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Long-Term Safety and Efficacy of Clomiphene Citrate for Hypogonadism
abstract
This abstract is available on the publisher's site.
Access this abstract nowPURPOSE
Clomiphene citrate may be used as an off label treatment of hypogonadism. There are little long-term data on clomiphene citrate efficacy and safety when administered for more than 3 years. We assessed improvements in testosterone and hypogonadal symptoms while on clomiphene citrate for extended periods.
MATERIALS AND METHODS
We performed a retrospective review to identify patients treated with clomiphene citrate for hypogonadism (baseline testosterone less than 300 ng/dl) at a total of 2 institutions from 2010 to 2018. We assessed the duration of clomiphene citrate therapy, serum testosterone levels, symptom improvement and clomiphene citrate side effects.
RESULTS
A total of 400 patients underwent clomiphene citrate treatment for a mean ± SD of 25.5 ± 20.48 months (range 0 to 84). Of the patients 280 received clomiphene citrate for 3 years or longer (mean 12.75 ± 9.52 months) and 120 received it for more than 3 years (mean 51.93 ± 10.52 months). Of men on clomiphene citrate for more than 3 years 88% achieved eugonadism, 77% reported improved symptoms and 8% reported side effects. Estradiol was significantly increased following clomiphene citrate treatment. Results did not significantly differ between patients treated for more than 3, or 3 or fewer years. The most common side effects reported by patients treated more than 3 years included changes in mood in 5, blurred vision in 3 and breast tenderness in 2. There was no significant adverse event in any patient treated with clomiphene citrate.
CONCLUSIONS
Clomiphene citrate is not typically offered as primary treatment of hypogonadism in men who do not desire fertility preservation. These data demonstrate that clomiphene citrate is safe and effective with few side effects when used as long-term treatment of hypogonadism.
Additional Info
Disclosure statements are available on the authors' profiles:
Long-Term Safety and Efficacy of Clomiphene Citrate for the Treatment of Hypogonadism
J Urol 2019 Nov 01;202(5)1029-1035, SC Krzastek, D Sharma, N Abdullah, M Sultan, GL Machen, JL Wenzel, A Ells, X Chen, M Kavoussi, RA Costabile, RP Smith, PK KavoussiFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Testosterone replacement therapy for aging men with symptomatic low T (with gels, injections, or implants) as well as oral therapy to increase testosterone endogenously (with clomiphene, tamoxifen, or anastrozole) are effective at raising testosterone levels, supported by AUA guidelines, and considered off-label use of these agents by the FDA. The authors provide real-life documentation of their experience in using clomiphene citrate in two different practice settings, where symptomatic men with low T were treated with 25 mg of clomiphene citrate daily. Mean serum testosterone levels increased from 222 to 649 ng/dL. The authors targeted the AUA guideline–recommended therapeutic range of 450 to 600 ng/dL and increased the dose to 50 mg if inadequate response was observed. If breast symptoms or high estradiol (>60 pg/mL or T/E ratio <10) was observed, then anastrozole 1 mg/day was added to clomiphene. The addition of anastrozole occurred for about 15% of treated men. Symptomatic benefit was reported for over 80% of men, although this was not rigorously investigated, and no controls were included in the study. These results reflect the largest (400 patients) experience in men with low T and strongly support the use of this medication for such men.
Indeed, I will offer this treatment for men, at least those with low T and borderline or low LH, as some studies suggest these men are the most likely to respond. It is a less-expensive, equally effective (at raising T levels), and apparently provides symptomatic relief for at least some men with low T. As with exogenous testosterone therapy, CBC follow-up should be obtained to avoid the risk of erythrocytosis associated with such treatment. The FDA’s reticence at supporting testosterone therapy appears to both focus on the lack of recognition of symptomatic low T in aging men as a disease as well as potential cardiovascular concerns.
Numerous articles and reviews have now suggested that restoring testosterone levels to normal in symptomatic men does not carry substantial cardiovascular risk and/or may actually improve diabetic control, help with weight loss, and may have a survival advantage. Those who are faced with men who are symptomatic with low T in the office setting recognize that some of these men have substantial symptomatic benefit from treatment. Clearly, clomiphene is an option for treating these men and appears to have therapeutic benefit, although the magnitude of that benefit would have been better quantified in a randomized, controlled trial.