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

International Journal of Obesityvolume 42pages953963 (2018) | Download Citation



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


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


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


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.


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


(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.


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.


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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  1. 1.

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

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 14.

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

  15. 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.

  16. 16.

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

  17. 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.

  18. 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. 19.

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

  20. 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.

  21. 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.

  22. 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.

  23. 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.

  24. 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.

  25. 25.

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

  26. 26.

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

  27. 27.

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

  28. 28.

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

  29. 29.

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

  30. 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.

  31. 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.

  32. 32.

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

  33. 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.

  34. 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.

  35. 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. 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.

  37. 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.

  38. 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.

  39. 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.

  40. 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.

  41. 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.

  42. 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.

  43. 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.

  44. 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.

  45. 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.

  46. 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.

  47. 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.

  48. 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.

  49. 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.

  50. 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.

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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.

Author information


  1. Grupo de Obesidade e Síndrome Metabólica, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil

    • Andressa Heimbecher Soares
    •  & Nidia Celeste Horie
  2. Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil

    • Lucas Augusto Piccinin Chiang
  3. Unidade de Medicina Interdisciplinar em Cardiologia, INCOR, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil

    • Bruno Caramelli
    •  & Mariana Gomes Matheus
  4. Hospital Israelita Albert Einstein, São Paulo, Brazil

    • Alexandre Holthausen Campos
  5. Experimental Research Center, Hospital Israelita Albert Einstein, São Paulo, Brazil

    • Luciana Cavalheiro Marti
    •  & Fernanda Agostini Rocha
  6. Grupo de Obesidade e Síndrome Metabólica and Laboratory of Carbohydrates and Raioimmunoassay (LIM/18), ICHC, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil

    • Marcio C. Mancini
    •  & Cintia Cercato
  7. Unidade de Endocrinologia do Desenvolvimento/Hormone and Molecular Genetics Laboratory (LIM/42), ICHC, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil

    • Elaine Maria Frade Costa


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The authors declare that they have no conflict of interest.

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Correspondence to Andressa Heimbecher Soares.

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