EMAS position statement: Testosterone replacement therapy in older men.

INTRODUCTION: Late-onset hypogonadism is the clinical entity characterised by low testosterone concentrations associated with clinical symptoms in the absence of organic disease in ageing men. It has been associated with metabolic syndrome, reduced bone mineral density, and increased cardiovascular morbidity and mortality risk. Although testosterone replacement therapy (TRT) reverses most of these conditions in young hypogonadal men, the risk/benefit ratio of TRT in older men is debatable. AIM: To update the 2015 EMAS statement on TRT in older men with new research on late-onset hypogonadism and TRT. MATERIALS AND METHODS: Literature review and consensus of expert opinion. SUMMARY RECOMMENDATIONS: TRT should be offered only to symptomatic older men with confirmed low testosterone concentrations after explaining the uncertainties regarding the long-term safety of this treatment. TRT may be offered to men with severe hypogonadism and erectile dysfunction to improve sexual desire, erectile, and orgasmic function. It should also be considered in hypogonadal men with severe insulin resistance or pre-diabetes mellitus. TRT may also be considered, in combination with proven treatment strategies, for osteoporosis, or for selected patients with persistent mild depressive symptoms and/or low self-perceived quality of life, combined with standard medical care for each condition. TRT is contraindicated in hypogonadal men actively seeking fertility treatment. Due to a lack of data, TRT should not be routinely used in older men to improve exercise capacity/physical function, improve cognitive function, or prevent cognitive decline. TRT must be avoided in older, frail men with known breast cancer or untreated prostate cancer and all men who have had myocardial infarction or stroke within the last four months, and those with severe or decompensated heart failure. The quality of evidence regarding patients with previous prostate cancer or cardiovascular disease is too low to draw definitive conclusions. Any limits on duration of use are arbitrary, and treatment should continue for as long as the man feels the benefits outweigh the risks for him, and decisions must be made on an individual basis. Withdrawal should be considered when hypogonadism is reversed after the resolution of underlying disorder. Short-acting transdermal preparations should be preferred for TRT initiation in older men, but injectable forms may be considered subsequently. Older men on TRT should be monitored at 3, 6, and 12 months after initiation and at least yearly thereafter, or earlier and more frequently if indicated. Evaluation should include assessment of the clinical response, and measurement of total testosterone, haematocrit, and prostate-specific antigen (PSA) concentrations. Bone density and/or quality should also be assessed. Obese and overweight patients should be encouraged to undergo lifestyle modifications, including exercise and weight loss, to increase endogenous testosterone.

Endocrine Follow-Up of Men with Non-Obstructive Azoospermia Following Testicular Sperm Extraction.

Testicular sperm extraction (TESE) is a surgical procedure which, combined with intracytoplasmic sperm injection, constitutes the main treatment for achieving biological parenthood for patients with infertility due to non-obstructive azoospermia (NOA). Although it is effective, TESE procedures might cause structural testicular damage leading to Leydig cell dysfunction and, consequently, temporary or even permanent hypogonadism with long-term health consequences. To a lesser extent, the same complications have been reported for microdissection TESE, which is considered less invasive. The resulting hypogonadism is more profound and of longer duration in patients with Klinefelter syndrome compared with other NOA causes. Most studies on serum follicle-stimulating hormone and luteinizing hormone concentrations negatively correlate with total testosterone concentrations, which depends on the underlying histology. As hypogonadism is usually temporary, and a watchful waiting approach for about 12 months postoperative is suggested. In cases where replacement therapy with testosterone is indicated, temporary discontinuation of treatment may promote the expected recovery of testosterone secretion and revise the decision for long-term treatment.

Imaging in gynecomastia.

BACKGROUND: Gynecomastia (GM) is the benign proliferation of glandular tissue in the male breast. It is a common condition, which may occur physiologically and shows three age peaks during a male's lifespan: infancy, puberty, and senescence. An underlying pathology may be revealed in 45%-50% of adult men with GM, such as aggravating medications, systemic diseases, obesity, endocrinopathies, or malignancy. OBJECTIVE: To discuss the role of imaging in the evaluation of GM and its contribution to therapeutic decision-making. MATERIALS/METHODS: The current literature was reviewed through PubMed, Scopus, and CENTRAL electronic databases to identify the best available evidence concerning imaging modalities in patients with GM. RESULTS: Most male breast lesions can be diagnosed on clinical grounds; however, in certain cases, when physical examination is inconclusive, imaging may be helpful. DISCUSSION: The main purpose of evaluating a patient with GM is to establish the diagnosis and differentiate true GM from pseudogynecomastia, exclude breast cancer, and detect the possible cause. GM is seen in mammography as a subareolar opacity and three mammographic patterns of GM are described: nodular, dendritic, and diffuse, corresponding to florid GM of early onset, fibrous persistent GM, and GM due to exogenous estrogen administration, respectively. In ultrasound (US), florid GM is depicted as a disk-shaped, hypoechoic area underlying the areola, whereas echogenicity of the lesions increases as fibrosis develops. Data on the use of MRI in the evaluation of the male breast and GM are still limited. Imaging findings can be classified according to the BIRADS (breast imaging reporting and data system) based on their malignant potential. CONCLUSION: Both mammography and US are sensitive and specific to diagnose GM and distinguish it from breast cancer. When clinical findings are suggestive of malignancy or imaging findings are inconclusive, a histological confirmation should be sought.

Cardiovascular Complications in Patients with Klinefelter's Syndrome.

More than 70 years have passed since the first description of Klinefelter Syndrome (KS), the most frequent chromosome disorder causing male infertility and hypogonadism. KS is associated with increased cardiovascular (CV) mortality due to several comorbidities, including hypogonadism, as well as metabolic syndrome and type 2 diabetes, which are highly prevalent in these patients. Aside from metabolic disturbances, patients with KS suffer from both acquired and congenital CV abnormalities, cerebrovascular thromboembolic disease, subclinical atherosclerosis and endothelial dysfunction, which may all contribute to increased CV mortality. The mechanisms involved in this increased risk of CV morbidity and mortality are not entirely understood. More research is needed to better characterise the CV manifestations, elucidate the pathophysiological mechanisms and define the contribution of testosterone replacement to restoring CV health in KS patients. This review explores the complex association between KS, metabolic syndrome and CV risk in order to plan future studies and improve strategies to reduce mortality in this high-risk population.

Measuring testosterone in women and men.

Measurement of serum testosterone (T) level is of utmost importance for the evaluation of hypogonadism in men and androgen excess in women. Despite the advances in steroid hormone assessment, substantial variability exists regarding measurement of T concentrations. Several factors affect T measurement in men, including circadian rhythms, intra-individual daily variability and transient stressors, while T concentrations in women vary mainly according to the phase of the menstrual cycle. Most of the available immunoassays lack the required accuracy when dealing with T concentrations at the lower end of the normal range for men and across the entire range for females. Consequently, there is no universally accepted lower T threshold for healthy adult men and most immunoassays fail to detect states of mild androgen excess in women. Mass spectrometry is considered the gold-standard method for T measurement; however, due to its complexity and cost, it has not been widely adopted. To increase accuracy, T in men should be measured with a fasting morning sample and repeated if the level is found to be low; in women, measurement must be performed at the follicular phase of the cycle. In both cases, borderline results may be clarified by the assessment of free testosterone (fT). Since most fT assays are unreliable, calculated surrogates should be used instead. Collaborative efforts have been undertaken, with rigorous internal and external quality controls and the establishment of reference methods, to harmonise the commercial assays.

Klinefelter syndrome: more than hypogonadism.

Klinefelter syndrome (KS) is the most frequent chromosome disorder in males (1:650 newborn males), defined by 47,XXY karyotype. The classical phenotype is that of a tall male with relatively long legs, small, firm testes and gynecomastia. Azoospermia and infertility are almost inevitably present, but may be overcome by TESE and ICSI. Nevertheless, a broad spectrum of phenotypes has been described and more than 70% of the actually existing KS men may remain undiagnosed throughout their lifespan. Accordingly, hypogonadism is usually not evident until early adulthood and progresses with ageing. KS patients present a series of comorbidities that increase morbidity and mortality by 40%. Such disturbances are the impaired metabolic profile (obesity, dyslipidemia, insulin resistance) and a tendency to thrombosis, which all favor cardiovascular disease. They also present susceptibility for specific neoplasias (breast cancer, extragonadal germ cell tumors), autoimmune diseases as well as osteoporosis and bone fractures. Moreover, KS has been associated with verbal processing and attention deficits as well as social skill impairments, leading KS individuals to academic and professional achievements inferior to those of their peers of comparable socio-economic status. Nevertheless, the majority fall within the average range regarding their intellectual abilities and adaptive functioning. Testosterone replacement therapy (TRT) is the mainstay of treatment in hypogonadal KS patients; however, randomized trials are needed to determine optimal therapeutic regimens and follow-up schedules.

Male contraception: a clinically-oriented review.

Despite the variety of available female contraceptive methods, many pregnancies (~50%) are still undesired. Many men (>60%) want to participate equally with their partner in family planning; however, male contraceptive methods (MCMs) account for only 14% of those used worldwide and no pharmaceutical MCM is available so far. The only two MCMs currently available are condoms, which despite protecting against sexually transmitted diseases have high failure rates (~19%), and vasectomy, which though very efficient (99%) is poorly reversible (<50%). Among MCMs under investigation, male hormonal contraceptives (MHCs) are those that have come closest to commercialization. The action of MHCs relies on the disruption of spermatogenesis that exogenous androgen administration evokes by suppressing the hypophyseal-gonadal axis. Various regimens of androgens as monotherapy or in combination with progestins have been tested in clinical trials achieving a Pearl Index <1.0 (equal to that of the female oral contraceptive pill); however, concerns regarding the variable response rates observed (non-responders: 5-20%), the impracticality of parenteral administration and long-term prostate-associated or cardiovascular morbidity have deflected the interest of the pharmaceutical industry from further research. Non-hormonal contraception methods may be, at least theoretically, more specific by selectively disrupting spermatogenesis and sperm transport or fertilizing ability. Nevertheless, only a few have been tested in clinical trials (Reversible Inhibition of Sperm Under Guidance, RISUG, and Intra Vas Plugs); most of them are still in pre-clinical development or have been abandoned due to toxicity (gossypol). Consequently, until a reliable, safe and practical MCM is developed, women will continue to bear most of the contraception burden.