Predicting Biochemical Response to Clomiphene Citrate in Men with Hypogonadism

Abstract

Introduction Clomiphene citrate (CC) is as an effective treatment for men with hypogonadism (HG). Identifying the ideal candidate for this strategy has to date largely relied upon a patient's interest in preservation of testicular volume and spermatogenesis. Aim This analysis was undertaken to define if predictors existed of robust elevation in serum testosterone (T) levels in response to CC. Methods Seventy-six men with a diagnosis of HG (two separate early morning total T levels <300 ng/dL) opting for CC therapy constituted the study population. Demographic, comorbidity data, and physical and laboratory characteristics were recorded. Laboratory tests were conducted 4 weeks after commencement and every 6 months thereafter. Multivariable analysis was conducted to define if predictors of biochemical response could be identified. Parameters included in the model were patient age, mean testicular volume, varicocele presence, and baseline total T, free T, and luteinizing hormone (LH) levels. Main Outcome Measure Successful biochemical response to CC, defined as an increase of ≥200 ng/dL in total T level at ≥6 months after commencing CC, was the main outcome measure. Results Mean age was 46 ± 22 years. Mean pretreatment testicular volume was 16 ± 8 mL. Mean baseline T and LH levels were 179 ± 72 ng/dL and 7.2 ± 5.6 IU/mL, respectively. Mean total T on CC was 467 ± 190 ng/dL. Forty-seven patients (62%) met the responder definition, with a mean increase in total T levels of 302 ± 76 (204–464) ng/dL. In CC responders, the mean LH rise was 5.6 ± 3.1 IU/mL. On multivariable analysis, factors predictive of CC response included: mean testicular volume (adjusted [adj.] r = 0.32, P < 0.01), mean testicular volume ≥14 mL (hazard ratio [HR] 2.2, P < 0.01), LH level (adj. r = 0.48, P < 0.001), and LH level ≤6 IU/mL (HR 3.5, P < 0.001). Conclusion These data indicate that two thirds of men with HG meet a robust responder definition and that pretreatment testicular volume and LH levels (in continuous and dichotomized fashions) are predictors of response.

Improvements in semen parameters in men treated with clomiphene citrate—A retrospective analysis

“…When they are, the definition is variable and sometimes arbitrary. Mazzola, Katz, Loghmanieh, Nelson, and Mulhall () analysed predictors of improvement in serum testosterone among hypogonadal men treated with CC. They found a testicular volume of >14 ml and a LH of less than or equal to 6 mIU/ml were independent predictors of a treatment response, which they admit was arbitrarily defined as an increase in TT of at least 200 ng/dl and a level of at least 400 ng/dl after 6 months of treatment.…”

“…Several definitions of treatment response were used, aiming to improve shared decision‐making with patients. Two definitions were borrowed from the literature: hormonal response from Mazzola et al () and response for azoospermic patients from Hussein et al (). The response for oligozoospermic patients was defined as a post‐treatment sperm concentration in the normal range, >15 million/ml by 2010 WHO 5th edition criteria.…”

The safety and efficacy of clomiphene citrate in hypoandrogenic and subfertile men

“…Previously, Guay et al 24 found that older age and multiple chronic medical conditions were associated with a poor improvement in serum testosterone among 178 hypoandrogenic men treated with CC. In a recent study by Mazzola et al, 23 nearly 40% of hypoandrogenic men on CC were non-responders (response defined as 4200 ng dl − 1 improvement in total testosterone levels after 6 months of CC treatment). On multivariate analysis, testicular volume and baseline LH level was predictive of a positive response in this cohort of hypoandrogenic men.…”

“…The overall response rates (improvement in testosterone) to CC in men ranged from 62 to 74%. 23,24 The characteristics and predictors of a positive response to CC are limited. 10 Several demographic factors such as age and BMI and baseline hormone values including FSH and LH, as well as testicular size, have been proposed as predictors of CC response among hypoandrogenic men.…”

Pregnancy after intracytoplasmic sperm injection following extended sperm preparation and hormone therapy in an azoospermic man with maturation arrest and microlithiasis: a case report and literature review

“…The patient was initially expected to respond well to CC therapy, as the mean testicular volume was ≥14 cc and the LH level was <6 IU/ml Thus, this relatively cost‐effective, well‐tolerated medication was initiated with a view to stimulating spermatogenesis and avoiding further invasive procedures. The patient was apparently sensitive to CC, as evidenced by a 200 ng/dl increase in the total testosterone level (Mazzola, Katz, Loghmanieh, Nelson, & Mulhall, ) and the presence of a few spermatozoa in two separate ejaculates. However, no high‐quality spermatozoa were available for cryopreservation.…”