Systems Medicine

In male sexual dysfunction (MSD), the presence of sexual comorbidities is relatively frequent. However, what is still a matter of controversy is what the first-line therapy in these patients should be. Methods. Three scientists and the editor of the Controversies section, all experts in the medical treatment of MSD, present different perspectives on the use of phosphodiesterase type 5 inhibitors (PDE5), testosterone and dapoxetine in erectile dysfunction (ED), hypogonadism, and premature ejaculation (PE). The psychological aspects are discussed by an outstanding expert in psychosexology. Main Outcome Measure. Expert opinion supported by the critical review of the currently available literature. Results. Testosterone should be used before PDE5s in hypogonadal men with comorbid ED; PDE5s should be used before dapoxetine in PE patients with comorbid ED, and counseling should be offered to all subjects with MSD.

The treatment of transsexual subjects is a challenging task for the endocrinologist who, in collaboration with the mental health professional and the surgeon, is called upon to confirm the diagnosis and adjust hormonal treatment aimed at suppressing endogenous sex hormones and to develop hormone characteristics of the desired gender. These guidelines are structured to provide evidence-based suggestions or, where evidence is lacking, expert recommendations on diagnostic procedures, hormonal treatment in adolescent and adult transsexuals, including long-term care and eligibility for surgery. The multidisciplinary approach to treatment, the additional diagnostic role of hormone administration and the need to maintain hormone levels within the physiological range are key suggestions stressed in the guidelines which are particularly important for an endocrinologist unfamiliar with this field. The need for psychological assessment before surgery is not common in many countries and should be stressed further in the guidelines. Some important issues such as time and method of hormone withdrawal before surgery together with when and which hormones should be administered after sex reassignment surgery has been completed, also remain unclear.

Objectives. It has been demonstrated that clitoral and vaginal tissues express nitric oxide synthase isoforms in a way that parallels that of the penile corpus cavernosum. Considering the role of the vagina in the female sexual response and the anatomic connection between the clitoris and the anterosuperior vaginal wall, our aim was to study the distribution of type 5 phosphodiesterase (PDE5) in the anterosuperior wall of the human vagina. Methods. Immunohistochemistry was performed on the vaginal tissue of 14 women obtained at autopsy and on exfoliated cells of the vaginal epithelium obtained from 5 healthy female donors. Specific antibodies against PDE5 were tested on both paraffin sections and cytologic smears. Immunoblotting experiments were performed in parallel with the same antibodies. Results. The histologic analysis of human cadaveric vaginal tissue revealed that PDE5 immunoreactivity was mostly localized in the smooth muscle of vessels, forming a pseudocavernous tissue in the vaginal wall and endothelium. The Skene periurethral glands and vaginal epithelium were also positive for the antibody. The latter finding was confirmed using exfoliated cells of the vaginal epithelium harvested in vivo. Conclusions. The presence and tissue distribution of PDE5 in the human vagina suggest that the integrated system of nitric oxide synthase-PDE5 may play a physiologic role not only in the male sexual response but also in female sexual arousal. UROLOGY 60: 191-195, 2002.

The aim of this study was to assess whether EPC number/function might be an explanatory factor for the observed relation between Type D personality (a joint tendency toward negative affectivity and social inhibition) and poor cardiovascular prognosis. We also assessed whether the effect of a single exercise bout on EPC number/function is affected by Type D personality. Methods and results: Thirty-five sedentary men with chronic heart failure (CHF; left ventricular ejection fraction ≤ 45%) underwent cardio-pulmonary exercise testing (CPET) and personality assessment with the 14-item Type D Scale. CD34+/KDR+ cells were quantified by flow cytometry before and immediately after CPET. Migration of early EPC towards vascular endothelial growth factor and stromal cellderived factor-1α was investigated. Type D (n=10) and non-Type D patients (n=25) were comparable with regards to demographics, disease severity and Framingham risk factor score. Circulating EPC numbers were reduced by 54% in Type D versus non-Type D patients (0.084 ± 0.055 vs. 0.183 ± 0.029, % of lymphocytes, P= 0.006). Exercise led to a 60% increase in EPC in Type D patients whereas the EPC number remained unchanged in the non-Type D group (P= 0.049). Baseline migratory capacity was related to disease severity but was not different comparing Type D and non-Type D patients. Exercise induced a highly significant enhancement of migratory capacity in both groups. Conclusions: Reduced EPC numbers might explain impaired cardiovascular outcome in Type D patients. The observed larger increase in circulating EPC in these patients suggests that acute exercise elicits a more pronounced stimulus for endothelial repair. Type D personality -a joint tendency toward negative affectivity (NA) and social inhibition (SI) -is associated with poor prognosis in cardiovascular patients [1]. The relation between emotional distress and cardiovascular disease has been linked to an unhealthy lifestyle, but also to more physiological processes such as disturbed autonomic control [2], impaired platelet function [3] and a pro-inflammatory environment [4]. Recently, decreased numbers of endothelial progenitor cells (EPC) have been put forward as another possible mediator of cardiovascular disorders in depressed patients [5]. In line with this, psychosocial risk factors are related to levels of circulating progenitor cells, independent of classical cardiovascular risk factors [6]. Accumulating evidence suggests that the quantity and function of circulating EPC play an important role in preserving endothelial integrity. These cells are released from the bone marrow in response to ischemia or endothelial injury and aim to repair damaged regions, either by producing angiogenic cytokines [7] or by differentiating into endothelial cells [8]. Besides re-endothelialization, EPC play a role in postischemic neoangiogenisis [9]. The therapeutic use of EPC and bone marrow mononuclear cells after vascular injury seems promising [10,11], but safety issues need to be further addressed [12]. In patients at cardiovascular risk , in those with coronary artery disease (CAD) and in chronic heart failure (CHF) patients , the number of circulating EPC is reduced. In addition to this quantitative deficit, subnormal function of EPC correlates with impaired endothelial function . Diversity in terms of EPC definition and quantification methods has complicated cross study comparisons , sometimes leading to paradoxical findings, such as increased numbers of EPC in patients with higher cardiovascular risk . Psychological distress promotes immune dysregulation , which in turn might mediate bone-marrow suppression or cause depletion of EPC in the peripheral circulation. We previously demonstrated that Type D personality in CHF patients is independently associated with increased circulating levels of TNF-α and its soluble receptors [20] that have been shown to predict poor outcome in CHF . Physical training has proved to be of clear benefit in cardiovascular patients. Besides the central haemodynamic effect, exercise tolerance is improved by partially restoring vascular reactivity. Shear stress induced up-regulation of endothelial nitric oxide synthase (eNOS) and reduction of oxidative stress play a central regulatory function. Moreover, recent studies demonstrate that regular physical exercise mobilizes EPC in CAD and CHF patients [23] which might explain the observed benefit on endothelial function. An acute exercise bout in sedentary patients, however, poses a threat to endothelial integrity by inducing vascular oxidative stress and a transient prothrombotic stimulus. In the present study, we investigated the relation between Type D personality and EPC numbers and their function in CHF patients before and after endothelial stress elicited by a symptom-limited cardio-pulmonary exercise test (CPET).

With the assumption that infertility and related diagnostic and therapeutic processes are stressful, an uncontrolled pilot study was designed to evaluate the effect of sildenafil citrate on sexual compliance and reproductive outcome. A group of sexually healthy men were studied after the administration of 50 mg sildenafil before semen collection for intrauterine artificial insemination (n ϭ 25) or planned intercourse for a postcoital test (n ϭ 12). We demonstrated that sexual dysfunction is highly prevalent in patients undergoing diagnostic procedures for infertility, and that sildenafil is effective in reversing stress-induced transitory impotence. Furthermore, sildenafil improved some seminal parameters, such as the percentage of spermatozoa with linear progressive motility, as well as the number of spermatozoa penetrating the cervical mucus. Two pregnancies were obtained after sildenafil administration. (Fertil Steril 2004;81:705-7.

While it is known that Retinoic Acid (RA) induces meiosis in mouse female fetal gonads, the mechanisms which regulate this process during spermatogenesis are poorly understood. We show that the All trans RA derivative (ATRA) and Kit Ligand (KL) increase meiotic entry of postnatal mouse spermatogonia in vitro without synergism. Competence to enter meiosis is reached by spermatogonia only at the stage in which they undergo

There are no psychometrically validated assessment tools designed to solely and specifically evaluate satisfaction with the quality of erections. Aim. To develop and psychometrically analyze the Quality of Erection Questionnaire (QEQ), a new patientreported measure developed to evaluate men's satisfaction with the quality of their erections. Methods. The questionnaire was developed through in-depth qualitative interviews of men with erectile dysfunction (ED) in the United States and Australia. An exploratory methodology study was conducted on 65 men with ED. Subsequently, the psychometric properties were confirmed in a larger dataset of 558 men with ED from two combined clinical trials. Main Outcome Measures. Identification of potential redundancy or outliers in items (Pearson inter-item correlations); exploratory factor analysis (unrotated and varimax rotated); internal consistency (Cronbach's alpha); convergent validity (Pearson correlation coefficients between the QEQ total score and domain scores of the International Index of Erectile Function); known-groups validity (ability of the QEQ scores to differentiate between ED severity groups); test-retest reliability (Pearson correlation coefficient). Results. The QEQ demonstrated excellent convergent and known-groups validity. Additional analysis demonstrated high internal consistency (Cronbach's alpha, 0.92). Item analysis demonstrated a unidimensional structure and suggested that satisfaction with hardness may be the key driver for satisfaction with overall quality of erections ( r = 0.8). The smaller exploratory study demonstrated good test-retest reliability ( r = 0.82). Conclusions. The QEQ is a six-item, patient-reported measure with a unidimensional structure, which produces a total score that may be transformed to a 0-100 scale. Psychometric analysis confirmed reliability and validity of the QEQ, which solely and specifically evaluates satisfaction of men with the quality of their erections. The QEQ is a potentially useful measure for monitoring and evaluating treatment in those who are bothered by, or concerned about, their erectile function. Porst H, Gilbert C, Collins S, Huang X, Symonds T, Stecher V, and Hvidsten K. Development and validation of the Quality of Erection Questionnaire. J Sex Med 2007;4:372-381.

Introduction. Debate continues on whether or not male homosexuality (MH) is a result of biological or cultural factors. The debate persists despite the fact that these two sides have different abilities to create a scientific environment to support their cause. Biological theorists produced evidence, however, that these are not always robust. On the other hand, social theorists, without direct evidence confirming their positions, criticize, with good argument, methods and results of the other side. The aim of this Controversy is to understand the reasons of both perspectives. Methods. Two scientists (R.B. and A.C.C.) with expertise in the area of biology of MH were asked to contribute their opinions. The nurture position is discussed by a third expert in sexology (J.B.). Main Outcome Measure. Expert opinion supported by the critical review of the currently available literature. Result. The role of the Controversy's editor (E.A.J.) is to highlight the strengths and weaknesses of both sides. The two experts of the biological issue answer with their data to the questions: "Is male homosexuality partly explainable by immunology?" and "How is male homosexuality a Darwinian paradox?", respectively. Genetic and immunological factors, birth order, and fertility of relatives are largely discussed. Finally, the expert sustaining the idea that culture and experiences are important determining factors in sexual orientation used a psychosocial and holistic perspective to explain his position. Conclusions. The JSM's readers should recognize that there are several biological factors in MH. However, these findings do not seem to be able to explain all cases of homosexuality. Some others may be due to particular environmental factors. The issue is complicated and multifactorial, suggesting that further research should be undertaken to produce the final answer to the question raised in this Controversy section. Jannini EA, Blanchard R, Camperio-Ciani A, and Bancroft J. Male homosexuality: Nature or culture? J Sex Med 2010;7:3245-3253.

Epidemiological studies conducted on erectile dysfunction (ED) have demonstrated its close correlation with cardiovascular disease. Since hyperhomocysteinemia is considered an important cardiovascular risk factor, it could also be involved in the pathogenesis of ED. Aim. To study the role of the C677T MTHFR mutation with subsequent hyperhomocysteinemia in the determination of ED. Methods. We studied 75 consecutive patients presenting with ED. Patients were interviewed using the International Index of Erectile Function. Blood samples were drawn for determination of MTHFR gene C677T mutation, homocysteine (Hcy) and folate levels. Penile color Doppler was also performed. Main Outcome Methods. Patients were administered sildenafil citrate for 2 months. The nonresponders were treated with combination of sildenafil, vitamin B6, and folic acid for 6 weeks. Patients were split into three groups, A, B, and C on the basis on their MTHFR genotype, and in a further group defined as "sildenafil nonresponders" (NR). Results. We found 20 patients homozygous for mutant MTHFR 677T, 36 heterozygous, and 19 wild type. Difference in baseline values for Hcy and folic acid was found between groups A and B, and A and C. The NR group (18 patients from group A and B), presented high levels of Hcy and low levels of folic acid. After combination treatment 16 of them (88.9%) revealed an improvement in the IIEF questionnaire. Moreover, it was measured a significant difference between the values of Hcy and folic acid at the baseline and at the end of the study for the nonresponders. Conclusions. Hyperhomocysteinemia in patients homozygotes for the C677T mutation may interfere with erection mechanisms and thus be responsible for ED. In case of hyperhomocysteinemia associated with low levels of folates, the administration of PDE5 inhibitors may fail if not preceded by the correction of the alterated levels of Hcy and folates. Lombardo F, Tsamatropoulos P, Piroli E, Culasso F, Jannini EA, Dondero F, Lenzi A, and Gandini L. Treatment of erectile dysfunction due to C677T mutation of the MTHFR gene with vitamin B6 and folic acid in patients non responders to PDE5i. J Sex Med 2010;7:216-223.

Endocrine factors represent an important and potentially treatable cause of sexual dysfunction. The availability of a correct endocrinological diagnosis allows correct identification of most cases of sexual dysfunction in which the endocrine apparatus is involved. Not only the most frequent causes of endocrine sexual dysfunction, such as hypogonadism and hyperprolactinaemia, but almost all extra-gonadal endocrinopathies (hyper-and hypothyroidism, hyper-and hypocortisolism, steroidal secreting tumours, etc.) may have importance to a greater or lesser extent in sexual function. It is, therefore, necessary that the diagnostic process for sexual dysfunctions of an endocrine nature be as integrated and wide as possible, especially as such pathologies are normally extremely responsive to medical or surgical therapy.