[Show abstract][Hide abstract] ABSTRACT: Hypogonadism (HG, testicular failure in men) has become a controversial and much misunderstood condition. Many men perceive testosterone as a panacea for the ills of ageing and "Low-T clinics" have sprung up to meet their demands, even though testosterone is often not the answer. In light of the unprecedented rise in testosterone prescriptions in recent years, particularly amongst middle-aged men, the US Food and Drug Administration (FDA) issued a Safety Communication in May 2015 intended to restrict the use of testosterone. This article is protected by copyright. All rights reserved.
BJU International 09/2015; DOI:10.1111/bju.13316 · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Steroids are important physiological orchestrators of endocrine as well as peripheral and central nervous system functions. One of the key processes for regulation of these molecules lies in their enzymatic processing by a family of 5α-reductase (5α-Rs) isozymes. By catalyzing a key rate-limiting step in steroidogenesis, this family of enzymes exerts a crucial role not only in the physiological control but also in pathological events. Indeed, both 5α-R inhibition and supplementation of 5α-reduced metabolites are currently used or have been proposed as therapeutic strategies for a wide array of pathological conditions. In particular, the potent 5α-R inhibitors finasteride and dutasteride are used in the treatments of benign prostatic hyperplasia (BPH), as well as in male pattern hair loss (MPHL) known as androgenetic alopecia (AGA). Recent preclinical and clinical findings indicate that 5α-R inhibitors evoke not only beneficial, but also adverse effects. Future studies should investigate the biochemical and physiological mechanisms that underlie the persistence of the adverse sexual side effects to determine why a subset of patients is afflicted with such persistence or irreversible adverse effects. Also a better focus of clinical research is urgently needed to better define those subjects who are likely to be adversely affected by such agents. Furthermore, research on the non-sexual adverse effects such as diabetes, psychosis, depression, and cognitive function are needed to better understand the broad spectrum of the effects these drugs may elicit during their use in treatment of AGA or BPH. In this review, we will summarize the state of art on this topic, overview the key unresolved questions that have emerged on the pharmacological targeting of these enzymes and their products, and highlight the need for further studies to ascertain the severity and duration of the adverse effects of 5α-R inhibitors, as well as their biological underpinnings.
Reviews in Endocrine and Metabolic Disorders 08/2015; DOI:10.1007/s11154-015-9319-y · 4.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In pre-pubertal boys ≥ 14 years, the differentiation between constitutional delay of growth and puberty (CDGP) and hypogonadotropic hypogonadism (HH) is challenging, as current diagnostic tools have limitations in sensitivity and specificity. The aim of this study was to assess the usefulness of markers of gonadal activity, growth axis activation and adrenarche in differentiation between pre-pubertal CDGP and HH. This retrospective study was carried out between 2006 and 2015 in an academic out-patient referral centre. The clinical data of 94 boys, aged 13.9–23.2 years and referred for “pubertal delay” were reviewed. Definite diagnoses were established on initial work-up and clinical follow-up: 24 boys were diagnosed with HH, 22 boys with CDGP, pre-pubertal (PP CDGP) at referral and 28 boys with CDGP, early pubertal at referral (EP CDGP), the latter serving as control group. Twenty patients were excluded from evaluation because of previous sex steroid treatment or associated chronic disease. Inhibin B and AMH were measured in all (n = 74); INSL3, IGF1, IGFBP3 and DHEAS in a subset of patients (n = 45) in serum of first presentation. Inhibin B and AMH were higher in boys with PP CDGP than in boys with HH: inhibin B: 87.6 ± 42.5 vs. 19.8 ± 13.9 pg/mL; p < 0.001; AMH: 44.9 ± 27.1 vs. 15.4 ± 8.3 ng/mL; p < 0.001. Receiver operating characteristics (ROC) for the diagnosis of PPCDGP vs. HH (inhibin B ≥ 28.5 pg/mL): sensitivity: 95%, specificity: 75%; AUC: 0.955. In combination with an AMH cut-off ≥20 ng/mL the specificity increased to 83%. INSL3, IGF1, IGFBP3 and DHEAS levels were not different. In boys with EP CDGP, inhibin B and IGF1 levels were highest (138.7 ± 59.9 pg/mL/289.7 ± 117 ng/mL), whereas AMH levels were lowest (11.7 ± 9.1 ng/mL). Sertoli cell markers are helpful for establishing a prognosis, whether a boy with pubertal delay will enter puberty spontaneously, whereas Leydig cell, growth and adrenal markers are not.
[Show abstract][Hide abstract] ABSTRACT: In 2014, the International Society for Sexual Medicine (ISSM) convened a panel of experts to develop an evidence-based process of care for the diagnosis and management of testosterone deficiency (TD) in adult men. The panel considered the definition, epidemiology, aetiology, physiological effects, diagnosis, assessment and treatment of TD. It also considered the treatment of TD in special populations and commented on contemporary controversies about testosterone replacement therapy, cardiovascular risk and prostate cancer.
The aim was to develop clearly worded, practical, evidenced-based recommendations for the diagnosis and treatment of diagnosis and management of TD for clinicians without expertise in endocrinology, such as physicians in family medicine and general urology practice.
A comprehensive literature review was performed, followed by a structured, three-day panel meeting and six-month panel consultation process using electronic communication. The final guideline was compiled from reports by individual panel members on areas reflecting their special expertise, and then agreed by all through an iterative process.
This article contains the report of the ISSM TD Process of Care Committee. It offers a definition of TD and recommendations for assessment and treatment in different populations. Finally, best practice treatment recommendations are presented to guide clinicians, both familiar and unfamiliar with TD.
Development of a process of care is an evolutionary process that continually reviews data and incorporates the best new research. We expect that ongoing research will lead to new insights into the pathophysiology of TD, as well as new, efficacious and safe treatments. We recommend that this process of care be re-evaluated and updated by the ISSM in 4 years. Dean JD, McMahon CG, Guay AT, Morgentaler A, Althof SE, Becher EF, Bivalacqua TJ, Burnett AL, Buvat J, El Meliegy A, Hellstrom WJG, Jannini EA, Maggi M, McCullogh A, Torres LO and Zitzmann M. The International Society of Sexual Medicine's Process of care for the Assessment and Management of Testosterone Deficiency in Adult Men. J Sex Med **;**:**-**.
This article is protected by copyright. All rights reserved.
Journal of Sexual Medicine 06/2015; 12(8). DOI:10.1111/jsm.12952 · 3.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction & Aim: According to standardized guidelines humans with GD receive cross-sex
hormone therapy (CSHT) for up to 2 years before SRS. In order to assess the effectiveness of CSHT
we evaluated changes of body constitution, testes and hormonal status in a multi-center study with
3 clinics advising different treatment strategies.
Material & Methods: Following written informed consent and ethical approval, 175 testicular tissues
from 114 patients were obtained from 3 German clinics. In clinic A CSHT was stopped 2 weeks
before SRS, in clinic B 4-6 weeks before and in clinic C not at all. Questionnaires were handed out
to patients about their CSHT. Hormone levels (LH, FSH, testosterone, estradiol, prolactin, free
testosterone, SHBG) were measured with standardized in-house assays and intratesticular
testosterone (ITT) levels with radioimmunoassay. Testicular tissues were histologically evaluated
for spermatogenic state and tubular diameter. Leydig cell ‘functionality’ was
immunohistochemically checked via LH-receptor stainings.
Results: Out of 83 subjects, 59 took a anti-androgens/estrogen combination. The 3 most prominent
changes of body constitution were breast growth, smooth skin, emotional instability. 20% of the
testicular tissues showed complete spermatogenesis, 28% meiotic arrest, 34% spermatogonial
arrest, 16% Sertoli-cell only and 2% tubular ghosts. The testicular mean weight decreased with the
drop of spermatogenic progress. Subjects from clinic B showed the highest LH, FSH, prolactin,
testosterone and free testosterone levels. Those from clinic C showed the highest SHBG, estradiol
and ITT-levels. Whilst percentages of tubules and interstitium increased, the percentage of lumen
dropped with the decrease of spermatogenic progress. The tubular diameter as well as the number
of LH-receptor positive cells decreased simultaneously.
Conclusion: A highly heterogeneous histological and endocrine picture was observed. Ongoing
CSHT provoked highly feminized endocrine parameters in clinic C when compared to the other
clinics. Hence we strongly recommend individually adapted CSHT, a close follow-up and hormonal
check-ups for GD patients before SRS.
[Show abstract][Hide abstract] ABSTRACT: Abstract Hypogonadism or Testosterone Deficiency (TD) in adult men as defined by low levels of serum testosterone accompanied by characteristic symptoms and/or signs as detailed further on can be found in long-recognized clinical entities such as Klinefelter syndrome, Kallmann syndrome, pituitary or testicular disorders, as well as in men with idiopathic, metabolic or iatrogenic conditions that result in testosterone deficiency. These recommendations do not encompass the full range of pathologies leading to hypogonadism (testosterone deficiency), but instead focus on the clinical spectrum of hypogonadism related to metabolic and idiopathic disorders that contribute to the majority of cases that occur in adult men.
The Aging Male 02/2015; 18(1):1-11. DOI:10.3109/13685538.2015.1004049 · 2.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Context: Klinefelter Syndrome (KS) is the most common chromosome disorder in men (47,XXY), exhibiting a phenotype with marked variation and increased morbidity. The pathophysiological link between the supernumerary X chromosome and the clinical phenotype remains unknown. Objective: To elucidate whether differential gene expression patterns can be detected in KS patients and whether these are related to inherent clinical features. Design, Setting, Participants: EXAKT (Epigenetics, X-chromosomal features and Clinical Applications in Klinefelter syndrome Trial) is a Münster-based prospective project involving 132 Klinefelter men and their parents. A range of cardiovascular, inflammatory and metabolic factors in comparison to age-matched male (n=50)/female controls (n=50) and in relation to genetic features is assessed. Main outcomes, measures: Predefined hypothesis: differential gene expression patterns in blood cells exist in KS patients vs male controls and are related to the clinical phenotype. Results: Differential expression of 36 X-chromosomal and autosomal genes put KS patients into a unique genetic setting vs male and female controls. The KS cohort exhibited increased insulin resistance, enhanced inflammatory and procoagulatory status, higher waist circumference, dyslipidemia and a markedly shorter 12-lead electrocardiogram QTc-interval (partly located within the pathological range) vs male controls (all p<0.001). Clinical dyshomeostasis was associated with expression patterns of dysregulated genes (all p<0.01). Parental origin of the supernumerary X-chromosome was a confounder regarding insulin resistance and cardiac phenotype (p<0.05). Results are considered preliminary as gene expression was measured in blood cells. Conclusions: The supernumerary X chromosome contributes to a number of pathologies in KS. The pattern of gene expression is altered in KS and the degree of differential gene expression is associated with the clinical phenotype.
[Show abstract][Hide abstract] ABSTRACT: Abstract 5α-reductases, a unique family of enzymes with a wide host of substrates and tissue distributions, play a key role in the metabolism of androgens, progestins, mineralocorticoids and glucocorticoids. These enzymes are the rate-limiting step in the synthesis of a host of neurosteroids, which are critical for central nervous system function. Androgens and glucocorticoids modulate mitochondrial function, carbohydrate, protein and lipid metabolism and energy balance. Thus, the inhibition of these regulatory enzymes results in an imbalance in steroid metabolism and clearance rates, which leads to altered physiological processes. In this report, we advance the hypothesis that inhibition of 5α-reductases by finasteride and dutasteride alters not only steroid metabolism but also interferes with the downstream actions and signaling of these hormones. We suggest that finasteride and dutasteride inhibit 5α-reductase activities and reduce the clearance of glucocorticoids and mineralocorticoids, potentiating insulin resistance, diabetes and vascular disease.
Hormone molecular biology and clinical investigation 12/2014; 20(3):73-80. DOI:10.1515/hmbci-2014-0025
[Show abstract][Hide abstract] ABSTRACT: 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.
European journal of human genetics: EJHG 07/2014; 23(5). DOI:10.1038/ejhg.2014.142 · 4.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Although there is no evidence that testosterone therapy increases the risk of prostate cancer, there is a paucity of long-term data. We determined whether the incidence of prostate cancer is increased in hypogonadal men receiving long-term testosterone therapy.
Materials and methods:
In 3 parallel, prospective, ongoing, cumulative registry studies 1,023 hypogonadal men received testosterone therapy. Two study cohorts were treated by urologists (since 2004) and 1 was treated at an academic andrology center (since 1996). Patients were treated when total testosterone was 12.1 nmol/l or less (350 ng/dl) and symptoms of hypogonadism were present. Maximum followup was 17 years (1996 to 2013) and median followup was 5 years. Mean baseline patient age in the urological settings was 58 years and in the andrology setting it was 41 years. Patients received testosterone undecanoate injections in 12-week intervals. Pretreatment examination of the prostate and monitoring during treatment were performed. Prostate biopsies were performed according to EAU guidelines.
Numbers of positive and negative biopsies were assessed. The incidence of prostate cancer and post-prostatectomy outcomes was studied. A total of 11 patients were diagnosed with prostate cancer in the 2 urology settings at proportions of 2.3% and 1.5%, respectively. The incidence per 10,000 patient-years was 54.4 and 30.7, respectively. No prostate cancer was reported by the andrology center. Limitations are inherent in the registry design without a control group.
Testosterone therapy in hypogonadal men does not increase the risk of prostate cancer. If guidelines for testosterone therapy are properly applied, testosterone treatment is safe in hypogonadal men.
The Journal of Urology 06/2014; 193(1). DOI:10.1016/j.juro.2014.06.071 · 4.47 Impact Factor