Background

Low testosterone and testosterone deficiency are usually treated with testosterone therapy. But for those who wish to preserve their fertility or may not tolerate testosterone therapy, SERMs are available. Selective estrogen receptor modulators (SERMs), including clomiphene citrate (CC), can increase gonadotropin and testosterone levels in men and have been in use as early as the 1960s.

CC works by blocking estrogen’s inhibitory effect on gonadotropin secretion in the pituitary gland. Luteinizing hormone (LH) can then be released in higher amounts and stimulate testosterone production in the testes.

Both the American Urological Association (AUA) and European Association of Urology (EAU) recognize CC as an option for treatment, including guidelines for dosage. However, the drug has shown a variable success rate (64-73% in recent studies) and has limited or inconsistent research around predictors of success.

Study Objective

• Researchers intended to determine predictors of biochemical treatment success when using CC.

Methods

• This retrospective study included 292 men who were referred to a sexual and reproductive health clinic between 2008 and 2024.
• Patients were diagnosed with testosterone deficiency based on AUA guidelines.
  • A minimum of 2 early-morning testosterone test levels ≤ 300 ng/dL
  • Symptoms of testosterone deficiency, such as muscle weakness, fatigue, and irritability
• Patients with borderline testosterone deficiency were also included.
• No patients prescribed testosterone therapy were included.
• CC was prescribed beginning at 25 mg every other day.
  • If levels were still <400 ng/dL after four weeks, the CC dose was increased to 50 mg every other day.
    • Dose adjustments were monitored monthly. After ideal levels were met, semi-annually.
  • Success was defined by two parameters.
    • Testosterone ≥400 ng/dL
    • A ≥200 ng/dL increase in testosterone from baseline
  • Failure was defined as those who stopped treatment altogether or transferred to another treatment type within the first 12 months of CC.

Key Results/Analysis

• 136 (46.6%) patients achieved an adequate response (success) within the first 12 weeks of CC.
• 156 (53.4%) failed to respond within the first 12 weeks of CC.
  • 59 (37.8%) achieved total testosterone ≥400 ng/dL but did not experience a ≥200 ng/dL increase from baseline.
  • 7 (4.5%) saw a ≥200 ng/dL increase from baseline but did not achieve total testosterone ≥400 ng/dL
  • 90 (57.7%) failed to meet either criterion.
• Between those considered responders and those considered non-responders, significant differences were found in median baseline LH levels and history of androgen deprivation therapy (ADT).
  • LH for responders: 3.3 mIU/mL
  • LH for non-responders: 3.7 mIU/mL
  • History of ADT in responders: 0.7%
  • History of ADT in non-responders: 8%
• Researchers found that response rates declined by approximately 20% with each 1 mIU/mL increase in baseline LH.
• History of ADT is likely predictive of treatment response (success) due to the irreversible changes that occur in the testicles.
  • Patients with a history of ADT should be advised that CC may not be the right option for them.
• No other predictors of response (age, etc.) were evident in the data.
• The results of this study were considerably “worse” than previous research in terms of treatment response (47% success rate vs. 60%).
  • Researchers state this may have to do with the strict standardization of protocol, as well as the age group included.
    • While age is not a predictor of CC treatment response, younger men may have different motivations for treatment, like fertility preservation.

Key Takeaways

• CC is often prescribed off-label to men with testosterone deficiency who either cannot tolerate testosterone therapy or wish to preserve fertility.
• Research is limited and inconsistent as to predictors of treatment response (success).
• This study suggests that baseline LH levels <6 mIU/mL may be predictive of CC treatment response.
  • Patients with higher baseline LH should be directed to other treatment options.
• Having no history of androgen deprivation therapy may also be predictive of CC treatment response.
  • Patients with a history of ADT should be warned that CC treatment may not be successful for them.
• Further research may include more subjective variables, such as improvement of symptoms.

Resources

• Kim, D. J., Assel, M., Elshafei, A., Liso, N., Vickers, A. J., Mulhall, J. P., & Flores, J. M. (2026). Predictors of clomiphene citrate response in the treatment of men with testosterone deficiency. The Journal of Sexual Medicine, 23(7). https://doi.org/10.1093/jsxmed/qdag159