Can the administration of testosterone to men with late-onset hypogonadism be discontinued?

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Can the administration of testosterone to men with late-onset hypogonadism be discontinued? Keywords Late-onset hypogonadism Ageing male Testosterone Metabolic syndrome

Louis Gooren, MD, PhD Department of Endocrinology, The Vrije Universiteit Medical Center, Amsterdam, the Netherlands E-mail: [email protected]

Online 20 November 2008

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Louis Gooren Abstract Over the last decade, in addition to the classical forms of hypogonadism attributable to defects in testicular steroidogenesis (primary hypogonadism) or defects of the hypothalamo–pituitary unit (secondary hypogonadism), a new form has been defined: late-onset hypogonadism (LOH). LOH is partially based on the ageing process of the hypothalamo–pituitary–testicular axis leading to a diminution of the efficacy of testicular steroidogenesis, but a more significant determinant of decline in testosterone levels with ageing is disease and, in particular, the so-called metabolic syndrome. The main components of the metabolic syndrome are abdominal obesity, insulin resistance, hypertension and dyslipidaemia and these components are, in principle, remediable. Administration of testosterone to elderly men with the metabolic syndrome and hypogonadal values of testosterone leads to an improvement in the components of the metabolic syndrome which, in turn, could lead to an improvement in the own testicular hormone production eventually obviating the need for testosterone administration. There is very limited experience with this approach but this strategy deserves further exploration. ß 2008 WPMH GmbH. Published by Elsevier Ireland Ltd.

Until a good decade ago traditional endocrinology recognised two classical forms of hypogonadism: primary hypogonadism, with a primary testicular defect in the production of adequate amounts of testosterone (T), and secondary hypogonadism. In the latter, the hypothalamo–pituitary unit fails to produce appropriate amounts of luteinising hormone (LH) for stimulation of testicular hormone secretion. Treatment usually consisted of administration of T, or gonadotropins in the case of secondary, hypogonadotropic, hypogonadism if fertility was an issue. The defects lying at the base of these two forms of hypogonadism are congenital or acquired and are almost always irreversible conditions requiring lifelong treatment with T. Over the last decade a third form of hypogonadism has been defined, the age-associated decline in T levels, for which the term ‘late-onset hypogonadism’ has been proposed.

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Late-onset hypogonadism It is now well documented that plasma levels of total, bio-available and free T fall with age (for reviews, see [1,2]). Even though age, with changes in the hypothalamo–pituitary–testicular axis itself, impacts on the decline of plasma T over the lifetime [1], a picture has emerged from the most authoritative studies that ill health, rather than ageing itself, is a more potent predictor of a decline in testosterone levels during a man’s life. This observation finds, for instance, support in several reports from the prestigious Massachusetts Male Aging Study (MMAS) [3–6]. In one study from the MMAS apparent good health, defined as the absence of chronic illness, prescription medication, obesity, or excessive drinking, added 10–15% to the level of several androgens and attenuated the cross-sectional trends in testosterone and LH but did not otherwise

ß 2008 WPMH GmbH. Published by Elsevier Ireland Ltd.

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affect longitudinal or cross-sectional trends of a decline in T levels with age [4]. Chronic disease and high body mass index (BMI) significantly decrease total, free and bio-available T concentrations. Apparently healthy men have significantly higher median hormone concentrations at most time points than do non-apparently healthy men [5,7]. The paradoxical finding of that study was that longitudinal age trends were steeper than crosssectional trends suggesting that incident poor health in an individual may accelerate the agerelated decline in androgen levels [4]. As indicated above, numerous studies have found associations between features of the metabolic syndrome and a depression in plasma T [8–11], and changes in lifestyle (diet/ exercise) might partially prevent or redress the decline in androgen levels with ageing [12–14]. As indicated above, one of the main determinants of declining T levels with ageing is the metabolic syndrome [8,9]. In a prospective follow-up of a population-based sample of 942 men from the Massachusetts Male Ageing Study with complete anthropometry and hormone data at baseline (1987–1989; age = 40–70 years) and follow-up (1995–1997), free and total T and sex hormone-binding globulin (SHBG) were assessed using standardised methods. Obesity was associated with decreased levels of total T (TT), free T (FT) and SHBG at follow-up relative to baseline. For any given baseline concentration of TT, FT or SHBG, follow-up levels were lowest among men who remained obese or who became obese during follow-up. Obesity may predict a greater decline in testosterone and SHBG levels with age. Central adiposity may be a more important predictor than BMI [15]. The association of plasma T levels with features of the metabolic syndrome appears to be independent of age [16]. Obviously, epidemiological studies cannot unravel causal relationships but the evidence is very convincing that the decline in testosterone levels with age is accounted for by (age-related) disease rather than the calendar age of men.

The suppressive effect of adipose tissue on the synthesis of testosterone The adipocyte functions as an endocrine cell, producing and secreting adipocytokines/adi-

pokines, of which leptin is a prominent member. Leptin receptors are present on the Leydig cell and inhibit the testosterone generated by the administration of human chorionic gonadotropin (hCG) [17,18]. This finding was supported by studies that found a negative correlation between adiposity, insulin and leptin on the one hand and testosterone levels on the other [19,20]. Hyperinsulinaemia, as encountered in insulin resistance, might impair testosterone secretion by the Leydig cell, possibly directly since there are insulin receptors on the Leydig cell [21]. Insulin resistance impairs basal and hCG-stimulated testosterone secretion from the Leydig cell. Overcoming the hyperglycaemia by using the hyperinsulinaemic euglycaemic clamp technique led to a rise in plasma T levels [21]. That study showed an effect of testosterone on insulin sensitivity within 48 hours, so this was not an indirect effect mediated through changes in body composition. It has also been found in obese men that there is an attenuated pulse amplitude of LH while the LH pulse frequency is unaffected, thus producing a less strong stimulation of testicular testosterone production [22,23].

Changes in body weight and circulating levels of T/SHBG From the above it is clear that a large visceral fat depot leads to low T/low SHBG levels. Therefore, the effects of weight changes on plasma T levels are illuminating. In one experiment, 12 pairs of identical twins of young age were overfed for 120 days resulting in an average weight gain of 8 kilograms [24]. The excess fat was accumulated both subcutaneously and abdominally/viscerally with a clear preference for the latter localisation. Plasma T levels did not decline but SHBG levels did. Even though plasma T did not decline there was a significant negative correlation between changes in visceral fat and in plasma T levels. In other words: a gain in visceral fat led to a decrease in plasma T. A further positive correlation appeared between fasting insulin and changes in abdominal fat and testosterone. The latter is interesting in view of the fact that plasma levels of insulin are negatively correlated

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with SHBG and T levels [25]. In vitro studies have shown that insulin inhibits hepatic production of SHBG [25]. Lower SHBG levels lead to a fall in total plasma T; this leads, in the first instance, to an increase in FT and, subsequently, to a higher metabolic breakdown of T. It could be shown that a higher degree of visceral obesity was correlated with lower SHBG levels and with higher levels of androstanediol glucuronide (3a-diol-G), a metabolite of testosterone, indicating that a lowering of SHBG had induced a larger degree of testosterone metabolism. Plasma insulin appeared positively associated with 3a-diol-G [26]. Conversely, weight loss either produced an increase in testosterone itself [27] and/or an increase in SHBG. The rise in T levels correlated inversely with loss of abdominal fat and with plasma insulin. Collectively, these studies suggest that a high degree of visceral adiposity is associated with high insulin levels, low SHBG levels, low total plasma T levels and with an increase in the metabolites of testosterone, and vice versa. The above observations were in healthy young men, but similar observations have been made in men with obesity. In obese men on a weight-loss programme, loss of weight increased their serum T levels [28]. This has also been found in men with the metabolic syndrome [29,30]. During weight loss there was a stable SHBG–insulin relationship strongly suggesting a close metabolic link between SHBG and insulin [30]. Rapid weight loss with successful weight maintenance in abdominally obese men with the metabolic syndrome produced a dramatic increase in SHBG during weight maintenance accompanied by a sustained increase in free T levels [29]. So, the conclusion seems warranted that increases/ decreases in body weight are associated with higher/lower insulin levels, with lower/higher SHBG levels and with lower/higher plasma T levels. Apart from the increase in SHBG, a reduction in obesity probably leads to an improvement in the other obesity-associated factors described above that suppress testosterone production.

Low testosterone induces disease So, while it is clear that disease and, in particular, features of the metabolic syndrome,

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suppress circulating T levels, it has also been documented that low T induces the metabolic syndrome [6,31,32], dramatically demonstrated by findings in men with prostate cancer who undergo androgen ablation therapy [33–35]. A recent study showed convincingly that acute androgen deprivation reduces insulin sensitivity in young men [36]. Also very well documented is the fact that androgen deprivation leads to osteoporosis and increases bone fractures [37]. So, it is evident that low levels of T are a factor in the aetiology of common ailments in elderly men such as the metabolic syndrome and osteoporosis, and restoration of plasma T to normal values could be salutary and, potentially, break in to the vicious circle of low T and the metabolic syndrome.

Late-onset hypogonadism: to be treated with testosterone or not? The pivotal question is, evidently, whether the age-related decline of testosterone must be viewed as hypogonadism, i.e. a deficiency of testosterone manifesting with the signs and symptoms of insufficient androgen action, in the best case reversed by testosterone treatment. There is increasing evidence for a beneficial effect of testosterone treatment on visceral fat and other elements of the metabolic syndrome [38–42]. Testosterone inhibits the expression of the activity of lipoprotein lipase (the main enzymatic regulator of triglyceride uptake in the fat cell), preferentially in abdominal fat and less so in femoral fat and, maybe, it mobilises lipids from the visceral fat depot. Several studies have indeed confirmed that testosterone treatment reduces the waist circumference which, despite its simplicity, appears to be a valid parameter for the degree of visceral obesity [43–46]. A study of testosterone administration restoring testosterone levels to mid-normal values over a duration of 8–9 months [47] found a decrease in the visceral fat mass, a decrease in fasting glucose and lipid levels and an improvement in insulin sensitivity. In addition, a decrease in diastolic blood pressure was observed [47]. This was confirmed in another study [48] and, more recently, by other reports [42,49,50], but some studies have not shown the same result [51]. In a recent study by Page et al [43] testosterone administra-

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tion improved body composition (reduction in trunk fat, increase in lean body mass, improvement in plasma triglycerides, total cholesterol and low density lipoprotein (LDL), no impairment in high density lipoprotein (HDL)). Several studies of androgen administration have shown that normalisation of plasma T leads to an improvement in the profiles of the cytokines that are related to cardiovascular disease [52,53]. A meta-analysis of randomised controlled trials evaluating the effects of testosterone administration to middle-aged and ageing men on body composition showed a reduction of 1.6 kg (Confidence Interval (CI) = 2.5 to 0.6) in total body fat, corresponding to a 6.2% (CI = 9.2 to 3.3) variation from initial body fat, an increase in fat free mass of 1.6 kg (CI = 0.6 to 2.6), corresponding to a +2.7% (CI = 1.1 to 4.4) increase over baseline and no change in body weight. Testosterone also reduced total cholesterol by 0.23 mmol/l (CI = 0.37 to 0.10), especially in men with lower baseline T concentrations, with no change in LDL-cholesterol. A significant reduction in HDL-cholesterol was found only in studies with higher mean T-values at baseline or when androgens were non-aromatisable (-0.085 mmol/l, CI = 0.017 to 0.003) [54]. Testosterone therapy reduced insulin resistance and improved glycaemic control in hypogonadal men with type 2 diabetes, with improvements in cholesterol and visceral adiposity that together represent an overall reduction in cardiovascular risk [55], confirming the

findings of an earlier study [56]. These effects of testosterone might be indirect (via an improvement in body composition: less adipose tissue, more lean body mass), although there is also evidence that testosterone directly improves insulin sensitivity [21,36]. At the cellular level, there is now insight into the effects of androgen deprivation/ administration on fat mass. Testosterone regulates lineage determination in mesenchymal pluripotent cells by promoting their commitment to the myogenic lineage and inhibiting their differentiation into the adipogenic lineage through an androgen receptor-mediated pathway. The observation that differentiation of pluripotent cells is androgen-dependent provides a unifying explanation for the reciprocal effects of androgens on muscle and fat mass in men [57,58].

Parameters for successful treatment of the metabolic syndrome with testosterone The main components of the metabolic syndrome are abdominal obesity, insulin resistance, hypertension and dyslipidaemia. There is debate in the literature on whether combining these components or conditions has an added diagnostic or prognostic value [59]. Furthermore, there are three main definitions of the metabolic syndrome (Table 1). These definitions overlap but differ in their points of emphasis for the various compo-

Table 1 Various definitions for the metabolic syndrome. Definition of the metabolic syndrome

Waist circumference (cm) Waist hip ratio Body mass index (BMI) Triglycerides (mg/dl) HDL-cholesterol (mg/dl) Blood pressure (mmHg)

Fasting glucose (mg/dl) Fasting insulin

NCEP

WHO

At least 2 of >102

At least 2 of  94 > 0.9  30  150 < 35  140/90 or medication AND  110 Upper quartile of non-diabetic

 150 < 40  130/85 or medication  110

IDF  94 > 0.9  30  150 < 35  140/90 or medication

Insulin resistance

NCEP, National Cholesterol Education Programme [60]. WHO, World Health Organization [71]. IDF, International Diabetes Federation [72].

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nents. Thus, the National Cholesterol Education programme definition places equal emphasis on the various components of the metabolic syndrome [60]. The definition adopted by the World Health Organization (WHO) assigns greater value to insulin resistance as a required component of the metabolic derangements [61]. Finally, professional organisations have, increasingly, proposed definitions and in April 2005, the International Diabetes Federation drafted a single unifying definition. The main emphasis in that definition is central obesity defined by waist circumference and two or more of the following four factors: elevated triglycerides, reduced HDL-cholesterol, elevated blood pressure and dysglycaemia [62]. There are now group-specific thresholds for waist circumference (WC) for defining central adiposity: Europid, sub-Saharan African men and Eastern- and Middle-Eastern men, WC 94 cm; South Asian, Chinese and ethnic Southand Central-American men, WC 90 cm; Japanese men, WC 85 cm; women except Japanese women, WC 80 cm [62]. In fact, testosterone treatment of the metabolic syndrome is not always associated with a reduction in weight [38,43]. Upon measurement of body weight, an increase in lean body mass may mask the actual reduction in fat mass. Therefore, measurement of WC provides a much better guideline for the assessment of successful treatment. There are numerous studies supporting the contention that WC, and not BMI, explains obesity-related health risk. For a given WC value, overweight and obese persons and normal-weight persons have comparable health risks. Modest reduction of WC is associated with improvements in insulin sensitivity and lipid profile, with potentially favourable changes in serum adipocytokines [63]. The WC is measured in standing subjects as the minimum abdominal circumference between the xyphoid process and the umbilicus. The correct technique for the measurement of WC is measurement to the nearest 0.5 cm using a 1 cm-wide measuring tape. Measurements show inter-observer differences and are, therefore, best carried out by a single observer [64].

Can testosterone administration to men with late-onset hypogonadism be discontinued? The above information argues that administration of testosterone to men with late-onset hypogonadism (LOH) and features of the metabolic syndrome may improve their metabolic condition, particularly if this could be combined with changes in lifestyle and diet [65,66]. Improvements in mood might also be helpful in this regard [67]. Since the metabolic syndrome is a factor in the suppression of testicular steroidogenesis, improvement could increase the body’s own testosterone production, leading to circulating levels of testosterone no longer qualifying as hypogonadal and no longer requiring treatment with testosterone. In fact, population studies indicate that hypogonadal values of testosterone in an elderly population need not be permanent. There are intra-individual variations over time [68]. Changes in plasma T over time correlated inversely with age and BMI [69], so a decrease in BMI has the potential to increase plasma T values over time. The question of whether administration of testosterone to men with LOH can be discontinued can not be answered satisfactorily at present. There is, so far, only one report in the literature that has addressed this issue [70]. That study concluded that improvement in symptoms may remain after discontinuation of administration in patients with LOH, even though plasma T declines upon cessation of testosterone administration. The authors concluded that it might be worthwhile to discontinue testosterone administration if the symptoms of LOH have shown improvement over several months following its administration. That study is encouraging and may lead to a break away from the reflex response that testosterone administration should be lifelong in all men; which is the case for all of the classical forms of hypogonadism mentioned above, but need not necessarily be the consequence for testosterone administration to men with symptoms of LOH.

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This article is made possible thanks to an educational grant from Bayer Schering Pharma AG

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