Abnormalities of reproductive function in male obesity before and after bariatric surgery - a comprehensive review - Beyond the Abstract

Overweight and obesity are known risk factors for several diseases, including diabetes, coronary heart disease, stroke, hypertension, and obstructive sleep apnea. All of these disorders, besides severe obesity itself, may negatively impact the sexual and reproductive health of both male and female individuals.

Sexual quality of life (QoL) is diminished in obese subjects, and increased body mass index (BMI) is correlated with reduced sexual activity as well as diminished performance in both genders (1). Moreover, erectile dysfunction (ED) is commonly reported in severely obese males, and it is related to several factors including the comorbidities of the metabolic syndrome (MS), the altered levels of male hormones, and the obesity-associated systemic inflammation leading to endothelial dysfunction (2-5).

Endocrine dysregulation, actions of adipokines ( adipose tissue-derived hormones) at different levels of the hypothalamic–pituitary–gonadal (HPG) axis, sleep apnea, altered lifestyle factors leading to increased scrotal temperatures, environmental toxins that are accumulated in the adipose tissue, altered sexual health, including ED, and genetic causes have been mentioned as potential triggers of reproductive disruption in obesity (6).

Total testosterone (TT) and sexual hormone-binding globulin (SHBG) levels are decreased in moderately obese men, while free testosterone (FT), the physiologically active form of T, has been reported within normal range or decreased (7). However, androgen levels are usually reduced in severe male obesity, which characterizes a hormonal profile described as hypogonadotropic hypogonadism (HH). In addition, testosterone is irreversibly converted to estradiol (E2) by the enzyme aromatase cytochrome P450, expressed at high levels in the white fatty tissue (8), which results in a decreased testosterone to estrogen ratio. In addition, low T levels increase lipoprotein lipase enzyme activity and triglyceride uptake, leading to increased body fat mass (particularly visceral fat deposition) (9), lipid dysregulation, and decreased insulin sensitivity (10).

Gonadotropin hormone secretion rates may also show alterations in obese males, and levels of luteinizing hormone (LH ) and LH pulse amplitude have been reported below normal or in the lower range of normality in severe obese men (11,12). This is probably related to an impaired secretion of gonadotropin-releasing hormone (GnRH) at the hypothalamic level, which points to a generalized HPG axis dysfunction in severe obese men (13).

Weight loss has been shown to improve male hormones, ED, and sexual QoL of men (14, 15). Bariatric intervention was more effective when compared with low-calorie diet, because of its superior effects on excess body weight. Multiple regression analysis addressing increase of TT levels confirmed that degree of body weight loss was the best determinant (16).

We recently documented levels of circulating androgens and sexual QoL, using the validated questionnaires International Index of Erectile Function/IIEF and Aging Males’ Symptoms, in bariatric patients with a long follow-up period (115.5 ± 35.6 months) (15). They were compared to a matched cohort of nonoperated obese individuals and to normal-weight men. Weight loss of bariatric patients was substantial (59.8 ± 12.1 preoperatively versus 35.1 ± 7.7 kg/m2 , P < .001, in the last follow-up after surgery), albeit residual obesity was the rule, with varying degrees of weight-related comorbities (i.e., sleep apnea, hypertension, and glucose/lipid aberrations).

Levels of TT, FT, and SHBG in the bariatric subjects were higher than those in nonoperated obese men, comparable to standard controls. In the same operated group, TT levels negatively correlated to leptin, insulin, BMI and waist circumference (WC), and SHBG negatively correlated to BMI, WC, triglycerides, and leptin. Although not statistically significant, gonadotropins (LH and FSH) in the bariatric population maintained slighter elevated levels than in the other groups.

Concerning sexual QoL, IIEF questionnaire scores tended to be better than among the obese subjects (bariatric 56.7 ± 14.5, nonoperated obese 49.1 ± 11.9 and controls 61.7 ± 7.5), although statistical difference was not achieved. The domains of erectile dysfunction (P = .015) and overall satisfaction (P = .028) in the bariatric group were better than those in the nonoperated obese, although still lower than those in the lean (control) group. The unfavorable response for erectile function in the bariatric, nonoperated obese, and lean controls was 54.5%, 78.6%, 35.7%, respectively (P = .015). We concluded that bariatric individuals, although anthropometrically still obese, had healthier sex life than nonoperated obese men and, regarding some variables, exhibited the same pattern as normal-weight controls.

However, differently from ED, sexual QoL, and hormone profile, which tend to normalize in males after bariatric weight loss, conflicting results remain concerning semen quality, at least in the first 1–2 years after surgery. Investigators reported no significant differences in sperm variables after bariatric surgery (17), secondary infertility (i.e., azoospermy with complete spermatogenic arrest), despite normal levels of circulating androgens, of previously fertile male subjects (18), and severe worsening of semen parameters (including oligoasthenoteratozoospermia), in the early follow-up after bariatric intervention (19). Surgery-induced nutrient malabsorption was postulated as the main mechanism responsible for secondary infertility.

In conclusion, men aged between 20 and 40 are at the highest risk of obesity (20), a period of time when sexual and reproductive health should be perfect. Yet, insulin resistance leading to reduced SHBG synthesis and low circulating SHBG levels, increased aromatization of testosterone towards E2, and the generalized dysfunction of the HPG axis, namely hypogonadotropic hypogonadism, may severely disrupt such functions. Bariatric procedures may revert many of the listed deleterious phenomenons, normalize HH, as well as ED, with lasting effects. However, preliminary findings concerning impaired semen quality are worrisome, and additional studies investigating the role of nutritional deficiencies, adipokines, and gut hormones on the reproductive potential of men after bariatric surgery are warranted.

References:

1. Kolotkin, R. L., Zunker, C., and Ostbye, T. (2012) Sexual Functioning and Obesity: A Review. Obesity (Silver Spring).

2. Muller, M., Grobbee, D. E., den Tonkelaar, I., Lamberts, S. W., and van der Schouw, Y. T. (2005) Endogenous sex hormones and metabolic syndrome in aging men. J Clin Endocrinol Metab. 90, 2618-23.

3. Solomon, H., Man, J. W., and Jackson, G. (2003) Erectile dysfunction and the cardiovascular patient: endothelial dysfunction is the common denominator. Heart. 89, 251-3.

4. Diaz-Arjonilla, M., Schwarcz, M., Swerdloff, R. S., and Wang, C. (2009) Obesity, low testosterone levels and erectile dysfunction. Int J Impot Res. 21, 89-98.

5. Giugliano, F., Esposito, K., Di Palo, C. et al. (2004) Erectile dysfunction associates with endothelial dysfunction and raised proinflammatory cytokine levels in obese men. J Endocrinol Invest. 27, 665-9.

6. Hotaling, J. M. Genetics of male infertility. Urol Clin North Am. 41, 1-17.

7. Pasquali, R., Casimirri, F., Cantobelli, S. et al. (1991) Effect of obesity and body fat distribution on sex hormones and insulin in men. Metabolism. 40, 101-4.

8. Roth, M. Y., Amory, J. K., and Page, S. T. (2008) Treatment of male infertility secondary to morbid obesity. Nat Clin Pract Endocrinol Metab. 4, 415-9.

9. Rebuffe-Scrive, M., Marin, P., and Bjorntorp, P. (1991) Effect of testosterone on abdominal adipose tissue in men. Int J Obes. 15, 791-5.

10. Boden, G., Chen, X., Kolaczynski, J. W., and Polansky, M. (1997) Effects of prolonged hyperinsulinemia on serum leptin in normal human subjects. J Clin Invest. 100, 1107-13.

11. Fariello, R. M., Pariz, J. R., Spaine, D. M. et al. Association between obesity and alteration of sperm DNA integrity and mitochondrial activity. BJU Int. 110, 863-7.

12. Evenson, D. and Wixon, R. (2006) Meta-analysis of sperm DNA fragmentation using the sperm chromatin structure assay. Reprod Biomed Online. 12, 466-72.

13. Vermeulen, A., Kaufman, J. M., Deslypere, J. P., and Thomas, G. (1993) Attenuated luteinizing hormone (LH) pulse amplitude but normal LH pulse frequency, and its relation to plasma androgens in hypogonadism of obese men. J Clin Endocrinol Metab. 76, 1140-6.

14. Reis, L. O., Favaro W., J., Barreiro, G. C. et al. (2010) Erectile dysfunction and hormonal imbalance in morbidly obese male is reversed after gastric bypass surgery: a prospective randomized controlled trial. Int J Androl. 33, 736-44.

15. Rosenblatt, A., Faintuch, J., and Cecconello, I. Sexual hormones and erectile function more than 6 years after bariatric surgery. Surg Obes Relat Dis.

16. Corona, G., Rastrelli, G., Monami, M. et al. (2013) Body weight loss reverts obesity-associated hypogonadotropic hypogonadism: a systematic review and meta-analysis. Eur J Endocrinol. 168, 829-43.

17. Reis, L. O., Zani, E. L., Saad, R. D. et al. (2012) Bariatric Surgery Does not Interfere With Sperm Quality--A Preliminary Long-Term Study. Reprod Sci. 19, 1057-62.

18. di Frega, A. S., Dale, B., Di Matteo, L., and Wilding, M. (2005) Secondary male factor infertility after Roux-en-Y gastric bypass for morbid obesity: case report. Hum Reprod. 20, 997-8.

19. Sermondade, N., Massin, N., Boitrelle, F. et al. (2012) Sperm parameters and male fertility after bariatric surgery: three case series. Reprod Biomed Online. 24, 206-10.

20. Ng, M., Fleming, T., Robinson, M. et al. (2014) Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 384, 766-81.

Written by:
Alberto Rosenblatt
Department of Gastroenterology, Hospital das Clinicas, ICHC, 9th Floor, Room 9077, Av. Eneias C. Aguiar 255, São Paulo, SP, Brazil.

AbstractAbnormalities of reproductive function in male obesity before and after bariatric surgery-a comprehensive review - Abstract

 

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