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Is hypogonadism, aka "andropause", the male version of menopause?

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Many 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.[1-5]
 
Therefore these conditions are frequently seen as being equivalent, and hypogonadism (which sometimes get the prefix "late onset") has therefore been called "andropause", "male climacteric", "male menopause" or "MANopause.[6, 7] 
 
However, this is very misleading. In this article I will contrast and comment on the differences between hypogonadism, also known as testosterone deficiency, and menopause.[8]
 

KEY POINTS

 
For several reasons, hypogonadism in men and menopause cannot be equated: 
 
* Menopause is universal and obvious and develops relatively rapidly. 
 
- Hypogonadism does not affect every man, and when it does, it develops slowly over a long time period.
 
* The hormones involved are different. 
 
- Estrogen and testosterone have contrasting effects on most physiological functions.
 
* Treatment vs. non-treatment has vastly different consequences. 
 
- 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.
 
- The consequences of reduced levels of estrogen in postmenopausal women are less well-documented, and treatment with estrogen (hormone replacement therapy, HRT) 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.[1, 5, 9, 10] This 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.
 

Why "andropause" should NOT be seen as equivalent to menopause

 
Hypogonadism, also known as testosterone deficiency, while common [11], 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.[12] This 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.[13] Thus, while menopause happens consistently in women between the ages of 45-55, the median age for natural final menstrual period is 52 years [14], hypogonadism in men can occur at any age because testosterone deficiency can be caused by several different factors.[10, 15] Therefore, 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 [16-21] and longitudinal studies [22-25], 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 difference consequences. While it is hypothesized that estrogen deficiency in women may be protective against cancer [26, 27] and may increase longevity [28], 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.[29] Testosterone deficiency in men may even be a risk factor for cardiovascular disease.[30, 31] In addition, there are also indications that testosterone deficiency in men contributes to the gender gap in cardiovascular morbidity and mortality.[32] When 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 insert link here.
 
When it comes to the issue of treatment vs. non-treatment, a rapidly expanding body of evidence justifies treatment of hypogonadism with testosterone therapy.[33-52] This is in stark contrast to menopause, whose treatment with estrogen HRT (hormone replacement therapy) with is controversial; studies show it doesn't always improve symptoms and in may pose an excessive risk for women with a family history of breast cancer.[53-57] The most serious concern about traditional HRT with synthetic estrogen and progesterone is its potential to increase risk for breast and endometrial cancer, blood clots, stroke and heart disease (I will cover the benefits of bioidentical estrogen and progesterone compared to synthetic in an upcoming article).[58] In contrast, treatment of hypogonadism in men with testosterone therapy that achieves adequate testosterone levels and is of long enough duration to allow benefits to manifest [59] improves symptoms and reduces risk of multiple chronic diseases, including cardiovascular disease, in the vast majority of men.[34, 36, 39-42, 45, 46, 48-51, 60-66] 
 
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."[67]
 
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.
 
 
References:

1.            Zitzmann, M., S. Faber, and E. Nieschlag, Association of specific symptoms and metabolic risks with serum testosterone in older men. J Clin Endocrinol Metab, 2006. 91(11): p. 4335-43.

2.            Bhasin, S., et al., Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab, 2010. 95(6): p. 2536-59.

3.            Blumel, J.E., et al., Is the Androgen Deficiency of Aging Men (ADAM) questionnaire useful for the screening of partial androgenic deficiency of aging men? Maturitas, 2009. 63(4): p. 365-8.

4.            Wang, C., et al., Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations. J Androl, 2009. 30(1): p. 1-9.

5.            Wu, F.C., et al., Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med, 2010. 363(2): p. 123-35.

6.            Varner, J.M., MANopause (andropause). Ala Nurse, 2013. 40(1): p. 7-8; quiz 9.

7.            Morales, A., J.P. Heaton, and C.C. Carson, 3rd, Andropause: a misnomer for a true clinical entity. J Urol, 2000. 163(3): p. 705-12.

8.            Saad, F. and L.J. Gooren, Late onset hypogonadism of men is not equivalent to the menopause. Maturitas, 2014.

9.            Dennerstein, L., Well-being, symptoms and the menopausal transition. Maturitas, 1996. 23(2): p. 147-57.

10.          Kelleher, S., A.J. Conway, and D.J. Handelsman, Blood testosterone threshold for androgen deficiency symptoms. J Clin Endocrinol Metab, 2004. 89(8): p. 3813-7.

11.          Zarotsky, V. and e. al, Systematic Literature Review of the Epidemiology of Nongenetic Forms of Hypogonadism in Adult Males. Journal of Hormones, 2014. Volume 2014, Article ID 190347.

12.          Sartorius, G., 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): p. 755-63.

13.          Haring, R., 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. Aging Male, 2010. 13(4): p. 247-57.

14.          Gold, E.B., et al., Factors related to age at natural menopause: longitudinal analyses from SWAN. Am J Epidemiol, 2013. 178(1): p. 70-83.

15.          Tajar, A., et al., Characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the European Male Ageing Study. J Clin Endocrinol Metab, 2010. 95(4): p. 1810-8.

16.          Vermeulen, A., Clinical review 24: Androgens in the aging male. J Clin Endocrinol Metab, 1991. 73(2): p. 221-4.

17.          Zumoff, B., 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): p. 534-8.

18.          Ferrini, R.L. and E. Barrett-Connor, 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): p. 750-4.

19.          Gray, A., et al., 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): p. 1016-25.

20.          Leifke, E., et al., 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): p. 689-95.

21.          Simon, D., et al., The influence of aging on plasma sex hormones in men: the Telecom Study. Am J Epidemiol, 1992. 135(7): p. 783-91.

22.          Harman, S.M., et al., 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): p. 724-31.

23.          Krithivas, K., 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): p. 137-42.

24.          Morley, J.E., et al., Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metabolism, 1997. 46(4): p. 410-3.

25.          Zmuda, J.M., et al., 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): p. 609-17.

26.          Neilson, H.K., S.M. Conroy, and C.M. Friedenreich, The Influence of Energetic Factors on Biomarkers of Postmenopausal Breast Cancer Risk. Curr Nutr Rep, 2014. 3: p. 22-34.

27.          Travis, R.C. and T.J. Key, Oestrogen exposure and breast cancer risk. Breast Cancer Res, 2003. 5(5): p. 239-47.

28.          Maggio, M., 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): p. 1810-5.

29.          Traish, A.M., Adverse health effects of testosterone deficiency (TD) in men. Steroids, 2014.

30.          Jones, T.H., Testosterone deficiency: a risk factor for cardiovascular disease? Trends Endocrinol Metab, 2010. 21(8): p. 496-503.

31.          Ullah, M.I., et al., Testosterone deficiency as a risk factor for cardiovascular disease. Horm Metab Res, 2011. 43(3): p. 153-64.

32.          Haring, R., et al., Low testosterone concentrations in men contribute to the gender gap in cardiovascular morbidity and mortality. Gend Med, 2012. 9(6): p. 557-68.

33.          Muraleedharan, V., et al., 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): p. 725-33.

34.          Isidori, A.M., 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): p. 280-93.

35.          Oskui, M.P., et al., Testosterone and the cardiovascular system: a comprehensive review of the clinical literature. J Am Heart Assoc, 2013. 2(6): p. e000272.

36.          Saad, F., et al., Testosterone as potential effective therapy in treatment of obesity in men with testosterone deficiency: a review. Curr Diabetes Rev, 2012. 8(2): p. 131-43.

37.          Shores, M.M., et al., Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab, 2012. 97(6): p. 2050-8.

38.          Srinivas-Shankar, U., 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): p. 639-50.

39.          Traish, A.M., Outcomes of testosterone therapy in men with testosterone deficiency (TD): Part II. Steroids, 2014.

40.          Francomano, D., et al., 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.

41.          Francomano, D., et al., 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): p. 167-73.

42.          Francomano, D., A. Lenzi, and A. Aversa, Effects of five-year treatment with testosterone undecanoate on metabolic and hormonal parameters in ageing men with metabolic syndrome. Int J Endocrinol, 2014. 2014: p. 527470.

43.          Hackett, G., et al., Testosterone replacement 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. J Sex Med, 2013. 10(6): p. 1612-27.

44.          Haider, A., et al., 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.

45.          Haider, A., et al., 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: p. Article ID 683515.

46.          Haider, A., et al., 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. Int J Endocrinol, 2014. 2014: p. 683515.

47.          Heufelder, A.E., et al., 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): p. 726-33.

48.          Saad, F., et al., Long-term treatment of hypogonadal men with testosterone produces substantial and sustained weight loss. Obesity (Silver Spring), 2013. 21(10): p. 1975-81.

49.          Yassin, A. and G. Doros, Testosterone therapy in hypogonadal men results in sustained and clinically meaningful weight loss. Clin Obes, 2013. 3(3-4): p. 73-83.

50.          Yassin, D.J., et al., 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. J Sex Med, 2014. 11(6): p. 1567-76.

51.          Zitzmann, M., et al., 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. J Sex Med, 2013. 10(2): p. 579-88.

52.          Carson, C.C., 3rd and G. Rosano, Exogenous testosterone, cardiovascular events, and cardiovascular risk factors in elderly men: a review of trial data. J Sex Med, 2012. 9(1): p. 54-67.

53.          Thomson, J. and I. Oswald, Effect of oestrogen on the sleep, mood, and anxiety of menopausal women. Br Med J, 1977. 2(6098): p. 1317-9.

54.          George, G.C., et al., Effect of exogenous oestrogens on minor psychiatric symptoms in postmenopausal women. S Afr Med J, 1973. 47(49): p. 2387-8.

55.          Barnabei, V.M., 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): p. 1063-73.

56.          Ortmann, O. and C. Lattrich, The treatment of climacteric symptoms. Dtsch Arztebl Int, 2012. 109(17): p. 316-23; quiz 324.

57.          Marjoribanks, J., et al., Long term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev, 2012. 7: p. CD004143.

58.          de Villiers, T.J., et al., Updated 2013 International Menopause Society recommendations on menopausal hormone therapy and preventive strategies for midlife health. Climacteric, 2013. 16(3): p. 316-37.

59.          Saad, F., et al., Onset of effects of testosterone treatment and time span until maximum effects are achieved. Eur J Endocrinol, 2011. 165(5): p. 675-85.

60.          Kelly, D.M. and T.H. Jones, Testosterone and cardiovascular risk in men. Front Horm Res, 2014. 43: p. 1-20.

61.          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: p. 52-9.

62.          Traish, A.M., et al., 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): p. 314-29.

63.          Haider, A., et al., Progressive Improvement of T-Scores in Men with Osteoporosis and Subnormal Serum Testosterone Levels upon Treatment with Testosterone over Six Years. Int J Endocrinol, 2014. 2014: p. 496948.

64.          Hackett, G., et al., Testosterone replacement therapy improves metabolic parameters in hypogonadal men with type 2 diabetes but not in men with coexisting depression: the BLAST study. J Sex Med, 2014. 11(3): p. 840-56.

65.          Traish, A.M., et al., Long-term testosterone therapy in hypogonadal men ameliorates elements of the metabolic syndrome: an observational, long-term registry study. Int J Clin Pract, 2013.

66.          Saad, F. and L.J. Gooren, The role of testosterone in the etiology and treatment of obesity, the metabolic syndrome, and diabetes mellitus type 2. J Obes, 2011. 2011.

67.          Morales, A., The andropause: bare facts for urologists. BJU Int, 2003. 91(4): p. 311-3.

Last modified on Thursday, 23 July 2015 22:30
Monica

Medical Writer & Nutritionist

MSc Nutrition

University of Stockholm & Karolinska Institute, Sweden 

   Baylor University, TX, USA

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