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Background: Based on the largely untested premise that it is a restorative hormone that may reverse the detrimental impacts of aging, prescription of testosterone (T) has increased in recent decades despite no new clinical indications. It is apparent that middle-aged and older men with low-normal serum T levels are considering T supplementation as an anti-aging strategy. At the same time, there is evidence that physical activity (PA) is at historical lows in the Western world. In this review, we compare the impacts of T treatment aimed at achieving physiological T concentrations in middle-aged and older men, alongside the impacts of ecologically relevant forms of exercise training. The independent, and possible combined, effects of T and exercise therapy on physiological outcomes such as aerobic fitness, body composition and muscular strength are addressed. Main Body: Our findings suggest that both T treatment and exercise improve lean body mass in healthy older men. If improvement in lean body mass is the primary aim, then T treatment could be considered, and the combination of T and exercise may be more beneficial than either in isolation. In terms of muscle strength in older age, an exercise program is likely to be more beneficial than T treatment (where the dose is aimed at achieving physiological concentrations), and the addition of such T treatment does not provide further benefit beyond that of exercise alone. For aerobic fitness, T at doses aimed at achieving physiological concentrations has relatively modest impacts, particularly in comparison to exercise training, and there is limited evidence as to additive effects. Whilst higher doses of T, particularly by intramuscular injection, may have larger impacts on lean body mass and strength, this must be balanced against potential risks. Conclusion: Knowing the impacts of T treatment and exercise on variables such as body composition, strength and aerobic fitness extends our understanding of the relative benefits of physiological and pharmacological interventions in aging men. Our review suggests that T has impacts on strength, body composition and aerobic fitness outcomes that are dependent upon dose, route of administration, and formulation. T treatment aimed at achieving physiological T concentrations in middle-aged and older men can improve lean body mass, whilst exercise training enhances lean body mass, aerobic fitness and strength. Men who are physically able to exercise safely should be encouraged to do so, not only in terms of building lean body mass, strength and aerobic fitness, but for the myriad health benefits that exercise training confers. [ABSTRACT FROM AUTHOR]

Summary: Glucocorticoid use in Duchenne and Becker muscular dystrophy prolongs ambulation but cause significant skeletal toxicity. Our analysis has immediate clinical implications, suggesting that growth hormone and testosterone have a stronger effect prior to first and subsequent vertebral fracture, respectively, relative to bisphosphonates alone in children with dystrophinopathies on chronic glucocorticoids. Purpose: Glucocorticoids prolong ambulation in boys with Duchenne muscular dystrophy; however, they have significant endocrine side effects. We assessed the impact of growth hormone (GH), testosterone, and/or zoledronic acid (ZA) on vertebral fracture (VF) incidence in patients with dystrophinopathies on chronic glucocorticoids. Methods: We conducted a longitudinal retrospective review of 27 males with muscular dystrophy. Accelerated failure time (AFT) models were used to estimate the relative time to VF while on GH, testosterone, and/or ZA compared to ZA alone. Results are reported as failure time ratio, where >1 indicates prolonged time versus <1 indicates shorter time to next VF. Results: The prevalence of growth impairment was 96% (52% utilized GH), pubertal delay was 86% (72% utilized testosterone), and low trauma fractures were 87% (72% utilized ZA). Multivariable analysis of the AFT models showed that participants on either GH or testosterone treatment relative to ZA alone experienced prolonged time to next VF (1.253, P<0.001), with GH being the significant contributor when analyzed independently from testosterone (1.229, P<0.001). Use of ZA with GH or testosterone relative to ZA alone resulted in prolonged time to next VF (1.171, P<0.001), with testosterone being a significant contributor (1.130, P=0.033). Conclusion: GH and testosterone each decreased VF risk in patients independent of or in combination with ZA, respectively. [ABSTRACT FROM AUTHOR]

Sarcopenia is a skeletal muscle disorder characterized by progressive and generalized decline in muscle mass and function. Although it is mostly known as an age-related disorder, it can also occur secondary to systemic diseases such as malignancy or organ failure. It has demonstrated a significant relationship with adverse outcomes, e.g., falls, disabilities, and even mortality. Several breakthroughs have been made to find a pharmaceutical therapy for sarcopenia over the years, and some have come up with promising findings. Yet still no drug has been approved for its treatment. The key factor that makes finding an effective pharmacotherapy so challenging is the general paradigm of standalone/single diseases, traditionally adopted in medicine. Today, it is well known that sarcopenia is a complex disorder caused by multiple factors, e.g., imbalance in protein turnover, satellite cell and mitochondrial dysfunction, hormonal changes, low-grade inflammation, senescence, anorexia of aging, and behavioral factors such as low physical activity. Therefore, pharmaceuticals, either alone or combined, that exhibit multiple actions on these factors simultaneously will likely be the drug of choice to manage sarcopenia. Among various drug options explored throughout the years, testosterone still has the most cumulated evidence regarding its effects on muscle health and its safety. A mas receptor agonist, BIO101, stands out as a recent promising pharmaceutical. In addition to the conventional strategies (i.e., nutritional support and physical exercise), therapeutics with multiple targets of action or combination of multiple therapeutics with different targets/modes of action appear to promise greater benefit for the prevention and treatment of sarcopenia. [ABSTRACT FROM AUTHOR]

Summary: Twenty men with spinal cord injury (SCI) were randomized into two 16-week intervention groups receiving testosterone treatment (TT) or TT combined with resistance training (TT + RT). TT + RT appears to hold the potential to reverse or slow down bone loss following SCI if provided over a longer period. Introduction: Persons with SCI experience bone loss below the level of injury. The combined effects of resistance training and TT on bone quality following SCI remain unknown. Methods: Men with SCI were randomized into 16-week treatments receiving TT or TT + RT. Magnetic resonance imaging (MRI) of the right lower extremity before participation and post-intervention was used to visualize the proximal, middle, and distal femoral shaft, the quadriceps tendon, and the intermuscular fascia of the quadriceps. For the TT + RT group, MRI microarchitecture techniques were utilized to elucidate trabecular changes around the knee. Individual mixed models were used to estimate effect sizes. Results: Twenty participants completed the pilot trial. A small effect for yellow marrow in the distal femur was indicated as increases following TT and decreases following TT + RT were observed. Another small effect was observed as the TT + RT group displayed greater increases in intermuscular fascia length than the TT arm. Distal femur trabecular changes for the TT + RT group were generally small in effect (decreased trabecular thickness variability, spacing, and spacing variability; increased network area). Medium effects were generally observed in the proximal tibia (increased plate width, trabecular thickness, and network area; decreased trabecular spacing and spacing variability). Conclusions: This pilot suggests longer TT + RT interventions may be a viable rehabilitation technique to combat bone loss following SCI. Clinical trial registration: Registered with clinicaltrials.gov: NCT01652040 (07/27/2012). [ABSTRACT FROM AUTHOR]

Voice is one of the most noticeably dimorphic traits in humans and plays a central role in gender presentation. Transgender males seeking to align internal identity and external gender expression frequently undergo testosterone (T) therapy to masculinize their voices and other traits. We aimed to determine the importance of changes in vocal masculinity for transgender men and to determine the effectiveness of T therapy at masculinizing three speech parameters: fundamental frequency (i.e., pitch) mean and variation (fo and fo-SD) and estimated vocal tract length (VTL) derived from formant frequencies. Thirty transgender men aged 20 to 40 rated their satisfaction with traits prior to and after T therapy and contributed speech samples and salivary T. Similar-aged cisgender men and women contributed speech samples for comparison. We show that transmen viewed voice change as critical to transition success compared to other masculine traits. However, T therapy may not be sufficient to fully masculinize speech: while fo and fo-SD were largely indistinguishable from cismen, VTL was intermediate between cismen and ciswomen. fo was correlated with salivary T, and VTL associated with T therapy duration. This argues for additional approaches, such as behavior therapy and/or longer duration of hormone therapy, to improve speech transition. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the efficacy of testosterone supplementation for improving aromatase inhibitor musculoskeletal symptoms (AIMSS). Methods: Postmenopausal women experiencing moderate-to-severe arthralgias while taking adjuvant aromatase inhibitors for breast cancer were enrolled in this trial. Initially, patients were randomly allocated to receive either a subcutaneous testosterone pellet versus a placebo pellet. Due to slow accrual, the protocol was modified such that additional participants were randomized to receive either a topical testosterone gel or a placebo gel. Changes in patient-reported joint pain were compared between patients receiving testosterone and those receiving placebo using a two-sample t test. Changes in hot flashes and other vasomotor symptoms were also analyzed. Further analyses were conducted to evaluate whether 27 single nucleotide polymorphisms (SNPs) in 14 genes previously associated with AIMSS were associated with testosterone supplementation benefit. Results: While 64% of patients reported an improvement in joint pain at 3 months, there were no significant differences in average pain or joint stiffness at 3 or 6 months between testosterone and placebo arms. Patients receiving testosterone did report improvements in strength, lack of energy, urinary frequency, and stress incontinence (p < 0.05). The subset of patients receiving subcutaneous testosterone also experienced improvements in hot flashes and mood swings. An inherited variant (rs7984870 CC genotype) in TNFSF11 was more likely to be associated with improvements in hot flashes in patients receiving testosterone. Conclusion: The doses of testosterone supplementation used in this study did not significantly improve AIMSS. Trial registration: ClinicalTrials.gov Identifier: NCT01573442 [ABSTRACT FROM AUTHOR]

Cardiac cachexia is a syndrome of progressive skeletal muscle and fat loss affecting a significant number of congestive heart failure patients. With the potential detrimental effects of cardiac muscle wasting, greater attention is needed to understanding the prevention and treatment of the condition. Potential therapeutic approaches are aimed at the various mechanisms for the pathogenesis of cardiac cachexia including neurohormonal abnormalities, immune activation and inflammation, metabolic hormonal imbalance, and gastrointestinal abnormalities. While there are no current guideline-recommended treatments for the prevention of cardiac cachexia, targeting an imbalance of the renin-angiotensin-aldosterone system with beta-blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers appears to be the most well-studied therapeutic approaches. Treatment of inflammation with monoclonal antibodies, hormonal imbalance with testosterone, and nutritional deficiencies with appetite stimulants has also been suggested. Proposed therapies may prove beneficial in heart failure patients; however, further studies specifically focusing on the cardiac component of cachexia are needed before definitive therapy options can be established. [ABSTRACT FROM AUTHOR]

An editorial is presented on the application of senolytics drug and snake oil in the pharmaceutical industry. Topics include minimal evidence for its use in humans especially in the age of personalized medicine which is dependent on genetic background of different individuals; and negligible research regarding its long-term effects in the development of medicines related to cancer.

Testosterone 2% (20 m/mL) transdermal gel (Testavan®, Testarzon®), is indicated to treat adult male hypogonadism, when testosterone deficiency has been confirmed by clinical features and biochemical tests. It is applied once daily using a hands-free applicator, with an initial recommended daily dosage equivalent to 23 mg testosterone, which may be increased to 46 or 69 mg/day. In clinical studies, once-daily application of Testavan 2% gel was associated with rapid and extensive absorption of testosterone, leading to normalization of testosterone levels in hypogonadal men. After application, testosterone levels achieve their peak in ≈ 2–4 h, then decrease to pre-application levels at ≈ 12 h, broadly mirroring the natural diurnal rhythm of male testosterone. Testavan 2% gel also improved sexual, physical and mental functioning, fatigue and health-related quality of life. The components of Testavan's novel gel enhance the transdermal transfer of testosterone into the blood, allowing the application of lower doses of testosterone in smaller gel volumes relative to the application of other transdermal testosterone gels. Testavan 2% gel is applied using the applicator cap rather than by hand, reducing the potential risk of secondary transfer of testosterone. [ABSTRACT FROM AUTHOR]

Phosphodiesterase type 5 inhibitors (PDE5Is) are the drug of choice for medical management of erectile dysfunction (ED). On-demand PDE5Is have an overall efficacy of 60-70% for ED; 30-35% of patients fail to respond to a PDE5I, and 30-50% of non-responders can be salvaged with detailed counseling on proper use and physician follow-up to ensure that the patient has been prescribed an appropriate and full PDE5I clinical trial. True non-responders may be offered intracavernosal injections of erectogenic drugs, intraurethral alprostadil, or surgical insertion of a penile prosthesis. Such options are not discreet and are associated with more adverse effects than PDE5Is. Thus patients may request additional non-invasive medical management options. This review describes published literature on patients who failed to respond to an on-demand PDE5I regimen and were treated with a non-invasive PDEI-based regimen, including switching from one PDE5I to another; increasing the dose of PDE5I above the labeled dosage range; using two PDE5Is concurrently; using a daily PDE5I regimen; or combining a PDE5I with a testosterone supplement, α-adrenergic antagonist, intraurethral or intracavernosal alprostadil, vacuum erection device, or low-intensity shock wave therapy. The limitations of published clinical trials do not allow for sufficient evidence to recommend one option over another. Therefore, in PDE5I-refractory patients, the choice of a specific next step should be individualized based on the preference of the patient and his sexual partner, the advantages and disadvantages of the various options, the concurrent medical illnesses and medications of the patient, and the patient’s response to treatment. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to analyze the hormone profiles, to detect the rate of hyperandrogenemia and to investigate the potential effect of Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) on ovarian reserve, as reflected by the serum Anti-Mullerian hormone (AMH) levels. Clinical implications were analyzed by including our own experiences with three patients after ovarian stimulation in preparation for uterus transplantation.Methods: Serum samples of 100 patients with MRKHS (50 patients with MRKHS type 1 and 50 with type 2) were analyzed and compared to 50 individually age-matched healthy controls. Blood samples for hormone analyses were collected routinely during the clinical visit.Results: The mean age was 20.0 years for MRKHS type 1, MRKHS type 2 and healthy controls. Compared to healthy controls, there was no significant difference in AMH values in the MRKH patients. As shown in previous studies, the proportion of hyperandrogenemia without clinical symptoms was significantly higher in MRKHS type 1 (52%; p < 0.001) and type 2 (56%; p < 0.001) patients when compared to age-matched controls. In preparation for uterus transplantation, three patients were stimulated with FSH/hMG for mean 14.2 days and the mean number of aspirated oocytes was 13.2 (3-22), while 8.3 (2-10) oocytes could be fertilized and cryopreserved. The mean fertilization rate was 51.2% (30-67%).Conclusion: The rate of hyperandrogenemia was significantly higher in MRKH patients compared to healthy age-matched controls. Though, ovarian reserve (AMH level) was not reduced compared to controls. Future studies are needed to identify optimal ovarian stimulation protocols as well as to implement a systematic multicenter reporting system. [ABSTRACT FROM AUTHOR]

Diffusion-weighted imaging (DWI) is used to measure gray matter tissue density and white matter fiber organization/directionality. Recent studies show that DWI also allows for assessing neuroplastic adaptations in the human hypothalamus. To this end, we investigated a potential influence of testosterone replacement therapy on hypothalamic microstructure in female-to-male (FtM) transgender individuals. 25 FtMs were measured at baseline, 4 weeks, and 4 months past treatment start and compared to 25 female and male controls. Our results show androgenization-related reductions in mean diffusivity in the lateral hypothalamus. Significant reductions were observed unilaterally after 1 month and bilaterally after 4 months of testosterone treatment. Moreover, treatment induced increases in free androgen index and bioavailable testosterone were significantly associated with the magnitude of reductions in mean diffusivity. These findings imply microstructural plasticity and potentially related changes in neural activity by testosterone in the adult human hypothalamus and suggest that testosterone replacement therapy in FtMs changes hypothalamic microstructure towards male proportions. [ABSTRACT FROM AUTHOR]

Objective: The pituitary production of human chorionic gonadotropin (hCG) can cause false-positive results during or after germ cell tumor (GCT) treatment. Because hypogonadism leads to pituitary hCG production, testosterone administration test (TAT) has been recommended for pituitary hCG diagnosis. However, little is known about its efficacy for the discrimination of pituitary hCG as detected by currently used hCG assays in treatment of GCT. We conducted a retrospective multicenter study to determine the usefulness of TAT. Materials and methods: The study included 60 patients who underwent TAT for the discrimination of pituitary hCG. In principle, serum hCG levels were measured 1 week after testosterone enanthate administration (250 mg). When the serum hCG levels decreased below the normal upper range, the results of TAT were determined positive. In this case, the elevated hCG was considered to be derived from pituitary and not from GCT. Results: Serum hCG levels were normalized after TAT in 36 of 60 patients (60%). Before TAT, the hCG levels were below 1.0 IU/L in 13 patients (36%), 1.0-1.9 IU/L in 11 (31%), 2.0-2.9 IU/L in 7 (19%), and >3.0 IU/L in 5 (14%) of TAT-positive patients. Of them, 28 (78%) patients were successfully managed without further treatment with chemotherapy after TAT. Pituitary hCG was associated with higher levels of LH and not necessarily associated with low levels of testosterone. Conclusion: Determining the TAT status of patients was effective in discriminating pituitary hCG production. [ABSTRACT FROM AUTHOR]

Hypospadiology is a rapidly evolving field. Progress in the understanding of how hormonal therapy affects the growth of the phallus has allowed surgeons to optimize the tissues for surgery. But conflicting data from a number of studies and a lack of consensus on drugs, their dosing, mode of delivery and timing of use means that the creation of protocols is unlikely to happen in the near future. Nonetheless, there is a hope and the standardization of scientific reporting will make it easier to compare data at the global level. There are reports of the increasing incidence of hypospadias and the etiology is thought to be multifactorial. Although complex interactions between genetic polymorphisms and the environment make it difficult to identify the exact factors responsible for hypospadias, the advent of massively parallel gene sequencing, large scale epigenetic screens and CRISPR technology will definitely ease the process. The knowledge of culprit genes will not only broaden our understanding of embryology and growth but will also enable us to predict and/or modify tissue healing. Advances in tissue engineering are also expected to provide a plethora of biomaterials for urethral reconstruction. The development of this field is directly linked with the elucidation of the processes of proliferation and vascularization coupled with the cataloguing of the growth factors involved. One can safely conclude that the exciting new advances in the field will have far reaching consequences on patient care and counselling. [ABSTRACT FROM AUTHOR]

Background: There has been concern about the growing off-label use of testosterone. Understanding the context within which testosterone is prescribed may contribute to interventions to improve prescribing.Objective: To evaluate patient characteristics associated with receipt of testosterone.Design: Cross-sectional.Setting: A national cohort of male patients, who had received at least one outpatient prescription within the Veterans Affairs (VA) system during Fiscal Year 2008- Fiscal Year 2012.Participants: The study sample consisted of 682,915 non-HIV male patients, of whom 132,764 had received testosterone and a random 10% sample, 550,151, had not.Main Measures: Conditions and medications associated with testosterone prescription.Key Results: Only 6.3% of men who received testosterone from the VA during the study period had a disorder of the testis, pituitary or hypothalamus associated with male hypogonadism. Among patients without a diagnosed disorder of hypogonadism, the use of opioids and obesity were the strongest predictors of testosterone prescription. Patients receiving >100 mg/equivalents of oral morphine daily (adjusted odds ratio = 5.75, p < 0.001) and those with body mass index (BMI) >40 kg/m2 (adjusted odds ratio = 3.01, p < 0.001) were more likely to receive testosterone than non-opioid users and men with BMI <25 kg/m2. Certain demographics (age 40-54, White race), comorbid conditions (sleep apnea, depression, and diabetes), and medications (antidepressants, systemic corticosteroids) also predicted a higher likelihood of testosterone receipt, all with an adjusted odds ratio less than 2 (p < 0.001).Conclusions: In the VA, 93.7% of men receiving testosterone did not have a diagnosed condition of the testes, pituitary, or hypothalamus. The strongest predictors of testosterone receipt (e.g., obesity, receipt of opioids), which though are associated with unapproved, off-label use, may be valid reasons for therapy. Interventions should aim to increase the proportion of testosterone recipients who have a valid indication. [ABSTRACT FROM AUTHOR]

Rationale: Alcohol and cannabis use have been implicated in aggression. Alcohol consumption is known to facilitate aggression, whereas a causal link between cannabis and aggression has not been clearly demonstrated. Objectives: This study investigated the acute effects of alcohol and cannabis on subjective aggression in alcohol and cannabis users, respectively, following aggression exposure. Drug-free controls served as a reference. It was hypothesized that aggression exposure would increase subjective aggression in alcohol users during alcohol intoxication, whereas it was expected to decrease subjective aggression in cannabis users during cannabis intoxication. Methods: Heavy alcohol ( n = 20) and regular cannabis users ( n = 21), and controls ( n = 20) were included in a mixed factorial study. Alcohol and cannabis users received single doses of alcohol and placebo or cannabis and placebo, respectively. Subjective aggression was assessed before and after aggression exposure consisting of administrations of the point-subtraction aggression paradigm (PSAP) and the single category implicit association test (SC-IAT). Testosterone and cortisol levels in response to alcohol/cannabis treatment and aggression exposure were recorded as secondary outcome measures. Results: Subjective aggression significantly increased following aggression exposure in all groups while being sober. Alcohol intoxication increased subjective aggression whereas cannabis decreased the subjective aggression following aggression exposure. Aggressive responses during the PSAP increased following alcohol and decreased following cannabis relative to placebo. Changes in aggressive feeling or response were not correlated to the neuroendocrine response to treatments. Conclusions: It is concluded that alcohol facilitates feelings of aggression whereas cannabis diminishes aggressive feelings in heavy alcohol and regular cannabis users, respectively. [ABSTRACT FROM AUTHOR]

Previous studies demonstrated that there is a significant change in speaking fundamental frequency after testosterone therapy in female-to-male gender dysphoric individuals. It is yet an open question how the satisfaction with voice alteration can be predicted because until now it is not clear whether a testosterone therapy is sufficiently effective. The aim of the current study was not only to measure satisfaction with voice, but additionally to detect factors that predict or explain satisfaction with voice after testosterone therapy. Therefore, nine female-to-male gender dysphoric individuals were examined during the first year of testosterone treatment at different points of time. The patients underwent several voice analyses within 1 year and had to fill out several questionnaires concerning their voice, depressive symptoms, quality of life and voice handicap index. Multiple regression analyses were performed to find the factors that explained satisfaction with altered voice after 1 year. The difference of voice frequency in semitones before the treatment and after 1 year is the only significant predictor for satisfaction after 1 year ( B = 0.442; SE = 0.049) and more important than the absolute fundamental frequency. [ABSTRACT FROM AUTHOR]

Objective: To study MAMLD1 gene polymorphisms, serum LH and testosterone levels amongst Indian children with isolated hypospadias (IH) and controls.Materials and Methods: Screening of the MAMLD1 gene was performed by PCR sequencing method in 100 Indian children aged 0-12 years presenting with IH and 100 controls. LH and testosterone hormone levels were also assessed (categorized in four age-wise groups).Results: IH subjects had significantly higher incidence of MAMLD1 polymorphism as compared to controls (33 vs 15 %, p = 0.01). Of various genomic variants identified in this study, the noteworthy novel ones were missense mutation P299A and single nucleotide polymorphism c.2960C>T in 3' UTR of Exon 7. While p 299A was found to cause protein structural instability consequent to amino acid change, eighty percent subjects with c.2960C>T in 3' UTR of Exon 7 (corresponding to newly discovered currently non-validated exon 11) were found to have lower testosterone levels when compared with their age group mean. IH showed statistically higher incidence of c.2960C>T in comparison to controls (22 vs 10 %, p value 0.046) and about 2.5-folds higher risk of this anomaly.Conclusion: Occurrence of MAMDL1 gene polymorphisms, specially of c.2960C>T in 3' UTR of its exon 7 is associated with a higher risk of IH in Indian children, probably by lowering androgenic levels. [ABSTRACT FROM AUTHOR]

Female-to-male gender dysphoric individuals rarely access medical services for voice problems arising out of hormonal treatment leading to 'voice reassignment'. The aim of this study was a close monitoring of voice deepening in the first year following the commencement of testosterone treatment. Voice recordings from nine female-to-male (FTM) were analyzed with Praat software and values for speaking fundamental frequency (SFF) were calculated. Audio recordings were made prior to and within the first year (mean 55.2 weeks) of testosterone treatment at a mean of 35.4 different time points. The values for speaking fundamental frequency were compared with values taken from 21 biological men with healthy voices. The 10th to 90th percentile range of FTM overlapped with those of biological men after about 36 weeks. The mean SFF change was a decrease of 8.78 seminotes at week 52 and at this point in time no significant difference between SSF in FTM and biological men was found. Testosterone treatment led to significant voice deepening within the first year with the degree of change decreasing over time. Mean SFF change in the first year was almost a sixth and thus less than one octave but nonetheless reached an SFF comparable with biological men. [ABSTRACT FROM AUTHOR]

Our objective was to evaluate the safety and efficacy of clomiphene citrate (CC) in infertile and hypoandrogenic men through a retrospective study between September 2013 and May 2014. We identified 47 men between 18 and 55 years placed on 50 mg CC every other day. We evaluated the effect of CC on testosterone after 2 weeks, rates of adverse effects and predictors of CC response. Mean baseline testosterone, bioavailable testosterone and estradiol were 246.8 ng dl−1, 125.5 ng dl−1 and 20.8 pg dl−1, respectively. At 2 weeks, mean testosterone, bioavailable testosterone and estradiol increased to 527.6 ng dl−1, 281.8 ng dl−1 and 32.0 pg dl−1 (all P<0.001). Two patients at 2 weeks and one patient at 3 months had a paradoxical decrease in testosterone. Mean total motile count (TMC) and concentration increased from 59.7 million (s.e.m.: 16.5) and 50.7 millions ml−1 (s.e.m.: 11.1) at baseline to 90.9 million (s.e.m.: 25.9) and 72.5 millions ml−1 (s.e.m.: 17.5), respectively, at 3 months, although this was nonsignificant (P=0.09, 0.09). No patient on CC experienced a paradoxical decrease in TMC or sperm concentration. On age-adjusted regression analysis, age, BMI, longitudinal testis axis, baseline follicle-stimulating hormone, LH and estradiol did not correlate with improvement in bioavailable testosterone at 2 weeks. CC improves testosterone and may improve semen parameters, although a small percentage of men may not demonstrate improvement in testosterone. [ABSTRACT FROM AUTHOR]

Klinefelter syndrome (47, XXY) is the most frequent genetic cause of male infertility and individuals share the endocrine hallmark of hypergonadotropic hypogonadism. Single-nucleotide polymorphisms located within the FSHB/FSHR gene were recently shown to impact serum follicle-stimulating hormone (FSH) levels and other reproductive parameters in men. The objective of this study was to analyse the effect of FSHB-211G>T (c.−280G>T, rs10835638) as well as FSHR c.2039G>A (rs6166) and FSHR c.−29G>A (rs1394205) on endocrine and reproductive parameters in untreated and testosterone-treated Klinefelter patients. Patients were retrospectively selected from the clientele attending a university-based andrology centre. A total of 309 non-mosaic Klinefelter individuals between 18 and 65 years were included and genotyped for the variants by TaqMan assays. The untreated group comprised 248 men, in which the FSHB −211G>T allele was significantly associated with the reduced serum follicle-stimulating hormone levels (−6.5 U/l per T allele, P=1.3 × 10−3). Testosterone treatment (n=150) abolished the observed association. When analysing patients before and under testosterone treatment (n=89), gonadotropin levels were similarly suppressed independently of the FSHB genotype. The FSHR polymorphisms did not exhibit any significant influence in any group, neither on the endocrine nor reproductive parameters. In conclusion, a hypergonadotropic setting such as Klinefelter syndrome does not mask the FSHB −211G>T genotype effects on the follicle-stimulating hormone serum levels. The impact was indeed more pronounced compared with normal or infertile men, whereas gonadotropin suppression under testosterone treatment seems to be independent of the genotype. Thus, the FSHB −211G>T genotype is a key determinant in the regulation of gonadotropins in different reproductive-endocrine pathopyhsiologies. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the effects of therapeutically relevant dose levels of bleomycin, etoposide and cisplatin (BEP) on testicular steroidogenic enzymes, and possible protective effects of an antioxidant cocktail (AC). Methods: Adult Sprague-Dawley rats received BEP with or without the AC (α-tocopherol, l-ascorbic acid, selenium and zinc) for either (a) 4 days (short term; 1.5, 15 and 3 mg/kg), or (b) three cycles of 21 days each (0.75, 7.5 and 1.5 mg/kg), or (c) the three cycles with a 63-day recovery period. The expression of steroidogenic enzymes were measured in the testes by Western blotting and immunofluorescent labeling. Results: The short-term BEP exposure resulted in a decrease in scavenger receptor class-B1 and an increase in luteinizing hormone receptor (LHR). The AC with or without BEP has increased the levels of LHR, 3β-hydroxysteroid dehydrogenase (3β-HSD) and 17β-HSD, but without significant changes in testosterone levels. The three cycles of BEP up-regulated the expression of steroidogenic acute regulatory protein (StAR) and down-regulated that of cholesterol side chain cleavage enzyme (P450scc), cytochrome p450 17A1 (Cyp17A1, recovered by the AC) and 17β-HSD, associated with significant reduction in testosterone levels. The three cycles with the recovery time led to decreases in LHR, StAR, P450scc and Cyp17A1 and increases in 3β-HSD and 17β-HSD. The AC did not enhance the recovery of the enzyme levels. Conclusion: The three cycles of BEP treatment inhibit the testosterone synthesis pathway even after the recovery time. The AC recovers the effects of BEP chemotherapy on a few steroidogenic enzymes. [ABSTRACT FROM AUTHOR]

Background:Testosterone replacement therapy (TRT) is a widely accepted form of treatment worldwide for aging men with late-onset hypogonadism syndrome. Urologists have been concerned about the possibility of TRT causing prostate cancer. The aim of this study was to assess the relationship between TRT and prostate cancer.Methods:A literature review was performed to identify all published, randomized controlled trials (RCTs) of testosterone treatment for hypogonadism. The search included the MEDLINE, Embase and the Cochrane Controlled Trials Register databases. Fixed-effect model was chosen for homogeneous studies; otherwise, a random-effect model was used. Inconsistency was quantified by using the I2 statistic, which tests the proportion of heterogeneity across studies.Results:Results of 22 RCTs involving a total of 2351 patients were analyzed. Eleven RCTs were short-term (<12 months) and 11 were long-term (12-36 months) comparisons of TRT with a placebo; TRT was administered transdermally, orally or by injection. Respective odds ratio (OR) and 95% confidence interval (CI) values for injection, transdermal administration and oral administration of short-term TRT were as follows: prostate cancer: 0.39 (0.06-2.45), 1.10 (0.26-4.65) and no oral; biopsy: 5.28 (0.24-113.87), 2.11 (0.32-13.73) and no oral; and prostate nodule: 1.01 (0.13-7.60), no injection and oral. Respective OR and 95% CI values for injection, transdermal administration and oral administration of long-term TRT were as follows: prostate cancer: 2.09 (0.18-24.73), 3.06 (0.12-76.70) and 0.19 (0.01-4.03); biopsy: 2.09 (0.18-24.73), 3.65 (0.88-15.20) and 0.97 (0.13-7.03); and prostate nodule: 3.13 (0.12-80.68), 1.00 (0.06-16.41) and 0.97 (0.13-7.03). Though for some routes of administration and some end points, the OR associated with testosterone administration were >1 indicating increased risk, none of these reached or even approached statistical significance (all P>0.10), which was consistent with the results of subgroup analyses and sensitivity analysis. Besides, sensitivity analysis indicated that short-term TRT was more likely to increase PSA levels than treatment with placebo (P<0.00001).Conclusions:This meta-analysis shows that regardless of the administration method, TRT is the short-term safety and does not promote prostate cancer development or progression but long-term data are warranted with justifiable end points. [ABSTRACT FROM AUTHOR]

Purpose: This study was designed to evaluate the protective effects of vitamin E (VitE) and testosterone on varicocele (VCL)-induced damage in testis and sperm parameters and their effects on Hsp70-2 chaperone expression and on antioxidant status. Methods: Wistar rats were divided into five groups: control-sham, VCL-induced, VitE-treated varicocelized (150 mg/kg, orally), testosterone-administrated varicocelized (400 μg/kg, intraperitoneally) and VitE + testosterone-received VCL-induced rats. The sperm count, DNA integrity, motility, viability and histone-protamine transition were evaluated after 60 days. The antioxidant status was analyzed by determining testicular malondialdehyde (MDA), total antioxidant capacity (TAC), superoxide desmutase (SOD) and glutathione peroxidase (GSH-Px). Endocrine status of the testicular tissue was estimated by evaluating the Leydig cells steroidogenic activity using fluorescent analyses for cytoplasmic steroid foci and by determination of serum testosterone. The expression of Hsp70-2 protein was analyzed using imunohistochemical and western blot analyses. RNA damage of the germinal cells was examined with epi-fluorescent examination. Results: VitE and testosterone administration ameliorated the varicocele-reduced Leydig cell and testosterone level. In addition, co-administration of these compounds recovered the VCL-induced reduction of TAC, SOD, and GSH-px and lowered significantly ( P < 0.05) the VCL-elevated content of MDA. The treated animals revealed with a significant ( P < 0.05) up-regulation of the VCL-reduced expression of Hsp70-2 protein. Moreover, VitE and testosterone significantly ( P < 0.05) inhibited the VCL-increased RNA damage in germinal cells. Conclusion: Our data suggest that the protective effects of VitE and testosterone on VCL-induced derangements may depend on enhancing testicular antioxidant status and up-regulating endocrine activities, which enhanced the Hsp70-2 chaperone expression. [ABSTRACT FROM AUTHOR]

Androgens play a primary role in female physiopathology. The age-related reduction in the production of ovarian and adrenal androgens may significantly affect women's health. The decline of circulating androgens results from a combination of two events: reduced ovarian production and aged-related decline in adrenal androgen synthesis. The relative androgen deficiency in pre- and postmenopausal women may induce impairment of sexual function, libido, well-being, energy and may contribute to reduced cognitive functions. Whether androgen deficiency also affects cardiovascular or bone biology in women during reproductive aging is still controversial. Both in the central nervous system and peripheral tissues, there are multiple ways whereby androgens target their specific actions through a particular tropism of the brain areas that are involved in sexual function, behavior and cognition. Among circulating available androgens that are involved in several domains of sexual response, adrenal androgens seem to be related to some sexual symptoms as well as diminished cognitive function in postmenopausal women. The possibilities of treating low sexual desire/hypoactive sexual desire disorder are multifaceted and should include the combination of both pharmacological treatments able to maximize biological signals that drive the sexual response as well as individualized psychosocial therapies to overcome personal and relational difficulties. Transdermal testosterone has been proved to be effective but the use of additional treatment like oral or vaginal dehydroepiandrosterone is still controversial, despite many evidences support it. The decision to treat premenopausal or postmenopausal women with signs/symptoms of androgen insufficiency is mainly based on the clinical judgment, together with estrogens co-administration and following informed consent related to the unknown long-term risks. [ABSTRACT FROM AUTHOR]

To date, the effects of long-term testosterone (T) administration on the human vagina are not completely understood. Thus, the aim of this study was to investigate the effects of long-term T treatment on vaginal tissue histology, estrogen receptor alpha (ERα) and beta (ERβ) expression and proliferation in female to male transsexual subjects (FtM). We compared vaginal samples from FtM subjects with those of premenopausal women (PrM) and postmenopausal women (M) not receiving any hormonal treatment for at least 2 years. Vaginal tissue samples from 16 FtM subjects treated with T (intramuscular injections of 100 mg Testoviron Depot/7-10 days for at least 1 year), undergoing sex reassignment surgery, and 16 PrM and 16 M subjects undergoing a vaginal hysterectomy for prolapse, were collected. For each sample, morphology, glycogen content, proliferation (ki-67), ERα and ERβ expression were evaluated. Vaginal samples from FtM showed a loss of normal architecture of the epithelium, intermediate and superficial layers were completely lost, and glycogen content was depleted. T administration resulted in a strong proliferation reduction when compared with both M and PrM subjects. Stromal and epithelial ERα as well as ERβ were significantly decreased in FtM when compared with PrM subjects. In conclusion, our data suggests that systemic T administration at supraphysiological dosage, determines profound changes in histomorphology and reduces ERs expression and proliferation of vaginal epithelium. [ABSTRACT FROM AUTHOR]

Background: Uncontrolled studies show fatigue, anorexia, depression, and mortality are associated with low testosterone in men with cancer. Testosterone replacement improves quality of life and diminishes fatigue in patients with non-cancer conditions. The primary objective was to evaluate the effect of testosterone replacement on fatigue in hypogonadal males with advanced cancer, by the Functional Assessment of Chronic Illness Therapy-Fatigue subscale (FACIT-Fatigue) at day 29. Methods: This is a randomized, double-blinded placebo-controlled trial. Outpatients with advanced cancer, bioavailable testosterone (BT) <70 ng/dL and fatigue score >3/10 on the Edmonton Symptom Assessment Scale were eligible. Intra-muscular testosterone or sesame seed oil placebo was administered every 14 days to achieve BT levels 70-270 ng/dL. Results: Sixteen placebo and 13 testosterone-treated subjects were evaluable. No statistically significant difference was found for FACIT-fatigue scores between arms (−2 ± 12 for placebo, 4 ± 8 for testosterone, p = 0.11). Sexual Desire Inventory score ( p = 0.054) and performance status ( p = 0.02) improved in the testosterone group. Fatigue subscale scores were significantly better ( p = 0.03) in those treated with testosterone by day 72. Conclusions: Four weeks of intramuscular testosterone replacement in hypogonadal male patients with advanced cancer did not significantly improve quality of life. Larger studies of longer duration are warranted. [ABSTRACT FROM AUTHOR]

In young men (defined as age <50 years) with classic hypogonadism caused by known diseases of the hypothalamus, pituitary or testes, testosterone replacement therapy induces a number of beneficial effects, for example, the development of secondary sex characteristics, improvement and maintenance of sexual function, and increases in skeletal muscle mass and BMD. Moreover, testosterone treatment in this patient population is associated with a low frequency of adverse events. Circulating testosterone levels decline progressively with age, starting in the second and third decade of life, owing to defects at all levels of the hypothalamic-pituitary-testicular axis. In cohort studies, testosterone levels are associated weakly but consistently with muscle mass, strength, physical function, anaemia, BMD and bone quality, visceral adiposity, and with the risk of diabetes mellitus, coronary artery disease, falls, fractures and mortality. However, the clinical benefits and long-term risks of testosterone therapy--especially prostate-related and cardiovascularrelated adverse events--have not been adequately assessed in large, randomized clinical trials involving older men (defined as age >65 years) with androgen deficiency. Therefore, a general policy of testosterone replacement in all older men with age-related decline in testosterone levels is not justified. [ABSTRACT FROM AUTHOR]

Purpose: Although hormones play fundamental roles in prostate growth, their clinical significance is not completely clear. Aims of present study were to assess whether testosterone and serum sex hormone levels are predictors of benign prostatic hyperplasia (BPH) or prostate cancer (PC) and to verify whether prostate cancer is associated with low testosterone levels, and to test association between testosterone levels and known prognostic factors in prostate cancer. Methods: In 206 consecutive patients with benign prostatic hyperplasia or prostate cancer testosterone, follicle-stimulating hormone, luteinizing hormone and prolactin levels were tested and correlated with disease. In patients with prostate cancer, hormone levels were also correlated with known prognostic factors. Predictive value was assessed for age, prostate-specific antigen (PSA), PSA ratio, PSA density, prostate volume and serum sex hormone levels using multiple logistic regression analysis and receiver operating characteristic curves. Results: Considering sex hormones, only testosterone levels were significantly lower in patients with prostate cancer than those with BPH; testosterone levels appear to be independent predictor of prostate cancer, enhancing predictive accuracy for BPH and PC. Testosterone levels do not seem to be associated with known clinical prognostic factors. Conclusions: This study supports experimental findings that testosterone levels are predictor of prostate cancer and that prostate cancer is frequently associated with low testosterone levels. In the diagnostic work-up for prostate cancer, adding testosterone determination to PSA test may improve predictive accuracy. [ABSTRACT FROM AUTHOR]

Purpose: We sought whether serum total testosterone (tT), estradiol (E), tT/E ratio, and sex hormone-binding globulin (SHBG) significantly fluctuate throughout time in men with prostate cancer (PCa). Methods: Circulating hormones were measured in a cohort of 631 candidates for radical prostatectomy. Hormone levels were analyzed according to either patient age, stratified into quartiles, or body mass index (BMI). Linear regression analyses tested the association between sex steroids and continuously coded patient age and BMI values. Results: No significant differences were found among age quartiles regarding serum tT levels and tT/E ratio. Conversely, E and SHBG levels significantly increased throughout time (all, p ≤ 0.001). Total T did not linearly change according to continuously coded patient age; in contrast, E and SHBG linearly increased (all, p ≤ 0.001), whereas tT/E decreased ( p = 0.016) with aging. Rate of hypogonadism significantly increased with aging ( p = 0.04). Total T, T/E ratio, and SHBG linearly decreased along with BMI increases (all p ≤ 0.02), whereas serum E did not significantly change. Rate of hypogonadism significantly increased with BMI increases ( p < 0.001). Conclusions: In contrast with longitudinal studies in the general male population, these data indirectly suggest that serum tT levels could be stable over time in PCa patients. This finding led to formulation of a 'time-dependency theory', which postulates that the endocrine biology of prostate tissue is dependent on the exposure time at a given concentration of sex steroid, which, in turn, fluctuates throughout the lifespan of the individual. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the clinical value of the pre-treatment calculated free testosterone (fT), total testosterone (tT), sexual hormone-binding globulin (SHBG) and estradiol (E2) levels as potential predictors of pathological stage and grade in patients with clinically localized prostate cancer. Methods: Preoperative sex hormone serum levels were prospectively measured in 137 patients who underwent radical prostatectomy at the University Hospital Ulm from February 2011 to February 2012. We related sex hormone levels to clinicopathologic data including tumour stage, Gleason score and prostate specific antigen (PSA). (Non)parametric statistical tests and receiver operating characteristics (ROC) analyses were performed. Results: Preoperative serum fT levels were significantly associated with advanced disease (pT3-4 and/or pN+; p = 0.047) and lymph node involvement (pN+) ( p = 0.027). Patients with low (<0.047 μg/l) vs. normal fT values (≥0.047 μg/l) were associated with higher tumour stage ( p = 0.049), positive lymph node status (pN+ , p = 0.038) and advance disease ( p = 0.016). Moreover, low tT values (≤0.193 μg/l; p = 0.018) and elevated SHBG levels (>48.4 nmol/l, p = 0.043) correlated with a higher Gleason score. Conversely, E2 levels were not associated with tumour stage or grade. Applying multivariate analysis, unlike tT, SHBG, and E2 levels, low fT levels were a significant independent predictor of advanced disease (relative hazard ratio 3.05, p = 0.028). Conclusions: Low pre-treatment fT levels were significantly associated with tumour stage and extraprostatic tumour spread and might-in addition or combination with PSA-serve as a useful prognostic parameter for prostate cancer patients prior to radical prostatectomy. [ABSTRACT FROM AUTHOR]

Purpose: At the time of castration resistance, it is recommended to realize hormonal manipulations before chemotherapy. We evaluated the impact of a switch from GnRH agonist to antagonist in patients with castration-resistant prostate cancer on PSA and testosterone levels at 3 months. Methods: Retrospectively, 17 patients from 5 different centers undergoing androgen deprivation therapy and presenting rising PSA confirmed on 3 blood samples 2 weeks apart and despite a castrate testosterone level (<0.5 ng/ml) were reviewed. Antiandrogen withdrawal syndrome had been tested before the switch. Degarelix was administered as followed: 240 mg for the first injection and then 80 mg every month, subcutaneously. We evaluated the PSA and testosterone level variation 3 months after the switch. Patients who experienced a variation in PSA of less than 10% compared to the baseline or who had a more than 10% PSA decrease were defined as responders. Results: Mean PSA level at the switch was 34.3 ± 50.3 ng/ml, with a mean testosterone level of 0.21 ± 0.13 ng/ml. Three months after the switch, mean PSA level was 59.9 ± 81.6 ng/ml ( P = 0.061), with a mean testosterone level of 0.19 ± 0.08 ng/ml ( P = 0.086). At 3 months, 4 patients (23%) responded to therapy. Thirteen patients (77%) experienced a rise in PSA of more than 10% compared to baseline; 41% of patients decreased their testosterone level. The limitations of this study are its retrospective nature and the limited number of patients. Conclusion: Switch from an agonist to an antagonist of GnRH has a limited impact on PSA at 3 months in castration-resistant prostate cancer patients. [ABSTRACT FROM AUTHOR]

Lichen sclerosus (LS) is a chronic, inflammatory, mucocutaneous disorder of genital and extragenital skin. LS is a debilitating disease, causing itch, pain, dysuria and restriction of micturition, dyspareunia, and significant sexual dysfunction in women and men. Many findings obtained in recent years point more and more towards an autoimmune-induced disease in genetically predisposed patients and further away from an important impact of hormonal factors. Preceding infections may play a provocative part. The role for Borrelia is still controversial. Trauma and an occlusive moist environment may act as precipitating factors. Potent and ultrapotent topical corticosteroids still head the therapeutic armamentarium. Topical calcineurin inhibitors are discussed as alternatives in the treatment of LS in patients who have failed therapy with ultrapotent corticosteroids, or who have a contraindication for the use of corticosteroids. Topical and systemic retinoids may be useful in selected cases. Phototherapy for extragenital LS and photodynamic therapy for genital LS may be therapeutic options in rare cases refractory to the already mentioned treatment. Surgery is restricted to scarring processes leading to functional impairment. In men, circumcision is effective in the majority of cases, but recurrences are well described. Anogenital LS is associated with an increased risk for squamous cell carcinoma of the vulva or penis. This review updates the epidemiology, clinical presentation, histopathology, pathogenesis, and management of LS of the female and male genitals and extragenital LS in adults and children. [ABSTRACT FROM AUTHOR]

Several studies have suggested combination therapy with testosterone supplementation in patients not responding to PDE5 inhibitors. Considering the pathophysiological basis for testosterone supplementation, the present study aims to identify whether combination therapy allows persistence of treatment effect after testosterone discontinuation. Furthermore, we evaluated whether the degree of testosterone depletion affects treatment outcome from combination therapy. Hypogonadal patients (<350 ng dl−1) with erectile dysfunction who previously did not respond to PDE5 inhibitors were treated with testosterone enanthate injections and daily tadalafil. Patients were stratified into two groups depending on the level of testosterone deficiency, with 250 ng dl−1 as a reference point. Following testosterone supplementation (12 weeks) and combination therapy (12 weeks), patients with severe testosterone deficiency showed higher IIEF (International Index of Erectile Function) erectile function (EF) domain score (16.47±4.019 vs 12.36±4.051, P=0.001) and more patients responding satisfactorily to treatment by general assessment (57.9 vs 16.0%, P=0.009), despite reaching similar levels of serum total testosterone (602±169 ng dl−1 vs 698±165 ng dl−1, P=0.057). Testosterone supplementation was then discontinued and patients were maintained only on daily tadalafil (12 weeks). The severe depletion group maintained higher EF domain scores than baseline (13.06±3.38 vs 7.20±2.24, P=0.0004), despite testosterone levels returning to baseline. The results suggest that combination therapy was more beneficial to patients with severe testosterone depletion, possibly by improving underlying pathophysiology. [ABSTRACT FROM AUTHOR]

Age-related hormonal decline is gradual and less recognized in men than in women. Symptoms are oftentimes ignored and non-specific. Fatigue, lack of concentration, mood swings, decreased sexual desire, erectile dysfunction, infertility, hair loss, reduced muscle and bone mass, and weight gain are a few of the symptoms of male hypogonadism. This disorder is linked to reduction in quality of life, and poorer health outcomes as it may increase the risk for cardiovascular disease, diabetes mellitus, metabolic syndrome, Alzheimer's disease and premature death. Different modalities of testosterone replacement therapy have evolved over 70 years, and sales continue to grow. Each preparation is differentiated by route of delivery, ease of use, cost and pharmacokinetics. Topical/transdermal testosterone replacement therapy, including patches and gels, are the most modern formulations on the market. These are more expensive treatments, but yield more physiological concentrations of testosterone. Restoration of testosterone levels to the eugonadal range reverses signs and symptoms of hypogonadism, except for infertility, and may alleviate co-morbidities associated with hypogonadism. Patient understanding of and compliance with both treatment and monitoring are of utmost importance to achieve clinical success with maximum benefit and minimum risk. The aim of our review is to summarize the indications, contraindications, benefits and risks of testosterone replacement therapy as they relate to transdermal administration. Further, we compare the various testosterone preparations, focusing on the newest topical/transdermal routes of administration that are currently available. [ABSTRACT FROM AUTHOR]

Study design:Male rats with complete transections of the spinal cord were administered vehicle or methylprednisolone (MP) for 24 h, with or without infusion, for 7 days, of testosterone at either a replacement or low pharmacological doses. Muscles were collected at 7 days after SCI.Objective:The objective of this study is to determine, in a rat model of complete spinal cord transection, whether testosterone reduces muscle atrophy or upregulates muscle atrophy-linked genes, induced by 24 h of MP administration at doses comparable to those prescribed in man during the period immediately following acute spinal cord injury (SCI) in an attempt to preserve neurological function.Results:MP significantly reduced the mass of triceps, soleus and plantaris, and significantly increased expression of genes that promote atrophy. Testosterone significantly reduced muscle atrophy induced by MP, but did not prevent it; there was no difference between low- or high-dose testosterone in reducing MP-induced muscle loss. High-dose testosterone reduced expression of muscle atrophy genes more than did low dose. Testosterone-induced declines in mRNA levels for these atrophy-associated genes did not correlate well with protection against MP-induced muscle atrophy.Conclusions:MP induces marked and lasting changes in the biology of muscle that persisted for at least 7 days, or 6 days after MP has been eliminated from the body. Testosterone partially protected against muscle atrophy and gene expression changes caused by 1 day of MP. [ABSTRACT FROM AUTHOR]

The neuroactive steroid hormone progesterone attenuates cocaine's abuse-related effects in women and in rodents under some conditions, but the effects of testosterone are unknown. We compared the acute effects of progesterone (0.1, 0.2, and 0.3 mg/kg, intramuscularly (i.m.)), testosterone (0.001, 0.003, and 0.01 mg/kg, i.m.), and placebo on cocaine self-administration and cocaine discrimination dose-effect curves in female rhesus monkeys. Cocaine self-administration (0.03 mg/kg per inj.) was maintained on a fixed ratio 30 schedule of reinforcement, and monkeys had unlimited access to cocaine for 2 h each day. Cocaine doses were administered in an irregular order during each dose-effect curve determination, and the same dose order was used in each subject in all treatment conditions. Blood samples for hormone analysis were collected at the end of each test session. Banana-flavored food pellets (1 g) were also available in three 1-h daily sessions. In drug discrimination studies, the effects of pretreatment with progesterone (0.032-0.32 mg/kg, i.m.) and testosterone (0.001-0.01 mg/kg, i.m.) on the discriminative stimulus effects of cocaine (0.18 mg/kg, i.m.) were examined. Progesterone and testosterone did not alter cocaine discrimination, and did not substitute for cocaine. In contrast, progesterone and testosterone each significantly decreased cocaine self-administration, and produced a downward and rightward shift in the cocaine self-administration dose-effect curve. These findings are concordant with clinical reports that progesterone administration may decrease ratings of positive subjective effects of cocaine in women, and suggest the possible value of neuroactive steroid hormones for the treatment of cocaine abuse and reduction of risk for relapse. [ABSTRACT FROM AUTHOR]

Background: Aggressive fibromatosis (desmoid tumour) is a locally invasive tumour caused by mutations resulting in β-catenin protein stabilisation. Apc1638N mice are predisposed to developing aggressive fibromatosis tumours, and male mice develop greater numbers of tumours than female mice, suggesting a role for androgens in this tumour type.Methods: Human aggressive fibromatosis tumours were examined for the expression of the androgen receptor, and primary human tumour cell cultures were treated with testosterone. Orchidectomised Apc1638N mice were investigated for the development of tumours, and were treated with testosterone to study the effect of tumour formation and the level of β-catenin.Results: Androgen receptors are universally expressed in human aggressive fibromatosis tumours. Testosterone increased the proliferation rate and β-catenin protein level in a dose-dependent manner in human aggressive fibromatosis tumours. Orchiectomy reduced the number and size of tumours that formed in male Apc1638N mice to a similar level as observed in female mice. Testosterone treatment increased the number of tumours that formed in orchidectomised male mice, and resulted in a marked increase in β-catenin protein levels.Conclusion: Testosterone regulates β-catenin protein level and proliferation rate in this mesenchymal tumour. This work identifies the therapeutic use of testosterone blockade in aggressive fibromatosis as an area for further investigation. [ABSTRACT FROM AUTHOR]

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This study provides a critical review of the literature on depressive symptoms of partial androgen deficiency PADAM) and their treatment with Testosterone (T). PADAM in aging males is responsible for a variety of behavioral symptoms, such as weakness, decreased libido and erectile dysfunction, lower psychological vitality, depressive mood, anxiety, insomnia, difficulty in concentrating, and memory impairment. The psychological and behavioural aspects of PADAM may overlap with signs and symptoms of major depression. Evidence of the relationship between androgen deficiency and deficiency and male depression comes from studies that have assessed depression in hypogonadal subjects, the association between low T level and male depressive illness, and the antidepressant action of androgen replacement. The etiology of depressive symptoms of PADAM is multifactorial, and results from the interaction of the biological and psychosocial changes that take place during the mid-life transition. Although data derived from androgen treatment trials and androgen replacement do not support T treatment or replacement as more efficacious than placebo for major depressive disorder (MDD), the clinical impression is that, in some sub-threshold depressive syndromes, T may lead to antidepressant benefits. [ABSTRACT FROM AUTHOR]

This paper provides a systematic review of the literature about prostate cancer risk associated with testosterone therapy for hypogonadism. A comprehensive search of MEDLINE, EMBASE and other resources was conducted to identify articles that highlight occurrences of prostate cancer in men receiving testosterone therapy for hypogonadism treatment. Articles that met study inclusion criteria were assessed for causality between testosterone treatment and prostate cancer, increased prostate-specific antigen or abnormal digital rectal examination findings. Of 197 articles relating to testosterone therapy, 44 met inclusion criteria: 11 placebo-controlled, randomized studies; 29 non-placebo-controlled studies of men with no prostate cancer history; and 4 studies of hypogonadal men with history of prostate cancer. Of studies that met inclusion criteria, none demonstrated that testosterone therapy for hypogonadism increased prostate cancer risk or increased Gleason grade of cancer detected in treated vs untreated men. Testosterone therapy did not have a consistent effect on prostate-specific antigen levels.International Journal of Impotence Research (2009) 21, 9–23; doi:10.1038/ijir.2008.31; published online 11 September 2008 [ABSTRACT FROM AUTHOR]

Evidence-based drug therapy for male infertility is often difficult because 30% of all cases of male infertility are classified as idiopathic, and another 30% need surgical treatment. Without knowledge of the underlying pathology, there is no foundation for a specific and causal treatment. Most of the currently used drug therapies are empirical at best; moreover, many of the studies on drug treatment for male infertility do not fulfill the required standards of evidence-based medicine (randomized, prospective, placebo-controlled), and the statistical endpoints used (sperm quality, pregnancy rate, baby take-home rate) are not uniform. This article, which is based on a literature survey and the current guidelines concerning drug therapy for male infertility, covers the most common treatment options. Regarding the currently insufficient scientific data for drug therapy and dietary supplements on male infertility, there is a demand for critical indications that take into consideration the possible side effects and the treatment costs. In the case of insufficient drug therapy for male infertility, reproductive medicine seems to be promising. [ABSTRACT FROM AUTHOR]

Purpose: To study the gender assignment and hormonal treatment advocated for disorders of sexual differentiation (DSD).Methods: A study was done on patients who were reviewed in the Pediatric Intersex Clinic to evaluate the pattern of gender assignment and hormonal treatment advocated.Results and Conclusion: The patients included male pseudohermaphrodite (MPH) 169; congenital adrenal hyperplasia (CAH) 91; mixed gonadal dysgenesis (MGD) 29; true hermaphrodite (TH) 25; pure gonadal dysgenesis (PGD) 2; persistent mullerian duct syndrome (PMDS) 2 and others (micropenis, severe hypospadias with cryptorchidism, 46XX male) 39. Out of 91 cases of CAH, 70 (76.9%) were on steroids (prednisolone, hydrocortisone) and/or mineralocorticoids (fluoricortisone) for adrenal suppression. Out of 146 cases of male pseudohermaphrodite and 21 cases of true hermaphrodite and 3 cases of mixed gonadal dysgenesis reared as males, testosterone was given for local application for phallic growth in 101 and/or as systemic injection for mental makeup after puberty in 41 cases. Systemic testosterone injection was also given for 7 cases of CAH reared as males. Out of 26, 15 cases with mixed gonadal dysgenesis and one out of 2 cases of pure gonadal dysgenesis that attained puberty after being reared as females, after female genitoplasty, were given conjugated oestrogen (Premarin) supplemented with progesterone, as the uterus was preserved. For 12 post-pubertal cases of complete androgen insensitivity syndrome (AIS), only premarin was given as there was no uterus. Growth hormone and Gn RH analogue was given in 2 patients with CAH to tide over the early bone maturation induced by hormones with equivocal results. Thus judicious hormonal supplementation based upon type of DSD and gender assigned can provide a psychological and cosmetic benefit to patients with DSD. [ABSTRACT FROM AUTHOR]

By retrospectively collecting data from nine Italian centres of pediatric endocrinology, we assessed the different management and final outcome of children with short stature and idiopathic delayed puberty. Data were obtained in 77 patients (54 males, 23 females) diagnosed and followed-up in the various centres during the last 15 years. Inclusion criteria were short stature at initial observation and idiopathic delayed puberty diagnosed during follow-up. At first observation, age was 13.8 ± 1.0 years and height standard deviation score (SDS) was –2.6 ± 0.6 in males. In females age was 13.1 ± 0.9 years and height SDS –2.6 ± 0.4. Local diagnostic and therapeutic protocols included testing for growth-hormone deficiency (six centres) and treatment in case of deficiency or, in the remaining centres, testosterone or no treatment in males, and no treatment in females. At diagnosis, both in males and in females, the auxological features (height SDS, target height SDS and bone age delay) were similar in the patients treated with growth hormone, testosterone or not treated. Overall 32 patients received growth hormone (25 males, 7 females), 33 no treatment (17 males, 16 females) and 12 testosterone. There was no difference in the adult height of males and females in the different treatment groups. In males there were no differences between adult and target height SDSs (growth hormone-treated 0.31 ± 0.79, untreated 0.10 ± 0.82, testosterone-treated 0.05 ± 0.95), between adult and initial height SDSs (growth hormone-treated 1.70 ± 0.93, untreated 1.55 ± 0.92, testosterone-treated 1.53 ± 1.43) and percentage of subjects with adult height above target height. In females, there were no differences between adult and target height SDSs (growth hormone-treated –0.49 ± 1.13; untreated 0.10 ± 0.97) and between adult and initial height SDSs (growth hormone-treated 1.76 ± 0.92; untreated 1.77 ± 0.98), whereas a significantly higher percentage of patients remained below target height in the growth hormone-treated group (6/7, 85.7% vs 5/11, 31.3%) ( P = 0.02). In conclusion, the diagnostic and therapeutic management of the patients with short stature and delayed puberty is different among Italian pediatric endocrinologists. Our data do not support the usefulness of growth-hormone therapy in improving adult height in subjects with short stature and delayed puberty, particularly in the female sex. [ABSTRACT FROM AUTHOR]

Desmoplastic small round cell tumor (DSRCT) is a highly fatal, mainly peritoneal cell origin cancer which predominantly affects young adult males. This predilection in young males led us to examine the role of androgen receptors (AR), testosterone, and growth factors in the biology of DSRCT. Slides were prepared from 27 multi-institutional patients all with end-stage DSRCT. Slides were stained for AR, c-Kit, various growth factors, and drug resistance-associated proteins. Immunohistochemical (IHC) expression was scored semi-quantitatively. Western blot and MTT studies were performed to validate the IHC findings of over-expression of the AR and its functional status by stimulation of growth by dihydrotestosterone, respectively. Six patients with positive AR status were treated solely with combined androgen blockade (CAB) as used for prostate cancer. Twenty-two patients were male (81%) and five were female (19%) with a median age at diagnosis of 23. All patients had failed at least two prior multi-agent chemotherapy regimens and 44% had progressed after autologous stem cell transplant. DSRCT samples from 10 of 27 patients were ≥2+ IHC positive for AR (37%, P = 0.0045) and 7 of 20 patients were ≥2+ IHC positive for c-Kit (35%, P = 0.018). We found elevated IHC expression of GST-pi, MRP and thymidylate synthase in smaller subsets of patients. In vitro studies for AR by Western blot and stimulation of growth by dihydrotestosterone in MTT assays suggest that the AR in DSRCT cells is functional. Six patients with positive AR status were treated with CAB alone and three of six attained clinical benefit (1-PR, 1-MR, 1-SD) in a range of 3–4 months. The three patients who responded to CAB had normal testosterone levels before CAB, while the three who did not respond to CAB had baseline castrate levels of testosterone. DSRCT has significant IHC expression of AR and c-Kit in heavily pre-treated patients. The presence of significant AR expression in 37% suggests that these patients could possibly respond to CAB. The significance of c-Kit expression in 35% of DSRCT patients is unknown and warrants further investigation. [ABSTRACT FROM AUTHOR]

Recently, testosterone undecanoate (TU), a new parenteral testosterone (T) preparation has been introduced. Two of its distinctive features are (a) its prolonged action: after two initial loading injections 6 weeks apart, usually only one injection every 12 weeks is needed (b) over the full interval between two injections, plasma T levels are in the physiological range. New research presents convincing evidence that T has profound effects on tissues of the penis involved in the mechanism of erection and that testosterone deficiency impairs the anatomical and physiological substrate of erectile capacity, which is, at least, in part reversible upon androgen therapy. Our studies with TU demonstrated that venous leakage could be corrected with T treatment in a number of patients. We further could show that sexual functions, in a substantial number of elderly men, can be restored with treatment with T only. So, these results argue for determination of T levels in elderly men with sexual problems. If the levels are subnormal, T treatment is warranted. [ABSTRACT FROM AUTHOR]

Recently, testosterone undecanoate (TU), a new parenteral testosterone (T) preparation has been introduced. Two of its distinctive features are (a) its prolonged action: after two initial loading injections 6 weeks apart, usually only one injection every 12 weeks is needed (b) over the full interval between two injections, plasma T levels are in the physiological range. New research presents convincing evidence that T has profound effects on tissues of the penis involved in the mechanism of erection and that testosterone deficiency impairs the anatomical and physiological substrate of erectile capacity, which is, at least, in part reversible upon androgen therapy. Our studies with TU demonstrated that venous leakage could be corrected with T treatment in a number of patients. We further could show that sexual functions, in a substantial number of elderly men, can be restored with treatment with T only. So, these results argue for determination of T levels in elderly men with sexual problems. If the levels are subnormal, T treatment is warranted. [ABSTRACT FROM AUTHOR]

Examines the effect of testosterone replacement therapy (TRT) on skeletal muscle after complete spinal cord injury (SCI). Muscle characteristics on control rats; Effect of SCI on rat muscle; Information on the potential benefits of TRT to patients with SCI.

Evidence from studies in patients with prostate cancer of intermittent hormone therapy combined with results from rechallenge of hormone resistant patients with testosterone demonstrate that the majority of prostate cancers retain a similar degree of dependence on male sex hormone milieu as normal prostate cells. Yet there has so far been no conclusive evidence, despite 34 studies, that levels of circulating testosterone in individuals developing prostate cancer are higher than in controls. The aim of this article was to critically evaluate this evidence and seek clues to other mechanisms whereby sex hormones could influence the development of prostate cancer. Additionally, epidemiological data were examined to investigate the interplay between sex hormone levels and environmental factors to help understand the development of prostate cancer and identify a safe way to provide hormone replacement therapy (HRT). Three overviews provide similar evidence that there is no significant difference in mean testosterone levels between patients and controls. However in the most recent review of studies, though there was no difference in means between cases and controls, there was a significant risk (adjusted odds ratio 2.34) for individuals identified by comparing incidence of prostate cancer in men in the upper and lower quartile of testosterone level. This report, taken with epidemiological data demonstrating that prostate cancer risk is increased by early age of onset of sexual activity and multiple nonspecific sexually transmitted diseases (STDs), has led to the hypothesis that the link between sex hormones and prostate cancer is indirect. Those individuals with high testosterone levels were more at risk of acquisition of multiple nonspecific STDs. This promotes transformation of prostate cells and damage to Leydig cells in the testis leading to there being no difference in testosterone compared with controls by the time the tumour is diagnosed. Because of the observed relationship between testosterone and prostate cancer development there has been anxiety about marketing HRT for men. Two observations support the view that the prostate cancer risks from use of testosterone hormone replacement may not be as great as first feared. Firstly, prostate cancers arising in men with low serum testosterone levels are more malignant and frequently nonresponsive to hormones. Secondly, breast cancers diagnosed in women on HRT though increased in number are less malignant possibly because of enhanced sensitivity to hormone therapy, and the situation may prove to be analogous with prostate cancer and testosterone replacement. [ABSTRACT FROM AUTHOR]

Height predictions based on three different methods (Bayley-Pinneau [BP], Tanner-Whitehouse Mark II [TW II], Roche-Wainer-Thissen [RWT]) were compared to adult heights in 19 males with constitutional tall stature previously treated with high-dose testosterone oenanthate for 6 months (group A) and 25 untreated tall males (group B). Their chronological ages (CA) at the initial evaluation of tall stature ranged from 12.1 to 16.6 years in group A and from 10.4 to 15.7 years in group B; at the time of assessment of adult height ages ranged from 18.0 to 26.5 years and from 18.4 to 25.1 years, respectively. Height measurements and predicted adult heights were expressed as height standard deviation scores (height SDS) for chronological age using the tables of Reinken and van Oost [14]. Height SDS in group A were 2.8 (range = 1.8–5.4) before testosterone treatment, 3.0 (range = 2.0–4.8) thereafter and finally 3.0 (range = 2.1–4.2) (P=NS) and in group B 2.7 (range = 0.5–4.3) and 2.4 (range = 1.3–3.5) (P=NS). A significant difference between adult height SDS and predicted height SDS according to BP was detected both in group A (3.0; range = 2.1–4.2 vs 3.6; range = 2.4–5.0; P≤0.004) and group B (2.4; range = 1.3–3.5 vs 3.0; range = 2.0–4.9; P≤0.0002), whereas no significant difference between adult height SDS and predicted height SDS according to TW II and RWT was found in either group. These data indicate that BP height predictions overestimated adult height in our patient group of treated and untreated males with constitutional tall stature. In contrast, the TW II and RWT methods were more accurate in predicting adult height in these patients, but also failed to demonstrate that testosterone therapy in boys with constitutional tall stature can be limited to a 6-month period in order to reduce adult height.Conclusion The widely used height prediction method of BP is inaccurate in... [ABSTRACT FROM AUTHOR]