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9. Urologic Endocrinology
Keywords
AndrologyTestosteroneReplacement therapyHypogonadismDefinition of Hypogonadism in Elderly
Male hypogonadism is the failure of the testis to produce normal amounts of T, with the presence of symptoms and signs of androgen deficiency, and a normal number of spermatozoa resulting from a disruption of one or more levels of the HPG axis. Maintaining normal T levels is important in sustaining male secondary sexual characteristics, bone mass, muscle mass and strength, erythropoiesis, sexual and cognitive function, and well-being. The significant decrease in androgen action is associated with a syndrome consisting of osteoporosis, weakness, redistribution of body fat, hypoproliferative anemia, decreased libido and sexual function, malaise, and cognitive abnormalities.
Patients with primary hypogonadism often have a decrease in T levels, sperm count, or both, along with an increase in the concentration of pituitary gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Hypogonadotropic hypogonadism is characterized by a reduction of T production, sperm, or both, in the presence of normal or low concentrations of gonadotropins. Combined primary and secondary testicular failure may occur in several conditions, such as hemochromatosis, sickle cell disease, alcoholism, glucocorticoid treatment, and also in older men.
Several longitudinal studies have shown that aging is accompanied by a decrease in T levels. The Baltimore Longitudinal Study showed that the average annual decrease in total T was 3.2 ng/dL in men older than 53 years, representing approximately 1% per year for a normal lower limit of 325 ng/dL. The rate of fall in serum T with age varies among individuals and is affected by chronic diseases and medications. Aging is also accompanied by an increase in the concentration of sex hormone binding globulin (SHBG), whereby the concentration of free T (FT) is further reduced. Age-related androgen deficiency may be exacerbated in the presence of abdominal obesity that results in elevated estrogen levels and SHBG.
In some older men, this fall in T can lead to clinical signs and symptoms such as decreased libido, impotence, decreased growth of body hair, reduced muscle mass, fatigue, and decreased bone mass. This situation has been described as androgen deficiency in the elderly male, andropause, or LOH. The International Society of Andrology and the International Society for the Study of the Aging Male define the LOH as a clinical and biochemical syndrome associated with advanced age and characterized by typical symptoms and a deficiency in serum T levels. It may result in significant detriment in the quality of life and adversely affect the function of multiple organ systems. The symptoms most associated with hypogonadism are loss of libido, erectile dysfunction, decreased muscle mass and strength, increased body fat, decreased bone mineral density (BMD) and osteoporosis, decreased vitality, and depressed mood. None of these symptoms are specific of the low androgen state.
Epidemiology
One of the challenges of diagnosing and treating AOH is that its true prevalence is unclear. Epidemiological studies vary in how androgen deficiency (AD) was defined and in whether signs and symptoms were considered. In addition, even when men are categorized as having primary vs. secondary hypogonadism, the designation of secondary hypogonadism does not establish the extent to which the low T level is truly the consequence of inadequate gonadotropinsdsome of these men may well have a primary testicular failure component.
The breakdown of the primary vs. secondary distinction highlights the need for a more accurate definition of these patients (e.g., AOH).
These studies provide useful information, however, given that AOH is conceptualized as a subgroup of men with signs and symptoms who have an inadequate pituitary response to low T levels.
In the EMAS, the prevalence of hypogonadism was 13.8%; of these men, 85.5% were classified as having secondary hypogonadism [1]. The prevalence of hypogonadism in a group of 990 men seeking care for sexual dysfunction was 36% (359); of these men, 83.8% (301 out of 359) had secondary hypogonadism [2]. Similarly, 87.1% (727/835) of men with hypogonadism were classified as having secondary hypogonadism by Maseroli et al. [3] when reporting on a large series of patients presenting at an emergency department clinic (n°3847). Another report on an overlapping cohort from the same clinic noted that approximately 87.5% (724/827) of men with hypogonadism had secondary hypogonadism [4]. Importantly, among men with secondary hypogonadism, only 11% had a specific medical condition (e.g., genetics, surgery, radiotherapy, and trauma) that could account for the hypogonadism; the etiology in the remaining 89% was unknown [5].
Association with Common Comorbidities
Adult-onset hypogonadism more often occurs in men who have chronic disease states that are more common as men age, making it difficult to separate the influence of comorbidities from the influence of aging. High body mass index (BMI; calculated as the weight in kilograms divided by the height in meters squared), central adiposity, and the MetS are associated with low serum total T and to a esser extent low free T levels [6]. Low serum total T level predicts the development of central obesity and accumulation of intraabdominal fat [7]. Low total and free T levels are associated with an increased risk of developing MetS, independent of age and obesity. Lowering serum T levels in men with prostate cancer by treatment with GnRH analogs increased body fat mass [8]. These data are derived from observational studies and from meta-analyses of these studies; definitive answers regarding the causal relationship between T levels and obesity and the MetS require properly designed and adequately powered longitudinal studies. Ding et al. reported a meta-analysis of the relationship between diabetes, T, SHBG, and estradiol in cross-sectional and prospective studies [9]. Cross-sectional studies revealed that T levels were significantly lower among men with DM2. Prospective studies indicated that men with higher T levels had a 42% lower risk of DM2. Men with higher SHBG levels had a 52% lower risk of DM2. Estradiol levels were significantly elevated among men with diabetes compared to nondiabetic men. Kupelian et al. [10] analyzed data from the Massachusetts Male Aging Study and reported that low serum SHBG, low total T, and clinical AD were significantly associated with increased risk of developing MetS over time; this relationship was particularly strong among normal-weight, middle-aged men. Among veterans, men with low T levels had higher BMIs and were more likely to have diabetes than were men with normal T levels [11].
At a mean follow-up of 4.3 years, all-cause mortality was lower (20.1%) among men with normal T levels than among men with low T levels (34.9%).
In the EMAS, BMI was significantly associated with the risk for secondary hypogonadism [1]. In an overlapping population, Maseroli et al. [3] found that most men with secondary hypogonadism had metabolic disease, with BMI of 30 kg/m2 or more tripling the risk of LOH (defined as low T levels þ sexual symptoms). Among normal-weight men, only 1 of 6 men was diagnosed with LOH in contrast to nearly two-thirds of men with a BMI of more than 35 kg/m2 who had low T levels and inadequate gonadotropins. Men with other types of comorbidities also may present with AOH. The presence of one or more comorbidities was significantly associated with secondary hypogonadism in the EMAS. In the Hypogonadism in Males study, men were significantly more likely to have hypogonadism if they also had diabetes, hypertension, hyperlipidemia, asthma/chronic obstructive pulmonary disease, and/or prostate disease compared with men without these conditions [12]. The presence of low T level, therefore, may be a marker of poor health and the possible presence of comorbidities.
Diagnosis
It is critical that men presenting with possible signs and symptoms of AOH be systematically evaluated, accurately diagnosed, carefully counseled regarding the risks and benefits of treatment, and followed regularly if testosterone therapy (TT) is initiated.
Patients presenting with possible signs and symptoms of AOH should have a history and physical examination and morning total T level measured by a reliable assay. Men who are acutely or subacutely ill may have a low T level because of illness and their evaluation should be deferred. A low or borderline low total T value should be interpreted in the context of other known causes of low T level (e.g., medication effects). If a low value is found, then a second morning total T level should be measured in conjunction with LH and FSH values to assess for testicular vs. HP components of hypogonadism. The SHBG levels should be measured if there is reason to suspect an SHBG abnormality; in this case, free T or bioavailable T level should be assessed.
If the T level is low and the LH level is elevated, then the patient has primary hypogonadism. If the T (and free/bioavailable T when indicated) level is low and LH þ FSH levels are low or normal and the patient has signs and symptoms of AOH, then the patient may have AOH. If the total T level is extremely low (i.e., <150 ng/dL), then an endocrine pituitary workup including prolactin and a magnetic resonance imaging study is indicated. If no cause is identified, then a trial of TT after exclusion of contraindications and with lifestyle modifications and comorbidity management is appropriate. The panel strongly recommends that TT be combined with lifestyle modifications (e.g., dietary changes, exercise, and stress management) if the patient is overweight or obese, deconditioned, or sedentary, has other comorbidities such as hypertension or dyslipidemia, and/or reports elevated psychosocial stress levels. Patients who report signs or symptoms consistent with sleep apnea should be referred as necessary for the management of this condition. Obesity, DM2, and other comorbidities should be managed medically as necessary to optimize the patient’s overall health and to maximize the potential positive impact of TT. Once a man commences a trial of TT, he should be followed regularly for TT effectiveness and for adverse events. The panel endorses the timing and content of the Endocrine Society’s guidelines for monitoring of patients on TT.
Testosterone Replacement Therapy and Cardio Vascular Disease
Low Testosterone levels are associated with an increased risk of CVD. Meta-analyses suggest that T level is lower among patients with CVD but conflict regarding whether low T level is associated with increased CVD related mortality or risks are similar for hypogonadal and eugonadal men.
Several retrospective analyses have raised concern that T treatment may increase CVD risk [13]. Because of these concerns, the Food and Drug Administration recently required manufacturers of prescription T products to change their labeling to clarify the approved uses of these medications and to add information about a possible increased risk of heart attacks and strokes in patients who take T. Definitive evidence, however, regarding the short- and long-term cardiovascular risks of T treatment is not yet available because the published prospective trials were not designed or powered to examine cardiovascular end points. Findings reviewed below from meta-analyses that pooled findings across individual studies with these weaknesses, therefore, must be interpreted with caution.
There are multiple published meta-analyses that evaluated possible CVD risks associated with T treatment. Challenges to interpreting findings across meta-analyses include that these publications varied in study inclusion criteria, outcomes evaluated, and data analytic strategies. In addition, most authors report that the methodological quality of the included trials was poor to moderate.
A meta-analysis of 75 placebo-controlled randomized trials revealed no increase in CVD risk and a protective effect of T in men with metabolic disorders [14]. A meta-analysis of 24 placebo-controlled TT trials revealed no increased risk for major adverse cardiovascular events among men treated with T compared with men treated with placebo. Another meta-analysis of 19 randomized placebocontrolled trials also reported no increased risk for any cardiovascular event among T-treated men compared with placebo-treated men [15]. Fernández-Balsells et al. [16] conducted a meta-analysis of comparative, randomized, and nonrandomized studies and reported no differences between T-treated men and none T-treated men in all-cause mortality, need for coronary bypass surgery, or myocardial infarction. Haddad et al. [17] conducted a meta-analysis of 30 randomized placebo-controlled trials of TT and reported no significantly increased risk of CVD-related adverse events. However, although odds ratios (ORs) for any cardiovascular event (1.82; 95% CI, 0.78–4.23; P > 0.05) and for myocardial infarction (2.24; 95% CI, 0.50–10.0; P > 0.05), were nonsignificant, the ORs are large enough to call attention to the possibility that there may be CVD risk associated with TT. In this meta-analysis, men randomized to TT had twice the number of CVD-related adverse events as men in the placebo arm. An additional meta-analysis has reported that TT is significantly associated with an increased risk of CVD-related adverse events (OR, 1.54; 95% CI, 1.09–2.18; P < 0.05) [18]. These authors also note that CVD risks appear to be higher in trials not funded by the pharmaceutical industry (OR, 2.06; 95% CI, 1.34–3.17).
The need for definitive trials that can yield unambiguous findings is underscored by several recent publications that report possible risks of TT. Specifically, Layton et al. [19] reported findings from a retrospective cohort study using administrative insurance claims data. Men who received T injections had significantly higher rates of CVD events, hospitalizations, and death than did men who used T-containing gels; event rates for men using T-containing patches were similar to rates for gels. These data are potentially important but difficult to interpret because the study did not include assessment of whether men met criteria for TT (e.g., were hypogonadal) or compare event rates to those in none T-using men. Finkle et al. [20] reported that T-treated men had a higher rate of nonfatal myocardial infarction in the 90 days after receiving a T prescription compared with the 12 months before the prescription. These data are also difficult to interpret because of the lack of a control group of untreated men with low T level and the use of a comparison group of men prescribed phosphodiesterase type 5 inhibitors. Furthermore, Vigen et al. [13] reported that T-treated men had a higher rate of CVD adverse events (myocardial infarction, stroke, or death) compared with untreated men. These findings also are difficult to interpret given the statistical limitations of the analytic procedures.
Testosterone Replacement Therapy and Severe LUTS
In aging men lower urinary tract symptoms (LUTS) and benign prostatic hypertrophy (BPH) increase and adult hypogonadism/testosterone deficiency increases as well. Hypogonadism affects approximately 20% of elderly men with LUTS [21]. So, the combination is a common clinical scenario. There is a general, not proven, believe that Testosterone Replacement Therapy (TT) may exacerbate LUTS because of the growth-promoting effect of Testosterone(T) on the prostate during and after puberty. Therefore the question arises if patients with LUTS/BPH and hypogonadism can be treated with testosterone safely.
The EAU-Guidelines on Male Hypogonadism 2016 stated that “severe LUTS due to BPH is a contraindication against TT”, but no data are given [22]. The Endocrine Society Guidelines recommended in 2010 “no TT if the IPSS > 19” [23].
A recent systematic review on 14 RCT’s revealed only data from patients with mild LUTS and TRT. This review showed no statistically significant difference in IPSS from baseline to follow up after 1 year [24]. In a long term prospective non-randomised study TRT could decrease the IPSS significantly with only a marginal increase in prostate volume [25]. Other authors showed similar results in mild to moderate LUTS-patients on long term TRT [26]. But there are no data on TRT in men with severe LUTS (IPSS > 19).
Therefore, from clinical epidemiological studies, TRT can be given safely to patients with mild to moderate LUTS/BPH without fear of increasing LUTS and prostate volume; for severe LUTS no data are available. Further basic scientific research is necessary and RCT’s on TRT in patients with severe LUTS are needed.
Testosterone Replacement Therapy and Prostate Cancer
Historically, TT in the presence of previous or current Pca was contraindicated [27]. However the relationship between PCa and TT is not clear. Recent literature does not link high intrinsic testosterone levels with Pca [28] and low testosterone is associated with higher Gleason score cancers and poor prognosis [29]. Recent data from observational or controlled studies among hypogonadalmen without PCa and treated with TT found no evidence of higher risk of PCa development. The same lack of higher PCa risk is found in studies among men receiving TT after curative treatment for low-risk Pca [30]. The major criticism is the still short follow-up for these trials, which limits the possibility of detecting new-onset or recurrent PCa at a later stage. No trials have evaluated patients treated for high-risk PCa. Reports on TT in men on active surveillance are too scarce to draw meaningful conclusions.
Testosterone Replacement Therapy and Male Fertility
A key pathophysiological feature of hypogonadism is the testicular failure to T, either for a central disorder (hypothalamus or pituitary) or a primary deficiency. The phenotypes of these two clinical entities are very similar; the main difference is that in primary hypogonadism spermatogenesis tends to be impaired to a greater degree than Leydig cell function, whereas both functions are impaired to the same degree in men with secondary hypogonadism [31]. In both conditions, TT can lead to impaired spermatogenesis. Indeed, exogenous T reduces endogenous testosterone production by negative feedback on the hypothalamic-pituitary-gonadal axis and thus can lead to hypospermatogenesis with a severe reduction in sperm production up to azoospermia [32]. Therefore, both EAU guidelines on male infertility and on male hypogonadism highlight that generally TT should not be given to men who are considering fathering in the future or in case of male infertility. In this context, a Cochrane database review detailed that there is not enough evidence to evaluate the use of exogenous T for male subfertility [33]. Conversely, a number of studies discussed the recovery of spermatogenesis after use of exogenous T; overall, success rates of recovering spermatogenesis after exogenous T use are quite good. Of clinical importance, Liu et al. [34] reported that after TT suspension there were higher rates of sperm recovery with older age, Asian origin, shorter treatment duration, shorter-acting T preparations, higher sperm concentrations at baseline, faster suppression of spermatogenesis, and lower blood concentrations of LH at baseline. However, data outlines that not all men may recover spermatogenesis after TT, even long time after exogenous T discontinuation [35].
European Association of Urology Position Statement on the Role of the Urologist in the Management of Male Hypogonadism and Testosterone Therapy
Testosterone is a crucial sex hormone linked to the physiological development of the male gender across all stages of growth. It leads the integrity and maintains functioning of several systems and organs (including the male sexual and reproductive system, erythropoiesis, and bone, lipid, and glucose metabolism).
Obesity and poor general health are the main causes of late-onset male hypogonadism. Losing weight and improving lifestyle are important advice points for men with hypogonadism, since these will result in normalization of testosterone and reduce associated health risks.
Testosterone deficiency is linked to a number of signs and symptoms potentially affecting every man in his complexity and masculinity, and is therefore of close urological interest. For this reason, the urologist should attach importance to the need for knowledge, vocational education, and training in this specific area.
TT should be given only to symptomatic men in whom the deficiency has been confirmed by laboratory tests. Testosterone levels should be monitored regularly during treatment, along with hemoglobin, hematocrit, PSA and liver function.
Testosterone has beneficial effects on sexual function; TT may increase the effect of PDE5 inhibitor mono-therapy in men with LOH.
TT can be given to patients with mild to moderate LUTS. Further research in men with severe LUTS is needed. Caution should be exercised for men with significant prostatic enlargement and significant residual urine in the bladder.
Men wishing to preserve their fertility should be informed that TT may cause impairment of fertility, ranging from oligozoospermia to even azoospermia. Therefore, TT should not be used by hypogonadal (infertile) men who have an active wish to conceive children or undergo infertility treatment.
Current evidence does not support an association between TT and higher risk of developing PCa. However, sufficiently powered trials with long-term follow-up are needed to reach definite conclusions. PSA testing and digital rectal examination should be offered to men older than 45 year before commencing TTH, along with a discussion of the potential benefits and harms according to the EAU guidelines on PCa. TTH can be given to hypogonadal patients after curative treatment for low-risk PCa under close observation and after a prudent interval. Active PCa is still considered a contraindication to TTH.
Mammary carcinoma is an absolute contraindication to TTH.
Careful monitoring with clinical assessment is warranted during TTH in men with pre-existing CVD. TTH is contraindicated in men with severe chronic cardiac failure (New York Heart Association grade IV).
In men with elevated hematocrit (>0.54%) TTH is contraindicated; whenever possible the underlying condition should be corrected before TTH.
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