Clomiphene citrate therapy for testosterone deficiency: a proposed clinical care pathway

Introduction

Several testosterone (T) therapy options are currently available, including oral, intranasal, transdermal (gel, patches), intramuscular, and subcutaneous agents. The practice guidelines of some professional societies, including the American Urological Association and the European Association of Urology but not all international societies,^1,2 suggest treating with aromatase inhibitors or selective estrogen receptor modulators for men with infertility. However, selective estrogen receptor modulators (ie, clomiphene citrate [CC]) may be a reasonable alternative for men experiencing low T with infertility or a wish to maintain their fertility.³ In clinical practice, CC—a nonsteroidal triphenylethylene derivative distantly related to diethylstilbestrol and a selective estrogen receptor modulator—is also used as an effective treatment for men with low T to improve T levels and T deficiency symptoms. CC is an oral agent that acts centrally. CC is a mixture of enclomiphene (62%), which is a trans isomer with pure antiestrogen effect, and zuclomiphene (38%), which is a cis isomer that has a mixed action with a predominant estrogen receptor agonistic property. It selectively binds to estrogen receptors primarily in the hypothalamus to produce a partial estrogen agonist effect resulting in an estrogenic negative feedback inhibition, thus increasing the hypothalamic gonadotropin-releasing hormone pulse frequency and, as a result, elevating luteinizing hormone (LH) secretion to stimulate the gonads to increase sexual hormones—for men, the Leydig cells to raise T levels.⁴ In vitro data have also suggested that CC has a pituitary site of action where it causes an increase in the gonadotropin response to gonadotropin-releasing hormone.⁵

It is known that CC needs an intact pituitary to increase LH and normal testicular tissue to produce T.⁶ The T levels reached on CC are similar to those of patients treated with T gel. CC also raises follicle-stimulating hormone levels to potentially improve spermatogenesis. CC was developed by Frank P. Palopoli, MS, in 1956 and commercialized by William S. Merrell Pharmaceutical Company, and the US Food and Drug Administration approved its use in the treatment of ovulatory dysfunction and infertility in women in 1967. Currently, CC is used off-label for T deficiency and male infertility.⁷ CC is well tolerated, with only a minority of patients in clinical trials experiencing adverse events, such as vasomotor flushing (10%), abdominopelvic discomfort (6%), nausea and vomiting (2%), breast discomfort (2%), headache (1%), and visual symptoms (eg, blurred vision, photophobia, and diplopia). The adverse events occur more frequently with higher doses of CC. CC has <1% rate of venous thrombosis, and most reports have been in men with family thrombophilia predisposition or history of deep vein thrombosis.⁸

Proposed clinical care pathway

The American Urological Association and European Association of Urology guidelines recommend CC as an off-label treatment option, mainly in men with low T who have interest in fertility and in men with T deficiency who have infertility (for pathway, see Figure 1).⁹ Patients who have expressed concerns about testicular atrophy observed with exogenous T during T therapy counseling are also excellent candidates for CC. In our clinical practice, our initial T panel includes total T, free T, LH, sex hormone–binding globulin (SHBG), estradiol, dual x-ray absorptiometry scan, prostate-specific antigen (PSA), and complete blood count (CBC). We measure LH levels in all men with low T at baseline prior to initiation of T therapy. A serum LH level can guide clinical decision making in the evaluation of the patient’s candidacy for CC. Prior studies have suggested that the ability to achieve therapeutic T levels decreases with increasing baseline LH levels.¹⁰ If LH levels are >6 IU/mL, we do not recommend CC, as low T levels are likely due to testicular dysfunction.¹⁰

Figure 1.

Clinical care pathway for clomiphene citrate therapy with testosterone deficiency.

The dosing for CC in men is empiric with a typical starting dose in our program of 25 mg orally every other day.⁷ Every-other-day dosing is preferred, given the potential for the tachyphylaxis phenomenon associated with the drug.¹¹ While not completely understood, the mechanism of this with CC is likely due to chronic and continuous stimulation of receptors, which leads to these becoming desensitized or possibly to a decrease in the number of available receptors. Most tachyphylaxis data in men treated with CC are limited to case reports of men who had a decrease in LH and T levels or a reduction of sperm concentration with extended use.^11,12 CC tachyphylaxis is considered a diminishing response to CC, as evidenced by a reduced LH response and subsequent lower T level.¹⁰ However, there is no standard clinical definition for the tachyphylaxis observed with CC. In our clinical practice, we define tachyphylaxis in patients treated with CC, as a decrease in T levels is usually associated with a reduced LH response. In our experience, about 1 in 10 of men meet the definition of tachyphylaxis.

After CC is initiated, T laboratory assessments should be scheduled every 4 weeks until therapeutic T levels are reached. During follow-up, the T panel includes total T, free T, sex hormone–binding globulin, LH, estradiol, prostate-specific antigen, and complete blood count. The on-treatment LH level will inform the clinician whether the pituitary is responding (increase in LH level) or not (no or minimal increase in LH level). If T levels are low but LH levels have increased, the patient probably has testicular dysfunction, and CC dose escalation will unlikely increase T levels. Patients with a less-than-satisfactory increase in serum T, whose LH level does not rise or rises minimally, may benefit from a CC dose increase. In our experience, about two-thirds of men meet a robust responder definition by using 25 mg of CC every other day (on-treatment total T level >400 ng/dL³ and a 200-point total T improvement after commencing CC), and an up-titrating permits most men who have not responded to 25 mg every other day to reach adequate T levels. To reach therapeutic T levels, CC is increased to 50 mg every other day, but we typically avoid daily dosing because of tachyphylaxis risk. In men with poor testicular response to CC, we begin exogenous T. After T levels are in the therapeutic range with CC, laboratory testing is performed every 6 months.

We routinely monitor LH and estradiol levels after initiation of CC. We maintain estradiol levels between 20 to 40 pg/mL. In men with elevated estradiol levels (≥60 pg/mL), decreasing the CC dose usually results in normalization of estradiol levels; however, some patients may require the addition of an aromatase inhibitor. For patients using an aromatase inhibitor for extended periods, some concern exists for bone density loss due to a reduction of the estradiol levels. In our practice, in patients using aromatase inhibitors, bone density scans to evaluate bone density changes are done periodically, even in men with normal baseline bone densitometry.³ Finally, even without the addition of an aromatase inhibitor, some concern exists for bone density loss in men undergoing long-term CC; these men have bone densitometry performed every 2 years, although our 3-year data thus far show no bone density changes.

Conclusion

CC is an oral agent still used off-label for low T and infertility in males. In carefully selected patients, especially those with low or low-normal LH levels, it has an excellent chance of increasing serum T levels. Long-term monitoring should include LH levels assessing for tachyphylaxis and periodic bone densitometry assessing for bone mineral density reduction.

Author contributions

Jose M. Flores: conceptualization, data curation, formal analysis, writing–original draft, writing–review and editing. Carolyn A. Salter: conceptualization, data curation. John P. Mulhall: conceptualization, writing–original draft, writing–review and editing.

Funding

Sidney Kimmel Center for Prostate and Urologic Cancers and the National Institutes of Health, National Cancer Institute, to Memorial Sloan Kettering Cancer Center through the Cancer Center Support Grant (P30 CA008748).

Conflicts of interest: No conflicts of interest to be declared.