Serum levels of enclomiphene and zuclomiphene in men with hypogonadism on long‐term clomiphene citrate treatment

Abstract

ObjectivesTo determine the relative concentrations of enclomiphene (ENC) and zuclomiphene (ZUC) isomers in men with hypogonadism on long-term clomiphene citrate (CC) therapy, and to determine whether patient age, body mass index (BMI) or duration of therapy were predictive of relative concentrations of ENC and ZUC. Patients and methodsMen already receiving CC 25 mg daily therapy for secondary hypogonadism for a minimum of 6 weeks were recruited to have their ENC and ZUC levels assessed. Total testosterone, free testosterone, oestradiol, follicle stimulating hormone (FSH), and luteinizing hormone (LH) before initiation of and while on CC therapy were recorded for all patients. Patient demographics including age, BMI and medical comorbidites were recorded. Serum samples were obtained at the time of enrolment to determine ENC and ZUC concentrations. ResultsA total of 15 men were enrolled in the period from June 2015 to August 2015. The median (range) patient age was 36 (22-70) years, BMI 32.0 (21.1-40.3) kg/m 2 and duration of treatment 25.9 (1.7-86.6) months. Baseline median total testosterone, oestradiol and LH levels were 205.0 ng/dL, 17.0 pg/mL and 4.0 mlU/mL, respectively. The post-treatment median total testosterone, oestradiol and LH level increased to 488.0 ng/dL, 34.0 pg/mL and 6.1 mIU/mL, respectively (all P<0.001). The median ENC and ZUC concentrations were 2.2 and 44.0 ng/mL, respectively. After at least 6 weeks of CC therapy, the median ZUC: ENC serum concentration ratio was 20:1. On linear regression analysis.patient age, BMI, duration of treatment and serum testosterone levels were not predictive of ENC or ZUC concentrations. ConclusionsLong-term CC therapy resulted in a significant alteration of ENC and ZUC concentrations, with ZUC as the predominant isomer. Given the vastly different biochemical and toxicological properties of ENC and ZUC, this study supports the need for the development of a pure selective oestrogen receptor antagonist for the treatment of men with hypogonadism.

High‐throughput liquid chromatography tandem mass spectrometry assay as initial testing procedure for analysis of total urinary fraction

“…In agreement with earlier findings 41–43 in 77% of the samples where the metabolite was identified, LGD4033 was not detectable at all. On the contrary, cis‐clomiphene was often detected alone or present in much higher concentration than 4‐hydroxyclomiphene, corroborating observations of Guddat et al 44 and Miller et al 45 Only one sample was found to contain 4‐hydroxyclomiphene in the absence of parent drug, which may be ascribed to administration of enclomiphene 46,47 …”

Combination therapy with clomiphene citrate and anastrozole is a safe and effective alternative for hypoandrogenic subfertile men

“…The literature may not provide enough evidence to support using CC to improve semen outcomes . Additionally, recent evidence suggests that long‐term use of racemic CC, which is a mixture of enclomiphene and zuclomiphene isomers with different biological actions, leads to increased zuclomiphene concentrations which can potentially arrest spermatogenesis and limit the clinical effects of CC . Alternatively, other studies have shown that the use of aromatase inhibitors increases the testosterone:oestradiol ratio and can lead to improved sperm concentration and motility in oligozoospermic men .…”

Hipogonadismo associado à obesidade: efeitos do tratamento com citrato de clomifeno

“…-O paciente 67 (placebo) foi excluído da análise por ter apresentado recaída de tabagismo durante o seguimento. O uso do CC no tratamento do HG masculino, considerando sua capacidade na manutenção de fertilidade, tem se tornado uma opção emergente nos últimos anos, conforme verificado em literatura 6,15,[27][28][29]220,222,[225][226][227]234,[262][263][264] . No entanto, sua indicação em pacientes obesos com diagnóstico de HG ainda é bastante reduzida se comparada à sua aplicação no tratamento de infertilidade como terapia antiestrogênica para oligoespermia 35,231,262,265 .…”

“…Os parâmetros hormonais são compatíveis com os resultados encontrados por Moskovic et al 15 durante tratamento de 46 pacientes durante 36 meses e com outros estudos descritos na literatura 6,14,226,227,229,282 .…”

“…Observou-se, no entanto, que não houve diferenças em relação ao relato dos sintomas, apesar da diferença com relação aos níveis de testosterona entre os grupos.O citrato de clomifeno é constituído de uma mistura de dois diastereisômeros: citrato de (cis)zuclomifeno (38%) e citrato de (trans)enclomifeno225 . O uso do citrato de enclomifeno tem sido prosposto para o tratamento de pacientes com hipogonadismo secundário pois o zuclomifeno é associado à alguns efeitos adversos226 . A ideia da utilização do enclomifeno, assim como do clomifeno é seu uso no HG disfuncional, porém reversível.…”