Is There Room for SERMs or SARMs as Alternative Therapies for Adult Male Hypogonadism?

Abstract

Hypogonadotropic hypogonadism (HH) can be sustained by organic or functional alterations of the hypothalamic-pituitary-testicular axis. Functional HH is related to systemic alterations, such as obesity or chronic inflammatory diseases, but could contribute to a negative course of the illness. For such situation, according to results obtained in infertile women, the administration of selective estrogen receptor modulators (SERMs) has been proposed in males too, with positive results on both metabolic and sexual function. This class of medications increases gonadotropin levels via antagonism to the estrogenic receptor; similar biological effects are also exerted by aromatase inhibitors (AIs), despite different mechanism of action. After a brief review of trials regarding SERMs and AIs use in male HH, we describe the structure and function of the androgen receptor (AR) as a basis for clinical research about compounds able to bind to AR, in order to obtain specific effects (SARMs). The tissue selectivity and different metabolic fate in comparison to testosterone can potentiate anabolic versus androgenic effects; therefore, they might be a valid alternative to testosterone replacement therapy avoiding the negative effects of testosterone (i.e., on prostate, liver, and hematopoiesis). Trials are still at an early phase of investigation and, at the moment, the application seems to be more useful for chronic disease with catabolic status while the validation as replacement for hypogonadism requires further studies.

Improvement Effect of Metformin on Female and Male Reproduction in Endocrine Pathologies and Its Mechanisms

“…One clinical study investigated the effect of a combined three-month treatment of men with impaired glucose tolerance or with T2DM using MF at a daily dose of 2000 mg and CC at a low dose (25 mg) on their androgenic status [ 434 ]. The CC is characterized by the ability to significantly improve hormonal parameters in men with hypogonadotropic hypogonadism, primarily by normalizing the secretion of gonadotropins [ 437 , 438 ]. The combined therapy with MF plus CC led to an increase in the blood testosterone, LH and FSH levels, while MF monotherapy in this case was ineffective [ 434 ].…”

Treatment of Men with Central Hypogonadism: Alternatives for Testosterone Replacement Therapy

“…In the central nervous system, some SERMs, namely clomiphene citrate and tamoxifen, function as antagonists to the estrogen receptor, thereby, inhibiting the negative feedback of estrogen to the hypothalamus and pituitary gland. This results in increased endogenous gonadotropin levels which stimulate testosterone production [4,17,47].…”

Age-Related Male Hypogonadism and Cognitive Impairment in the Elderly: Focus on the Effects of Testosterone Replacement Therapy on Cognition

“…Male hypogonadism may be considered as a risk factor for cognitive decline especially in the elderly, and it is attributable to the loss of several neuroprotective effects provided by T at the level of the central nervous system. Moreover, normal levels of serum T seems to prevent cardiometabolic and coagulative disturbances that might be considered as risk factors for cognitive impairment and MCI [ 79 , 80 , 81 , 82 , 83 , 84 , 85 ]. Despite these evidences, T supplementation—even in eugonadal men—normally failed to demonstrate protective effects [ 86 , 87 , 88 ], and the results of the examined trials confirmed this trend.…”