Skip to main content

Androgen Adjuncts

hCG, selective estrogen receptor modulators (SERMs) and aromatase inhibitors can raise endogenous testosterone in selected men. 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 . It states that clinicians should not prescribe exogenous testosterone to a man interested in current or future fertility . It calls the literature on adding hCG or other agents to exogenous testosterone too limited to recommend that approach. For idiopathic infertility it advises telling the patient that SERMs have limited benefit relative to assisted reproductive technology , and it allows an FSH analogue to be considered .[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​

AgentMechanismUS status for the use discussed here
Urinary-derived hCG (e.g., Pregnyl)LH-receptor agonism directly stimulates Leydig cellsApproved 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 agonismIts US approval is for female ovulation/ART indications. Male use is off-label; do not assume interchangeable units or dosing with urinary hCG.
ClomipheneEstrogen-feedback antagonism increases pituitary LH/FSH when that axis can respondApproved for female ovulatory dysfunction; male hypogonadism/fertility use is off-label.
EnclomipheneThe trans isomer of clomiphene; increases LH/FSHNot FDA-approved. A compounded preparation is not an FDA-approved alternative formulation.[6][19]
AnastrozoleAromatase inhibition lowers estradiol and can increase endogenous LH/testosteroneApproved for specified postmenopausal breast-cancer indications; male endocrine use is off-label.
Tamoxifen / raloxifeneSERMs with tissue-specific estrogen effectsHypogonadism/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.[3] 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. The AUA testosterone table lists hCG 500–4,000 IU subcutaneously or intramuscularly two to three times weekly.[1][2] Elsewhere, the guideline says clinicians may offer 250 or 500 IU every other day with exogenous testosterone, based on a single small study of intratesticular testosterone.[2] The Pregnyl label separately lists IM regimens for selected male HH.[3]

The label retains a cryptorchidism indication; AUA guidance favors timely surgical management and recommends against hormones to induce descent.[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.[10]

Response depends on etiology, testicular development and prior cryptorchidism; some patients need prolonged treatment or assisted reproduction. Favorable predictors of spermatogenic response in hypogonadotropic hypogonadism are post-pubertal onset, no history of undescended testes, larger baseline testicular volume and higher baseline inhibin B.[22] EAU 2026 calls gonadotropin therapy the standard for men with secondary hypogonadism who want paternity and reports comparable effects for recombinant and urinary preparations. Its hypogonadism chapter favors combined hCG and FSH on the cited meta-analysis, while its infertility chapter permits hCG first for postpubertal-onset secondary hypogonadism, adding FSH if spermatogenesis is inadequate, or combination from the start; it recommends semen analysis every three months. The preparation table lists hCG 1,000–2,000 IU and FSH 75–150 IU, each three times weekly.[36] Combined hCG and FSH for 12–24 months is the conventional gonadotropin regimen in these patients; the review of Boeri and colleagues describes testicular growth in almost all, spermatogenesis in roughly 80% and pregnancy in about half, figures that come from selected hypogonadotropic cohorts (see Muir above for the pooled sperm-concentration data).[22] In a 2026 meta-analysis of gonadotropin therapy, including hCG alone and hCG/FSH regimens, for azoospermic men with hypogonadotropic hypogonadism, 24 studies involving 463 men with a child wish yielded a pooled 52% pregnancy rate by any route.[38] Only four studies reported time to pregnancy (mean 19 months), and the pooled spontaneous-conception fraction was 32% among achieved pregnancies in 19 studies reporting route.[38] Forty of 50 included studies were rated weak, limiting individual prognostic use.[38]

hCG alone or with a SERM can help recover testosterone production and spermatogenesis after prior exogenous testosterone or anabolic-steroid use. Return of sperm to the ejaculate is highly variable: it can take up to two years after stopping exogenous testosterone, and some men never recover sperm.[2] In a randomized trial in older men with androgen deficiency (mean age 67), hCG raised total testosterone by about 150%, showing that the aging testis can still respond to gonadotropin.[2]

The often-cited Hsieh series involved only 26 men receiving testosterone plus hCG 500 units every other day.[11] It reported no azoospermia and nine partner pregnancies, but was retrospective without a control group.[11][1]

Safety and access​

Gynecomastia is the most common adverse effect of gonadotropin therapy; hCG stimulates aromatase and raises estradiol.[22] The AUA table also lists headache, irritability, depression, fatigue, edema and injection-site pain.[2] Monitoring includes gynecomastia or breast symptoms, edema, headache, mood symptoms and injection reactions; anaphylaxis is possible. The Pregnyl label advises caution in men with cardiac or renal disease, hypertension, epilepsy, migraine or asthma because hCG-induced androgen secretion may cause fluid retention.[3] The reviewed PREGNYL label lists breast or prostate tumors in males and uncontrolled non-gonadal endocrinopathies (for example, thyroid, adrenal or pituitary disorders) among its contraindications.[3]

Urinary and recombinant products are not automatically interchangeable. A 2024 pharmacology study (crossover volunteers plus 52 gonadotropin-deficient men) found similar testosterone responses at the tested urinary and recombinant hCG doses despite lack of formal pharmacokinetic bioequivalence and proposed a recombinant starting dose of 62.5 µg (6 clicks of the adapted Ovidrel pen studied).[12] Of 98 pens returned after nominal partial dosing, 20 from 4 of 10 men had no fluid left; the US Ovidrel label instead describes a single-dose prefilled syringe.[12][4]

Following the March 2020 biologic transition, hCG products are not eligible for the usual 503A/503B compounded-drug exemptions.[13] Confirm the specific authorized product and pharmacy supply.[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.[2] Titration requires reassessment of symptoms, testosterone and the endocrine response.

What the studies can and cannot tell us​

  • Habous 2018 randomized 282 men who wished to preserve fertility to clomiphene 50 mg, hCG 5,000 IU twice weekly or both for three months. Testosterone rose in all groups without a significant difference between them; the combination had greater questionnaire improvement.[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.[15]
  • The small randomized clomiphene/anastrozole comparison found biochemical differences but no significant improvement in semen or patient-reported outcomes over 12 weeks.[16]

Other clomiphene series​

StudynDesignFindings
Keihani 2020332Two-center retrospectiveMean testosterone rise 329 ng/dL; 73% rose by at least 200 ng/dL; median 6 weeks to first follow-up. Baseline LH and FSH did not predict response.[23]
Ramasamy 201493Age-matched retrospective, clomiphene vs testosterone injection vs gel (31 each)Median testosterone 247 to 504 ng/dL on clomiphene, versus 224 to 1,104 (injection) and 230 to 412 (gel). Symptom satisfaction (qADAM) was similar in all arms; injection users reported higher libido than clomiphene users (4 vs 3).[24]
Taylor 2010104 (65 clomiphene; 39 gel)Retrospective; clomiphene 50 mg every other day vs testosterone gelMean post-treatment testosterone 573 vs 553 ng/dL; in the clomiphene group assessed by telephone, ADAM score 4.9 before treatment to 2.1 at follow-up. Monthly drug cost was about $83 versus $265–270 for gel (2009 prices).[25]
Anno 202654One-year retrospective; 50 mg every other dayTestosterone rose and stayed up over 12 months and the Aging Males' Symptoms score fell, but the sexual-function domain did not improve significantly. Baseline LH was the only independent predictor of testosterone rise.[26]

All are uncontrolled or retrospective.

Titration and monitoring​

The AUA testosterone guideline gives practical rules for SERM treatment:[2]

  • A serum LH after starting the SERM guides decisions.
  • If testosterone stays low and LH is low or normal, consider dose escalation.
  • If testosterone is low and LH is high, the testis is likely the problem and escalation is unlikely to help.
  • First follow-up blood work is best no sooner than four weeks after starting clomiphene, anastrozole or hCG, then every 6–12 months. The guideline notes anecdotal concern about clomiphene tachyphylaxis, which is one reason for regular testosterone checks.

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. 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. Clomiphene labeling mentions thromboembolism only in the setting of ovarian hyperstimulation in women, and the AUA table lists venous thromboembolism and stroke for tamoxifen; the male thrombotic risk of clomiphene is not quantified, so weigh the patient's own risk factors.[2][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.[17]

The 2014 Wiehle phase II trial also found increased hormones with conserved sperm counts.[18]

The 2013 Wiehle phase II pharmacodynamic study randomized 48 men with secondary hypogonadism (screening testosterone below 350 ng/dL on two occasions and low-to-normal LH; four exceeded 350 ng/dL at treatment baseline) to enclomiphene 6.25, 12.5 or 25 mg daily or 5 g of transdermal testosterone gel for six weeks.[27] Day-42 morning testosterone was 604 ng/dL on 25 mg versus 500 ng/dL on gel (not significantly different). Enclomiphene raised LH and FSH, gel suppressed them, and the effects of enclomiphene persisted for at least a week after stopping. IGF-1 fell in both groups, more with enclomiphene.[27]

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. No FDA-approved male dosing schedule exists.[6]

Anastrozole and estradiol management​

Aromatase inhibition can lower estradiol and raise testosterone in selected men with low testosterone and elevated estradiol. For infertile men with low serum testosterone, AUA/ASRM 2024 allows clinicians to consider aromatase inhibitors. Address reversible contributors and inappropriate testosterone dosing first.[1] A T/E2 ratio is assay- and unit-dependent.[1]

A 2026 randomized trial in 296 men with nonobstructive azoospermia, cryptozoospermia or severe oligozoospermia (excluding hypogonadotropic hypogonadism) compared letrozole 2.5 mg daily plus vitamins C/E with vitamins alone for three months. World Health Organization sperm-concentration category improved in 21/147 (14.3%) versus 8/149 (5.4%), but median sperm concentration and total motile count remained zero in both arms; pregnancy and live birth were not assessed. Decreased libido occurred in 18/147 versus 8/149.[37]

The AUA table lists anastrozole 0.05–1 mg every one to three days (not FDA-approved in men); male studies have used several schedules, including 1 mg daily, and this is not a default prescription for every man receiving testosterone.[2][16][2][16] The AUA guidance advises against extended aromatase-inhibitor courses because of bone loss, careful titration to keep estradiol in range, and stopping the drug if estradiol stays high.[2] 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.[16] 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]

Dose-response and other data​

Leder 2004 randomized 37 men aged 62–74 years with testosterone below 350 ng/dL to anastrozole 1 mg daily, 1 mg twice weekly or placebo for 12 weeks. Both regimens raised testosterone and lowered estradiol modestly, staying within the normal male range. Hematocrit, quality-of-life, IIEF and AUA symptom scores did not change; PSA rose only in the twice-weekly group.[28]

Regimen (n)Bioavailable T (ng/dL)Total T (ng/dL)Estradiol (pg/mL)
1 mg daily (12)99 to 207343 to 57226 to 17
1 mg twice weekly (11)115 to 178397 to 52027 to 17

Other applications reported for anastrozole:

  • Hypoandrogenic subfertility. In an 86-man retrospective series (78 with a low T/E2 ratio and 8 with a prior adverse reaction to clomiphene) treated with anastrozole 1 mg daily, 95.3% had higher testosterone and lower estradiol. Among 21 oligozoospermic men (24% of the 86-man cohort), 18 improved sperm concentration and total motile count; within this subgroup, the total motile-count gain correlated with the increase in T/E2. Men with azoospermia, cryptozoospermia or normozoospermia showed no semen improvement.[29]
  • Testosterone pellets. In a retrospective review of 38 men (65 insertions), adding anastrozole 1 mg daily to pellets was associated with a longer time to reinsertion (198 vs 128 days), higher testosterone at more than 120 days and less gonadotropin suppression.[30]

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.[21] Avoid excessive estradiol suppression; assess skeletal risk and reconsider long-term use rather than automatically adding an osteoporosis drug to compensate.[21][7]

In the 12-week Leder study, anastrozole did not change bone-resorption or formation markers or total-body BMD.[31] For scale, in the ATAC bone substudy of postmenopausal women, the five-year primary analysis included 108 of 197 women recruited; anastrozole reduced median lumbar-spine BMD by 6.08% and total-hip BMD by 7.24% versus small gains on tamoxifen. Extrapolation to men is directional only.[32] A review of estradiol in men concludes that estradiol supports the hypothalamic-pituitary-testicular axis, bone, body composition and glucose metabolism, and that testosterone rather than an aromatase inhibitor is the treatment of choice for male hypogonadism.[33]

AUA guidance treats aromatase inhibitors as an option only in the fertility-preserving pathway, and its Table 6 lists anastrozole adverse effects of hot flashes, hypertension, nausea, back and bone pain, dyspnea and peripheral edema.[2]

Do not routinely add anastrozole simply to extend pellet intervals, normalize a laboratory estradiol result or prevent hypothetical gynecomastia. If breast symptoms persist, evaluate their cause and reassess the primary testosterone regimen before choosing additional treatment.[1][2]

Tamoxifen, raloxifene and combinations​

EAU 2026 describes SERMs and aromatase inhibitors as off-label options for functional secondary hypogonadism with an intact hypothalamic-pituitary axis, particularly in obesity and metabolic disease, and calls the evidence poor. It cautions that SERMs may raise venous thromboembolism risk (data lacking) and that long-term use can lower bone density and raise fracture risk.[36]

Clomiphene dominates SERM use in urologic practice. The AUA table lists tamoxifen 20 mg orally daily (half-life 5–7 days; adverse effects include liver enzyme changes, ocular disturbances including cataracts, and thromboembolic events including DVT and stroke).[2]

In a crossover study of 10 healthy men given each drug for 2 weeks, both SERMs raised LH, FSH and testosterone, but tamoxifen (20 mg) had the stronger gonadal effect (LH about +70% vs +30%; testosterone about +40% vs +25% with raloxifene 60 mg).[34] Tamoxifen alone lowered IGF-1 by about 25% and raised SHBG by about 20%, which can blunt free-testosterone gains; raloxifene did not lower IGF-1.[34] In 284 men with idiopathic oligozoospermia, tamoxifen 20 mg, toremifene 60 mg and raloxifene 60 mg each increased gonadotropins, more with tamoxifen and toremifene than with raloxifene.[35] These are hormone data in small or uncontrolled studies.

Short endocrine studies report LH/testosterone changes without establishing fertility benefit; doses from oncology or osteoporosis require a defined endocrine rationale here. 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. When fertility is the goal, follow semen outcomes and couple-level factors alongside hormonal response, and discuss assisted reproduction when appropriate.[1][10]

Combination strategies at a glance​

CombinationRationaleWhat the evidence shows
Clomiphene + hCGCentral SERM plus peripheral LH-receptor agonistHabous 2018 RCT: testosterone rose in all arms without significant difference; combination had greater questionnaire improvement.[14]
Clomiphene + anastrozoleSERM raises testosterone but also estradiol; AI limits the estradiol riseLimited published data.
Testosterone + low-dose hCGMaintain intratesticular testosteroneHsieh 2013, retrospective, 26 men; AUA/ASRM 2024 finds the evidence insufficient to guarantee fertility.[11][1]
Testosterone pellets + anastrozoleLimit aromatization; lengthen intervalMechlin 2014, retrospective, 38 men: 198 vs 128 days.[30]
hCG + FSHhCG drives Leydig cells, FSH drives Sertoli cells and spermatogenesisMuir 2025 meta-analysis: better sperm outcomes than hCG alone in gonadotropin deficiency.[10]

Comparative summary​

AgentMechanismFDA-approved in menPreserves fertilityAdvantageLimitation
hCGLH-receptor agonistYes, selected HH (and cryptorchidism label)Stimulates intratesticular testosterone; in HH, hCG alone or with FSH can induce spermatogenesis, with semen response monitored[3][10]Direct testicular stimulation2–3 injections weekly; gynecomastia; biologic supply and cost[2][3]
ClomipheneSERM raising LH/FSHNoIn men with a responsive axis, semen concentration and motility may improve; natural-pregnancy benefit in idiopathic infertility remains uncertain[39][40]Oral; low cost; large retrospective experienceOff-label; raises estradiol; visual warning; sexual symptoms may not improve[2][5][26]
Enclomiphenetrans-isomer of clomipheneNoSperm concentration maintained in short trialsIsolates the anti-estrogenic isomerUnapproved; compounded supply; little long-term data[17][19]
AnastrozoleAromatase inhibitorNoImproves T/E2; semen benefit in a subset onlyTargets high estradiol with low testosteroneBone loss with prolonged use; lower testosterone than clomiphene in the head-to-head trial[2][16][21]
TamoxifenSERMNot for hypogonadism or infertilityRaises gonadotropinsStronger axis effect than raloxifeneLowers IGF-1, raises SHBG; thromboembolic risk[2][34]

Clinical decision-making​

  • Fertility desired now: avoid exogenous testosterone. hCG (with FSH if hypogonadotropic) or a SERM, chosen by cause and semen response.[1]
  • Fertility desired later: a stimulatory agent as primary therapy is preferable to testosterone; adding low-dose hCG to testosterone rests on limited evidence.[1][11]
  • Fertility not a concern: Testosterone remains a standard treatment for symptomatic, confirmed deficiency; clomiphene may be considered by selected men preferring endogenous stimulation, and hCG may be used in hypogonadotropic hypogonadism.[3][36] Clomiphene comparisons report testosterone, symptom, satisfaction and cost outcomes.[24][25] In a retrospective comparison, polycythemia occurred in 1.7% of 188 clomiphene-treated and 11.2% of 175 testosterone-treated men, who differed in age and treatment duration.[41]
  • Raised estradiol with symptoms on testosterone: first review the testosterone dose and formulation; if an aromatase inhibitor is used, titrate to estradiol (AUA table 0.05–1 mg every 1–3 days), stop it if estradiol stays high, and avoid prolonged courses.[2]
  • Obesity-related low testosterone: treat reversible contributors; anastrozole plus weight loss did not improve symptoms beyond weight loss alone.[20]
  • After testosterone-induced azoospermia: stop exogenous testosterone, follow recovery with serial semen analyses, and consider hCG with or without FSH or a SERM when needed for the fertility timeline; recovery is variable and can take up to two years.[1][2]
  • Primary testicular failure (high LH/FSH): SERMs and aromatase inhibitors are unlikely to work.[2]

See Also​

References​

1. Schlegel PN, Sigman M, Collura B, et al. Diagnosis and Treatment of Infertility in Men: AUA/ASRM Guideline (2020; amended 2024, approved by the AUA Board of Directors July 2024). Statements 40 to 47 cover hormonal treatment and exogenous testosterone. 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. Foster J, et al. British Society of Sexual Medicine: position statement for the potential use of enclomiphene in the treatment of male hypogonadism. World J Mens Health. 2026;44(3):480-483. 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 intramuscular human chorionic gonadotropin preserves spermatogenesis in men undergoing testosterone replacement therapy. J Urol. 2013;189(2):647-650. Source.

12. Handelsman DJ, et al. Single and multi-dose pharmacology of recombinant and urinary human chorionic gonadotrophin in men. Clin Endocrinol (Oxf). 2024;101(1):42-50. Source.

13. FDA. Empower Pharmacy warning letter, October 15, 2021. Biological-product transition and 503A/503B exemptions. Source.

14. Habous M, et al. Clomiphene citrate and human chorionic gonadotropin are both effective in restoring testosterone in hypogonadism: a short-course randomized study. BJU Int. 2018;122(5):889-897. Source.

15. Krzastek SC, et al. Long-term safety and efficacy of clomiphene citrate for the treatment of hypogonadism. J Urol. 2019;202(5):1029-1035. Source.

16. Helo S, et al. A randomized prospective double-blind comparison trial of clomiphene citrate and anastrozole in raising testosterone in hypogonadal infertile men. J Sex Med. 2015;12(8):1761-1769. Source.

17. 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. Source.

18. Wiehle RD, et al. Enclomiphene citrate stimulates testosterone production while preventing oligospermia: a randomized phase II clinical trial comparing topical testosterone. Fertil Steril. 2014;102(3):720-727. Source.

19. FDA. Human Drug Compounding. Compounded drugs are not FDA-approved. Source.

20. Colleluori G, et al. Aromatase inhibitors plus weight loss improves the hormonal profile of obese hypogonadal men without causing major side effects. Front Endocrinol (Lausanne). 2020;11:277. Source.

21. Burnett-Bowie SA, et al. Effects of aromatase inhibition on bone mineral density and bone turnover in older men with low testosterone levels. J Clin Endocrinol Metab. 2009;94(12):4785-4792. Source.

22. Boeri L, Capogrosso P, Salonia A. Gonadotropin Treatment for the Male Hypogonadotropic Hypogonadism. Curr Pharm Des. 2021;27(24):2775-2783. doi:10.2174/1381612826666200523175806

23. Keihani S, Wright LN, Alder NJ, et al. Baseline Gonadotropin Levels and Testosterone Response in Hypogonadal Men Treated With Clomiphene Citrate. Urology. 2020;142:119-124. doi:10.1016/j.urology.2020.04.074

24. Ramasamy R, Scovell JM, Kovac JR, et al. Testosterone supplementation versus clomiphene citrate for hypogonadism: an age matched comparison of satisfaction and efficacy. J Urol. 2014;192(3):875-879. doi:10.1016/j.juro.2014.03.089

25. Taylor F, Levine L. Clomiphene citrate and testosterone gel replacement therapy for male hypogonadism: efficacy and treatment cost. J Sex Med. 2010;7(1 Pt 1):269-276. doi:10.1111/j.1743-6109.2009.01454.x

26. Anno Y, Tsujimura A, Kasai R, et al. Efficacy and Safety of Clomiphene Citrate for Late-Onset Hypogonadism as Evaluated by Aging Male Symptom Rating Scale Over One Year. Int J Urol. 2026;33(1):e70289. doi:10.1111/iju.70289

27. Wiehle R, Cunningham GR, Pitteloud N, et al. Testosterone Restoration by Enclomiphene Citrate in Men with Secondary Hypogonadism: Pharmacodynamics and Pharmacokinetics. BJU Int. 2013;112(8):1188-1200. doi:10.1111/bju.12363

28. Leder BZ, Rohrer JL, Rubin SD, et al. Effects of aromatase inhibition in elderly men with low or borderline-low serum testosterone levels. J Clin Endocrinol Metab. 2004;89(3):1174-1180. doi:10.1210/jc.2003-031467

29. Shoshany O, Abhyankar N, Mufarreh N, et al. Outcomes of anastrozole in oligozoospermic hypoandrogenic subfertile men. Fertil Steril. 2017;107(3):589-594. doi:10.1016/j.fertnstert.2016.11.021

30. Mechlin CW, Frankel J, McCullough A. Coadministration of anastrozole sustains therapeutic testosterone levels in hypogonadal men undergoing testosterone pellet insertion. J Sex Med. 2014;11(1):254-261. doi:10.1111/jsm.12320

31. Leder BZ, Finkelstein JS. Effect of aromatase inhibition on bone metabolism in elderly hypogonadal men. Osteoporos Int. 2005;16(12):1487-1494. doi:10.1007/s00198-005-1890-8

32. Eastell R, Adams JE, Coleman RE, et al. Effect of anastrozole on bone mineral density: 5-year results from the anastrozole, tamoxifen, alone or in combination trial 18233230. J Clin Oncol. 2008;26(7):1051-1057. doi:10.1200/JCO.2007.11.0726

33. Russell N, Grossmann M. Mechanisms in endocrinology: estradiol as a male hormone. Eur J Endocrinol. 2019;181(1):R23-R43. doi:10.1530/EJE-18-1000

34. Birzniece V, Sata A, Sutanto S, Ho KK. Neuroendocrine regulation of growth hormone and androgen axes by selective estrogen receptor modulators in healthy men. J Clin Endocrinol Metab. 2010;95(12):5443-5448. doi:10.1210/jc.2010-1477

35. Tsourdi E, Kourtis A, Farmakiotis D, et al. The effect of selective estrogen receptor modulator administration on the hypothalamic-pituitary-testicular axis in men with idiopathic oligozoospermia. Fertil Steril. 2009;91(4 Suppl):1427-1430. doi:10.1016/j.fertnstert.2008.06.002

36. EAU. Guidelines on Sexual and Reproductive Health, Limited Update March 2026, sections 3.4.3.b.6 and 3.4.3.b.7 and Table 3.5.

37. Sun Y, Yao C, Liu G, et al. "Letrozole and infertility among males with spermatogenic failure: a randomized clinical trial." JAMA Netw Open. 2026;9(6):e2618422. doi:10.1001/jamanetworkopen.2026.18422

38. Huijben M, Prinsen A, de Kort L, van Breda J. "Boosting male fertility: the impact of gonadotropin therapy on hypogonadotropic hypogonadism—a systematic review and meta-analysis." Andrology. 2026;14(7):1971-1987. doi:10.1111/andr.70226

39. Huijben M, Huijsmans RLN, Lock MTWT, de Kemp VF, de Kort LMO, van Breda JHM. "Clomiphene citrate for male infertility: a systematic review and meta-analysis." Andrology. 2023;11(6):987-996. doi:10.1111/andr.13388

40. Khashaba S, Khashaba S, Krishan A, et al. "Efficacy of clomiphene citrate and tamoxifen on pregnancy rates in idiopathic male subfertility: A systematic review and meta-analysis." Asian J Urol. 2025;12(1):15-22. doi:10.1016/j.ajur.2024.09.001

41. Wheeler KM, Smith RP, Kumar RA, Setia S, Costabile RA, Kavoussi PK. "A comparison of secondary polycythemia in hypogonadal men treated with clomiphene citrate versus testosterone replacement: a multi-institutional study." J Urol. 2017;197(4):1127-1131. doi:10.1016/j.juro.2016.10.068