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Dipeptidyl peptidase 4 (DPP-4) inhibitors are a new pharmacological class of drugs for treating Type 2 diabetes. They improve the capacity of the organism to control glycemia by increasing the levels of active incretins. Their mechanism of action is thus radically different from those of other anti-diabetic drugs currently available. DDP-4 inhibitors use a physiological mechanism to control hyperglycemia, by stimulating the secretion of insulin from beta-cells, decreasing the secretion of glucagon from pancreatic alpha-cells, and at the same time reducing the production of glucose by the liver. DDP-4 inhibitors have shown significant efficacy in maintaining reduced levels of glycosylated hemoglobin for up to 1 year. In vitro and animal studies have shown that they can inhibit apoptosis of beta-cells and favor their regeneration and differentiation. The oral DPP-4 inhibitors vildagliptin, sitagliptin, and saxagliptin are efficacious both alone and in association with other oral anti-diabetic agents and may be administered in a single daily dose. Lastly, they have substantial advantages with respect to other anti-diabetic drugs, since they involve a low risk of hypoglycemia and do not affect body weight.

Erectile dysfunction (ED) increases in prevalence and severity because of aging processes and related organic, iatrogenic and social problems. Decline of testosterone (T) levels is observed with age and also in illnesses with a common basis of endothelial damage. The T deficiency may lead to decreased energy, mood depression, reduction of sexual desire, but no correlation has been reported between T level and severity of ED, which is mainly a neurovascular disease. In facts, inhibition of phosphodiesterase type 5 (PDE5) isoenzyme with sildenafil, tadalafil and vardenafil enhances vasodilatation in the corpus cavernosum and subsequent penile erection. Absolute pharmacological potency of PDE5 inhibitors is similar and non-selectivity defines the side-effects profile, while their elimination half-life explains not only the different duration of action, but also short and long-term tolerability. Efficacy of PDE5 inhibitors in younger patients is greater in respect to older subjects because of associated pathologies and the decline in hypothalamic-pituitary-gonadal function. T is essential in erectile function, controlling the expression and activity of PDE5 and therefore, androgen supplementation improves therapeutic response to PDE5 inhibitors in hypogonadal subjects. Since sexual behavior is a complex interplay of physical, psychological, and social factors, the possible effect of these drugs on androgen levels and brain function need to be deeply investigated. The ubiquitarious distribution of PDE5 and the availability of selective inhibitory molecules foster newer studies in the treatment of heart failure, pulmonary hypertension, inflammation, and depression. This new progress is certainly contributing to a better medical approach to sexuality and quality of life in aging people.

Although erectile dysfunction (ED) in older subjects needs a holistic approach, the pathophysiology consists mainly in chronic ischemia with deterioration of cavernous smooth muscles followed by development of corporeal fibrosis. Therefore, phosphodiesterase type 5 (PDE5) inhibition, enhancing vasodilatation in corpora cavernosa, represents a first-line therapy for ED. PDE5 is in fact the major cGMP hydrolizing enzyme in penile corpus cavernosum. The mechanisms of action, the pharmacokinetics and the contraindications of selective PDE5 inhibitors, are described in details. Furthermore, attention is focused on the interaction of PDE5 inhibitors on hypothalamus-pituitary gonadol (HPG) function. Finally, considering that androgens may influence sexual behavior by modifying the central nervous system neurotransmitter targeted system, the potentiation of PDE5 inhibitors with testosterone supplementation may be considered to improve erectile function and quality of life in older males.

The quest for eternal youth has been prevalent in civilised societies in many cultures for many centuries. Preventing or deferring the disabilities and morbidities associated with aging through judicious pharmacotherapy has become a particularly relevant healthcare target with the rapid and relentless global demographic shift towards an increasingly elderly population in the 21th century. Aging men commonly loose muscle, become frail, have impaired sexual and cognitive functions, low mood, develop osteopenia and/or osteoporosis with increased risk for fractures and gain visceral fat which predisposes to diabetes, dyslipidaemia, and ischemic heart disease. These alterations in body function are reminiscent of states of androgen deficiency in younger patients. Indeed, aging is associated with a progressive age-related but variable decline in sex hormones. This condition has been named partial androgen deficiency in aging men (PADAM) and consists in a gradual decline in sex hormone levels over years resulting in physical and psychological changes as depression, impotence, decreased sex drive, loss of muscle tone or strength and lethargy. In this review we have tried to give a real identity to PADAM and quantify its entitiy, using the power of the epidemiology.

The relevant age-related changes in male body composition are mainly related to the progressive decrease in the level of circulating anabolic hormones, among which testosterone (T) is rather important. Its decline, between the ages of 35 and 75, is associated to a loss of muscle mass and fibers number, a doubling of fat mass and a decrease in bone mineral density by 0.3% per yr after age 35; thus the relationship between age-related changes in body composition and T bioactivity reflects an important endocrine aspect of the aging male. The assessment of human body composition and in particular the evaluation of fat tissue and its distribution, is currently standardized by the use of dual-energy x-ray absorpiometry (DXA). In the present paper we review the mechanisms through which testosterone may inhibit adipogenesis, restore the myogenic programme enhancing the protein turnover at muscle level and maintain bone mineral density in elderly men.

Erectile dysfunction (ED) has a negative impact on the quality of life of elderly men, but impotence is not an absolute concomitant of aging. Aging changes influencing sexual function in men consist of a decreased capacity to reach arousal by imagination or view, fragility of erection, and an increase in the refractory period. These events may be part of the andropause syndrome, which includes a decrease in intellectual activity, fatigue, depression, decreases in body hair, lean body mass and bone mineral density, accompanied by an increase in weight. As a consequence, the overlap of aging processes, concurrent diseases and social situations to which elderly men are subject, results in the great variability reported in epidemiological studies. In the same way, the complex physiology of erection depends on the social, environmental, or physical context in which it occurs. New achievements in research on intracellular mechanisms of erection and on the neuroendocrinology of aging contribute to better understanding the pathophysiology of ED in the elderly. For example, testosterone declines with age with great interindividual variability, since other hormonal changes are also involved. What currently can be easily identified is the alteration of LH-testosterone feedback alterations, although hormone levels fall in the normal range. Nevertheless, the extent to which age-dependent decline in hormones leads to health problems that may affect the quality of life remains to be clarified. Several concepts on aging-related processes have been challenged, and conditions that were once accepted as physiologically age-related are now thought to lead to medical problems, but until now erectile dysfunction remains underreported, underdiagnosed, and undertreated, especially in the elderly. Nowadays, we are witnessing a rapid growth in available pharmacotherapies, from intracavernous injections of vasoactive drugs, to powerful new oral agents, with differing pharmacological dynamic and kinetic properties. New options for treatment are therefore possible, taking into account both the possibility of changing ineffective drugs and augmenting efficacy by means of synergistic associations. This rich generation of progress is certainly contributing to a better medical approach to sexuality in aging people.

The maturation and physiologic functions of male sexual apparatus are under the control of the hypothalamic-pituitary-gonadal (HPG) axis. The determination of gonadotropins and testosterone as secretory products of pituitary and gonads, respectively, represents the first step in the evaluation of male sexual function and the diagnosis of disorders in male reproductive axis. However, there are several clinical situations that require a dynamic evaluation of this system and the measurement of basal gonadotropins and testosterone must be combined with specific dynamic tests. These mainly consist in GnRH stimulation, which evaluates the endocrine reserve capacity of the pituitary, and human chorionic gonadotropin (hCG) stimulation, which is used in the assessment of Leydig cells activity. The paper illustrates the technical aspects, the normal/pathological responses and the role of these two tests in assessing the male HPG axis in respect to different clinical diagnostic queries.

Excess upper-body (android) fat is considered an health hazard. Exercise training is known to have the potential to modify body composition and to induce a preferential loss of abdominal fat. We studied and compared the composition of whole body and major body regions using dual-energy X-ray absorptiometry (DEXA) in 21 exercising (3-4 hours of intense physical activity/day) and 21 sedentary eumenorrhoic women of similar ages, body mass index (BMI), waist-to-hip ratio (WHR) and age of menarche. In a small number of women in each group (6 out of 21), the ACTH and cortisol response to CRH test and the 24-h urinary cortisol excretion was evaluated. Exercising women had 10% higher total and leg lean mass (p<0.05), and 38% lower total fat mass (p<0.01) than sedentary women. Furthermore, the proportion of android fat was 22% lower in exercising than sedentary women (p<0.01), while the proportion of lower-body (gynoid fat) was unchanged. BMI and WHR were not different between the two groups, while the android/gynoid fat ratios were 16% lower in exercising than in sedentary women (p<0.01). In the exercising women, ACTH and cortisol plasma levels, as well as the 24-h urinary cortisol excretion, were significantly (p<0.01) higher than in the sedentary women studied. In these subjects, a direct relationship between the peak delta percentage increases of ACTH and cortisol after the CRH test and the proportion of android fat was found (r=0.60, p<0.05 and r=0.69, p<0.02, respectively). These results demonstrate that in women who practise intense exercise there are significant differences in body fat distribution in comparison to sedentary women, with a marked less amount of android fat, and suggest that this difference may be related to a reduced response of the pituitary-adrenal axis to CRH.

We investigated ACTH and cortisol responses after ovine CRF injection (1 microgram/kg one bolus) in a group of 11 drug-free patients suffering from major depression. When compared to sex- and age-matched normal controls, our depressed patients showed: Higher ACTH basal values (p less than 0.002); higher cortisol basal values (p less than 0.009); blunted ACTH response to oCRF administration (p less than 0.23); higher cortisol response to oCRF (p less than 0.001). Our data show that in depressed patients the feed-back mechanism is functionally intact at the pituitary level on one hand, while on the other, a hyperresponsiveness of adrenal cortex (even to minimal stimuli) seems to be present. Moreover, a hypersecretion of endogenous CRF in these patients seems to be likely.