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

Abstract

What is known and objective: Metformin was found to reduce elevated gonadotropin levels. The aim of the present study was to determine whether metformin modulates the impact of discontinuation of testosterone therapy on hypothalamic-pituitarygonadal axis activity and sexual function in men with low testosterone levels. Methods:The study included 28 men with late-onset hypogonadism (defined according to the criteria of the European Male Aging Study group) receiving testosterone undecanoate (120 mg in three equal doses), 12 of whom had been treated with oral metformin (1.7-3 g daily). Both testosterone and metformin had been administered for at least six months before enrolment. In all patients, testosterone replacement required to be discontinued. The control group included 16 testosterone-and metformin-treated men with late-onset hypogonadism who during the entire study period continued their treatment. Glucose homeostasis markers, as well as plasma levels of insulin, gonadotropins, testosterone, calculated bioavailable testosterone, dehydroepiandrosterone-sulphate, oestradiol, thyrotropin, free thyroxine, prolactin, insulin-growth factor-1 and cortisol were measured at the beginning of the study and four months later. Moreover, at the beginning and the end of the study, all enrolled patients completed a questionnaire assessing their sexual functioning (IIEF-15).Results and discussion: Discontinuation of testosterone therapy resulted in a decrease in total testosterone and bioavailable testosterone (by 42% and 45% in metformintreated patients, and by 52% and 54% in metformin-naïve patients), as well as impaired all aspects of male sexual function. Changes in bioavailable testosterone, as well as in erectile function, orgasmic function and sexual desire were less pronounced if subjects received metformin. Only in metformin-naïve men, follow-up FSH and LH levels were higher than at baseline (by 75% and 62%). Moreover, discontinuation of testosterone therapy in metformin-naïve men increased glycated haemoglobin, as well as worsened insulin sensitivity. There were no differences between baseline and follow-up levels of the remaining hormones. In metformin-naïve subjects, the increase in gonadotropin levels correlated with the changes in testosterone levels and insulin sensitivity. No effect on glucose homeostasis markers, hormone levels and sexual functioning was observed in the control group.

Association between life’s essential 8 and testosterone deficiency in men: NHANES 2011–2016

“…On the other hand, the LE8 encompasses four health factors: body mass index, blood lipids, blood sugar, and blood pressure. Hypogonadism frequently accompanies metabolic complications like obesity and diabetes; a reduction or absence of testosterone can precipitate metabolic disorders by elevating visceral lipids and worsening insulin resistance ( 34 , 35 ). Furthermore, the interplay between hypogonadism and metabolic disorders is recognized as bidirectional, affecting both functional and delayed forms of hypogonadism ( 29 ); Hyperglycemia can directly trigger a reduction in testosterone synthesis within Leydig cells by activating the TLR4-mediated oxidative stress pathway ( 36 ).…”

A negative association between triglyceride glucose-body mass index and testosterone in adult males: a cross-sectional study

“…Souteiro et al (11) found IR is the primary risk factor of low testosterone levels in obese men, and some males with testosterone deficiency even have a higher IR index than patients with mild diabetes. Another pilot study found that Metformin, a diabetes drug, can restore the testosterone level of male patients with type II diabetes through improved IR (12). On the other hand, the decrease or deficiency of testosterone may lead to the development of metabolic disorders through increased visceral lipids and insulin resistance (13).…”