Health consequences of subclinical hypogonadism
April 2015
Characteristics of compensated hypogonadism in patients with sexual dysfunction. Corona G, Maseroli E, Rastrelli G, et al. The journal of sexual medicine. 2014;11(7):1823-1834.
In discussions about diagnosis and health consequences of hypogonadism, 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 which specifically was conducted to investigate the potential health ramifications of subclinical hypogonadism, shows that it should not be neglected.6
KEY POINTS
- There are three types of hypogonadism:
- Primary:
- low testosterone with elevated LH (due primarily to insufficient testicular function);
- Secondary:
low testosterone with low-normal LH (due primarily to insufficient hypothalamic-pituitary function);
- Subclinical (also called compensated hypogonadism):
normal testosterone levels with elevated LH levels.
- Primary:
Men with subclinical hypogonadism have more hypogonadal symptoms (primarily psychological) than 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 sufficient 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.
-
- low testosterone with elevated LH;
- 2. Secondary hypogonadism (also known as hypogonadotropic hypogonadism)
- low testosterone with low-normal LH;
-
due primarily to insufficient hypothalamic-pituitary function.
-
- low testosterone with low-normal LH;
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 study by Corona et al. sought to investigate the association of subclinical (compensated) hypogonadism with clinical and psychological characteristics of male subjects complaining of sexual dysfunction, studying in detail both subjective and objective sexual parameters. In addition, possible associations between subclinical hypogonadism and major cardiovascular event morbidity and mortality were examined.
By definition, total testosterone was significantly lower in men with overt hypogonadism (7.9 nmol/L) vs. men with subclinical hypogonadism (18.9 nmol/L) or men who were testosterone replete (17.6 nmol/L). LH levels were higher in subclinical hypogonadism (12.4 mU/L) vs. overt (3.4 mU/L) or testosterone replete (3.7 mU/L) men. When compared with testosterone replete (eugonadal) individuals, men with subclinical hypogonadism had higher SHBG levels, and therefore lower free testosterone levels (that is, less active testosterone).
While hypogonadism-related symptoms 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 testosterone replete men. Furthermore, subjects with subclinical hypogonadism more often reported psychiatric symptoms, when compared with both testosterone replete and overtly hypogonadal subjects, even after adjusting for age and smoking and drinking habits. In contrast, no difference in psychiatric symptoms was observed between testosterone replete and overt hypogonadal men.
Compared with testosterone replete men, men with subclinical or overt hypogonadism had an increased predicted cardiovascular risk, even after adjustment for BMI and drinking habits. No difference was observed between subclinical and overt hypogonadism. Thus, this study found that men with subclinical hypogonadism have a similar cardiovascular risk as do men with overt hypogonadism.
In a follow up of 4.3 years of these men19 it was found that major cardiovascular event related mortality was significantly higher in men with either subclinical or overt hypogonadism compared with testosterone replete 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 testosterone replete men, and have an equally elevated cardiovascular risk as do men with overt hypogonadism. Perhaps the most striking finding is that major cardiovascular event related mortality was similarly elevated in men with subclinical hypogonadism as in men with overt hypogonadism, 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 sufficient 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 heart disease.20 In addition, subclinical hypogonadism has been significantly associated with physical symptoms21, and an inverse relationship exists between LH and muscle strength and frailty, 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 testosterone replete 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 Aging 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 range25,26, 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
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- Bhasin S, Basaria S. Diagnosis and treatment of hypogonadism in men. Best practice & research. Clinical endocrinology & metabolism. 2011;25(2):251-270. 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
- Tajar A, Huhtaniemi IT, O'Neill TW, 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):1508-1516. Return to content
- Giannetta E, Gianfrilli D, Barbagallo F, Isidori AM, Lenzi A. Subclinical male hypogonadism. Best practice & research. Clinical endocrinology & metabolism. 2012;26(4):539-550. Return to content
- Corona G, Maseroli E, Rastrelli G, et al. Characteristics of compensated hypogonadism in patients with sexual dysfunction. The journal of sexual medicine. 2014;11(7):1823−1834. Return to content
- Isidori AM, Giannetta E, Lenzi A. Male hypogonadism. Pituitary. 2008;11(2):171-180. 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
- Dandona P, Dhindsa S. Update: Hypogonadotropic hypogonadism in type 2 diabetes and obesity. J. Clin. Endocrinol. Metab. 2011;96(9):2643-2651. Return to content
- Dhindsa S, Prabhakar S, Sethi M, Bandyopadhyay A, Chaudhuri A, Dandona P. Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. J. Clin. Endocrinol. Metab. 2004;89(11):5462-5468. Return to content
- Wu FC, Tajar A, Pye SR, 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):2737-2745. Return to content
- Harkonen K, Huhtaniemi I, Makinen J, et al. The polymorphic androgen receptor gene CAG repeat, pituitary-testicular function and andropausal symptoms in aging men. Int. J. Androl. 2003;26(3):187-194. Return to content
- Baumgartner C, Blum MR, Rodondi N. Subclinical hypothyroidism: summary of evidence in 2014. Swiss Med Wkly. 2014;144:w14058. Return to content
- Surks MI. TSH reference limits: new concepts and implications for diagnosis of subclinical hypothyroidism. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2013;19(6):1066-1069. Return to content
- McDermott MT, Ridgway EC. Subclinical hypothyroidism is mild thyroid failure and should be treated. J. Clin. Endocrinol. Metab. 2001;86(10):4585-4590. Return to content
- Rodondi N, den Elzen WP, Bauer DC, et al. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA. 2010;304(12):1365-1374. Return to content
- Gencer B, Collet TH, Virgini V, Auer R, Rodondi N. Subclinical thyroid dysfunction and cardiovascular outcomes among prospective cohort studies. Endocrine, metabolic & immune disorders drug targets. 2013;13(1):4−12. Return to content
- Tseng FY, Lin WY, Lin CC, et al. Subclinical hypothyroidism is associated with increased risk for all-cause and cardiovascular mortality in adults. J. Am. Coll. Cardiol. 2012;60(8):730-737. Return to content
- Corona G, Monami M, Boddi V, et al. Low testosterone is associated with an increased risk of MACE lethality in subjects with erectile dysfunction. The journal of sexual medicine. 2010;7(4 Pt 1):1557−1564. Return to content
- Hyde Z, Norman PE, Flicker L, et al. Elevated LH predicts ischaemic heart disease events in older men: the Health in Men Study. Eur. J. Endocrinol. 2011;164(4):569-577. 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
- van den Beld A, Huhtaniemi IT, Pettersson KS, et al. Luteinizing hormone and different genetic variants, as indicators of frailty in healthy elderly men. J. Clin. Endocrinol. Metab. 1999;84(4):1334-1339. Return to content
- Bhasin S, Woodhouse L, Casaburi R, 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):678-688. 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
- Yun YM, Botelho JC, Chandler DW, 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):1703-1710. Return to content
- Collier CP, Morales A, Clark A, Lam M, Wynne-Edwards K, Black A. 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):2294-2299. Return to content
- Liu PY, Pincus SM, Takahashi PY, 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):E34-E41. Return to content
