Research news

Late onset hypogonadism of men is not equivalent to menopause

December 2014

Saad F, Gooren LJ. Maturitas. 2014 Sep;79(1):52−7.

In their review paper, Saad and Gooren elegantly contrast the differences between late onset hypogonadism, also known as testosterone deficiency, and menopause.¹Many men who reach middle-age start to experience symptoms that resemble those of menopause; reduced libido, lack of energy, weight gain, fatigue, depression and osteoporosis, to name a few.^2-6

Therefore these conditions are frequently seen as being equivalent, and late onset hypogonadism has therefore been called "andropause", "male climacteric", "male menopause" or "MANopause. However, as Saad and Gooren correctly point out, this is very misleading.

KEY POINTS

Menopause is universal and obvious and develops relatively rapidly.
1. Hypogonadism does not affect every man, and when it does, it develops slowly over a long time period.
The hormones involved are different.
1. Estrogen and testosterone have contrasting effects on most physiological functions.
Treatment vs. non-treatment has vastly different consequences.
1. Reduced levels of testosterone in men contribute to the development of cardiovascular disease, and may, despite long-held beliefs to the opposite, have a negative impact on the prostate. It is also well documented that hypogonadism increases mortality and that testosterone therapy may reduce mortality and may even increase longevity.
2. The consequences of reduced levels of estrogen in postmenopausal women are less well-documented, and treatment with estrogen (hormone replacement therapy, HRT) likely confers a different risk-benefit ratio than treatment of hypogonadism with testosterone therapy.

What is known

Testosterone deficiency often manifests with symptoms in men that resemble those of menopausal women.^2,6,10,11This has given rise to the idea of "andropause", "male climacteric" and "male menopause". However, for several reasons, this parallel is fraught with misinformation and irrational logic that lacks a scientific base.

What this study adds

Hypogonadism, also known as testosterone deficiency, while common¹², does not universally affect every man. It has been shown that testosterone levels display no decrease associated with age among men over 40 years of age who self-report very good or excellent health.¹³This may indicate that a large part of the age-related decline in testosterone levels is due to accumulating age-related co-morbidities, rather than an age-specific phenomenon. This view is supported by data showing that besides age per se, obesity, metabolic syndrome, diabetes and dyslipidemia are risk factors of incident hypogonadism.¹⁴Thus, while menopause happens consistently in women between the ages of 45-55, the median age for natural final menstrual period is 52 years¹⁵, hypogonadism in men can occur at any age because testosterone deficiency can be caused by several different factors.^11,16Therefore, the term "late onset hypogonadism" is inappropriate. The terms testosterone deficiency and hypogonadism are more accurate.

Male testosterone deficiency develops slower and more progressively over time, while menopause signifies a relatively abrupt cessation of estradiol production. In both cross-sectional^17-22and longitudinal studies^23-26, beginning in the third decade in men, testosterone levels start to decline gradually and progressive at a rate of approximately 1% per year.

Equating late onset hypogonadism and menopause also disguises the facts that these phenomena are caused by different hormones, and that their respective deficiencies result in vastly different consequences. While it is hypothesized that estrogen deficiency in women may be protective against cancer^27,28and may increase longevity²⁹, testosterone deficiency in men is associated with a myriad of detrimental health outcomes, including obesity, increased waist circumference, insulin resistance, type 2 diabetes, hypertension, inflammation, atherosclerosis and cardiovascular disease, erectile dysfunction (ED) and increased mortality.³⁰Testosterone deficiency in men may even be a risk factor for cardiovascular disease.^31,32In addition, there are also indications that testosterone deficiency in men contributes to the gender gap in cardiovascular morbidity and mortality.³³When it comes to the prostate, testosterone deficiency may actually - to the contrary of old dogma - have a negative impact on prostate health, as we have reported in a previous editorial “Testosterone and prostate cancer - a paradigm shift”.

When it comes to the issue of treatment vs. non-treatment, a rapidly expanding body of evidence justifies treatment of hypogonadism with testosterone therapy.^34-53This is in stark contrast to menopause, whose treatment with estrogen replacement therapy (HRT) is controversial^54-58The most serious concern about traditional estrogen HRT is its potential to increase risk for breast and endometrial cancer, blood clots, stroke and heart disease.⁵⁹While HRT has benefited many women, the guidelines underscore that HRT must be individualized and tailored according to symptoms and the need for prevention, as well as personal and family history of morbidity.⁵⁹In contrast, treatment of hypogonadism in men with testosterone therapy that achieves adequate testosterone levels and is of long enough duration to allow benefits to manifest⁶⁰improves symptoms and reduces risk of multiple chronic diseases, including cardiovascular disease, in the vast majority of men.^{35,37,40-43,46,47,49-52,61-67}

An important reason to distinguish hypogonadism from menopause is because of concerns about HRT in postmenopausal women have been inappropriately extrapolated to men; "such extrapolation is not only inappropriate but it lacks any scientific evidence or validity - predicting the effects of testosterone replacement in hypogonadal men by relying on studies of estrogen (with or without progesterone) in postmenopausal women is baseless and should be condemned."⁶⁸

The conclusion by Saad and Gooren that testosterone treatment in hypogonadal men is far more compelling than estrogen treatment of postmenopausal women is well backed up by solid scientific research and provides a timely message to practicing clinicians who still think that "andropause" or "male climacteric" should be approached like menopause.

Recommendations

Long term therapy with Nebido^®

Resources

Related topics

Hypogonadism Therapy Product Information

References

Saad F, Gooren LJ. Late onset hypogonadism of men is not equivalent to the menopause. Maturitas. 2014;79(1):52−57. Return to content
Zitzmann M, Faber S, Nieschlag E. Association of specific symptoms and metabolic risks with serum testosterone in older men. J. Clin. Endocrinol. Metab. 2006;91(11):4335−4343. Return to content
Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 2010;95(6):2536−2559. Return to content
Blumel JE, Chedraui P, Gili SA, Navarro A, Valenzuela K, Vallejo S. Is the Androgen Deficiency of Aging Men (ADAM) questionnaire useful for the screening of partial androgenic deficiency of aging men? Maturitas. 2009;63(4):365−368. Return to content
Wang C, Nieschlag E, Swerdloff R, et al. Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations. J. Androl. 2009;30(1):1−9. Return to content
Wu FC, Tajar A, Beynon JM, et al. Identification of late-onset hypogonadism in middle-aged and elderly men. N. Engl. J. Med. 2010;363(2):123−135. Return to content
Varner JM. MANopause (andropause). The Alabama nurse. 2013;40(1):7−8; quiz 9. Return to content
Morales A, Heaton JP, Carson CC, 3rd. Andropause: a misnomer for a true clinical entity. J. Urol. 2000;163(3):705−712. Return to content
Heinemann LA, Thiel C, Assmann A, Zimmermann T, Hummel W, Vermeulen A. Sex differences in 'climacteric symptoms' with increasing age? A hypothesis-generating analysis of cross-sectional population surveys. The aging male : the official journal of the International Society for the Study of the Aging Male. 2000;3(3):124−131. Return to content
Dennerstein L. Well-being, symptoms and the menopausal transition. Maturitas. 1996;23(2):147−157. Return to content
Kelleher S, Conway AJ, Handelsman DJ. Blood testosterone threshold for androgen deficiency symptoms. J. Clin. Endocrinol. Metab. 2004;89(8):3813−3817. Return to content
Zarotsky V, al e. Systematic Literature Review of the Epidemiology of Nongenetic Forms of Hypogonadism in Adult Males. Journal of Hormones. 2014;Volume 2014, Article ID 190347. Return to content
Sartorius G, Spasevska S, Idan A, et al. Serum testosterone, dihydrotestosterone and estradiol concentrations in older men self-reporting very good health: the healthy man study. Clin. Endocrinol. (Oxf). 2012;77(5):755−763. Return to content
Haring R, Ittermann T, Volzke H, et al. Prevalence, incidence and risk factors of testosterone deficiency in a population-based cohort of men: results from the study of health in Pomerania. The aging male : the official journal of the International Society for the Study of the Aging Male. 2010;13(4):247−257. Return to content
Gold EB, Crawford SL, Avis NE, et al. Factors related to age at natural menopause: longitudinal analyses from SWAN. Am. J. Epidemiol. 2013;178(1):70−83. Return to content
Tajar A, Forti G, O'Neill TW, et al. Characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the European Male Aging Study. J. Clin. Endocrinol. Metab. 2010;95(4):1810−1818. Return to content
Vermeulen A. Clinical review 24: Androgens in the aging male. J. Clin. Endocrinol. Metab. 1991;73(2):221−224. Return to content
Zumoff B, Strain GW, Kream J, et al. Age variation of the 24-hour mean plasma concentrations of androgens, estrogens, and gonadotropins in normal adult men. J. Clin. Endocrinol. Metab. 1982;54(3):534−538. Return to content
Ferrini RL, Barrett-Connor E. Sex hormones and age: a cross-sectional study of testosterone and estradiol and their bioavailable fractions in community-dwelling men. Am. J. Epidemiol. 1998;147(8):750−754. Return to content
Gray A, Feldman HA, McKinlay JB, Longcope C. Age, disease, and changing sex hormone levels in middle-aged men: results of the Massachusetts Male Aging Study. J. Clin. Endocrinol. Metab. 1991;73(5):1016−1025. Return to content
Leifke E, Gorenoi V, Wichers C, Von Zur Muhlen A, Von Buren E, Brabant G. Age-related changes of serum sex hormones, insulin-like growth factor-1 and sex-hormone binding globulin levels in men: cross-sectional data from a healthy male cohort. Clin. Endocrinol. (Oxf). 2000;53(6):689−695. Return to content
Simon D, Preziosi P, Barrett-Connor E, et al. The influence of aging on plasma sex hormones in men: the Telecom Study. Am. J. Epidemiol. 1992;135(7):783−791. Return to content
Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J. Clin. Endocrinol. Metab. 2001;86(2):724−731. Return to content
Krithivas K, Yurgalevitch SM, Mohr BA, et al. Evidence that the CAG repeat in the androgen receptor gene is associated with the age-related decline in serum androgen levels in men. J. Endocrinol. 1999;162(1):137−142. Return to content
Morley JE, Kaiser FE, Perry HM, 3rd, et al. Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metabolism. 1997;46(4):410−413. Return to content
Zmuda JM, Cauley JA, Kriska A, Glynn NW, Gutai JP, Kuller LH. Longitudinal relation between endogenous testosterone and cardiovascular disease risk factors in middle-aged men. A 13-year follow-up of former Multiple Risk Factor Intervention Trial participants. Am. J. Epidemiol. 1997;146(8):609−617. Return to content
Neilson HK, Conroy SM, Friedenreich CM. The Influence of Energetic Factors on Biomarkers of Postmenopausal Breast Cancer Risk. Current nutrition reports. 2014;3:22−34. Return to content
Travis RC, Key TJ. Oestrogen exposure and breast cancer risk. Breast cancer research : BCR. 2003;5(5):239−247. Return to content
Maggio M, Ceda GP, Lauretani F, et al. Relationship between higher estradiol levels and 9-year mortality in older women: the Invecchiare in Chianti study. J. Am. Geriatr. Soc. 2009;57(10):1810−1815. Return to content
Traish AM. Adverse health effects of testosterone deficiency (TD) in men. Steroids. 2014. Return to content
Jones TH. Testosterone deficiency: a risk factor for cardiovascular disease? Trends in endocrinology and metabolism: TEM. 2010;21(8):496−503. Return to content
Ullah MI, Washington T, Kazi M, Tamanna S, Koch CA. Testosterone deficiency as a risk factor for cardiovascular disease. Horm. Metab. Res. 2011;43(3):153−164. Return to content
Haring R, John U, Volzke H, et al. Low testosterone concentrations in men contribute to the gender gap in cardiovascular morbidity and mortality. Gender medicine. 2012;9(6):557−568. Return to content
Muraleedharan V, Marsh H, Kapoor D, Channer KS, Jones TH. Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur. J. Endocrinol. 2013;169(6):725−733. Return to content
Isidori AM, Giannetta E, Greco EA, et al. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis. Clin. Endocrinol. (Oxf). 2005;63(3):280−293. Return to content
Mesbah Oskui P, French WJ, Herring MJ, Mayeda GS, Burstein S, Kloner RA. Testosterone and the cardiovascular system: a comprehensive review of the clinical literature. Journal of the American Heart Association. 2013;2(6):e000272. Return to content
Saad F, Aversa A, Isidori AM, Gooren LJ. Testosterone as potential effective therapy in treatment of obesity in men with testosterone deficiency: a review. Current diabetes reviews. 2012;8(2):131−143. Return to content
Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM. Testosterone treatment and mortality in men with low testosterone levels. J. Clin. Endocrinol. Metab. 2012;97(6):2050−2058. Return to content
Srinivas-Shankar U, Roberts SA, Connolly MJ, et al. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J. Clin. Endocrinol. Metab. 2010;95(2):639−650. Return to content
Traish AM. Outcomes of testosterone therapy in men with testosterone deficiency (TD): Part II. Steroids. 2014. Return to content
Francomano D, Bruzziches R, Barbaro G, Lenzi A, Aversa A. Effects of testosterone undecanoate replacement and withdrawal on cardio-metabolic, hormonal and body composition outcomes in severely obese hypogonadal men: a pilot study. J. Endocrinol. Invest. 2014. Return to content
Francomano D, Ilacqua A, Bruzziches R, Lenzi A, Aversa A. Effects of 5-year treatment with testosterone undecanoate on lower urinary tract symptoms in obese men with hypogonadism and metabolic syndrome. Urology. 2014;83(1):167−173. Return to content
Francomano D, Lenzi A, Aversa A. Effects of five-year treatment with testosterone undecanoate on metabolic and hormonal parameters in aging men with metabolic syndrome. International journal of endocrinology. 2014;2014:527470. Return to content
Hackett G, Cole N, Bhartia M, Kennedy D, Raju J, Wilkinson P. Testosterone therapy with long-acting testosterone undecanoate improves sexual function and quality-of-life parameters vs. placebo in a population of men with type 2 diabetes. The journal of sexual medicine. 2013;10(6):1612−1627. Return to content
Haider A, Saad F, Doros G, Gooren L. Hypogonadal obese men with and without diabetes mellitus type 2 lose weight and show improvement in cardiovascular risk factors when treated with testosterone: an observational study. Obes Res Clin Pract 2013. Return to content
Haider A, Yassin A, Doros G, Saad F. Effects of Long-Term Testosterone Therapy on Patients with “Diabesity”: Results of Observational Studies of Pooled Analyses in Obese Hypogonadal Men with Type 2 Diabetes. International Journal of Endocrinology. 2014:Article ID 683515. Return to content
Haider A, Yassin A, Doros G, Saad F. Effects of long-term testosterone therapy on patients with "diabesity": results of observational studies of pooled analyses in obese hypogonadal men with type 2 diabetes. International journal of endocrinology. 2014;2014:683515. Return to content
Heufelder AE, Saad F, Bunck MC, Gooren L. Fifty-two-week treatment with diet and exercise plus transdermal testosterone reverses the metabolic syndrome and improves glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone. J. Androl. 2009;30(6):726−733. Return to content
Saad F, Haider A, Doros G, Traish A. Long-term treatment of hypogonadal men with testosterone produces substantial and sustained weight loss. Obesity (Silver Spring). 2013;21(10):1975−1981. Return to content
Yassin A, Doros G. Testosterone therapy in hypogonadal men results in sustained and clinically meaningful weight loss. Clinical obesity. 2013;3(3-4):73−83. Return to content
Yassin DJ, Doros G, Hammerer PG, Yassin AA. Long-term testosterone treatment in elderly men with hypogonadism and erectile dysfunction reduces obesity parameters and improves metabolic syndrome and health-related quality of life. The journal of sexual medicine. 2014;11(6):1567−1576. Return to content
Zitzmann M, Mattern A, Hanisch J, Gooren L, Jones H, Maggi M. IPASS: a study on the tolerability and effectiveness of injectable testosterone undecanoate for the treatment of male hypogonadism in a worldwide sample of 1,438 men. The journal of sexual medicine. 2013;10(2):579−588. Return to content
Carson CC, 3rd, Rosano G. Exogenous testosterone, cardiovascular events, and cardiovascular risk factors in elderly men: a review of trial data. The journal of sexual medicine. 2012;9(1):54−67. Return to content
Thomson J, Oswald I. Effect of oestrogen on the sleep, mood, and anxiety of menopausal women. Br. Med. J. 1977;2(6098):1317−1319. Return to content
George GC, Utian WH, Beaumont PJ, Beardwood CJ. Effect of exogenous oestrogens on minor psychiatric symptoms in postmenopausal women. S. Afr. Med. J. 1973;47(49):2387−2388. Return to content
Barnabei VM, Cochrane BB, Aragaki AK, et al. Menopausal symptoms and treatment-related effects of estrogen and progestin in the Women's Health Initiative. Obstet. Gynecol. 2005;105(5 Pt 1):1063−1073. Return to content
Ortmann O, Lattrich C. The treatment of climacteric symptoms. Deutsches Arzteblatt international. 2012;109(17):316-323; quiz 324. Return to content
Marjoribanks J, Farquhar C, Roberts H, Lethaby A. Long term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev. 2012;7:CD004143. Return to content
de Villiers TJ, Pines A, Panay N, et al. Updated 2013 International Menopause Society recommendations on menopausal hormone therapy and preventive strategies for midlife health. Climacteric : the journal of the International Menopause Society. 2013;16(3):316−337. Return to content
Saad F, Aversa A, Isidori AM, Zafalon L, Zitzmann M, Gooren L. Onset of effects of testosterone treatment and time span until maximum effects are achieved. Eur. J. Endocrinol. 2011;165(5):675−685. Return to content
Kelly DM, Jones TH. Testosterone and cardiovascular risk in men. Front. Horm. Res. 2014;43:1−20. Return to content
Saad F. Androgen therapy in men with testosterone deficiency: can testosterone reduce the risk of cardiovascular disease? Diabetes. Metab. Res. Rev. 2012;28 Suppl 2:52−59. Return to content
Traish AM, Haider A, Doros G, Saad F. Long-term testosterone therapy in hypogonadal men ameliorates elements of the metabolic syndrome: an observational, long-term registry study. Int. J. Clin. Pract. 2014;68(3):314−329. Return to content
Haider A, Meergans U, Traish A, et al. Progressive Improvement of T-Scores in Men with Osteoporosis and Subnormal Serum Testosterone Levels upon Treatment with Testosterone over Six Years. International journal of endocrinology. 2014;2014:496948. Return to content
Hackett G, Cole N, Bhartia M, Kennedy D, Raju J, Wilkinson P. Testosterone therapy improves metabolic parameters in hypogonadal men with type 2 diabetes but not in men with coexisting depression: the BLAST study. The journal of sexual medicine. 2014;11(3):840-856. Return to content
Traish AM, Haider A, Doros G, Saad F. Long-term testosterone therapy in hypogonadal men ameliorates elements of the metabolic syndrome: an observational, long-term registry study. Int. J. Clin. Pract. 2013. Return to content
Saad F, Gooren LJ. The role of testosterone in the etiology and treatment of obesity, the metabolic syndrome, and diabetes mellitus type 2. Journal of obesity. 2011;2011. Return to content
Morales A. The andropause: bare facts for urologists. BJU Int. 2003;91(4):311−313. Return to content