Alessandra D. Fisher

Low Testosterone is Associated with an Increased Risk of MACE Lethality in Subjects with Erectile Dysfunction

INTRODUCTION Although testosterone (T) has been suggested to play a protective role against the development of atherosclerosis, studies demonstrating an association between low T and incident major adverse cardiovascular events (MACE) are scanty in the general population and absent in subjects with erectile dysfunction (ED). AIM To investigate whether low T in subjects with ED predict incident fatal or nonfatal MACE. METHODS This is an observational prospective cohort study evaluating a consecutive series of 1687 patients attending our andrological unit for ED. Patients were interviewed using the structured interview on erectile dysfunction (SIEDY) and ANDROTEST structured interviews measuring components relative to ED and hypogonadal-related symptoms, respectively. MAIN OUTCOME MEASURES Total T was evaluated at baseline. Information on MACE was obtained through the City of Florence Registry Office. RESULTS Among the patients studied, 5.2, 13.8, and 22.4% were hypogonadal according to different thresholds (T < 8, 10.4 and 12 nmol/L or 230, 300 and 350 ng/dL, respectively). During a mean follow-up of 4.3 + or - 2.6 years, 139 MACE, 15 of which were fatal, were observed. Unadjusted incidence of MACE was not associated with T levels. Conversely, the proportion of lethal events among MACE was significantly higher in hypogonadal patients, using either 10.4 nmol/L (300 ng/dL) or 8 nmol/L (230 ng/dL) thresholds. However, after adjustment for age and Chronic Diseases Score in a Cox regression model, only the association between incident fatal MACE and T < 8 nmol/L (230 ng/dL) was confirmed (HR = 7.1 [1.8-28.6]; P < 0.001). Interestingly, measuring hypogonadal-related symptoms and signs through ANDROTEST, only fatal MACE were also associated with a higher score (HR = 1.2 [1.0-1.5] for each ANDROTEST score increment; P = 0.05 after adjustment for age and Chronic Diseases Score). CONCLUSIONS T levels are associated with a higher mortality of MACE. The identification of low T levels should alert the clinician thus identifying subjects with an increased cardiovascular risk.

ORIGINAL RESEARCH—ENDOCRINOLOGY: ANDROTEST©: A Structured Interview for the Screening of Hypogonadism in Patients with Sexual Dysfunction

INTRODUCTION Detecting hypogonadism, which is important in the general population, becomes crucial in patients with sexual dysfunctions, because hypogonadism can have a causal role for them and testosterone (T) substitution represents a milestone for the therapy. AIM No inventories are available for the screening of hypogonadism in patients with sexual dysfunction. We wished to set up a brief structured interview providing scores useful for detecting hypogonadism defined as low total T (<10.4 nmol/L, 300 ng/dL) in a symptomatic population (sexual dysfunction). METHODS A minimum set of items was identified within a larger structured interview through iterative receiver-operating characteristic curve analysis, with assessment of sensitivity and specificity for hypogonadism in a sample of 215 patients. MAIN OUTCOME MEASURES Sensitivity and specificity were verified in a further sample of 664 patients. Correlation of test scores with prostate-specific antigen (PSA), testis volume, and others clinical and psychological parameters, was assessed for concurrent validity. RESULTS In the validation sample, the final 12-item version of the interview (ANDROTEST) had a sensitivity and specificity of 68% and 65%, in detecting low total T (<10.4 nmol/L) and of 71% and 65%, in the screening for low free T (<37 pmol/L). Furthermore, patients with a pathological test (i.e., score >8) showed higher prevalence of hypogonadism-related signs, such as lower testis volume and higher depressive symptoms. Finally, when only younger patients (<54 years, which represents the median age of the sample) were considered, Log10 [PSA] levels were significantly lower in those with ANDROTEST score >8. CONCLUSION ANDROTEST is a quick and easy-to-administer interview that provides scores for the screening of male hypogonadism in patients with sexual dysfunction.

Low Levels of Androgens in Men with Erectile Dysfunction and Obesity

INTRODUCTION The relationship between obesity and erectile dysfunction (ED) has not been completely clarified. AIM The aim of this study is to investigate the association between different obesity class (the World Health Organization definition) with several hormonal and instrumental parameters, in a large sample of patients with ED. METHODS A consecutive series of 2,435 (mean age 52.1 +/- 13.0 years) male patients with ED was investigated. MAIN OUTCOME MEASURES Several hormonal and biochemical parameters were studied, along with a structured interview on erectile dysfunction (SIEDY), a psychometric questionnaire (Middle Hospital Questionnaire), and penile doppler ultrasound (PDU). RESULTS Among patients studied, 41.5% were normal weight, while 42.4%, 12.1% and 4.0% showed a BMI of 25-29.9, 30-34.9 and 35 kg/m(2 )or higher, respectively. Androgen levels (including sex hormone-binding globuline bound and unbound testosterone) decreased as a function of obesity class, while luteinising hormone levels did not show any significant change. Obesity was significantly associated with a higher organic contribution to ED (as assessed by SIEDY scale 1 score), and worse PDU parameters. At multivariate linear regression analysis, after adjustment for confounders (including metabolic syndrome), low androgens remained associated with BMI, while both basal and dynamic (after prostaglandin E1 [PGE1] stimulation) peak systolic velocity (PSV) at PDU resulted significantly associated with age and elevated blood pressure (Adj. r = -0.179, -0.285 and -0.094, -0.071 for age, hypertension and for basal and dynamic PSV, respectively; all P < 0.05). CONCLUSIONS Obesity is characterized by low levels of androgens in men with ED, after adjustment for comorbidities. Obesity associated comorbidities, particularly hypertension, are the most important determinants of arteriogenic obesity-associated ED.

Different Testosterone Levels Are Associated with Ejaculatory Dysfunction

INTRODUCTION The role of testosterone (T) in pathogenesis of ejaculatory symptoms has not been completely clarified. AIM To evaluate the possible contribution of T and hypogonadism in the control of the ejaculatory reflex, comparing subjects with premature ejaculation (PE) or delayed ejaculation (DE) to those without ejaculatory dysfunction. METHODS A consecutive series of 2,437 (mean age 51.9 +/- 13.0 years) male patients with sexual dysfunction was studied. MAIN OUTCOME MEASURE Several hormonal and biochemical parameters were studied, along with the structured interview on erectile dysfunction (SIEDY) structured interview. Hypogonadism were defined when total testosterone (TT) was lower than 10.4 nmol/L. RESULTS Among the patients studied, 714 (25.9%) and 121 (4.4%) reported PE and DE, respectively. In the youngest age band (25-40 years), subjects with PE reported higher TT and free testosterone (FT) levels when compared to the other groups (subjects with DE or those without PE and DE; P < 0.05 for both). Conversely, in the oldest age band (55-70 years), lower TT and FT levels were observed in DE subjects. Accordingly, patients with PE showed the lowest (12%) and subjects with DE the highest (26%) prevalence of hypogonadism. These differences were confirmed even after adjustment for confounders such as age and libido (HR = 0.75 [0.57-0.99] and 1.83 [1.14-3.94] for PE and DE, respectively; both P < 0.05). CONCLUSIONS Our data seem to suggest that T plays a facilitatory role in the control of ejaculatory reflex. Both central and peripheral mechanisms have been advocated to explain this association. Clinical studies are currently in progress to further establish the role of T in the ejaculatory dysfunction, attempting to revert DE by androgen administration.

ORIGINAL RESEARCH—ENDOCRINOLOGY: A Comparison of NCEP‐ATPIII and IDF Metabolic Syndrome Definitions with Relation to Metabolic Syndrome‐Associated Sexual Dysfunction

INTRODUCTION Metabolic syndrome (MetS) is a clustering of cardiovascular and metabolic risk factors, often associated with erectile dysfunction (ED) and hypogonadism. Recently, the International Diabetes Federation (IDF) proposed a substantial revision of the National Cholesterol Education Program-Third Adult Treatment Panel (NCEP-ATPIII) MetS criteria, essentially lowering the diagnostic cutoff values. Aim. To investigate the associations between these two recently proposed definitions of MetS with the relative risk of arteriogenic ED and hypogonadism in a large cohort of patients with male sexual dysfunction. METHODS A consecutive series of 1086 patients with sexual dysfunction (mean age 51.9 +/- 12.8 years) was studied. MAIN OUTCOME MEASURES Several hormonal, biochemical, and instrumental (penile Doppler ultrasound) parameters were studied, along with ANDROTEST, a 12-item validated structured interview, specifically designed for the screening hypogonadism in a sexual dysfunction population. In particular, a score >8 is predictive of low testosterone (<10.4 nmol/L) with a sensitivity and specificity of about 70%. RESULTS The prevalence of MetS was 32.0% and 44.7% according to NCEP-ATPIII and IDF criteria, respectively. After adjustment for confounding factors, only NCEP-ATPIII was significantly associated with dynamic prostaglandin E(1)-stimulated penile flow (Vpmax, B = -7.7 +/- 3.8; P < 0.05). Patients with MetS defined according to both criteria reported lower total and free testosterone levels, higher prevalence of hypogonadism, and higher ANDROTEST score. However, when IDF, but not NCEP-ATPIII, criteria were fulfilled, the prevalence of hypogonadism was significantly lower than that observed in patients fulfilling both criteria (15.6% vs. 34.8%, respectively; P < 0.00001). Conversely, patients fulfilling NCEP-ATPIII, but not IDF, criteria did not show a significant different prevalence of hypogonadism than those positive for both sets of criteria (30.8% vs. 34.8%; P = NS). CONCLUSIONS In patients with ED, NCEP-ATPIII criteria seem to be a better predictor of hypogonadism and impaired penile blood flow than IDF ones.

ORIGINAL RESEARCH—ENDOCRINOLOGYORIGINAL RESEARCH—ENDOCRINOLOGY: ANDROTEST©: A Structured Interview for the Screening of Hypogonadism in Patients with Sexual Dysfunction

INTRODUCTION Detecting hypogonadism, which is important in the general population, becomes crucial in patients with sexual dysfunctions, because hypogonadism can have a causal role for them and testosterone (T) substitution represents a milestone for the therapy. AIM No inventories are available for the screening of hypogonadism in patients with sexual dysfunction. We wished to set up a brief structured interview providing scores useful for detecting hypogonadism defined as low total T (<10.4 nmol/L, 300 ng/dL) in a symptomatic population (sexual dysfunction). METHODS A minimum set of items was identified within a larger structured interview through iterative receiver-operating characteristic curve analysis, with assessment of sensitivity and specificity for hypogonadism in a sample of 215 patients. MAIN OUTCOME MEASURES Sensitivity and specificity were verified in a further sample of 664 patients. Correlation of test scores with prostate-specific antigen (PSA), testis volume, and others clinical and psychological parameters, was assessed for concurrent validity. RESULTS In the validation sample, the final 12-item version of the interview (ANDROTEST) had a sensitivity and specificity of 68% and 65%, in detecting low total T (<10.4 nmol/L) and of 71% and 65%, in the screening for low free T (<37 pmol/L). Furthermore, patients with a pathological test (i.e., score >8) showed higher prevalence of hypogonadism-related signs, such as lower testis volume and higher depressive symptoms. Finally, when only younger patients (<54 years, which represents the median age of the sample) were considered, Log10 [PSA] levels were significantly lower in those with ANDROTEST score >8. CONCLUSION ANDROTEST is a quick and easy-to-administer interview that provides scores for the screening of male hypogonadism in patients with sexual dysfunction.

Risk Factors for Sexual Dysfunction Among Women and Men: A Consensus Statement From the Fourth International Consultation on Sexual Medicine 2015

INTRODUCTION This article presents a review of previous research concerning risk factors for sexual dysfunction in women and men. AIM The aim is to evaluate past research studies to determine the contribution of all risk factors to the development and maintenance of sexual dysfunction among women and men. METHODS Studies were organized under a biopsychosocial framework, with the bulk of studies of women and men having investigated the role of biological factors. MAIN OUTCOME MEASURES The outcome measures were the data on factors for sexual dysfunction. RESULTS Many more studies investigated risk factors for sexual dysfunction in men than in women. For women and men, diabetes, heart disease, urinary tract disorders, and chronic illness were significant risk factors for sexual dysfunction. Depression and anxiety and the medications used to treat these disorders also were risk factors for sexual dysfunction in women and men. In addition, substance abuse was associated with sexual dysfunction. Many other social and cultural factors were related to sexual dysfunction in women and men. CONCLUSION Psychosocial factors are clearly risk factors for sexual dysfunction. Women and men with sexual dysfunction should be offered psychosocial evaluation and treatment, if available, in addition to medical evaluation and treatment. The impact of social and cultural factors on sexual function requires substantially more research. The evidence that erectile dysfunction is a harbinger of other forms of cardiovascular disease is strong enough to recommend that clinical evaluation for occult cardiovascular disease should be undertaken in men who do not have known cardiovascular disease but who develop organic erectile dysfunction, especially in men younger than 70 years.

Incidence and Prevalence of Sexual Dysfunction in Women and Men: A Consensus Statement from the Fourth International Consultation on Sexual Medicine 2015

INTRODUCTION The incidence and prevalence of various sexual dysfunctions in women and men are important to understand to designate priorities for epidemiologic and clinical research. AIM This manuscript was designed to conduct a review of the literature to determine the incidence and prevalence of sexual dysfunction in women and men. METHODS Members of Committee 1 of the Fourth International Consultation on Sexual Medicine (2015) searched and reviewed epidemiologic literature on the incidence and prevalence of sexual dysfunctions. Key older studies and most studies published after 2009 were included in the text of this article. MAIN OUTCOME MEASURES The outcome measures were the reports in the various studies of the incidence and prevalence of sexual dysfunction among women and men. RESULTS There are more studies on incidence and prevalence for men than for women and many more studies on prevalence than incidence for women and men. The data indicate that the most frequent sexual dysfunctions for women are desire and arousal dysfunctions. In addition, there is a large proportion of women who experience multiple sexual dysfunctions. For men, premature ejaculation and erectile dysfunction are the most common sexual dysfunctions, with less comorbidity across sexual dysfunctions for men compared with women. CONCLUSION These data need to be treated with caution, because there is a high level of variability across studies caused by methodologic differences in the instruments used to assess presence of sexual dysfunction, ages of samples, nature of samples, methodology used to gather the data, and cultural differences. Future research needs to use well-validated tools to gather data and ensure that the data collection strategy is clearly described.

ORIGINAL RESEARCH–ENDOCRINOLOGY: Pulse Pressure, an Index of Arterial Stiffness, Is Associated with Androgen Deficiency and Impaired Penile Blood Flow in Men with ED

INTRODUCTION Pulse pressure (PP; i.e., the arithmetic difference between systolic and diastolic blood pressure) reflects arterial stiffness and has been suggested to be an independent cardiovascular risk factor. AIM The aim of the present study is to asses the possible contribution of PP to arteriogenic erectile dysfunction (ED) and ED-associated hypogonadism. METHODS A consecutive series of 1,093 (mean age 52.1 +/- 13.0 years) male patients with ED and without a previous history of hypertension or not taking any antihypertensive drugs were investigated. MAIN OUTCOME MEASURES Several hormonal and biochemical parameters were studied, along with structured interview on erectile dysfunction (SIEDY), ANDROTEST structured interviews, and penile Doppler ultrasound. RESULTS Subjects with higher PP quartiles showed worse erectile function and higher prevalence of arteriogenic ED even after adjustment for confounding factors. Furthermore, sex hormone binding globulin-unbound testosterone levels declined as a function of PP quartiles. Accordingly, the prevalence of overt hypogonadism (calculated free testosterone < 180 pmol/L or free testosterone < 37 pmol/L) increased as a function of PP quartiles (17.% vs. 39.7%, and 30.8% vs. 58.6% for the first vs. fourth quartile, respectively, for calculated free testosterone and free testosterone; all P < 0.0001 for trend). This association was confirmed even after adjustment for confounders (Adjusted [Adj]) r = 0.090 and 0.095 for calculated free testosterone < 180 pmol/L and free testosterone < 37 pmol/L, respectively; all P < 0.05). CONCLUSIONS PP is an easy method to estimate and quantify patient arterial stiffness. We demonstrated here for the first time that elevated PP is associated with arteriogenic ED and male hypogonadism. The calculation of PP should became more and more familiar in the clinical practice of health care professionals involved in sexual medicine.

Cross‐Sex Hormone Therapy in Trans Persons Is Safe and Effective at Short‐Time Follow‐Up: Results from the European Network for the Investigation of Gender Incongruence

INTRODUCTION Data on the effects of cross-sex hormone therapy (CHT) are limited due to the low prevalence of gender dysphoria, small number of subjects treated at each center, lack of prospective studies, and wide variations in treatment modalities. AIM The aim of this study is to report the short-term effects of CHT on hormonal and clinical changes, side effects, and adverse events in trans men (female-to-male gender dysphoric persons) and trans women (male-to-female gender dysphoric persons). METHODS This was a multicenter 1-year prospective study in 53 trans men and 53 trans women. Trans men received injections of testosterone undecanoate every 3 months. Trans women younger than 45 years received 50 mg cyproterone acetate (CA) and 4 mg estradiol valerate daily, whereas those older than 45 years received 50 mg CA daily together with 100 μg/24 hours transdermal 17-β estradiol. MAIN OUTCOME MEASURES Sex steroids, prolactin, liver enzymes, lipids, hematocrit, blood pressure, anthropometrics, Ferriman and Gallwey score, and global acne grading scale were measured. Side effects, adverse events, and desired clinical changes were examined. RESULTS No deaths or severe adverse events were observed. Two trans men developed erythrocytosis, and two had transient elevation of the liver enzymes. Trans men reported an increase in sexual desire, voice instability, and clitoral pain (all P ≤ 0.01). Testosterone therapy increased acne scores, facial and body hair, and prevalence of androgenetic alopecia. Waist-hip ratio, muscle mass, triglycerides, total cholesterol (C), and LDL-C increased, whereas total body fat mass and HDL-C decreased. Three trans women experienced transient elevation of liver enzymes. A significant increase in breast tenderness, hot flashes, emotionality, and low sex drive was observed (all P ≤ 0.02). Fasting insulin, total body fat mass, and prolactin levels increased, and waist-hip ratio, lean mass, total C, and LDL-C decreased. CONCLUSIONS Current treatment modalities were effective and carried a low risk for side effects and adverse events at short-time follow-up.