Treatment of Functional Hypogonadism Besides Pharmacological Substitution

Giovanni Corona, Giulia Rastrelli, Annamaria Morelli, Erica Sarchielli, Sarah Cipriani, Linda Vignozzi, Mario Maggi, Giovanni Corona, Giulia Rastrelli, Annamaria Morelli, Erica Sarchielli, Sarah Cipriani, Linda Vignozzi, Mario Maggi

Abstract

A dichotomic distinction between "organic" and "functional" hypogonadism is emerging. The former is an irreversible condition due to congenital or "acquired" "organic" damage of the brain centers or of the testis. Conversely, the latter is a potentially reversible form, characterized by borderline low testosterone (T) levels mainly secondary to age-related comorbidities and metabolic derangements, including metabolic syndrome (MetS). Life-style modifications, - here reviewed and, when possible, meta-analyzed -, have documented that weight-loss and physical exercise are able to improve obesity-associated functional hypogonadism and its related sexual symptoms. A rabbit experimental model, of MetS originally obtained in our lab, showed that endurance training (PhyEx) completely reverted MetS-induced hypogonadotropic hypogonadism by reducing hypothalamus inflammation and testis fibrosis eventually allowing for a better corpora cavernosa relaxation and response to sildenafil. Physicians should strongly adapt all the reasonable strategies to remove/mitigate the known conditions underlying functional hypogonadism, including MetS and obesity. Physical limitations, including reduced muscle mass and increased fat mass, along with low self-confidence, also due to the sexual problems, might limit a subject's propensity to increase physical activity and dieting. A short term T treatment trial, by improving muscle mass and sexual function, might help hypogonadal obese patients to overcome the overfed, inactive state and to become physically and psychologically ready for changing their lifestyle.

Keywords: Male hypogonadism; Obesity; Physical exercise; Testosterone; Weight loss.

Conflict of interest statement

The authors have nothing to disclose.

Copyright © 2020 Korean Society for Sexual Medicine and Andrology.

Figures

Fig. 1. Weighted differences (with 95% confidence…
Fig. 1. Weighted differences (with 95% confidence interval [CI]) of mean total testosterone (TT; A), calculated free testosterone (B), sex hormone binding globulin (C) and before and after weight loss. aLow calorie diet only group. bLow energy diet group. (D) Influence of Δ-weight loss on TT weighted mean differences before and after low calorie diet as derived from meta-regression analysis.
Fig. 2. Summary of the results obtained…
Fig. 2. Summary of the results obtained by available the meta-analyses, which evaluated the effects of bariatric surgery on sex hormones, gonadotropins, and SHBG. SHBG: sex hormone binding globulin, LH: luteinizing hormone, FSH: follicle stimulating hormone.
Fig. 3. (A) Weighted differences (with 95%…
Fig. 3. (A) Weighted differences (with 95% confidence interval [CI]) of mean total testosterone (TT), after physical activity. aExercise only group. (B) Change in TT (dependent variable) as a function of weight change, exercise duration and age (independent variables) as derived from a multivariate linear regression weighted for trial participants. Data derive from the meta-analysis of the available trials on the effect of physical exercise on testosterone levels. The independent variables were transformed as z-values (standardized parameters). The value corresponding to 1 standard deviation is reported below each independent variable.
Fig. 4. Effects of physical exercise on…
Fig. 4. Effects of physical exercise on hormonal circulating levels in regular diet (RD) and high fat diet (HFD) rabbits. Testosterone (A) and luteinizing hormone (LH; B) plasma levels were measured in rabbits fed a RD or a HFD with and without physical exercise (PhyEx), according to a previous protocol [62]. Results obtained in rabbits treated with the gonadotropin-releasing hormone (GnRH) analog triptorelin [60] were also shown, for comparison. Numbers of experimental observations are reported below each group. Statistical analysis between groups was performed with Kruskal-Wallis and post-hoc Mann-Whitney non-parametric tests. p-values are reported in each panel. NS: non-significant.
Fig. 5. Gonadotropin-releasing hormone (GnRH) immunohistochemical analysis…
Fig. 5. Gonadotropin-releasing hormone (GnRH) immunohistochemical analysis in experimental rabbits. (A) Representative images of coronal hypothalamic sections, including the preoptic region lining the 3rd ventricle (3V). (B) Quantification of GnRH-positive cells, as calculated by counting at least ten fields of three independent experiments (mean±standard error; n=3 for each group; ap<0.001 vs. RD, bp<0.001 vs. HFD, cp<0.001 vs. RD+PhyEx). Scale bar 50 µm. RD: regular diet, HFD: high fat diet, PhyEx: physical exercise.
Fig. 6. Immunohistochemical analysis of Kiss1 receptor…
Fig. 6. Immunohistochemical analysis of Kiss1 receptor (Kiss1R) in rabbit hypothalamus. (A) Representative images of coronal hypothalamic sections, including the preoptic region lining the 3rd ventricle (3V). (B) Quantification of Kiss1R-positive cells, as calculated by counting at least ten fields of three independent experiments (mean±standard error; n=3 for each group; ap<0.001 vs. RD, bp<0.001 vs. HFD, cp<0.05 vs. RD+PhyEx). Scale bar 50 µm. RD: regular diet, HFD: high fat diet, PhyEx: physical exercise.

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