Enclomiphene citrate

Background: The last several decades have witnessed an increase in metopic craniosynostosis incidence. Population-based studies suggest that pharmacological exposure in utero may be responsible. This study examined effects of the fertility drug clomiphene citrate (CC) on calvarial development in an established model for craniofacial development, the zebrafish Danio rerio. Results: Zebrafish larvae were exposed to clomiphene citrate or its isomer enclomiphene for five days at key points during calvarial development. Larvae were then raised to adulthood in normal rearing water. Zebrafish were analyzed using whole-mount skeletal staining. We observed differential effects on survivability, growth and suture formation depending on the treatment. Treatments with CC or enclomiphene at 5.5 mm SL led to increased fusion of the interfrontal suture (p < .01) compared to controls. Conclusions: Exposure to fertility drugs appears to affect development of the cranial vault, specifically the interfrontal suture, in zebrafish. Further research is required to identify the signaling mechanisms at play. This work suggests that fertility drug treatment may contribute to the increased incidence of metopic craniosynostosis observed globally.

Although selective estrogen receptor modulators have been proposed as a treatment for men with central functional hypogonadism, only a few data have been produced in men with obesity‐related functional androgen deficiency.

To determine whether and to what extent selective estrogen receptor modulators are an effective and safe therapy in men with obesity‐related functional androgen deficiency.

A thorough search of PubMed, Web of Science, Scopus, and Cochrane Library databases was performed to identify studies comparing testosterone levels before and after treatment. Mean differences with 95% coefficient intervals were combined using random effects models. Funnel plot, Egger's test, and trim‐and‐fill analysis were used to assess publication bias.

Seven studies met the inclusion criteria providing information on 292 men with obesity‐related functional androgen deficiency treated with clomiphene citrate (12.5–50 mg daily) or enclomiphene citrate (12.5–25 mg daily) for 1.5–4 months. The pooled estimates indicated a significant increase in testosterone levels both with clomiphene (mean difference: 11.56 nmol/L; 95% coefficient interval: 9.68, 13.43; I2 = 69%, pfor heterogeneity = 0.01) and enclomiphene citrate (mean difference: 7.50 nmol/L; 95% coefficient interval: 6.52, 8.48; I2 = 4%, pfor heterogeneity = 0.37). After the exclusion of one study on severely obese men, who exhibited the highest response rate to clomiphene citrate, the heterogeneity disappeared (mean difference: 10.27 nmol/L; 95% coefficient interval: 9.39, 11.16; I2 = 0%, pfor heterogeneity = 0.66). No publication bias was revealed by Egger's test and trim‐and‐fill analysis. No treatment‐related unexpected findings regarding safety profile were registered.

Treatment with clomiphene citrate and enclomiphene citrate may be an effective and safe alternative to testosterone replacement therapy in men with obesity‐related functional androgen deficiency. Further long‐term studies are warranted to define clinical reflections of the selective estrogen receptor modulators‐induced increase in testosterone levels and to better clarify the safety profile.