Health Consequences of Subclinical Testosterone Deficiency - riskier than previously thought

 
In discussions about diagnosis and health consequences of hypogonadism, aka testosterone deficiency, the prime focus is given to testosterone levels and signs/symptoms.[1-3] However, emerging research has identified a less clinically evident gonadal dysfunction called “subclinical” hypogonadism (or “compensated” hypogonadism).[4, 5]
 
Subclinical hypogonadism is characterized by normal testosterone levels in the presence of elevated LH level. As testosterone levels are not markedly reduced in subclinical hypogonadism, intuitively one may think it does not confer negative health consequences.
 
However, a recent study by Corona et al., which specifically was conducted to investigate the potential health ramifications of subclinical hypogonadism, shows that it should not be neglected. Surprisingly, subclinical hypogonadism is associated with an almost 10-fold increased risk of cardiovascular mortality, which is comparable to that for overt hypogonadism! [6]
 
 
 
KEY POINTS
 
• There are three types of hypogonadism (aka testosterone deficiency):
 
1) Primary hypogonadism (also known as hypergonadotropic hypogonadism):
 
- low testosterone with elevated LH;  due primarily to insufficient testicular function.
 
2) Secondary hypogonadism (also known as hypogonadotropic hypogonadism):
 
- low testosterone with low-normal LH;  due primarily to insufficient hypothalamic-pituitary function.
 
3) Subclinical hypogonadism (also called compensated hypogonadism): 
 
- normal testosterone levels with elevated LH levels.
 
 
• Men with subclinical hypogonadism have more hypogonadal symptoms (primarily psychological) than eugonadal (testosterone replete) men, and have an equally elevated cardiovascular risk as do men with overt hypogonadism.
 
• Subclinical hypogonadism is associated with an almost 10-fold increased risk of cardiovascular mortality, comparable to that for overt hypogonadism.
 
• Elevated LH in the context of apparently eugonadal total testosterone levels may be an indicator of a general poor health status, and should be followed up with a more comprehensive medical examination.
 

What is known

 
Male hypogonadism is defined as inadequate production of testosterone and/or spermatozoa in the presence of elevated or reduced levels of gonadotropins (LH and FSH, respectively).[7] In the past, two types of hypogonadism have been identified:
 
1) Primary hypogonadism (also known as hypergonadotropic hypogonadism):
 
- low testosterone with elevated LH;  due primarily to insufficient testicular function.
 
2) Secondary hypogonadism (also known as hypogonadotropic hypogonadism):
 
- low testosterone with low-normal LH;  due primarily to insufficient hypothalamic-pituitary function.
 
Older men are more likely to have primary hypogonadism while obese men, regardless of age, most often present with secondary hypogonadism.[8] Thus, measuring both testosterone and LH can shed light on whether a man’s hypogonadism is caused by testicular or hypothalamic-pituitary dysfunction, and help guide therapeutic efforts. For example, because obesity and diabetes are strongly associated with secondary hypogonadism (low testosterone and low-normal LH) [9, 10], monitoring testosterone together with LH can give an indication about the adequacy of treatment interventions targeted at reducing excess body fat and improving metabolic control.
 
However, over the past few years an additional form of hypogonadism has been identified - subclinical hypogonadism (also called compensated hypogonadism) - which is characterized by normal testosterone levels in the presence of elevated LH levels.[8, 11, 12]  
 
In endocrinology, subclinical disorders are characterized by normal levels of a hormone, with altered levels, outside the reference range, of the hormone that stimulates or inhibits its production. A prime well recognized example is subclinical hypothyroidism, often characterized by normal thyroid hormone levels in the presence of elevated TSH levels.[13-15] Accumulating research shows that subclinical hypothyroidism, like the overt condition, is associated with a greater risk of heart disease, cardiovascular death and all-cause mortality.[16-18] This indicates that even though subclinical endocrine disorders represent milder forms of the clinically overt disease, they can have a significant negative impact on health outcomes.
 
Along those lines, it has been hypothesized that subclinical hypogonadism - normal testosterone levels in the presence of elevated LH levels – may be associated with neurological, psychological, and cardiovascular disturbances, including alterations of bone and glucose metabolism, as well as lipid profile abnormalities.[5] 
 
However, while there are numerous studies on the health consequences of subclinical hypothyroidism and subclinical Cushing’s syndrome, subclinical hypogonadism has only recently begun to receive attention in medical research. 
 

What this study adds

 
The findings by Corona et al. are quite unexpected. They sought to investigate the association of subclinical hypogonadism with clinical and psychological characteristics of 4,173 male subjects complaining of sexual dysfunction, studying in detail both subjective and objective (penile color Doppler ultrasound) sexual parameters. In addition, possible associations between subclinical hypogonadism and major cardiovascular events (MACE) morbidity and mortality were examined.
 
By definition, total testosterone was significantly lower in overt hypogonadism (288 ng/dL) vs. subclinical hypogonadism (545 ng/dL) or eugonadism (508 ng/dL) (note that the difference in testosterone levels between men with subclinical hypogonadism and men who are eugonadal is not significantly different), and LH levels were higher in subclinical hypogonadism (12.4 mU/L) vs. overt (3.4 mU/L) or eugonadal (3.7 mU/L) subjects. When compared with eugonadal individuals, men with subclinical hypogonadism had higher SHBG levels, and therefore lower calculated free testosterone.
 
While hypogonadism-related symptoms (assessed by ANDROTEST scores) were more frequently present in overtly hypogonadal men than in subclinical hypogonadal men, men with subclinical hypogonadism still had significantly more hypogonadism-related symptoms compared with eugonadal men. Furthermore, subjects with subclinical hypogonadism more often reported psychiatric symptoms (assessed by the total MHQ score), when compared with both eugonadal and overtly hypogonadal subjects, even after adjusting for age and smoking and drinking habits. In contrast, no difference in psychiatric symptoms was observed between eugonadal and overt hypogonadal men. 
 
Compared with eugonadal men, men with subclinical or overt hypogonadism had an increased predicted cardiovascular risk (as assessed by Progetto Cuore risk algorithm), even after adjustment for BMI and drinking habits. No difference was observed between subclinical and overt hypogonadism.
 
In the whole sample, during a mean follow up of 4.3, 139 major cardiovascular events (MACEs) were observed, as previously reported.[19] Unadjusted incidence of MACEs was not different among hypogonadal classes. In contrast, MACE-related mortality was significantly higher in men with either subclinical or overt hypogonadism compared with eugonadal men, even after adjusting for age and concomitant morbidities.
 

Commentary

 
The main finding in this study is that subclinically hypogonadal men present with significantly more hypogonadal symptoms (primarily psychological) than eugonadal men, and have an equally elevated cardiovascular risk as do men with overt hypogonadism. Perhaps the most striking finding is that MACE-related mortality in this study is significantly higher in men with either subclinical or overt hypogonadism compared with eugonadal men, regardless of age and concomitant morbidities. Specifically, men with subclinical hypogonadism had an almost 10-fold increase in odds (risk) of cardiovascular mortality, comparable to that for overt hypogonadism. Thus, elevated LH in the context of apparently eugonadal total testosterone levels may be an indicator of a general poor health status. Support for this possibility comes from a previous prospective study showing that an elevated LH level may be a risk factor for ischaemic heart disease.[20] In addition, subclinical hypogonadism has been significantly associated with physical symptoms [21], and an inverse relationship exists between LH and muscle strength and lean mass, independent of testosterone levels.[22] The previously observed relation between LH and muscle strength and frailty, independent of testosterone, suggests that LH reflects serum androgen activity in a different way than do testosterone levels; it could possibly mirror the combined feedback effect of estrogen and androgen on the HPG axis.[22]
 
Overall, these data indicate that the biological action of testosterone is indeed reduced in subclinical hypogonadism, even though total testosterone levels are the same as in eugonadal men. This is supported by the elevated SHBG and lower free testosterone levels in subclinical hypogonadism, which was also previously reported in the EMAS (European Male Ageing Study) study.[21] Another explanation may be that although testosterone levels in men with subclinical hypogonadism remain above the thresholds for sexual symptoms, they may be insufficient to maintain “younger” levels of physical capacities.[23, 24] Given the wide normal testosterone range [25, 26], it is possible that testosterone levels in men with subclinical hypogonadism have declined from previously high normal to current low normal. High LH in this case may therefore be a biomarker for testosterone decline within the reference range, indicating a readjustment of the HPT feedback set point trying to compensate for deficiencies in testicular function, and/or defective testosterone feedback at the hypothalamic-pituitary level.[27]
 
All this lends support for the view that measuring only total testosterone may give an incomplete clinical picture of men’s health status, and lead to missed opportunities for early intervention and prevention of further health deterioration. 
 
References:

1.            Buvat, J., et al., Testosterone deficiency in men: systematic review and standard operating procedures for diagnosis and treatment. J Sex Med, 2013. 10(1): p. 245-84.

2.            Bhasin, S. and S. Basaria, Diagnosis and treatment of hypogonadism in men. Best Pract Res Clin Endocrinol Metab, 2011. 25(2): p. 251-70.

3.            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.

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.            Giannetta, E., et al., Subclinical male hypogonadism. Best Pract Res Clin Endocrinol Metab, 2012. 26(4): p. 539-50.

6.            Corona, G., et al., Characteristics of compensated hypogonadism in patients with sexual dysfunction. J Sex Med, 2014. 11(7): p. 1823-34.

7.            Isidori, A.M., E. Giannetta, and A. Lenzi, Male hypogonadism. Pituitary, 2008. 11(2): p. 171-80.

8.            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.

9.            Dandona, P. and S. Dhindsa, Update: Hypogonadotropic hypogonadism in type 2 diabetes and obesity. J Clin Endocrinol Metab, 2011. 96(9): p. 2643-51.

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

11.          Wu, F.C., et al., Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European Male Aging Study. J Clin Endocrinol Metab, 2008. 93(7): p. 2737-45.

12.          Harkonen, K., et al., The polymorphic androgen receptor gene CAG repeat, pituitary-testicular function and andropausal symptoms in ageing men. Int J Androl, 2003. 26(3): p. 187-94.

13.          Baumgartner, C., M.R. Blum, and N. Rodondi, Subclinical hypothyroidism: summary of evidence in 2014. Swiss Med Wkly, 2014. 144: p. w14058.

14.          Surks, M.I., TSH reference limits: new concepts and implications for diagnosis of subclinical hypothyroidism. Endocr Pract, 2013. 19(6): p. 1066-9.

15.          McDermott, M.T. and E.C. Ridgway, Subclinical hypothyroidism is mild thyroid failure and should be treated. J Clin Endocrinol Metab, 2001. 86(10): p. 4585-90.

16.          Rodondi, N., et al., Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA, 2010. 304(12): p. 1365-74.

17.          Gencer, B., et al., Subclinical thyroid dysfunction and cardiovascular outcomes among prospective cohort studies. Endocr Metab Immune Disord Drug Targets, 2013. 13(1): p. 4-12.

18.          Tseng, F.Y., et al., Subclinical hypothyroidism is associated with increased risk for all-cause and cardiovascular mortality in adults. J Am Coll Cardiol, 2012. 60(8): p. 730-7.

19.          Corona, G., et al., Low testosterone is associated with an increased risk of MACE lethality in subjects with erectile dysfunction. J Sex Med, 2010. 7(4 Pt 1): p. 1557-64.

20.          Hyde, Z., et al., Elevated LH predicts ischaemic heart disease events in older men: the Health in Men Study. Eur J Endocrinol, 2011. 164(4): p. 569-77.

21.          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.

22.          van den Beld, A., et al., Luteinizing hormone and different genetic variants, as indicators of frailty in healthy elderly men. J Clin Endocrinol Metab, 1999. 84(4): p. 1334-9.

23.          Bhasin, S., et al., Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle. J Clin Endocrinol Metab, 2005. 90(2): p. 678-88.

24.          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.

25.          Yun, Y.M., et al., Performance criteria for testosterone measurements based on biological variation in adult males: recommendations from the Partnership for the Accurate Testing of Hormones. Clin Chem, 2012. 58(12): p. 1703-10.

26.          Collier, C.P., et al., The significance of biological variation in the diagnosis of testosterone deficiency, and consideration of the relevance of total, free and bioavailable testosterone determinations. J Urol, 2010. 183(6): p. 2294-9.

27.          Liu, P.Y., et al., Aging attenuates both the regularity and joint synchrony of LH and testosterone secretion in normal men: analyses via a model of graded GnRH receptor blockade. Am J Physiol Endocrinol Metab, 2006. 290(1): p. E34-E41.

Last modified on Saturday, 14 October 2017 02:46
Monica Mollica

Medical Writer & Nutritionist

MSc in Nutrition

University of Stockholm & Karolinska Institute, Sweden 

   Baylor University, TX, USA

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