Effects of Three Different Testosterone Formulations in Female‐to‐Male Transsexual Persons

IntroductionGender dysphoria is characterized by a strong discomfort with the gender assigned at birth and the urge to live as a member of the opposite gender. The acquisition of phenotypic features of the desired gender requires the use of cross‐sex hormones. Female‐to‐male (FtM) transsexual persons are treated with testosterone to induce virilization.AimThe aim of the study was to assess the effects of three different testosterone formulations on body weight and composition and metabolic and bone parameters.MethodsForty‐five FtM transsexuals were randomly assigned to receive testoviron depot (i.m.: 100 mg/10 days; n = 15), testosterone gel (50 mg/die; n = 15), and testosterone undecanoate (i.m.: 1,000 mg every 6 weeks for the first 6 weeks and then every 12 weeks, n = 15). FtM individuals were studied before, at week 30, and at week 54 of testosterone treatment.Main Outcome MeasuresAnthropometric, metabolic, bone, hematological, and biochemical parameters were evaluated at baseline and after 12 months of treatment.ResultsLean body mass significantly increased and fat mass decreased in all groups. No modifications were reported in fasting insulin and insulin sensitivity index. High‐density plasma lipoprotein levels declined significantly and low‐density lipoprotein concentrations increased significantly in the three groups. The activated partial thromboplastin time and factor I did not change while prothrombin time significantly increased in all groups. At week 54, all subjects were amenorrheic and time to amenorrhea did not differ between the three groups. Current general life satisfaction was increased in all subjects after 1 year of treatment.ConclusionsOne‐year testosterone administration in FtM transsexuals appears to be very safe with no differences among the testosterone formulations used. Our study is preliminary, and the detection of subtle or long‐term differences in the effects of the three formulations may require further larger and longer term studies in this and other populations. Pelusi C, Costantino A, Martelli V, Lambertini M, Bazzocchi A, Ponti F, Battista G, Venturoli S, and Meriggiola MC. Effects of three different testosterone formulations in female‐to‐male transsexual persons. J Sex Med 2014;11:3002–3011.     

Short‐ and Long‐Term Clinical Skin Effects of Testosterone Treatment in Trans Men

IntroductionOur knowledge concerning the effects of testosterone (T) therapy on the skin of trans men (female‐to‐male transsexuals) is scarce.AimThe aim of this study was to evaluate the short‐ and long‐term clinical effects of T treatment on the skin of trans men.MethodsWe conducted a prospective intervention study in 20 hormone naive trans men and a cross‐sectional study in 50 trans men with an average of 10 years on T therapy.Main Outcome MeasuresAcne lesions were assessed using the Gradual Acne Grading Scale, hair patterns using the Ferriman and Gallwey classification (F&G), and androgenetic alopecia using the Norwood Hamilton Scale.ResultsT treatment increased facial and body hair growth. The F&G score increased progressively from a median value of 0.5 at baseline to a value of 12 after 12 months of T administration. After long‐term T treatment, all but one trans man achieved an F&G score indicative of hirsutism in women, with a median value of 24. Only one trans man acquired mild frontotemporal hair loss during the first year of T treatment, whereas 32.7% of trans men had mild frontotemporal hair loss and 31% had moderate to severe androgenetic alopecia after long‐term T therapy. The presence and severity of acne increased during the first year of T therapy, and peaked at 6 months. After long‐term T treatment, most participants had no or mild acne lesions (93.9%). Dermatological outcome was not demonstrably related to individual serum T or dihydrotestosterone levels.ConclusionsT treatment increased facial and body hair in a time‐dependent manner. The prevalence and severity of acne in the majority of trans men peaked 6 months after beginning T therapy. Severe skin problems were absent after short‐ and long‐term T treatment. Wierckx K, Van de Peer F, Verhaeghe E, Dedecker D, Van Caenegem, E, Toye K, Kaufman JM, and T'Sjoen G. Short‐ and long‐term clinical skin effects of testosterone treatment in trans men. J Sex Med 2014;11:222–229.     

Testosterone/Estradiol Ratio Regulates NO‐Induced Bladder Relaxation and Responsiveness to PDE5 Inhibitors

IntroductionThe efficacy of phosphodiesterase type 5 inhibitors (PDE5i) in treating lower urinary tract symptoms is supported by the extremely high expression and activity of PDE5 in male bladder. Although bladder function regulation is similar among genders, no data are available on PDE5 expression and activity in female bladder.AimTo investigate sex differences in PDE5 expression and biological activity in female bladder, as opposed to the male counterpart.Main Outcome MeasureGene and protein expression and enzymatic activity of PDE5.MethodsWe studied gene and protein expression, and enzymatic activity of PDE5 in bladder of male and female rats. A subgroup of female rats was ovariectomized and alternatively replaced with estradiol (E2), progesterone, and testosterone (T) alone or in combination with letrozole to completely abrogate T‐induced E formation. As a readout of PDE5 activity, we studied vardenafil efficacy in potentiating sodium nitroprusside (SNP)‐induced relaxation in bladder of the different experimental groups.ResultsSNP was three‐log unit less potent in relaxing the male bladder than the female one. On the contrary, the PDE5‐resistant cyclic guanosine monophosphate (cGMP) analog (Bromo‐β‐phenyl‐1, N²‐ethenoguanosine‐3′, 5′‐cyclic monophosphorothioate, Sp‐isomer [SP‐8‐Br‐PET‐cGMPS]) was equipotent in relaxing male and female bladder. Vardenafil was more effective in potentiating SNP‐induced bladder relaxation in male than in female. Accordingly, the cGMP‐hydrolyzing activity of PDE5 was higher in male vs. female homogenates. In ovariectomized female rats, with or without sex‐steroid replacement, vardenafil activity in potentiating SNP‐induced bladder relaxation was associated with an increased T/E2 ratio. In particular, masculinization of ovariectomized rats—by the administration of T + letrozole—dramatically increased vardenafil capacity to potentiate SNP‐induced relaxation.ConclusionIn this study, we demonstrated that PDE5 activity is more pronounced in male as compared with female bladder and that T/E ratio positively regulates responsiveness to PDE5i, thus suggesting that male bladder is a more suitable target for PDE5i than the female counterpart. Vignozzi L, Filippi S, Morelli A, Comeglio P, Cellai I, Sarchielli E, Maneschi E, Mancina R, Gacci M, Vannelli GB, and Maggi M. Testosterone/estradiol ratio regulates NO‐induced bladder relaxation and responsiveness to PDE5 inhibitors. J Sex Med 2012;9:3028–3040.     

Retrospective Investigation of Testosterone Undecanoate Depot for the Long‐term Treatment of Male Hypogonadism in Clinical Practice

IntroductionTestosterone undecanoate depot (TUD) administered intramuscularly is an effective form of testosterone replacement therapy (TRT) for male hypogonadism. Because of the ease of administration, TUD therapy may be preferable to subcutaneously implanted extended release T pellet implants (TI).AimThe primary objective was to retrospectively assess the efficacy and safety of long‐term (≥2 years therapy) TUD therapy in the clinical setting. The secondary objective was to retrospectively compare TUD with TI therapy.MethodsRetrospective data were collected from the Waikato Hospital Endocrine Database for 179 hypogonadal men treated with TUD for ≥2 years from 1998–2011, with 124 of these men receiving previous TI therapy.Main Outcome MeasuresThe main outcome measure for efficacy was serum trough total testosterone (TT), and for safety an increase in hemoglobin (Hb) and/or hematocrit (Hct), rise in prostate‐specific antigen (PSA) and/or prostatic biopsy and alteration in body mass index and lipid profile. Additional outcome measures were changes in the dosing and/or interval regimens for TUD therapy.ResultsOverall, 72% of trough TT levels were in the normal range for TUD therapy compared with 53% of trough TT levels during TI therapy. TUD therapy was well tolerated with 162 men (90.5%) completing 2 years of treatment, and only seven men (3.9%) stopping TUD because of adverse effects. A rise in Hb and/or Hct occurred in 25 men (14%), and a significant rise in PSA in 20 men (13%) at some stage during TUD therapy. At 2 years, 91% of men received the standard 1,000 mg TUD dose with 66% at the standard dosing interval of 10–14 weekly.ConclusionsTUD is an efficacious, safe, and well tolerated form of TRT, and individual optimisation of the dose and/or interval is only required in the minority of men. Particularly given the ease of administration, TUD was the preferred TRT for both patients and clinicians. Conaglen HM, Paul RG, Yarndley T, Kamp J, Elston MS, and Conaglen JV. Retrospective investigation of testosterone undecanoate depot for the long‐term treatment of male hypogonadism in clinical practice. J Sex Med 2014;11:574–582.     

Effects of Intravenous Injection of Adipose‐Derived Stem Cells in a Rat Model of Radiation Therapy‐Induced Erectile Dysfunction

IntroductionRadiation therapy (RT) for prostate cancer is frequently associated with posttreatment erectile dysfunction (ED).AimTo investigate whether injection of adipose‐derived stem cells (ADSCs) can ameliorate RT‐associated ED.MethodsThirty male rats were divided into three groups. The control + phosphate‐buffered saline (PBS) group received tail‐vein injection of PBS. The radiation + PBS group received radiation over the prostate and tail‐vein injection of PBS. The radiation + ADSC group received radiation over the prostate and tail‐vein injection of ADSCs, which were labeled with 5‐ethynyl‐2‐deoxyuridine (EdU). Seventeen weeks later, erectile function was evaluated by intracavernous pressure (ICP) in response to electrostimulation of cavernous nerves (CNs). Penile tissue and major pelvic ganglia (MPG) were examined by immunofluorescence (IF) and EdU staining.Main Outcome MeasuresErectile function was measured by ICP. Protein expression was examined by IF, followed by image analysis and quantification.ResultsRadiation over the prostate caused a significant decrease in erectile function and in the expression of neuronal nitric oxide synthase (nNOS) in penis and MPG. Cavernous smooth muscle (CSM) but not endothelial content was also reduced. Injection of ADSCs significantly restored erectile function, nNOS expression, and CSM content in the irradiated rats. EdU‐positive cells were visible in MPG.ConclusionsRadiation appears to cause ED via CN injury. ADSC injection can restore erectile function via CN regeneration. Qiu X, Villalta J, Ferretti L, Fandel TM, Albersen M, Lin G, Dai Y, Lue TF, and Lin C‐S. Effects of intravenous injection of adipose‐derived stem cells in a rat model of radiation therapy‐induced erectile dysfunction. J Sex Med 2012;9:1851–1858.     

Long‐Term Testosterone Treatment in Elderly Men with Hypogonadism and Erectile Dysfunction Reduces Obesity Parameters and Improves Metabolic Syndrome and Health‐Related Quality of Life

IntroductionLate‐onset hypogonadism (LOH) is diagnosed when declining testosterone concentrations in the aging male cause unwanted symptoms such as erectile dysfunction (ED), reduced bone density and muscle strength, and increased visceral obesity. Testosterone deficiency is also associated with insulin resistance and the metabolic syndrome (MetS). Restoring testosterone to physiological concentrations has beneficial effects on many of these symptoms; however, it is not known whether these effects can be sustained in the long term.AimsTo investigate whether treatment with testosterone undecanoate (TU) has a long‐term and sustained effect on parameters affected by the MetS in men with LOH and ED, to determine whether long‐term testosterone treatment can improve the overall health‐related quality of life in these men, and to establish the safety of long‐term testosterone treatment.MethodsTwo hundred sixty‐one patients (mean age 59.5 ± 8.4 years) diagnosed with LOH and ED were treated with long‐acting TU in a prospective, observational, and longitudinal registry study. Men received intramuscular injections of 1,000 mg TU at day 1, at week 6, and every 3 months thereafter.Main Outcome MeasuresParameters affected by the MetS, including obesity parameters (body weight, waist circumference, and body mass index [BMI]), total cholesterol, low‐density lipoprotein (LDL), high‐density lipoprotein (HDL), triglycerides, glucose, HbA_1c (glycated hemoglobin), and blood pressure, as well as total testosterone levels and health‐related quality of life, were assessed.ResultsWe found TU significantly improved obesity parameters (body weight, waist circumference, and BMI) and lowered total cholesterol, LDL cholesterol, triglycerides, fasting blood glucose, HbA_1c, and blood pressure over the 5‐year study. HDL cholesterol was increased. TU treatment resulted in a sustained improvement in erectile function and muscle and joint pain, which contributed to an improvement in long‐term health‐related quality of life. Furthermore, we found a relationship between health‐related quality of life and waist circumference. Finally, we found no evidence that long‐term treatment with TU increases the risk of prostate carcinoma.ConclusionLong‐term TU in men with LOH and ED reduces obesity parameters and improves metabolic syndrome and health‐related quality of life. Yassin DJ, Doros G, Hammerer PG, and Yassin AA. Long‐term testosterone treatment in elderly men with hypogonadism and erectile dysfunction reduces obesity parameters and improves metabolic syndrome and health‐related quality of life. J Sex Med 2014;11:1567–1576.     

Effects of Testosterone Deficiency and Angiotensin II–Induced Hypertension on the Biomechanics of Intramural Coronary Arteries

BackgroundAndropause and hypertension also increase the risk of coronary artery damage.AimTo investigate the effect of testosterone deficiency and hypertension on intramural coronary vessels.Methods4 groups of 8-week-old Sprague-Dawley rats were studied: control male (Co, n=10), orchidectomized male (OCT, n=13), angiotensin (AII) hypertensive male (AII, n=10), and AII hypertensive and OCT (AII + OCT, n=8). Surgical orchidectomy was performed, and an osmotic minipump was inserted for chronic angiotensin II infusion (100 ng/min/kg). After 4 weeks, spontaneous tone and biomechanical properties of the intramural coronary resistance artery were investigated in vitro, by pressure microarteriography.OutcomesMorphology and biomechanics of the intramural coronaries were evaluated: the outer diameter, wall thickness–to–lumen diameter ratio, and tangential wall stress in the contracted and relaxed states.ResultsThe outer diameter was reduced in OCT and AII + OCT groups (on 50 mmHg 315 ± 20 Co; 237 ± 21 OCT; 291 ± 16 AII, and 166 ± 12 μm AII + OCT). The increased wall thickness–to–lumen diameter ratio resulted in lower tangential wall stress in AII + OCT rats (on 50 mmHg 19 ± 2 Co; 24 ± OCT; 26 ± 5 AII, and 9 ± 1 kPa AII + OCT). Spontaneous tone was increased in the hypertensive rats (AII and AII + OCT groups) (on 50 mmHg 7.7 ± 1.8 Co; 6.1 ± 1.4 OCT; 14.5 ± 3.0 AII, and 17.4 ± 4.1 % AII + OCT).Clinical ImplicationsAndropause alone can be considered as a cardiovascular risk factor that will further exacerbate vascular damage in hypertension.Strengths & LimitationsA limitation of our study is that it was performed on relatively young rats, and the conclusions might not apply to coronary remodelling in older animals with slower adaptation processes.ConclusionsTestosterone deficiency and hypertension damage the mechanical adaptation of the vessel wall additively: double noxa caused inward eutrophic remodeling and increased tone.Jósvai A, Török M, Mátrai M, et al. Effects of Testosterone Deficiency and Angiotensin II–Induced Hypertension on the Biomechanics of Intramural Coronary Arteries. J Sex Med 2020;17:2322–2330.     

Mitochondrial Impairment and Oxidative Stress in Leukocytes after Testosterone Administration to Female‐To‐Male Transsexuals

IntroductionTestosterone undecanoate (T) treatment is common in female‐to‐male transsexuals (FtMs) but can induce impairment of mitochondrial function and oxidative stress.AimThe effect of T treatment on the mitochondrial function and redox state of leukocytes of FtMs subjects was evaluated.MethodsThis was an observational study conducted in a university hospital. Fifty‐seven FtMs were treated with T (1,000 mg) for 12 weeks, after which anthropometric and metabolic parameters and mitochondrial function were evaluated.Main Outcome MeasuresAnthropometric and metabolic parameters were evaluated. Mitochondrial function was studied by assessing mitochondrial oxygen (O₂) consumption, membrane potential, reactive oxygen species (ROS) production, glutathione levels (GSH), and the reduced glutathione/oxidized glutathione (GSH)/(GSSG) ratio in polymorphonuclear cells.ResultsT treatment led to mitochondrial impairment in FtMs as a result of a decrease in mitochondria O₂ consumption, the membrane potential, GSH levels, and the (GSH)/(GSSG) ratio and an increase in ROS production. Mitochondrial O₂ consumption and membrane potential negatively correlated with T levels, which was further confirmed that the T treatment had induced mitochondrial dysfunction. T also produced a significant increase in total testosterone, free androgenic index, and atherogenic index of plasma, and a decrease in sex hormone‐binding globulin and high‐density lipoprotein cholesterol.ConclusionsTreatment of FtMs with T can induce impairment of mitochondrial function and a state of oxidative stress. This effect should be taken into account in order to modulate possible comorbidities in these patients. Victor VM, Rocha M, Bañuls C, Rovira‐Llopis S, Gómez M, and Hernández‐Mijares A. Mitochondrial impairment and oxidative stress in leukocytes after testosterone administration to female‐to‐male transsexuals. J Sex Med 2014;11:454–461.     

Effect of Mucuna pruriens (Linn.) on Sexual Behavior and Sperm Parameters in Streptozotocin‐Induced Diabetic Male Rat

IntroductionSexual dysfunction is one of the major secondary complications in the diabetic. Mucuna pruriens, a leguminous plant identified for its antidiabetic, aphrodisiac, and improving fertility properties, has been the choice of Indian traditional medicine.AimObjective of the present study was to analyze the efficacy of M. pruriens on male sexual behavior and sperm parameters in long‐term hyperglycemic male rats.MethodsMale albino rats were divided as group I control, group II diabetes induced (streptozotocin [STZ] 60 mg/kg of body weight (b.w.) in 0.1 M citrate buffer), group III diabetic rats administered with 200 mg/kg b.w. of ethanolic extract of M. pruriens seed, group IV diabetic rats administered with 5 mg/kg b.w. of sildenafil citrate (SC), group V administered with 200 mg/kg b.w. of extract, and group VI administered with 5 mg/kg b.w. of SC. M. pruriens and SC were administered in single oral dosage per day for a period of 60 days. The animals were subjected to mating behavior analyses, libido, test of potency, and epididymal sperms were analyzed.Main Outcome MeasureThe mating behavior, libido, test of potency, along with epididymal sperms were studied.ResultsThe study showed significant reduction in sexual behavior and sperm parameters in group II. Daily sperm production (DSP) and levels of follicular stimulating hormone, luteinizing hormone, and testosterone were significantly reduced in group II, whereas the animals with diabetes administered with seed extract of M. pruriens (group III) showed significant improvement in sexual behavior, libido and potency, sperm parameters, DSP, and hormonal levels when compared to group II.ConclusionThe present work reveals the potential efficacy of ethanolic seed extract of M. pruriens to improve male sexual behavior with androgenic and antidiabetic effects in the STZ‐induced diabetic male rats. This study supports the usage of M. pruriens in the Indian system of medicine as sexual invigorator in diabetic condition and encourages performing similar study in men. Suresh S, and Prakash S. Effect of Mucuna pruriens (Linn.) on sexual behavior and sperm parameters in streptozotocin‐induced diabetic male rat. J Sex Med 2012;9:3066–3078.     

ORIGINAL RESEARCH—ENDOCRINOLOGY: A Comparative Study of the Effects of Local Estrogen With or Without Local Testosterone on Vulvovaginal and Sexual Dysfunction in Postmenopausal Women

IntroductionA significant number of postmenopausal women suffer from distressing problems because of urogenital atrophy secondary to the decline in circulating estrogen levels. Treatment with topical hormones may provide relief in such women when used judiciously.AimTo study the effects of local estrogen with or without local testosterone on urogenital and sexual health in postmenopausal women.MethodsSeventy-five postmenopausal women symptomatic for urogenital atrophy and sexual dysfunction were randomly divided into two study groups and one control group. The women in study group 1 received local estrogen cream; study group 2 received local estrogen and testosterone cream; the control group received nonhormonal lubricant KY gel for 12 weeks. The urogenital and sexuality score, along with the vaginal health index and the vaginal maturation index (VMI), was calculated at the beginning of therapy and 12 weeks later.Main Outcome MeasuresChanges in the urogenital and sexuality score along with vaginal health index and VMI.ResultsAfter 12 weeks of therapy, there was a significant improvement in all the four study parameters, which correlated well with the improvement in symptoms of urogenital atrophy and sexual dysfunction in both the study groups as compared with the control group. Improvement in sexuality score was greatest with combined estrogen–androgen therapy. There were no adverse effects and the therapies were well accepted without any compliance issue.ConclusionLocal estrogen either alone or with androgen is highly effective in relieving symptoms of urogenital atrophy and in improving sexual function in symptomatic postmenopausal women. Raghunandan C, Agrawal S, Dubey P, Choudhury M, and Jain A. A comparative study of the effects of local estrogen with or without local testosterone on vulvovaginal and sexual dysfunction in postmenopausal women.     

Impaired Masturbation‐Induced Erections: A New Cardiovascular Risk Factor for Male Subjects with Sexual Dysfunction

Introduction.Erectile dysfunction (ED) is considered an early surrogate marker of silent, or even overt, cardiovascular diseases (CVD). However, epidemiological studies take into account only sexual intercourse‐related erections. Although autoeroticism is a very common practice, data on masturbation‐induced erections as a possible predictor of major adverse cardiovascular events (MACE) are lacking.Aim.To evaluate the clinical correlates of impaired masturbation‐induced erections and to verify the importance of this sexual aspect in predicting MACE.Methods.A consecutive series of 4,031 male patients attending the Outpatient Clinic for sexual dysfunction for the first time was retrospectively studied. Among these subjects, 64% reported autoeroticism during the last 3 months, and only this subset was considered in the following analyses. In the longitudinal study, 862 subjects reporting autoeroticism were enrolled.Main Outcome Measures.Several clinical, biochemical, and instrumental (Prostaglandin E1 [PGE₁] test and penile color Doppler ultrasound) parameters were studied.Results.Subjects with an impaired erection during masturbation (46% of those reporting autoeroticism) had more often a positive personal or family history of CVD, a higher risk of reduced intercourse‐ and sleep‐related erections, hypoactive sexual desire and perceived reduced ejaculate volume, and impaired PGE₁ test response. Prolactin levels were lower in those having impaired erection during masturbation. In the longitudinal study, unadjusted incidence of MACE was significantly associated with impaired masturbation‐induced erections. When dividing the population according to the median age and diagnosis of diabetes, the association between impaired masturbation‐induced erections and incidence of MACE was maintained only in the youngest (<55 years old) and in nondiabetic subjects, even after adjusting for confounders (hazard ratio [HR] = 3.348 [1.085–10.335], P = 0.032 and HR = 2.108 [1.002–4.433], P = 0.049; respectively).Conclusion.This study indicates that, in subjects with male sexual dysfunction, evaluating an often neglected sexual parameter, such as masturbation‐induced erections, can provide further insights on forthcoming MACE in particular in “low risk” subjects.     

5‐HT2A Receptor ‐1438 G/A Polymorphism and Serotonergic Antidepressant‐Induced Sexual Dysfunction in Male Patients with Major Depressive Disorder: A Prospective Exploratory Study

IntroductionTo date, few studies have specifically investigated the genetic determinants of antidepressant‐induced sexual dysfunction (SD).AimThe aim of this prospective study was to examine whether the 5‐HT_2A receptor ‐1438 G/A polymorphism has functional consequences on sexual well‐being in young adult men presenting with their first episode of major depressive disorder (MDD) after serotonergic antidepressant treatment.MethodsBetween May 2010 and June 2011, a total of 56 drug‐naïve patients presenting with their first episode of MDD were recruited from a psychiatric hospital and received either a selective serotonin reuptake inhibitor or venlafaxine monotherapy; the patients were then genotyped. Over the course of antidepressant treatment, the population was divided into a SD group (N = 16) and a non‐SD group (N = 29) based on the Arizona Sexual Experience Scale (ASEX). Participants who did not achieve a significant improvement, as assessed by the Hamilton Depression Rating Scale (HAMD‐17), were excluded from the final data analysis.Main Outcome MeasuresThe primary outcome measures were the differences in the genotype distribution and allele frequencies between groups.ResultsIn the SD group, the AA genotype was significantly overrepresented (P = 0.004), and the mean baseline HAMD‐17 score, the mean baseline ASEX score, and the mean end‐point ASEX score were significantly higher than those in the non‐SD group (P = 0.026, P = 0.004, and P < 0.001, respectively). The mean end‐point HAMD‐17 score (P = 0.115) did not differ significantly between the two groups.ConclusionThese results suggest that the AA genotype may be a genetic trait offering an opportunity to strengthen early detection of serotonergic antidepressant‐induced SD in young adult male patients with MDD, whereas the G allele is protective against SD in this population. Liang C‐S, Ho P‐S, Chiang K‐T, and Su H‐C. 5‐HT_2A receptor ‐1438 G/A polymorphism and serotonergic antidepressant‐induced sexual dysfunction in male patients with major depressive disorder: A prospective exploratory study. J Sex Med 2012;9:2009–2016.     

TNF‐α, Erectile Dysfunction,and NADPH Oxidase‐Mediated ROS Generation in Corpus Cavernosum in High‐Fat Diet/Streptozotocin‐Induced Diabetic Rats

IntroductionPatients with diabetes‐associated erectile dysfunction (ED) are characterized by an increase in circulating tumor necrosis factor‐alpha (TNF‐α). However, no study has indicated whether and how TNF‐α plays a role in the pathogenesis of ED associated with diabetes.AimWe examined the effects and potential mechanism of infliximab (INF), a chimeric monoclonal antibody to TNF‐α, on reactive oxygen species (ROS) generation in corpus cavernosum and ED in diabetic rats.MethodsFour groups of male rats were used: age‐matched normal controls; diabetic rats induced by a high‐fat diet (HFD) combined with a single streptozotocin (STZ) injection (35 mg/kg body weight, intraperitoneal [i.p.]); nondiabetic rats receiving INF (5 mg/kg body weight/week, i.p.), and diabetic rats receiving INF. Erectile function was assessed with electrical stimulation of the cavernous nerve after 8 weeks. The blood and penile tissues were harvested for plasma biochemical determinations, serum TNF‐α measurement, penile ROS detection, and molecular assays of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, endothelial nitric oxide synthase (eNOS), phospho‐eNOS, and neural nitric oxide synthase (nNOS) in the penis.Main Outcome MeasuresThe effect of INF on HFD/STZ‐induced diabetic ED and NADPH oxidase‐mediated ROS generation was studied in diabetic corpus cavernosum.ResultsUntreated diabetic rats displayed significantly decreased erectile parameters, and increased plasma TNF‐α levels, penile ROS production, p47^phox and gp91^phox expression compared with nondiabetic controls. INF neutralized TNF‐α and significantly reduced ED in diabetic rats, in which marked decreases in p47^phox and gp91^phox expression and ROS generation in corpus cavernosum were noted. The ratio of phospho‐eNOS to eNOS and expression of nNOS in the penis were significantly increased in INF‐treated vs. untreated diabetic rats.ConclusionsIncreased TNF‐α expression associated with diabetes contributes to ED by promoting NAPDH oxidase‐mediated ROS generation in corpus cavernosum. INF protects against diabetic ED by neutralizing TNF‐α. Long T, Liu G, Wang Y, Chen Y, Zhang Y, and Qin D. TNF‐α, erectile dysfunction, and NADPH oxidase‐mediated ROS generation in corpus cavernosum in high‐fat diet/streptozotocin‐induced diabetic rats. J Sex Med 2012;9:1818–1831.     

Increased Risk of Sexual Dysfunction in Male Patients with Psoriasis: A Nationwide Population‐Based Follow‐Up Study

IntroductionAn association between psoriasis and sexual dysfunction (SD) has been explored. However, the risk of SD after the diagnosis of psoriasis relative to the age‐matched general population remains unknown.AimTo clarify the risk of developing SD in male patients with psoriasis.MethodsFrom 2000 to 2001, we identified 12,300 male patients with newly diagnosed psoriasis and 61,500 matching controls from National Health Insurance Database in Taiwan.Main Outcome MeasuresThe two cohorts were followed up until 2008, and we observed the occurrence of SD by registry of SD diagnosis in the database. Stratified Cox proportional hazard regressions were used to calculate the 7‐year SD risk for these two groups.ResultsOf the 73,800 sampled patients, 1,812 patients (2.46%) experienced SD during the 7‐year follow‐up period, including 373 (3.03% of patients with psoriasis) in the study group and 1,439 (2.34% of patients without psoriasis) in the comparison group. The hazard ratio (HR) for SD for patients with psoriasis was 1.27 times (95% confidence interval [CI], 1.11–1.46; P = 0.001) as high as that for patients without psoriasis after adjusting for age, monthly income, number of health‐care visits, systemic treatment, and other comorbidities. Stratified analysis showed that the risk of SD was higher in patients older than 60 years old (HR: 1.42, 95% CI: 1.12–1.81) and patients with psoriatic arthritis (HR: 1.78, 95% CI: 1.08–2.91). However, the risk of SD was not significantly elevated in patients receiving systemic treatment, including retinoid, methotrexate, and cyclosporine.ConclusionsMale patients with psoriasis are at increased risk of developing SD. Physicians should pay attention to the impact of psoriasis on psychosocial and sexual health, especially in old‐aged patients.     

Effect of Intracavernous Administration of Angiopoietin‐4 on Erectile Function in the Streptozotocin‐Induced Diabetic Mouse

IntroductionErectile dysfunction (ED) is a highly prevalent complication of diabetes, and the severity of endothelial dysfunction is one of the most important factors in reduced responsiveness to oral phosphodiesterase type 5 inhibitors.AimTo study the effects of human angiopoietin‐4 (Ang‐4) protein on erectile function in diabetic mice.MethodsDiabetes was induced by intraperitoneal injection of streptozotocin into 8‐week‐old C57BL/6J male mice. At 8 weeks after the induction of diabetes, the animals were divided into four groups: control nondiabetic mice and diabetic mice receiving two successive intracavernous injections of phosphate buffered saline (days ?3 and 0), a single intracavernous injection of Ang‐4 protein (day 0), or two successive intracavernous injections of Ang‐4 protein (days ?3 and 0).Main Outcome MeasuresOne week after treatment, we measured erectile function by electrical stimulation of the cavernous nerve. The penis was harvested and stained with hydroethidine or antibodies to Ang‐4, platelet/endothelial cell adhesion molecule‐1, and phosphorylated endothelial nitric oxide synthase (eNOS). We also determined the differential expression of Ang‐4 in cavernous tissue in the control and diabetic mice. The effect of Ang‐4 protein on the phosphorylation of Tie‐2, Akt, and eNOS was determined in human umbilical vein endothelial cells (HUVECs) by Western blot.ResultsThe cavernous expression of Ang‐4 was downregulated in diabetic mice; Ang‐4 was mainly expressed in endothelial cells. Local delivery of Ang‐4 protein significantly increased cavernous endothelial content, induced eNOS phosphorylation, and decreased the generation of superoxide anion and apoptosis in diabetic mice. Ang‐4 protein strongly increased the phosphorylation of Tie‐2, Akt, and eNOS in HUVECs. Repeated intracavernous injections of Ang‐4 induced significant restoration of erectile function in diabetic mice (87% of control values), whereas a single intracavernous injection of Ang‐4 protein elicited modest improvement.ConclusionsCavernous endothelial regeneration by use of Ang‐4 protein may have potential for the treatment of vascular disease‐induced ED, such as diabetic ED. Kwon M‐H, Ryu J‐K, Kim WJ, Jin H‐R, Song K‐M, Kwon K‐D, Batbold D, Yin GN, Koh GY, and Suh J‐K. Effect of intracavernous administration of angiopoietin‐4 on erectile function in the streptozotocin‐induced diabetic mouse. J Sex Med 2013;10:2912–2927.     

Clinical and Biopsychosocial Determinants of Sexual Dysfunction in Middle‐Aged and Older Australian Men

IntroductionErectile dysfunction (ED) and other related sexual dysfunctions in men have recently been shown to associate with a range of conditions and biopsychosocial factors. However, few studies have been able to control for these related factors simultaneously.AimTo determine the prevalence of and associated risk factors for ED and low solitary and dyadic sexual desire.Main Outcome MeasuresErectile function (International Index of Erectile Function‐erectile function) and sexual desire (Sexual Desire Inventory 2), as well as associated sociodemographic, lifestyle, biological, and clinical risk factors.MethodsData were collected from 1,195 randomly selected, community‐dwelling men as part of the Florey Adelaide Male Ageing Study.ResultsThe prevalence of ED, low solitary, and dyadic sexual desire was 17.7%, 67.7%, and 13.5%, respectively. Increasing age, abdominal fat mass, obstructive sleep apnea risk, and the absence of a regular partner were associated with both degrees of ED severity. Insufficient physical activity, low alcohol consumption, and hypertension were associated with mild ED only, and voiding lower urinary tract symptoms, diabetes, and lower plasma testosterone were independently associated with moderate to severe ED. Increasing age, lower alcohol consumption, insufficient physical activity, and a diagnosis of depression, anxiety, or insomnia were associated with both low dyadic and solitary sexual desire. Postschool qualifications and lower plasma testosterone were associated with low dyadic desire, whereas lower education and income, unemployment, and migration were associated with low solitary sexual desire. The absence of a regular partner and postschool qualifications were associated with higher solitary sexual desire.ConclusionsWhile ED and low dyadic and solitary sexual desire share some risk factors, we were able to demonstrate that unique factors exist for each of these domains. Attention should first be given to addressing these modifiable risk factors. Martin S, Atlantis E, Wilson D, Lange K, Haren MT, Taylor A, Wittert G, and Members of the Florey Adelaide Male Ageing Study. Clinical and biopsychosocial determinants of sexual dysfunction in middle‐aged and older Australian men. J Sex Med 2012;9:2093–2103.     

Estrogen Mediates Metabolic Syndrome‐Induced Erectile Dysfunction: A Study in the Rabbit

IntroductionEstrogen receptor (ER) α is critical in mediating the harmful effects of hyperestrogenism in fetal or neonatal life on the developing penis. In contrast, little is known on the impact of an excess of estrogens on penile function in adulthood.AimTo investigate the effect of estrogens on metabolic syndrome (MetS)‐associated erectile dysfunction (ED).MethodsWe employed a recently established animal model of high fat diet (HFD)‐induced MetS. Subgroups of MetS rabbits were dosed with either testosterone (T) or tamoxifen. We evaluated penile responsiveness to acetylcholine (Ach) as well as the expression of genes related to penile smooth muscle relaxation and contractility.Main Outcome MeasureAssociations between MetS‐induced penile alterations and sex steroids were investigated in an animal model of HFD‐induced MetS. To understand the role of either androgen deficiency or estrogen excess on ED, we treated subgroups of MetS rabbits with either T or tamoxifen, a classical ER antagonist.ResultsFeeding an HFD‐induced MetS was associated to elevated estradiol (E2) and low T levels. E2, but not T, was independently and negatively associated with genes able to affect penile erection. Smooth muscle‐related markers decreased as a function of E2 and were positively associated with all the variables investigated. Increasing concentrations of circulating E2 were negatively associated with Ach‐induced relaxation. In HFD rabbits, in vivo T dosing significantly improved MetS and completely normalized circulating E2. Conversely, in vivo tamoxifen dosing reduced visceral adiposity and partially restored T level. Ach‐induced relaxation was severely impaired by HFD and significantly restored, up to the control level, by both tamoxifen and T dosing. In rabbit smooth muscle cells cultures 17β‐E2 (1 nM) significantly reduced the expression of α‐smooth muscle actin, transgelin, and phosphodiesterase type 5. The effects of 17β‐E2 were completely reverted by tamoxifen (100 nM).ConclusionsThis study demonstrates, for the first time, that HFD‐induced ED is more associated with a high E2, rather than to a low T, milieu. HFD‐induced ED is partially restored by in vivo treatment not only with T but also with the nonsteroidal ER antagonist, tamoxifen. Vignozzi L, Filippi S, Comeglio P, Cellai I, Morelli A, Marchetta M, and Maggi M. Estrogen mediates metabolic syndrome‐induced erectile dysfunction: A study in the rabbit. J Sex Med 2014;11:2890–2902.