Endocrine DOI 10.1007/s12020-014-0254-6
MINI REVIEW
Endocrine evaluation of erectile dysfunction Andrea Sansone • Francesco Romanelli Daniele Gianfrilli • Andrea Lenzi
•
Received: 13 March 2014 / Accepted: 25 March 2014 Springer Science+Business Media New York 2014
Abstract Erectile dysfunction is highly prevalent, affecting up to half of men in their 50–70s, and has been variably associated to a variety of causes including unhealthy lifestyles, such as smoking or overweight, or comorbidities such as hypertension, diabetes mellitus, and neurological disorders. General interest toward ED has exploded since the introduction of phosphodiesterase type 5 inhibitors—oral drugs that are widely accepted as the first line treatment in patients suffering from this conditions. In the last decade, the time lapse between first symptoms of sexual disorders and seeking of medical advice has greatly reduced. Unfortunately, none of the PDE5i has been proven curative, but rather acts as a symptomatic treatment. The availability of very active and safe drugs, however, diminished the space for diagnosis and search of etiological treatments. This is particularly true for the several endocrinopathies associated with ED. A number of epidemiological data support an inverse relationship between sexual health and testosterone levels, and it is well accepted that testosterone deficiency is a good marker of sexual and physical frailty. However, several other hormones, including LH, prolactin, TSH, and FT4 are involved in sexual functioning and should be investigated in a proper work-out of ED. Existing guidelines provide information almost entirely focusing on late-onset hypogonadism and therapeutic strategies; this mini-review aims to provide a wider spectrum of the diagnostic endocrine work-out of ED
A. Sansone (&) F. Romanelli D. Gianfrilli A. Lenzi Section of Medical Pathophysiology, Food Science and Endocrinology, Department of Experimental Medicine, ‘‘Sapienza’’ University of Rome, Viale Regina Elena, 324, 00161 Rome, Italy e-mail: [email protected]
patients unrevealing the complexity of conditions, overt or subclinical, which can affect ED. Keywords Erectile dysfunction Hormones Testosterone
Introduction Erectile dysfunction (ED) is defined by the DSM V as ‘‘a marked difficulty in obtaining an erection during sexual activity, a marked difficulty in maintaining an erection until the completion of sexual activity, or a marked decrease in erectile rigidity which have persisted for at least 6 months and which have caused significant distress in the individual’’ [1]. As recently reported [2], prevalence of erectile disorders increases steadily with aging [3]: ranging from 1 to 10 % in men younger than 40 and up to 70–100 % in men older than 70 years. Because of the increasingly otherwise healthy elderly population, ED has become a major health problem, and interest in male sexual health has greatly increased in the recent decades [4]. Patients have come to understand that sexual disorders are symptoms of underlying diseases which might lead to worse outcomes if untreated, and ask for medical assistance more often and with shorter delay than in the past [5]: ED might be the first sign of a silent coronary disease and a predictor of severe cardiovascular events [6], especially in diabetes [7]. However, the use of phosphodiesterase type 5 inhibitors, which have greatly helped overcome the ‘‘taboo’’ of ED, has on the other hand, led to a significant amount of missed diagnoses: patients often self-prescribe these drugs in order to improve their erectile function, but fail to treat the disease which caused this symptom [8]. Endocrine alterations are often involved [9, 10]: the aim of
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this mini-review is to provide a quick, easy-to-read reference which might be helpful to all endocrinologists during their practice.
Testosterone Testosterone is undoubtedly the most extensively studied hormone involved in male sexual health. Androgens modulate endothelial function in penile vessels and act on structure, function, and innervation of trabecular smooth muscle cells [11, 12]: still, the European Male Aging Study (EMAS) showed that two-thirds of the patients who experienced ED are eugonadal [13], proving that testosterone deficiency (TD) could be one, but certainly not the only factor behind sexual impairment. TD is a clinical and biochemical syndrome associated with age and comorbidities, characterized by a deficiency of testosterone and by relevant symptoms, which vary depending on the age of onset, from defects of virilization in fetal or early life to milder, often unspecified symptoms in adult age [14]. Signs of TD are frequently mild and nonspecific, including reduced testicular size, gynecomastia, alterations in testicular consistency and hair distribution [15]. Among the unspecified symptoms of TD in adult age—also defined as late-onset hypogonadism (LOH)—the most specific ones are undoubtedly reduced sexual desire and decreased spontaneous erections [16, 17]. ED, although more prevalent in patients with lower serum testosterone, is less clearly associated with androgen deficiency [18]. Questionnaires and structured interviews [19–21] have been introduced in order to facilitate screening for TD; however, a diagnosis of TD cannot be made without biochemical confirmation. A serum sample for the determination of total testosterone is recommended: blood samples should be drawn in the morning, after a night’s fasting. Existing guidelines [22–25] do not provide universal consensus on lower limits of normal for testosterone measurements; however, total serum testosterone [12 nmol/l is by common agreement considered normal, and levels \8 nmol/l might eventually require treatment. Impairment of sexual function is frequent with total testosterone levels below 8 nmol/l, leaving a ‘‘grey zone’’ within 8 and 12 nmol/l in which the effects of testosterone are dependent on individual sensitivity to androgens. In this gray area, measuring free testosterone might be helpful in diagnosing TD; free testosterone should not be requested, unless measured by equilibrium dialysis [26]; in most circumstances, calculating free testosterone from total testosterone and sex hormone-binding globulin (SHBG) provides an adequate result [27]. A tool for calculating free testosterone has been made available from the International Society for the Study
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of the Aging Male (ISSAM) and is freely available online [28]. Outside of the gray area, guidelines suggest repeating testing for total testosterone together with SHBG, luteinizing hormone (LH) and prolactin should the first sample result in low total testosterone concentration: LH allows for differential diagnosis between primary and secondary TD, and prolactin measurement is indicated in secondary TD, as will be explained later in this article. Of particular interest are those subjects with subclinical hypogonadism [29] since there is growing consensus that these subjects, as in Klinefelter’s syndrome, may benefit from androgen replacement therapy; however, no data are currently available on ED. For the practical point of the present review, an elevated LH requires a full clinical assessment of testicular function. SHBG is usually requested as a second-level determination in the endocrine assessment of sexual disorders. Many drugs and conditions may increase SHBG levels in men: this might lead to reduced free and bioavailable testosterone in patients using antiepilectic drugs, tamoxifen, and estrogens, or suffering from hyperthyroidism or liver disease [30–36]. HIV and anti-retroviral therapies are also associated with a significant increase of SHBG, masking the diagnosis of hypogonadism based only on total testosterone measurement. On the contrary, SHBG can be lowered by a number common conditions, among which the most important are obesity and hyperinsulinemia [37]. As for total testosterone, there is no definite consensus on normal levels for free testosterone: however, a lower limit of 225 pmol/l is accepted by most authors. It has been hypothesized that erectile function is maintained at lower threshold values of testosterone; however, in the presence of comorbidities, this threshold value might be different, thus explaining how different levels of testosterone might cause different effects in young men and in elderly people [38]. In patients presenting symptoms of TD with total testosterone levels between 8 and 12 nmol/l, testosterone replacement therapy may be envisaged for at least 6 months, with continuation only in case of substantial benefits to the patients [39]. Elevated estradiol levels have been associated to more severe ED and greater sexual distress: it has been hypothesized that an estradiol-to-testosterone imbalance might reduce NO-mediated cavernosal smooth muscle relaxation and intracavernosal pressure, thus playing a role in the pathogenesis of erectile disorders, but more studies are required in order to fully investigate the role of estradiol in the mechanisms of erection [40–42]. Decreased dihydrotestosterone (DHT) has been recently investigated as another possible cause of ED [43]: however, this contrasts with the results of the EMAS, in which DHT was not associated with changes in overall sexual function [44]. Until its involvement in erectile function
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becomes clearer, DHT should not be routinely measured in patients suffering from ED.
Prolactin Mean prevalence of hyperprolactinemia is 10 per 100,000 in men and approximately 30 per 100,000 in women [45]. There are many causes of hyperprolactinemia, from physiological (like stress, orgasm, and physical exercise) to pathological conditions [46]. A detailed description on differential causes of hyperprolactinemia is beyond the scope of this mini-review, but we wish to highlight that drug-induced hyperprolactinemia is far more prevalent than generally thought. In addition, hypothyroidism is an often neglected cause of hyperprolactinemia in men. The thyrotropin-releasing hormone (TRH) also acts as a stimulus for prolactin production, and the feedback mechanisms leading to increased TSH in hypothyroidism also cause elevated prolactin levels [47, 48]. Pituitary tumors— prolactinomas—are the most frequent primary cause of organic hyperprolactinemia [49]. The diagnosis requires magnetic resonance imaging of the pituitary gland, to be requested only after a secondary form of hyperprolactinemia is excluded by accurate medical and drug history and retesting of prolactin. Of notice, prolactinomas produced several fold elevations of PRL levels (usually [10 times the upper limit of normal range), while secondary forms produced more often two- to five-fold increase. On practical basis, serum prolactin should be measured after a rest of at least 20 min; in the case of prolactin [20 ng/ml, the testing should be repeated after discontinuation of any drugs which might increase prolactin levels, possibly at least 20 min after insertion of a cannula. Dynamic testing of prolactin secretion is a second line investigation. If elevated prolactin levels are confirmed after retesting and after ruling out any other possible cause of hyperprolactinemia, magnetic resonance imaging should be performed: guidelines suggest suspecting a pituitary tumor if prolactin levels are [250 ng/ml, with values [500 ng/ml diagnostic of a macroprolactinoma [50]. In men, hyperprolactinemia is frequently associated with hypoactive sexual desire [51]; this might be explained by the reduced secretion of LH secondary to the inhibition of the pulsatile secretion GnRH, but also by a direct effect of prolactin on sexual desire [52, 53]. Based on experimental studies on dogs, a direct role of prolactin on erectile function has been hypothesized [54, 55]: direct inhibition of smooth muscle relaxation of the penile corpus cavernosum has been proposed as the cause of prolactininduced ED. In human males, a marked decrease in nocturnal erections has been observed in patients with severe hyperprolactinemia [56]; however, in more recent studies,
ED has been considered secondary to the prolactin-related testosterone decrease more than to prolactin per se. Although there still seems to be no definite evidence of the role of prolactin in ED, it is worth noting that sexual dysfunctions, mainly ED and reduced libido, are the most common clinical presentations of patients with hyperprolactinemia [57].
Thyroid hormones Hyperthyroidism has a 0.2 % prevalence in men [58], and overt hypothyroidism, though strongly decreased in the last few years, is still up to 0.12 % [59]. Hyperthyroidism is a common cause of acquired premature ejaculation [60, 61], and a relationship between hypothyroidism and low sexual drive has been suggested. As for what concerns ED, no definite evidence has been acquired: previous studies had found a correlation between both hypothyroidism and hyperthyroidism and erectile disorders [62, 63], but a recent evaluation by the EMAS study team [64] has concluded that performing an universal screening of thyroid function in every patient with ED is not cost-effective. However, considering the role of TRH in stimulating both TSH and prolactin, the mood disturbances associated with both forms of thyroid disease, and the increase in SHBG secondary to hyperthyroidism, this matter of debate is far from conclusive. In conclusion, the assessment should be performed on the basis of an accurate history-taking investigating the other more specific symptoms of hypo- or hyperthyroid function.
Growth hormone Secretion of GH is increased by androgens and, similarly to testosterone, is negatively affected by aging [65]. GH excess is mostly due to a pituitary GH-secreting tumor, with a prevalence of 20–60 cases per million. The presence of a tumoral mass might lead to impaired production of other pituitary hormones: hypogonadism is a common presentation of acromegaly [66]. Compression of the pituitary stalk might also cause hyperprolactinemia; furthermore, due to the similarities between the two receptors, GH might also mimic the effects of prolactin [67], inducing galactorrhea and ED. However, considering the rarity of the disease and the peculiarity of its signs and symptoms, first-line examination of GH for ED is not recommended. GH deficit in young age has serious consequences, whereas in adult age it becomes more difficult to diagnose and treat; there is no definite consensus if treatment should be required or suggested in all patients, or if there is only a specific subset of subjects in which treatment might be
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Endocrine Table 1 Suggestions for and against hormonal evaluation: survey of available guidelines and statements regarding endocrine assessment of ED Hormone Testosterone
Prolactin
FT3/FT4
GH, IGF-1
DHEA, DHEAS
Cortisol
Author(s)
Year
Quote
Wang et al. [22]
2008
‘‘Manifestations of hypogonadism include erectile dysfunction’’
Ghanem et al. [10]
2013
‘‘Fasting blood sugar, serum total testosterone, prolactin levels, and a lipid profile may reveal significant comorbid conditions’’
Buvat et al. [14]
2013
‘‘Hypoactive sexual desire and reduced nocturnal and morning erections are clearly associated with estosterone deficiency, while the association with reduced sex-induced erection is less evident’’
Wespes et al. [23]
2013
‘‘Patients should be screened for symptoms of possible hypogonadism; hormonal test include a morning sample of total testosterone’’
Galdiero et al. [51]
2012
‘‘Chronic hyperprolactinemia is responsible for an inhibition in sexual behavior and activity […] and penile erection in men’’
Ghanem et al. [10]
2013
‘‘Fasting blood sugar, serum total testosterone, prolactin levels, and a lipid profile may reveal significant comorbid conditions’’
Carani et al. [61]
2005
‘‘The main sexological complaint found in our cohort of hyperthyroid patients was PE, whereas in hypothyroid subjects, it was DE […] Most patients with a chronic thyroid disease experience some sexual symptoms, such as PE in hyperthyroidism, DE in hypothyroidism, and HSD and ED in both conditions’’
Veronelli et al. [62]
2006
‘‘ED is a frequent finding in patients affected by thyroid disease […] we found no association between ED and kind of disease, duration of disease, presence or absence of thyroid antibodies, kind of treatment and TSH levels’’
Krassas et al. [63]
2008
‘‘Screening for thyroid dysfunction in men presenting with ED is recommended’’
Corona et al. [64]
2012
‘‘Erectile function should be evaluated in all individuals with hyperthyroidism. Conversely, assessment of thyroid function cannot be recommended as routine practice in all ED patients’’
Galdiero et al. [51]
2012
‘‘Sexual function has not been extensively studied in patients with GHD… No study has ever specifically evaluated the effect of GH replacement therapy on sexual function’’
Maggi et al. [53]
2013
‘‘GH or IGF-1 determinations are not recommended as first-line examination in male subjects with sexual dysfunction’’
Maggi et al. [53]
2013
‘‘Routine measurement of serum DHEA or DHEA/S is not recommended in men with sexual dysfunction’’
Reiter et al. [74]
1999
‘‘The results suggest that oral DHEA treatment may be of benefit in the therapy of ED’’
Morales et al. [75]
2009
‘‘This study did not suggest a clinical benefit of DHEA supplementation in men with hypoandrogenism and sexual dysfunction’’
¨ ckert et al. [79] U
2003
‘‘Our results strongly suggest an inhibitory role for cortisol in the mechanism of male sexual response and behaviours, including the control of penile erection’’
Kobori et al. [80]
2009
‘‘The active forms of cortisol (Bio-F and Sa-F) showed negative correlations with sexual function in men […] ED is thought to occur in patients with high levels of cortisol because of the relations between cortisol and stress’’
Granata et al. [84]
2013
‘‘Multiple linear regression analysis confirmed the role of cortisol, UFC, and upright PRA in the variation of EF’’
PE premature ejaculation, ED erectile dysfunction, GHD GH deficiency
beneficial [68, 69]. Only a small controlled trial assessed erectile function in patients treated with GH, finding no effect on mood and amount of sexual intercourse [70]. Further studies are required in order to shed a light on this topic.
DHEA and DHEAS In recent years, DHEA has come into the spotlight as a ‘‘youth hormone,’’ following its age-related reduction [71, 72]; the wide availability of DHEA as an over-the-counter drug in many countries has contributed to the widespread
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use of this drug as an alleged rejuvenation treatment. However, even if DHEAS was the only hormone whose concentration was inversely correlated to the prevalence of ED in the Massachusetts Male Aging Study [73], definite evidence of the usefulness of treatment with DHEA is still missing; in randomized, double-blind, placebo-controlled trials, ED either did [74] or did not [75] improve during treatment with DHEA. Decline in serum DHEAS seems to be an age-related process rather than a cause of ED [76]. The Italian Study Group on Geriatric Endocrinology concluded in a consensus document published in 2006 that treatment with DHEA does not improve mood, cognition, or well-being in elderly people [77]: recent reviews seem to
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confirm this [78]. Routine DHEAS evaluation is not recommended until more definite evidence of its role in erectile function is agreed upon.
disorders. Adequate biochemical monitoring should be performed in all patients, including blood glucose, lipid profile, and evaluation of kidney and liver functions [87, 88].
Cortisol
Conflict of interest
It has been speculated if cortisol, acting as a stress hormone, has a role in erectile function; however, data on this topic are sparse and far from conclusive. An inhibitory role for cortisol has been postulated in male sexual health [79]; however, since ED is a powerful stressor, it is difficult to discriminate whether hypercortisolism is the cause or consequence of an enhanced hypothalamic–pituitary– adrenal axis [80, 81], besides the obvious Cushing’s syndrome. The most common cause of hypercortisolism is an inadequate glucocorticoid treatment; Cushing’s syndrome on the other hand is a rare condition, with an incidence rate between 1.8 and 2.4 patients/million per year [82]. It is also important to remember that hypercortisolism perpetuates many features of metabolic syndrome, including impaired glucose tolerance, hypertension, dyslipidemia, atherosclerosis and hypercoagulability [83], which are also involved in the pathogenesis of ED. More interesting is the role of adrenal insufficiency and its replacement. Primary adrenal insufficiency, or Addison’s disease, is a rare disease with a prevalence of 100 per million; the secondary form of adrenal insufficiency, caused by a pituitary dysfunction, is far more common, its prevalence being 400 per million [84]. In a recent study in 12 patients diagnosed with Addison’s disease, it has been observed that the onset of adrenal insufficiency is also characterized by sexual dysfunctions, reversible with adequate hormone replacement therapy [85]. It is not possible yet to conclude that the simple correction of chronic hypercortisolism can revert metabolic alterations [86], but greater efforts in improving steroid replacement therapy are auspicable (Table 1).
Conclusion Many hormones are somehow involved in the pathogenesis of ED. Guidelines suggest testing for testosterone only as a first-line assessment; however, based on available evidence, in order to reduce time lag between first symptoms and complete diagnosis, evaluation of TSH, LH, and prolactin might be performed together with testosterone assessment. There is still no definite evidence of the role of estradiol, DHT, DHEA, DHEAS, cortisol, GH, or IGF-1 in ED; until their clinical significance is better described, measurement of these hormones should not be recommended in men with erection
None.
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MINI REVIEW
Endocrine evaluation of erectile dysfunction Andrea Sansone • Francesco Romanelli Daniele Gianfrilli • Andrea Lenzi
•
Received: 13 March 2014 / Accepted: 25 March 2014 Springer Science+Business Media New York 2014
Abstract Erectile dysfunction is highly prevalent, affecting up to half of men in their 50–70s, and has been variably associated to a variety of causes including unhealthy lifestyles, such as smoking or overweight, or comorbidities such as hypertension, diabetes mellitus, and neurological disorders. General interest toward ED has exploded since the introduction of phosphodiesterase type 5 inhibitors—oral drugs that are widely accepted as the first line treatment in patients suffering from this conditions. In the last decade, the time lapse between first symptoms of sexual disorders and seeking of medical advice has greatly reduced. Unfortunately, none of the PDE5i has been proven curative, but rather acts as a symptomatic treatment. The availability of very active and safe drugs, however, diminished the space for diagnosis and search of etiological treatments. This is particularly true for the several endocrinopathies associated with ED. A number of epidemiological data support an inverse relationship between sexual health and testosterone levels, and it is well accepted that testosterone deficiency is a good marker of sexual and physical frailty. However, several other hormones, including LH, prolactin, TSH, and FT4 are involved in sexual functioning and should be investigated in a proper work-out of ED. Existing guidelines provide information almost entirely focusing on late-onset hypogonadism and therapeutic strategies; this mini-review aims to provide a wider spectrum of the diagnostic endocrine work-out of ED
A. Sansone (&) F. Romanelli D. Gianfrilli A. Lenzi Section of Medical Pathophysiology, Food Science and Endocrinology, Department of Experimental Medicine, ‘‘Sapienza’’ University of Rome, Viale Regina Elena, 324, 00161 Rome, Italy e-mail: [email protected]
patients unrevealing the complexity of conditions, overt or subclinical, which can affect ED. Keywords Erectile dysfunction Hormones Testosterone
Introduction Erectile dysfunction (ED) is defined by the DSM V as ‘‘a marked difficulty in obtaining an erection during sexual activity, a marked difficulty in maintaining an erection until the completion of sexual activity, or a marked decrease in erectile rigidity which have persisted for at least 6 months and which have caused significant distress in the individual’’ [1]. As recently reported [2], prevalence of erectile disorders increases steadily with aging [3]: ranging from 1 to 10 % in men younger than 40 and up to 70–100 % in men older than 70 years. Because of the increasingly otherwise healthy elderly population, ED has become a major health problem, and interest in male sexual health has greatly increased in the recent decades [4]. Patients have come to understand that sexual disorders are symptoms of underlying diseases which might lead to worse outcomes if untreated, and ask for medical assistance more often and with shorter delay than in the past [5]: ED might be the first sign of a silent coronary disease and a predictor of severe cardiovascular events [6], especially in diabetes [7]. However, the use of phosphodiesterase type 5 inhibitors, which have greatly helped overcome the ‘‘taboo’’ of ED, has on the other hand, led to a significant amount of missed diagnoses: patients often self-prescribe these drugs in order to improve their erectile function, but fail to treat the disease which caused this symptom [8]. Endocrine alterations are often involved [9, 10]: the aim of
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this mini-review is to provide a quick, easy-to-read reference which might be helpful to all endocrinologists during their practice.
Testosterone Testosterone is undoubtedly the most extensively studied hormone involved in male sexual health. Androgens modulate endothelial function in penile vessels and act on structure, function, and innervation of trabecular smooth muscle cells [11, 12]: still, the European Male Aging Study (EMAS) showed that two-thirds of the patients who experienced ED are eugonadal [13], proving that testosterone deficiency (TD) could be one, but certainly not the only factor behind sexual impairment. TD is a clinical and biochemical syndrome associated with age and comorbidities, characterized by a deficiency of testosterone and by relevant symptoms, which vary depending on the age of onset, from defects of virilization in fetal or early life to milder, often unspecified symptoms in adult age [14]. Signs of TD are frequently mild and nonspecific, including reduced testicular size, gynecomastia, alterations in testicular consistency and hair distribution [15]. Among the unspecified symptoms of TD in adult age—also defined as late-onset hypogonadism (LOH)—the most specific ones are undoubtedly reduced sexual desire and decreased spontaneous erections [16, 17]. ED, although more prevalent in patients with lower serum testosterone, is less clearly associated with androgen deficiency [18]. Questionnaires and structured interviews [19–21] have been introduced in order to facilitate screening for TD; however, a diagnosis of TD cannot be made without biochemical confirmation. A serum sample for the determination of total testosterone is recommended: blood samples should be drawn in the morning, after a night’s fasting. Existing guidelines [22–25] do not provide universal consensus on lower limits of normal for testosterone measurements; however, total serum testosterone [12 nmol/l is by common agreement considered normal, and levels \8 nmol/l might eventually require treatment. Impairment of sexual function is frequent with total testosterone levels below 8 nmol/l, leaving a ‘‘grey zone’’ within 8 and 12 nmol/l in which the effects of testosterone are dependent on individual sensitivity to androgens. In this gray area, measuring free testosterone might be helpful in diagnosing TD; free testosterone should not be requested, unless measured by equilibrium dialysis [26]; in most circumstances, calculating free testosterone from total testosterone and sex hormone-binding globulin (SHBG) provides an adequate result [27]. A tool for calculating free testosterone has been made available from the International Society for the Study
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of the Aging Male (ISSAM) and is freely available online [28]. Outside of the gray area, guidelines suggest repeating testing for total testosterone together with SHBG, luteinizing hormone (LH) and prolactin should the first sample result in low total testosterone concentration: LH allows for differential diagnosis between primary and secondary TD, and prolactin measurement is indicated in secondary TD, as will be explained later in this article. Of particular interest are those subjects with subclinical hypogonadism [29] since there is growing consensus that these subjects, as in Klinefelter’s syndrome, may benefit from androgen replacement therapy; however, no data are currently available on ED. For the practical point of the present review, an elevated LH requires a full clinical assessment of testicular function. SHBG is usually requested as a second-level determination in the endocrine assessment of sexual disorders. Many drugs and conditions may increase SHBG levels in men: this might lead to reduced free and bioavailable testosterone in patients using antiepilectic drugs, tamoxifen, and estrogens, or suffering from hyperthyroidism or liver disease [30–36]. HIV and anti-retroviral therapies are also associated with a significant increase of SHBG, masking the diagnosis of hypogonadism based only on total testosterone measurement. On the contrary, SHBG can be lowered by a number common conditions, among which the most important are obesity and hyperinsulinemia [37]. As for total testosterone, there is no definite consensus on normal levels for free testosterone: however, a lower limit of 225 pmol/l is accepted by most authors. It has been hypothesized that erectile function is maintained at lower threshold values of testosterone; however, in the presence of comorbidities, this threshold value might be different, thus explaining how different levels of testosterone might cause different effects in young men and in elderly people [38]. In patients presenting symptoms of TD with total testosterone levels between 8 and 12 nmol/l, testosterone replacement therapy may be envisaged for at least 6 months, with continuation only in case of substantial benefits to the patients [39]. Elevated estradiol levels have been associated to more severe ED and greater sexual distress: it has been hypothesized that an estradiol-to-testosterone imbalance might reduce NO-mediated cavernosal smooth muscle relaxation and intracavernosal pressure, thus playing a role in the pathogenesis of erectile disorders, but more studies are required in order to fully investigate the role of estradiol in the mechanisms of erection [40–42]. Decreased dihydrotestosterone (DHT) has been recently investigated as another possible cause of ED [43]: however, this contrasts with the results of the EMAS, in which DHT was not associated with changes in overall sexual function [44]. Until its involvement in erectile function
Endocrine
becomes clearer, DHT should not be routinely measured in patients suffering from ED.
Prolactin Mean prevalence of hyperprolactinemia is 10 per 100,000 in men and approximately 30 per 100,000 in women [45]. There are many causes of hyperprolactinemia, from physiological (like stress, orgasm, and physical exercise) to pathological conditions [46]. A detailed description on differential causes of hyperprolactinemia is beyond the scope of this mini-review, but we wish to highlight that drug-induced hyperprolactinemia is far more prevalent than generally thought. In addition, hypothyroidism is an often neglected cause of hyperprolactinemia in men. The thyrotropin-releasing hormone (TRH) also acts as a stimulus for prolactin production, and the feedback mechanisms leading to increased TSH in hypothyroidism also cause elevated prolactin levels [47, 48]. Pituitary tumors— prolactinomas—are the most frequent primary cause of organic hyperprolactinemia [49]. The diagnosis requires magnetic resonance imaging of the pituitary gland, to be requested only after a secondary form of hyperprolactinemia is excluded by accurate medical and drug history and retesting of prolactin. Of notice, prolactinomas produced several fold elevations of PRL levels (usually [10 times the upper limit of normal range), while secondary forms produced more often two- to five-fold increase. On practical basis, serum prolactin should be measured after a rest of at least 20 min; in the case of prolactin [20 ng/ml, the testing should be repeated after discontinuation of any drugs which might increase prolactin levels, possibly at least 20 min after insertion of a cannula. Dynamic testing of prolactin secretion is a second line investigation. If elevated prolactin levels are confirmed after retesting and after ruling out any other possible cause of hyperprolactinemia, magnetic resonance imaging should be performed: guidelines suggest suspecting a pituitary tumor if prolactin levels are [250 ng/ml, with values [500 ng/ml diagnostic of a macroprolactinoma [50]. In men, hyperprolactinemia is frequently associated with hypoactive sexual desire [51]; this might be explained by the reduced secretion of LH secondary to the inhibition of the pulsatile secretion GnRH, but also by a direct effect of prolactin on sexual desire [52, 53]. Based on experimental studies on dogs, a direct role of prolactin on erectile function has been hypothesized [54, 55]: direct inhibition of smooth muscle relaxation of the penile corpus cavernosum has been proposed as the cause of prolactininduced ED. In human males, a marked decrease in nocturnal erections has been observed in patients with severe hyperprolactinemia [56]; however, in more recent studies,
ED has been considered secondary to the prolactin-related testosterone decrease more than to prolactin per se. Although there still seems to be no definite evidence of the role of prolactin in ED, it is worth noting that sexual dysfunctions, mainly ED and reduced libido, are the most common clinical presentations of patients with hyperprolactinemia [57].
Thyroid hormones Hyperthyroidism has a 0.2 % prevalence in men [58], and overt hypothyroidism, though strongly decreased in the last few years, is still up to 0.12 % [59]. Hyperthyroidism is a common cause of acquired premature ejaculation [60, 61], and a relationship between hypothyroidism and low sexual drive has been suggested. As for what concerns ED, no definite evidence has been acquired: previous studies had found a correlation between both hypothyroidism and hyperthyroidism and erectile disorders [62, 63], but a recent evaluation by the EMAS study team [64] has concluded that performing an universal screening of thyroid function in every patient with ED is not cost-effective. However, considering the role of TRH in stimulating both TSH and prolactin, the mood disturbances associated with both forms of thyroid disease, and the increase in SHBG secondary to hyperthyroidism, this matter of debate is far from conclusive. In conclusion, the assessment should be performed on the basis of an accurate history-taking investigating the other more specific symptoms of hypo- or hyperthyroid function.
Growth hormone Secretion of GH is increased by androgens and, similarly to testosterone, is negatively affected by aging [65]. GH excess is mostly due to a pituitary GH-secreting tumor, with a prevalence of 20–60 cases per million. The presence of a tumoral mass might lead to impaired production of other pituitary hormones: hypogonadism is a common presentation of acromegaly [66]. Compression of the pituitary stalk might also cause hyperprolactinemia; furthermore, due to the similarities between the two receptors, GH might also mimic the effects of prolactin [67], inducing galactorrhea and ED. However, considering the rarity of the disease and the peculiarity of its signs and symptoms, first-line examination of GH for ED is not recommended. GH deficit in young age has serious consequences, whereas in adult age it becomes more difficult to diagnose and treat; there is no definite consensus if treatment should be required or suggested in all patients, or if there is only a specific subset of subjects in which treatment might be
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Endocrine Table 1 Suggestions for and against hormonal evaluation: survey of available guidelines and statements regarding endocrine assessment of ED Hormone Testosterone
Prolactin
FT3/FT4
GH, IGF-1
DHEA, DHEAS
Cortisol
Author(s)
Year
Quote
Wang et al. [22]
2008
‘‘Manifestations of hypogonadism include erectile dysfunction’’
Ghanem et al. [10]
2013
‘‘Fasting blood sugar, serum total testosterone, prolactin levels, and a lipid profile may reveal significant comorbid conditions’’
Buvat et al. [14]
2013
‘‘Hypoactive sexual desire and reduced nocturnal and morning erections are clearly associated with estosterone deficiency, while the association with reduced sex-induced erection is less evident’’
Wespes et al. [23]
2013
‘‘Patients should be screened for symptoms of possible hypogonadism; hormonal test include a morning sample of total testosterone’’
Galdiero et al. [51]
2012
‘‘Chronic hyperprolactinemia is responsible for an inhibition in sexual behavior and activity […] and penile erection in men’’
Ghanem et al. [10]
2013
‘‘Fasting blood sugar, serum total testosterone, prolactin levels, and a lipid profile may reveal significant comorbid conditions’’
Carani et al. [61]
2005
‘‘The main sexological complaint found in our cohort of hyperthyroid patients was PE, whereas in hypothyroid subjects, it was DE […] Most patients with a chronic thyroid disease experience some sexual symptoms, such as PE in hyperthyroidism, DE in hypothyroidism, and HSD and ED in both conditions’’
Veronelli et al. [62]
2006
‘‘ED is a frequent finding in patients affected by thyroid disease […] we found no association between ED and kind of disease, duration of disease, presence or absence of thyroid antibodies, kind of treatment and TSH levels’’
Krassas et al. [63]
2008
‘‘Screening for thyroid dysfunction in men presenting with ED is recommended’’
Corona et al. [64]
2012
‘‘Erectile function should be evaluated in all individuals with hyperthyroidism. Conversely, assessment of thyroid function cannot be recommended as routine practice in all ED patients’’
Galdiero et al. [51]
2012
‘‘Sexual function has not been extensively studied in patients with GHD… No study has ever specifically evaluated the effect of GH replacement therapy on sexual function’’
Maggi et al. [53]
2013
‘‘GH or IGF-1 determinations are not recommended as first-line examination in male subjects with sexual dysfunction’’
Maggi et al. [53]
2013
‘‘Routine measurement of serum DHEA or DHEA/S is not recommended in men with sexual dysfunction’’
Reiter et al. [74]
1999
‘‘The results suggest that oral DHEA treatment may be of benefit in the therapy of ED’’
Morales et al. [75]
2009
‘‘This study did not suggest a clinical benefit of DHEA supplementation in men with hypoandrogenism and sexual dysfunction’’
¨ ckert et al. [79] U
2003
‘‘Our results strongly suggest an inhibitory role for cortisol in the mechanism of male sexual response and behaviours, including the control of penile erection’’
Kobori et al. [80]
2009
‘‘The active forms of cortisol (Bio-F and Sa-F) showed negative correlations with sexual function in men […] ED is thought to occur in patients with high levels of cortisol because of the relations between cortisol and stress’’
Granata et al. [84]
2013
‘‘Multiple linear regression analysis confirmed the role of cortisol, UFC, and upright PRA in the variation of EF’’
PE premature ejaculation, ED erectile dysfunction, GHD GH deficiency
beneficial [68, 69]. Only a small controlled trial assessed erectile function in patients treated with GH, finding no effect on mood and amount of sexual intercourse [70]. Further studies are required in order to shed a light on this topic.
DHEA and DHEAS In recent years, DHEA has come into the spotlight as a ‘‘youth hormone,’’ following its age-related reduction [71, 72]; the wide availability of DHEA as an over-the-counter drug in many countries has contributed to the widespread
123
use of this drug as an alleged rejuvenation treatment. However, even if DHEAS was the only hormone whose concentration was inversely correlated to the prevalence of ED in the Massachusetts Male Aging Study [73], definite evidence of the usefulness of treatment with DHEA is still missing; in randomized, double-blind, placebo-controlled trials, ED either did [74] or did not [75] improve during treatment with DHEA. Decline in serum DHEAS seems to be an age-related process rather than a cause of ED [76]. The Italian Study Group on Geriatric Endocrinology concluded in a consensus document published in 2006 that treatment with DHEA does not improve mood, cognition, or well-being in elderly people [77]: recent reviews seem to
Endocrine
confirm this [78]. Routine DHEAS evaluation is not recommended until more definite evidence of its role in erectile function is agreed upon.
disorders. Adequate biochemical monitoring should be performed in all patients, including blood glucose, lipid profile, and evaluation of kidney and liver functions [87, 88].
Cortisol
Conflict of interest
It has been speculated if cortisol, acting as a stress hormone, has a role in erectile function; however, data on this topic are sparse and far from conclusive. An inhibitory role for cortisol has been postulated in male sexual health [79]; however, since ED is a powerful stressor, it is difficult to discriminate whether hypercortisolism is the cause or consequence of an enhanced hypothalamic–pituitary– adrenal axis [80, 81], besides the obvious Cushing’s syndrome. The most common cause of hypercortisolism is an inadequate glucocorticoid treatment; Cushing’s syndrome on the other hand is a rare condition, with an incidence rate between 1.8 and 2.4 patients/million per year [82]. It is also important to remember that hypercortisolism perpetuates many features of metabolic syndrome, including impaired glucose tolerance, hypertension, dyslipidemia, atherosclerosis and hypercoagulability [83], which are also involved in the pathogenesis of ED. More interesting is the role of adrenal insufficiency and its replacement. Primary adrenal insufficiency, or Addison’s disease, is a rare disease with a prevalence of 100 per million; the secondary form of adrenal insufficiency, caused by a pituitary dysfunction, is far more common, its prevalence being 400 per million [84]. In a recent study in 12 patients diagnosed with Addison’s disease, it has been observed that the onset of adrenal insufficiency is also characterized by sexual dysfunctions, reversible with adequate hormone replacement therapy [85]. It is not possible yet to conclude that the simple correction of chronic hypercortisolism can revert metabolic alterations [86], but greater efforts in improving steroid replacement therapy are auspicable (Table 1).
Conclusion Many hormones are somehow involved in the pathogenesis of ED. Guidelines suggest testing for testosterone only as a first-line assessment; however, based on available evidence, in order to reduce time lag between first symptoms and complete diagnosis, evaluation of TSH, LH, and prolactin might be performed together with testosterone assessment. There is still no definite evidence of the role of estradiol, DHT, DHEA, DHEAS, cortisol, GH, or IGF-1 in ED; until their clinical significance is better described, measurement of these hormones should not be recommended in men with erection
None.
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