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Effects of clomiphene citrate on male obesity-associated hypogonadism: a randomized, double-blind, placebo-controlled study

Abstract

Background

Obesity causes secondary hypogonadism (HG) in men. Standard testosterone (T) replacement therapy improves metabolic parameters but leads to infertility.

Objective

To evaluate clomiphene citrate (CC) treatment of adult men with male obesity-associated secondary hypogonadism (MOSH).

Design

Single-center, randomized, double-blind, placebo-controlled trial.

Participants

Seventy-eight men aged 36.5 ± 7.8 years with a body mass index (BMI) > 30 kg/m2, total testosterone (TT) ≤ 300 ng/dL, and symptoms in the ADAM questionnaire.

Intervention

Random allocation to receive 50 mg CC or placebo (PLB) for 12 weeks.

Outcomes

(1) Clinical features: ADAM and sexual behavior questionnaires; (2) hormonal profile: serum TT, free T, estradiol (E2), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and sex hormone-binding globulin (SHBG); (3) body composition: BMI, waist circumference, and bioelectric impedance analysis; (4) metabolic profile: blood pressure, fasting blood glucose, HbA1c, insulin, HOMA-IR, and lipid profile; (5) endothelial function: flow-mediated dilation of the brachial artery, quantitative assessment of endothelial progenitor cells and serum sICAM-1, sVCAM-1, and selectin-sE levels; (6) safety aspects: hematocrit, serum prostate-specific antigen, International Prostate Symptom Score, and self-reported adverse effects.

Results

There was an improvement in one sexual complaint (weaker erections; P < 0.001); increases (P < 0.001) in TT, free T, E2, LH, FSH, and SHBG; and improvements in lean mass (P < 0.001), fat-free mass (P = 0.004), and muscle mass (P < 0.001) in the CC group. CC reduced HDL (P < 0.001). No statistically significant differences were seen in endothelial function.

Conclusions

CC appeared to effectively improve the hormonal profile and body composition. CC may be an alternative treatment for MOSH in adult men.

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References

  1. Roth MY, Amory JK, Page ST. Treatment of male infertility secondary to morbid obesity. Nat Clin Pract Endocrinol Metab. 2008;4:415–9.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Raven G, de Jong FH, Kaufman JM, de Ronde W. In men, peripheral estradiol levels directly reflect the action of estrogens at the hypothalamo-pituitary level to inhibit gonadotropin secretion. J Clin Endocrinol Metab. 2006;91:3324–8.

    Article  PubMed  CAS  Google Scholar 

  3. Caprio M, Isidori AM, Carta AR, Moretti C, Dufau ML, Fabbri A. Expression of functional leptin receptors in rodent Leydig cells. Endocrinology. 1999;140:4939–47.

    Article  PubMed  CAS  Google Scholar 

  4. Teerds KJ, de Rooij DG, Keijer J. Functional relationship between obesity and male reproduction: from humans to animal models. Hum Reprod Update. 2011;17:667–83.

    Article  PubMed  CAS  Google Scholar 

  5. Isidori AM, Caprio M, Strollo F, Moretti C, Frajese G, Isidori A, et al. Leptin and androgens in male obesity: evidence for leptin contribution to reduced androgen levels. J Clin Endocrinol Metab. 1999;84:3673–80.

    PubMed  CAS  Google Scholar 

  6. Saboor Aftab SA, Kumar S, Barber TM. The role of obesity and type 2 diabetes mellitus in the development of male obesity-associated secondary hypogonadism. Clin Endocrinol. 2013;78:330–7.

    Article  CAS  Google Scholar 

  7. Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95:2536–59.

    Article  PubMed  CAS  Google Scholar 

  8. Wang C, Nieschlag E, Swerdloff R, Behre HM, Hellstrom WJ, Gooren LJ, et al. Investigation, treatment and monitoring of late-onset hypogonadism in males. Int J Androl. 2009;32:1–10.

    Article  PubMed  Google Scholar 

  9. Alexander GC, Iyer G, Lucas E, Lin D, Singh S. Cardiovascular risks of exogenous testosterone use among men: a systematic review and meta-analysis. Am J Med. 2017;130:293–305.

    Article  PubMed  CAS  Google Scholar 

  10. Traish AM, Haider A, Haider KS, Doros G, Saad F. Long-term testosterone therapy improves cardiometabolic function and reduces risk of cardiovascular disease in men with hypogonadism: a real-life observational registry study setting comparing treated and untreated (control) groups. J Cardiovasc Pharmacol Ther. 2017;22:414–33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Moskovic DJ, Katz DJ, Akhavan A, Park K, Mulhall JP. Clomiphene citrate is safe and effective for long-term management of hypogonadism. BJU Int. 2012;110:1524–8.

    Article  PubMed  CAS  Google Scholar 

  12. Anderson DC, Marshall JC, Young JL, Fraser TR. Human chorionic gonadotrophin and clomiphene in the diagnosis and treatment of male hypogonadotrophic hypogonadism. J Endocrinol. 1970;48:xl–xli.

    Article  PubMed  CAS  Google Scholar 

  13. Glass AR, Swerdloff RS, Bray GA, Dahms WT, Atkinson RL. Low serum testosterone and sex-hormone-binding-globulin in massively obese men. J Clin Endocrinol Metab. 1977;45:1211–9.

    Article  PubMed  CAS  Google Scholar 

  14. Dandona P, Rosenberg MT. A practical guide to male hypogonadism in the primary care setting. Int J Clin Pract. 2010;64:682–96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Jankowska EA, Tkaczyszyn M, Wegrzynowska-Teodorczyk K, Majda J, von Haehling S, Doehner W, et al. Late-onset hypogonadism in men with systolic heart failure: prevalence, clinical associates, and impact on long-term survival. ESC Heart Fail. 2014;1:41–51.

    Article  PubMed  Google Scholar 

  16. Rosenfield RL. Clinical review 6: diagnosis and management of delayed puberty. J Clin Endocrinol Metab. 1990;70:559–62.

    Article  PubMed  CAS  Google Scholar 

  17. Liao CH, Wu YN, Lin FY, Tsai WK, Liu SP, Chiang HS. Testosterone replacement therapy can increase circulating endothelial progenitor cell number in men with late onset hypogonadism. Andrology. 2013;1:563–9.

    Article  PubMed  CAS  Google Scholar 

  18. McDougal WS, Wein AJ, Kavoussi LR, Partin AW, Peters C. Campbell-Walsh Urology Eleventh Edition Review 2nd edn, p. 595. xxvi (Elsevier, Philadelphia, PA, 2016). .

  19. Harris RA, Nishiyama SK, Wray DW, Richardson RS. Ultrasound assessment of flow-mediated dilation. Hypertension. 2010;55:1075–85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol. 2002;39:257–65.

    Article  PubMed  Google Scholar 

  21. Morley JE, Charlton E, Patrick P, Kaiser FE, Cadeau P, McCready D, et al. Validation of a screening questionnaire for androgen deficiency in aging males. Metabolism. 2000;49:1239–42.

    Article  PubMed  CAS  Google Scholar 

  22. Ma WY, Yang CY, Shih SR, Hsieh HJ, Hung CS, Chiu FC, et al. Measurement of waist circumference: midabdominal or iliac crest? Diabetes Care. 2013;36:1660–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Expert Panel on Detection E, Treatment of High Blood Cholesterol in A. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA. 2001;285:2486–97.

    Article  Google Scholar 

  24. Yoder MC, Mead LE, Prater D, Krier TR, Mroueh KN, Li F, et al. Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals. Blood. 2007;109:1801–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. (IBM) IBMC. IBM SPSS Statistics for Windows. 19.0 (International Business Machines Corp (IBM), Armonk, NY, 2010).

    Google Scholar 

  26. Padgett LV. Practical Statistical Methods: a SAS Programming Approach. p. 290 (CRC Press, Boca Raton, FL, 2011).

  27. GEP Box, Cox DR. An analysis of transformations. J R Stat Soc B. 1964; 26:211–52.

    Google Scholar 

  28. Maxwell DL, Satake E. Research and Statistical Methods in Communication Disorders. p. 333. xv (Williams & Wilkins, Baltimore, 1997).

  29. McCullough A. Alternatives to testosterone replacement: testosterone restoration. Asian J Androl. 2015;17:201–5.

    Article  PubMed  CAS  Google Scholar 

  30. Tancredi A, Reginster JY, Schleich F, Pire G, Maassen P, Luyckx F, et al. Interest of the androgen deficiency in aging males (ADAM) questionnaire for the identification of hypogonadism in elderly community-dwelling male volunteers. Eur J Endocrinol. 2004;151:355–60.

    Article  PubMed  CAS  Google Scholar 

  31. Mohamed O, Freundlich RE, Dakik HK, Grober ED, Najari B, Lipshultz LI, et al. The quantitative ADAM questionnaire: a new tool in quantifying the severity of hypogonadism. Int J Impot Res. 2010;22:20–4.

    Article  PubMed  CAS  Google Scholar 

  32. Katz DJ, Nabulsi O, Tal R, Mulhall JP. Outcomes of clomiphene citrate treatment in young hypogonadal men. BJU Int. 2012;110:573–8.

    Article  PubMed  CAS  Google Scholar 

  33. Guay AT, Bansal S, Heatley GJ. Effect of raising endogenous testosterone levels in impotent men with secondary hypogonadism - double-blind placebo-controlled trial with clomiphene citrate. J Clin Endocr Metab. 1995;80:3546–52.

    PubMed  CAS  Google Scholar 

  34. Guay AT, Jacobson J, Perez JB, Hodge MB, Velasquez E. Clomiphene increases free testosterone levels in men with both secondary hypogonadism and erectile dysfunction: who does and does not benefit? Int J Impot Res. 2003;15:156–65.

    Article  PubMed  CAS  Google Scholar 

  35. Bendre SV, Murray PJ, Basaria S. Clomiphene citrate effectively increases testosterone in obese, young, hypogonadal men. Reprod Syst Sex Disord. 2015;4. pii: 155.

  36. Pelusi C, Giagulli VA, Baccini M, Fanelli F, Mezzullo M, Fazzini A, et al. Clomiphene citrate effect in obese men with low serum testosterone treated with metformin due to dysmetabolic disorders: a randomized, double-blind, placebo-controlled study. PLoS ONE. 2017;12:e0183369.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Corona G, Giagulli VA, Maseroli E, Vignozzi L, Aversa A, Zitzmann M, et al. Testosterone supplementation and body composition: results from a meta-analysis of observational studies. J Endocrinol Invest. 2016;39:967–81.

    Article  PubMed  CAS  Google Scholar 

  38. Gopal RA, Bothra N, Acharya SV, Ganesh HK, Bandgar TR, Menon PS, et al. Treatment of hypogonadism with testosterone in patients with type 2 diabetes mellitus. Endocr Pract. 2010;16:570–6.

    Article  PubMed  Google Scholar 

  39. Zmuda JM, Fahrenbach MC, Younkin BT, Bausserman LL, Terry RB, Catlin DH, et al. The effect of testosterone aromatization on high-density lipoprotein cholesterol level and postheparin lipolytic activity. Metabolism. 1993;42:446–50.

    Article  PubMed  CAS  Google Scholar 

  40. Sorva R, Kuusi T, Taskinen MR, Perheentupa J, Nikkila EA. Testosterone substitution increases the activity of lipoprotein lipase and hepatic lipase in hypogonadal males. Atherosclerosis. 1988;69:191–7.

    Article  PubMed  CAS  Google Scholar 

  41. Lee D, Wosnitzer M, Winter A, Paduch D. Influence of clomiphene citrate on bmi and cholesterol levels in the treatment of hypogonadism. Fertil Steril. 2014;102:E269–70.

    Article  Google Scholar 

  42. Da Ros CT, Averbeck MA. Twenty-five milligrams of clomiphene citrate presents positive effect on treatment of male testosterone deficiency - a prospective study. Int Braz J Urol. 2012;38:512–8.

    Article  PubMed  Google Scholar 

  43. Haddad RM, Kennedy CC, Caples SM, Tracz MJ, Bolona ER, Sideras K, et al. Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc. 2007;82:29–39.

    Article  PubMed  CAS  Google Scholar 

  44. Foresta C, Caretta N, Lana A, De Toni L, Biagioli A, Ferlin A, et al. Reduced number of circulating endothelial progenitor cells in hypogonadal men. J Clin Endocr Metab. 2006;91:4599–602.

    Article  PubMed  CAS  Google Scholar 

  45. Graziani F, Leone AM, Basile E, Cialdella P, Tritarelli A, Bona RD, et al. Endothelial progenitor cells in morbid obesity. Circ J. 2014;78:977–85.

    Article  PubMed  CAS  Google Scholar 

  46. Wittert GA, Chapman IM, Haren MT, Mackintosh S, Coates P, Morley JE. Oral testosterone supplementation increases muscle and decreases fat mass in healthy elderly males with low-normal gonadal status. J Gerontol A Biol Sci Med Sci. 2003;58:618–25.

    Article  PubMed  Google Scholar 

  47. Snyder PJ, Peachey H, Berlin JA, Hannoush P, Haddad G, Dlewati A, et al. Effects of testosterone replacement in hypogonadal men. J Clin Endocrinol Metab. 2000;85:2670–7.

    PubMed  CAS  Google Scholar 

  48. Seftel AD, Kathrins M, Niederberger C. Critical update of the 2010 endocrine society clinical practice guidelines for male hypogonadism: a systematic analysis. Mayo Clin Proc. 2015;90:1104–15.

    Article  PubMed  Google Scholar 

  49. Kalinchenko SY, Tishova YA, Mskhalaya GJ, Gooren LJ, Giltay EJ, Saad F. Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study. Clin Endocrinol. 2010;73:602–12.

    Article  CAS  Google Scholar 

  50. Saad F, Yassin A, Doros G, Haider A. Effects of long-term treatment with testosterone on weight and waist size in 411 hypogonadal men with obesity classes I-III: observational data from two registry studies. Int J Obes. 2016;40:162–70.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo Grant 2013/16781-1 and Hospital das Clínicas, Universidade de São Paulo.

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Correspondence to Andressa Heimbecher Soares.

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Soares, A.H., Horie, N.C., Chiang, L.A.P. et al. Effects of clomiphene citrate on male obesity-associated hypogonadism: a randomized, double-blind, placebo-controlled study. Int J Obes 42, 953–963 (2018). https://doi.org/10.1038/s41366-018-0105-2

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