Effect of clomiphene citrate treatment on the Sertoli cells of dysmetabolic obese men with low testosterone levels

Abstract

Background: Clomiphene citrate (CC) has been shown to restore the hypothalamicpituitary-gonadal (HPG) axis by increasing testosterone (T) levels to physiological levels in patients with dysmetabolic conditions such as obesity, metabolic syndrome and type 2 diabetes mellitus (T2DM). However, the data are unclear regarding the effects on Sertoli cell (SC) function. Aim:To study SC function by assessing Inhibin B (IB) and anti-Mullerian hormone (AMH) levels at baseline and after 3 months of CC treatment. Materials and methods:This is an ancillary study of a cross-over, randomised, doubleblind, placebo-controlled trial performed to evaluate androgen response to CC treatment in dysmetabolic obese subjects with low T levels treated with metformin. We evaluated SC function by assessing IB and AMH levels at baseline and after 3 months of each treatment in ten dysmetabolic obese subjects with low T levels. In all subjects, the influence of the clinical characteristics, metabolic and hormonal baseline parameters on SC and Leydig (LC) function, evaluated respectively with AMH, IB, follicle-stimulating hormone (FSH) and T levels, was tested.Results: No significant changes were observed for IB and AMH concentrations after each treatment period. Whereas T and oestradiol (E2) levels were shown to be significantly higher in the CC plus metformin phase (CC/Met) only. No clinical, metabolic or hormonal parameters showed significant effects on serum AMH at baseline or after treatments. However, baseline T, dihydrotestosterone (DHT) and E2 positively affected IB levels during CC/Met therapy (P = .003, P = .038 and P = .049, respectively). Baseline leptin and FSH had a negative (P = 031) and positive (P = .048) respectively role on T levels during CC/Met, as they were statistically significant compared to the placebo period (Plac/Met). Conclusion:Unlike the LC activity, CC was unable to influence SC function, as shown by the lack of IB and AMH serum modifications, thus suggesting an intrinsic nonreversible defect of SC cells in patients with dysmetabolic conditions. K E Y W O R D SAMH, Inhibin B, obesity, testosterone | 39 PELUSI Et aL.

Impact of Clomiphene Citrate on the Steroid Profile in Dysmetabolic Men with Low Testosterone Levels

“…A similar mechanism would also explain the increased values of E and 17OH-P4. These data are in line with few studies on the CC effect on CBG which showed an increase in the protein related to the treatment through an estrogen-like effect [10,38]. However, we cannot completely rule out a synthesis by the adrenal gland, as apparently suggested by the CYP11B1 expression (F/11 S), nor a reduction in the oxidative metabolism at the target tissues, as suggested by the reduced 11βHDS2 activity (F/E).…”

“…In our previous studies we showed that, besides T, CC therapy results in increasing serum DHT, E2, the sex hormones binding globulin (SHBG), LH, and FSH [5,38]. In the present study, we added the novel finding that CC administration along with Met significantly increases circulating E1, 17αOH-P4, F, E, and CBG, but not other steroids including androgen and glucocorticoid precursors, such as 17αOH-P5, A, DHEA, and 11 S levels (see ▶Table 3).…”

Catch‐up fat in male adults induces low testosterone and consequently promotes metabolic abnormalities and cognitive impairment

“…Surprisingly, we found increased levels of FSH in CUFA individuals, though no significant increase in FSH levels was observed in CUFA rats, indicating that CUFA individuals might have a dysfunctional condition of Sertoli cells and, as a consequence, a hypothetical impairment of spermatogenesis. 35 Further semen analysis is still required to test fertility.…”

Hypothalamic‐pituitary‐gonadal axis and sexual functioning in metformin‐treated men after discontinuation of testosterone replacement therapy: A pilot study

“…39,40 To the best of our knowledge, only one research team investigated levels of this hormone in metformintreated men. Pelusi et al 41 observed that post-treatment concentrations of anti-Müllerian hormone did not differ between dysmetabolic obese men with low testosterone levels randomized to either metformin plus clomiphene citrate or to metformin plus placebo. In the current study, the impact of discontinuation of testosterone treatment differed, depending on whether patients received metformin treatment.…”