence.[5][15]
Enclomiphene
Two phase III trials reported by Kim 2016 compared enclomiphene with testosterone gel/placebo in overweight men with secondary hypogonadism over 16 weeks. Enclomiphene raised testosterone/LH/FSH and maintained sperm concentrations, while gel suppressed gonadotropins and sperm output. These are short-term endocrine/semen outcomes; they do not establish long-term reproductive success or superiority in symptoms/safety.[17]
The 2014 Wiehle phase II trial also found increased hormones with conserved sperm counts; these findings concern biochemical and semen outcomes, not established pregnancy benefit.[18]
The 2026 BSSM position statement regards enclomiphene as promising but recommends experienced specialist/research use, with counseling about its unlicensed status and limited long-term evidence. Its discussion of potentially fewer adverse effects rests mainly on small retrospective comparisons; it does not establish head-to-head randomized superiority over clomiphene. No FDA-approved male dosing schedule exists. Availability through compounding does not imply approval, proven product equivalence or proven long-term safety.[6][19]
Anastrozole and estradiol management
Aromatase inhibition can lower estradiol and raise testosterone in selected men with low testosterone and elevated estradiol. AUA/ASRM allows consideration in that phenotype, but obesity alone or an isolated estradiol result is not an automatic indication. Address reversible contributors and inappropriate testosterone dosing first. A T/E2 ratio is assay- and unit-dependent and should not be treated as a universal therapeutic target.[1]
Male studies have used several schedules, including 1 mg daily; this is not a default prescription for every man receiving testosterone. In the 26-man Helo trial, clomiphene 25 mg/day produced higher testosterone than anastrozole 1 mg/day over 12 weeks, while anastrozole increased the T/E2 ratio more. Neither arm significantly improved semen measures or patient-reported outcomes. A 23-man obesity trial likewise found better hormone values with anastrozole plus weight loss but no additional symptom or strength benefit over weight loss alone.[16][20]
Bone health is a material concern. A one-year randomized trial of 69 men aged ≥60 found reduced lumbar-spine BMD with anastrozole 1 mg/day versus placebo despite higher testosterone. Avoid excessive estradiol suppression; assess skeletal risk and reconsider long-term use rather than automatically adding an osteoporosis drug to compensate. Female breast-cancer fracture/lipid rates cannot be presented as male-event estimates.[21][7]
Do not routinely add anastrozole simply to extend pellet intervals, normalize a laboratory estradiol result or prevent hypothetical gynecomastia. Evidence for these strategies is limited and does not establish improved patient outcomes. If breast symptoms persist, evaluate their cause and reassess the primary testosterone regimen before choosing additional treatment.[1][2]
Tamoxifen, raloxifene and combinations
Tamoxifen and raloxifene are not routine testosterone substitutes. Short endocrine studies showing LH/testosterone changes do not establish improved fertility, and endocrine doses should not be imported from oncology or osteoporosis indications. Tamoxifen's separate male breast-cancer approval does not approve it for androgen deficiency. Consider its thromboembolic and other label risks before off-label use.[8]
Combining clomiphene, hCG and/or anastrozole is a specialist decision tied to a defined endocrine problem. More agents and higher testosterone do not necessarily produce better symptoms or fertility. When fertility is the goal, follow semen outcomes and couple-level factors alongside hormonal response, and discuss assisted reproduction when appropriate.[1][10]
See Also
References
1. AUA/ASRM. Diagnosis and Treatment of Infertility in Men, amended 2024. Hormonal treatment and exogenous testosterone recommendations. Source.
2. American Urological Association. Testosterone Deficiency Guideline, 2018. Statement 27 and Table 6. Source.
3. PREGNYL (chorionic gonadotropin). US prescribing information. Source.
4. OVIDREL (choriogonadotropin alfa). US prescribing information. Source.
5. Clomiphene citrate. US prescribing information: contraindications and visual warning. Source.
6. British Society of Sexual Medicine. Position statement for the potential use of enclomiphene in the treatment of male hypogonadism. World J Mens Health. 2026. Source.
7. ARIMIDEX (anastrozole). US prescribing information. Source.
8. Tamoxifen citrate. US prescribing information. Source.
9. American Urological Association. Cryptorchidism Guideline: hormonal therapy to induce descent. Source.
10. Muir CA, et al. Efficacy of gonadotropin treatment for induction of spermatogenesis in men with pathologic gonadotropin deficiency: meta-analysis. Clin Endocrinol. 2025. Source.
11. Hsieh TC, et al. Concomitant hCG and testosterone: retrospective semen outcomes. J Urol. 2013. Source.
12. Handelsman DJ, et al. Single and multidose pharmacology of recombinant and urinary hCG in men. Clin Endocrinol. 2024. Source.
13. FDA. Empower Pharmacy warning letter, October 15, 2021. Biological-product transition and 503A/503B exemptions. Source.
14. Habous M, et al. Clomiphene and hCG in hypogonadism: short-course randomized study. BJU Int. 2018. Source.
15. Krzastek SC, et al. Long-term safety and efficacy of clomiphene for hypogonadism. J Urol. 2019. Source.
16. Helo S, et al. Randomized comparison of clomiphene and anastrozole in hypogonadal infertile men. J Sex Med. 2015. Source.
17. Kim ED, et al. Enclomiphene raises testosterone and preserves sperm counts: two phase III trials. BJU Int. 2016. Source.
18. Wiehle RD, et al. Enclomiphene versus topical testosterone: randomized phase II trial. Fertil Steril. 2014. Source.
19. FDA. Human Drug Compounding. Compounded drugs are not FDA-approved. Source.
20. Colleluori G, et al. Aromatase inhibitors plus weight loss in obese hypogonadal men: randomized pilot trial. Front Endocrinol. 2020. Source.
21. Burnett-Bowie SA, et al. Aromatase inhibition and bone mineral density in older men: randomized trial. J Clin Endocrinol Metab. 2009. Source.