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Testosterone Deficiency - Prevalence and Treatment Rates

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Testosterone deficiency, also known as hypogonadism, is gaining recognition among both clinicians and the general population. This article summarizes the findings from a review on the prevalence of testosterone deficiency, as well as the proportion of hypogonadal men who are receiving testosterone treatment.[1]
 
While testosterone prescribing has increased lately, as you will find out here, the prevalence of testosterone deficiency far exceeds the prescribing rate; i.e. majority of men with low-T are still not being treated with testosterone therapy.
 
You may be surprised to find out that testosterone deficiency is still not well-understood by general practitioners and cardiologists, and that these key clinicians lack knowledge on its deleterious cardiovascular effects. Therefore, even man needs to take control of his own health and don't let any ignorant or old-school doctor deny you a prescription that you may need...
 
 
 
KEY POINTS
 
Abbreviations:   TT = total testosterone, FT = free testosterone
 
* In population-based studies, the prevalence of hypogonadism in men aged 47-60 years ranges from 2.1% to 12.8%.[2-5] The operational definition of hypogonadism used across studies varies considerably:
 
- the Study of Health in Pomerania (SHIP, 1997–2001) (Germany) [5] used the most liberal definition of hypogonadism (TT < 300 ng/dL, no symptom criteria) and reported the highest prevalence at 12.8%;
 
- the European Male Aging Study (EMAS, 2003–2005) [4] used the most stringent definition of symptomatic hypogonadism (TT < 317 ng/dL plus 3 specific symptoms of decreased frequency of morning erections, sexual thoughts, and erectile dysfunction) and reported the lowest prevalence at 2.1%.
 
- the Massachusetts Male Aging Study (MMAS,1987–1989) [2] defined hypogonadism as TT 200–400 ng/dL plus FT  <8.91 ng/dL plus ≥3 symptoms, and reported a prevalence of 6% at baseline and 12% after a 10 year follow-up.
 
* In community-based studies, cut-offs of TT ranging from <200 to <400 ng/dL, with and without low FT, and with and without symptoms, the prevalence of hypogonadism in men aged 54-76 years ranges from 9.5% to 31.2%.[6-8] 
 
* In primary care/screening-based studies, the prevalence of hypogonadism in men aged 53-62 years ranges from 12% to 38.7%:
 
- Using a cut-off for TT <300 ng/dL, prevalence was 19.3% [9], 19.8% [10] , 24.1% [11], 24.2% [12], and 38.7% [13]. 
 
- Adding symptoms as a criterion, the prevalence decreased from 24.1% to 12% [11] and from 24.2% to 20.4%.[12]
 
* Clinical condition-based studies assessed prevalence of hypogonadism among patients with specific medical conditions. The prevalence of hypogonadism in men aged 53-62 years with morbidities ranges up to 78.8% and varies considerably by medical condition.
 
- Hypogonadism occurs commonly among patients with obesity, type 2 diabetes, and/or the metabolic syndrome.
 
- The prevalence of hypogonadism in obese patients was found to be 57.7% and 35.6%, using the cut-offs TT <317 ng/dL and FT <78 pg/ml, respectively.[14] Another study using the cut-offs TT < 300 ng/dl or FT < 65 pg/ml found the prevalence in obese patients to be 78.8% and 51.5%, respectively.[15]
 
- The prevalence of hypogonadism in patients with type 2 diabetes ranges from 24.5% to 43% using the cut-off TT <10.4mmol/L (300 ng/dL). [16-19] With the cut-off TT <12nmol/L (346 ng/dL), the prevalence is 45%.[20]
 
- Even after adjusting for age and BMI, the prevalence of subnormal FT levels (<50 pg/ml  or 144 pmol/L) in men with type 2 diabetes is higher than in men without (45% versus 33%).[21]
 
- The prevalence of hypogonadism in patients with the metabolic syndrome ranges from 30 to 35%.[22-24] 
 
- The prevalence of hypogonadism in patients with type 2 diabetes who are also obese or have the metabolic syndrome is 51% [21] and 47% [25], respectively.
 
* The prevalence of hypogonadism in men with erectile dysfunction is 7%, 23%, 33%, and 47% for testosterone levels of less than 200, less than 300, less than 346, and less than 400 ng/dL, respectively.[26] 
 
*Prevalence of hypogonadism increases with age. An abrupt increase in hypogonadism prevalence occurred in men aged 45 to 50 yr.[26] 
Using the cut-off < 300 ng/dL, hypogonadism prevalence in primary care patients has been reported to be 34% in men aged 45–54 yr, 40.2%  in men aged 55–64 yr, 39.9% in men aged 65–74 yr, 45.5% in men aged 75–84 yr, and 50% in men aged 85 yr and older.[13] Every 10-year increase in age confers a 17% increase in risk of hypogonadism.[13]
 
* Population-based (BACH, Boston Area Community Health) [27] and clinical-based (HIM, Health In Men) [13]  studies report that only 10% to 12% of hypogonadal patients are receiving treatment for hypogonadism.
 

What is known

Diagnosis of hypogonadism is typically based on the signs and symptoms associated with a deficiency of testosterone levels or its actions, followed by biochemical confirmation of low testosterone levels.[28-30] It is well-documented that testosterone levels decline with age in men.  After the age of 40 years, total testosterone decreases on average -4 ng/dL ( -0.124 nmol/L) per year [31] or 1.6% per year [32], and bioavailable testosterone  by -2 to -3% per year. [32] In older men (over 60 years of age), the average rate of decrement in total testosterone levels has been found to be 110 ng/dL every decade.[33] The aging demography will thus cause a large increase in the burden of testosterone deficiency.[3]
 
Besides aging alone, lifestyle and different co-morbidities are associated with testosterone deficiency, suggesting that the age-related testosterone decline may be at least partly prevented through the management of potentially modifiable risk factors and health related behaviour.[5]
 

What this study adds

The prevalence of hypogonadism and suboptimal testosterone levels is high. It should be noted that most the prevalence numbers listed above are based on the cut-off of 300 ng/dL. Even conservative investigators find a TT cut-off of 12.1 nmol/L (348.3 ng/dl), as opposed to the 300 ng/dl (that some clinicians already think is too high), as the defining lower limit of the testosterone reference range.[34] Using this higher cut-off, the prevalence of testosterone deficiency is likely much greater.
 
Notable is the lack of a standardized definition for hypogonadism diagnosis. As outlined here, the hypogonadism literature reports wide-ranging prevalence based not only on the different populations or subpopulations studied, but also on the use of diverse biochemical cut points or varied choices of symptoms.
 
Co-morbidities 
 
Besides age per se, obesity, metabolic syndrome, diabetes and dyslipidaemia are risk factors of incident testosterone deficiency.[5] This is underscored by a head-to-head comparison of the prevalence of subnormal free testosterone levels in lean, overweight, and obese non-diabetic men, which was found to be 26%, 29% and 40%, respectively (P < 0.001 for trend).[21] In lean, overweight, and obese diabetic men, the prevalence of subnormal free testosterone levels is even higher; 44% , 44% and 50%, respectively (P = 0.46 for trend within group and P < 0.05 compared with non-diabetic men).[21] 
 
The analysis reported here also brings to the attention that in every BMI category, the prevalence of subnormal total testosterone levels is consistently higher than that of free testosterone levels.[14] In type 2 diabetics, the reverse is true, i.e. the prevalence of subnormal free testosterone levels is consistently higher than that of total testosterone levels.[19, 20] One study found that 43% of men with type 2 diabetes had a reduced total testosterone level, while 57% had a reduced free testosterone levels.[19] The corresponding numbers in a more recent study are 45% and 61%, respectively.[20]
 
Another important finding is the greatly increased prevalence of hypogonadism among men with obesity, type 2 diabetes and/or the metabolic syndrome. The prevalence of obesity and the metabolic syndrome among men aged 20 yr and older is 35.5% [35] and 36.1%, respectively.[36] 26.9%  of adults aged 65 years or older have diabetes.[37] Because these clinical conditions have become more and more prevalent in all age groups [36, 38] and have reached epidemic proportions, an alarming increase of non-aging related prevalence of hypogonadism may be expected. It is therefore imperative that clinicians are aware of the impact of co-morbidities on testosterone, and screen their patients for hypogonadism.
 
Testosterone Prescribing
 
Testosterone prescribing has increased over the past decade.[39-41] From 2001 through 2011, testosterone supplementation among men 40 years or older increased more than 3-fold, from 0.81% in 2001 to 2.91% in 2011. The increase was seen in all age groups. By 2011, 2.29% of men in their 40s and 3.75% of men in their 60s were taking some form of testosterone therapy.[39] However, despite an increased use of testosterone therapy, population-based (BACH, Boston Area Community Health) and clinical-based studies (HIM) report that only 10% [27] and 12% [13] of patients were receiving treatment for hypogonadism, respectively. 
 
It is notable that in the BACH study 40% of men met the Endocrine Society definition for testosterone deficiency (symptoms and/or signs coupled with total testosterone < 300 ng/dL or free testosterone < 5 ng/dL), but only 10% received testosterone therapy.[27] In the HIM study, the prevalence of testosterone deficiency (defined by TT <300 ng/dl) was 38.7%. Based on free testosterone (<52 pg/ml) and bioavailable testosterone levels (<95 ng/dl for men <70 years of age and <60 ng/dl for men 70 and older), approximately 40% and 45% of men were hypogonadal, respectively. In this study, a similarly low proportion of men were receiving testosterone therapy (12%). Reasons for this low frequency of hypogonadism treatment may include inadequate knowledge among physicians regarding hypogonadism and uncertainty about diagnostic criteria. Also, patients may not be able to afford therapy in countries that do not provide coverage for testosterone prescriptions. 
 
Another reason is safety concerns. Two world-wide surveys found that concerns about potential side effects of testosterone therapy among doctors is increasing, and that concerns were predominantly related to prostate cancer and cardiovascular disease.[42, 43] This is not congruent with the growing body of research showing that testosterone therapy is safe for prostate and cardiovascular outcomes.[44-46] I have covered prostate and cardiovascular safety issues in previous editorials, see:
 
 
 
An assessment of beliefs, knowledge and practice patterns of general practitioners and cardiologists found that testosterone deficiency is not well-understood by general practitioners and cardiologists, and that these key clinicians lack knowledge on its deleterious cardiovascular effects.[47]
 
Thus, it is critical to look at both sides of the prescribing - need equation; citing increases in testosterone prescribing without looking at hypogonadism prevalence and men's health status will give a very misleading picture. The review reported here indicates that the reported increase in testosterone prescribing still does not offer treatment for the vast majority of men who need it for their health and wellbeing. 
 

References:

1.            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.

2.            Araujo, A.B., et al., Prevalence and incidence of androgen deficiency in middle-aged and older men: estimates from the Massachusetts Male Aging Study. J Clin Endocrinol Metab, 2004. 89(12): p. 5920-6.

3.            Araujo, A.B., et al., Prevalence of symptomatic androgen deficiency in men. J Clin Endocrinol Metab, 2007. 92(11): p. 4241-7.

4.            Tajar, A., et al., Characteristics of androgen deficiency in late-onset hypogonadism: results from the European Male Aging Study (EMAS). J Clin Endocrinol Metab, 2012. 97(5): p. 1508-16.

5.            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.

6.            Khoo, E.M., H.M. Tan, and W.Y. Low, Erectile dysfunction and comorbidities in aging men: an urban cross-sectional study in Malaysia. J Sex Med, 2008. 5(12): p. 2925-34.

7.            Ponholzer, A., et al., Vascular risk factors and their association to serum androgen levels in a population-based cohort of 75-year-old men over 5 years: results of the VITA study. World J Urol, 2010. 28(2): p. 209-14.

8.            Wong, S.Y., et al., Prevalence of and risk factors for androgen deficiency in middle-aged men in Hong Kong. Metabolism, 2006. 55(11): p. 1488-94.

9.            Schneider, H.J., et al., Prevalence of low male testosterone levels in primary care in Germany: cross-sectional results from the DETECT study. Clin Endocrinol (Oxf), 2009. 70(3): p. 446-54.

10.          Nardozza Junior, A., et al., Age-related testosterone decline in a Brazilian cohort of healthy military men. Int Braz J Urol, 2011. 37(5): p. 591-7.

11.          Liu, C.C., et al., The prevalence of and risk factors for androgen deficiency in aging Taiwanese men. J Sex Med, 2009. 6(4): p. 936-46.

12.          Goel, A., et al., Andropause in Indian men: a preliminary cross-sectional study. Urol J, 2009. 6(1): p. 40-4; discussion 44-6.

13.          Mulligan, T., et al., Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract, 2006. 60(7): p. 762-9.

14.          Hofstra, J., et al., High prevalence of hypogonadotropic hypogonadism in men referred for obesity treatment. Neth J Med, 2008. 66(3): p. 103-9.

15.          Pellitero, S., et al., Hypogonadotropic hypogonadism in morbidly obese males is reversed after bariatric surgery. Obes Surg, 2012. 22(12): p. 1835-42.

16.          Corona, G., et al., Association of hypogonadism and type II diabetes in men attending an outpatient erectile dysfunction clinic. Int J Impot Res, 2006. 18(2): p. 190-7.

17.          Dhindsa, S., et al., Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. J Clin Endocrinol Metab, 2004. 89(11): p. 5462-8.

18.          Grossmann, M., et al., Low testosterone and anaemia in men with type 2 diabetes. Clin Endocrinol (Oxf), 2009. 70(4): p. 547-53.

19.          Grossmann, M., et al., Low testosterone levels are common and associated with insulin resistance in men with diabetes. J Clin Endocrinol Metab, 2008. 93(5): p. 1834-40.

20.          Biswas, M., et al., Total and free testosterone concentrations are strongly influenced by age and central obesity in men with type 1 and type 2 diabetes but correlate weakly with symptoms of androgen deficiency and diabetes-related quality of life. Clin Endocrinol (Oxf), 2012. 76(5): p. 665-73.

21.          Dhindsa, S., et al., Testosterone concentrations in diabetic and nondiabetic obese men. Diabetes Care, 2010. 33(6): p. 1186-92.

22.          Caldas, A.D., et al., Relationship between insulin and hypogonadism in men with metabolic syndrome. Arq Bras Endocrinol Metabol, 2009. 53(8): p. 1005-11.

23.          Laaksonen, D.E., et al., The metabolic syndrome and smoking in relation to hypogonadism in middle-aged men: a prospective cohort study. J Clin Endocrinol Metab, 2005. 90(2): p. 712-9.

24.          Singh, S.K., R. Goyal, and D.D. Pratyush, Is hypoandrogenemia a component of metabolic syndrome in males? Exp Clin Endocrinol Diabetes, 2011. 119(1): p. 30-5.

25.          Ogbera, A.O., Relationship between serum testosterone levels and features of the metabolic syndrome defining criteria in patients with type 2 diabetes mellitus. West Afr J Med, 2011. 30(4): p. 277-81.

26.          Kohler, T.S., et al., Prevalence of androgen deficiency in men with erectile dysfunction. Urology, 2008. 71(4): p. 693-7.

27.          Hall, S.A., et al., Treatment of symptomatic androgen deficiency: results from the Boston Area Community Health Survey. Arch Intern Med, 2008. 168(10): p. 1070-6.

28.          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.

29.          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.

30.          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.

31.          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.

32.          Feldman, H.A., et al., Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab, 2002. 87(2): p. 589-98.

33.          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.

34.          Bhasin, S., et al., Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham Heart Study and applied to three geographically distinct cohorts. J Clin Endocrinol Metab, 2011. 96(8): p. 2430-9.

35.          Flegal, K.M., et al., Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999-2010. JAMA, 2012. 307(5): p. 491-7.

36.          Ford, E.S., C. Li, and G. Zhao, Prevalence and correlates of metabolic syndrome based on a harmonious definition among adults in the US. J Diabetes, 2010. 2(3): p. 180-93.

37.          American Diabetes Association Statistics About Diabetes: Data from the National Diabetes Statistics Report, 2014 (released June 10, 2014), avaliable at http://www.diabetes.org/diabetes-basics/statistics (accessed July 21, 2014).

38.          Svartberg, J., et al., Waist circumference and testosterone levels in community dwelling men. The Tromso study. Eur J Epidemiol, 2004. 19(7): p. 657-63.

39.          Baillargeon, J., et al., Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Intern Med, 2013. 173(15): p. 1465-6.

40.          Gan, E.H., et al., A UK epidemic of testosterone prescribing, 2001-2010. Clin Endocrinol (Oxf), 2013. 79(4): p. 564-70.

41.          Layton, J.B., et al., Testosterone lab testing and initiation in the United Kingdom and the United States, 2000 to 2011. J Clin Endocrinol Metab, 2014. 99(3): p. 835-42.

42.          Gooren, L.J., et al., Diagnosing and treating testosterone deficiency in different parts of the world. Results from global market research. Aging Male, 2007. 10(4): p. 173-81.

43.          Gooren, L.J. and H.M. Behre, Diagnosing and treating testosterone deficiency in different parts of the world: changes between 2006 and 2010. Aging Male, 2012. 15(1): p. 22-7.

44.          Calof, O.M., et al., Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci, 2005. 60(11): p. 1451-7.

45.          Fernandez-Balsells, M.M., et al., Clinical review 1: Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab, 2010. 95(6): p. 2560-75.

46.          Haddad, R.M., et al., Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc, 2007. 82(1): p. 29-39.

47.          Wallis, C.J., H. Brotherhood, and P.J. Pommerville, Testosterone deficiency syndrome and cardiovascular health: An assessment of beliefs, knowledge and practice patterns of general practitioners and cardiologists in Victoria, BC. Can Urol Assoc J, 2014. 8(1-2): p. 30-3.

Last modified on Tuesday, 26 December 2017 00:41
Monica

Medical Writer & Nutritionist

MSc Nutrition

University of Stockholm & Karolinska Institute, Sweden 

   Baylor University, TX, USA

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