Alexander Bolyakov

NEW CONCEPTS IN KLINEFELTER SYNDROME

Purpose of review Klinefelter syndrome, 47,XXY and its variants, is the most common chromosomal aberration among men, with estimated frequency of 1: 500 among newborns. Men with Klinefelter syndrome present with sequels of hormonal and spermatogenic testicular failure like infertility, low testosterone, erectile dysfunction, and low bone mineral density. This review is aimed to provide the practicing urologist with an important source of clinically relevant information about Klinefelter syndrome. Recent findings Sperm can be found in over 50% of men with Klinefelter syndrome, thus men with Klinefelter syndrome are not sterile. Recent evidence suggests that children with Klinefelter syndrome are born with spermatogonia and lose large numbers of germ cells during puberty. Early diagnosis and treatment can improve the quality of life and the overall health of men with Klinefelter syndrome. Summary Growing interest in Klinefelter syndrome among translational scientists and clinicians will result in better understanding of the pathophysiology of testicular failure. In some states, screening programs for Klinefelter syndrome are already in place, which will increase the number of patients with Klinefelter syndrome seen by practicing urologists in the near future. Diagnosis and management of patients with Klinefelter syndrome is within the scope and training of urologists. Development of randomized clinical trials comparing different forms of interventions in men and children with Klinefelter syndrome will allow us to standardize the care of these patients.

Reproduction in men with Klinefelter syndrome: the past, the present, and the future.

Klinefelter syndrome (KS) is the most common chromosomal aberration in men. There are approximately 250,000 men with KS in the United States, and the prevalence of KS in male reproductive practices is 3 to 4%; however, most men are never diagnosed. KS has an effect on normal development, growth, social interactions, bone structure, and sexual and reproductive function, thus a multidisciplinary approach to men with KS is important in providing state of the art care to children and men with KS. Over the last 10 years, with advancements in artificial reproductive techniques and the successful delivery of healthy children from men with KS, the involvement of reproductive endocrinologists and urologists in the care of patients with KS is becoming commonplace. The new areas of intense research investigate optimal methods of hormonal manipulations, preservation of fertility in adolescents, and development of universal early screening programs for KS. This review provides the latest update in our understanding of the pathophysiology, natural history, and evolving paradigms of therapy in adolescents and men with KS.

Successful testicular sperm retrieval in adolescents with Klinefelter syndrome treated with at least 1 year of topical testosterone and aromatase inhibitor.

OBJECTIVE To evaluate surgical sperm retrieval rates in adolescents with Klinefelter syndrome and testosterone replacement therapy (TRT). DESIGN Case series. SETTING Academic medical center. PATIENT(S) Ten patients with Klinefelter syndrome, aged 14-22 years, treated with testosterone replacement and aromatase inhibitor therapy for a period of 1-5 years before surgical sperm retrieval. INTERVENTION(S) Microsurgical testis sperm extraction with cryopreservation of harvested tissue. MAIN OUTCOME MEASURE(S) Presence of spermatozoa within testis tissue. RESULT(S) Successful sperm retrieval in 7/10 patients (70%). CONCLUSION(S) Use of topical TRT did not appear to suppress spermatogenesis in adolescents with KS. It is uncertain whether sperm retrieval rates would be higher or lower without testosterone replacement in these young males. Sperm cryopreservation should be discussed in all KS adolescents who are either receiving or considering initiating TRT.

Activation of GPER-1 Estradiol Receptor Downregulates Production of Testosterone in Isolated Rat Leydig Cells and Adult Human Testis

Purpose Estradiol (E2) modulates testicular functions including steroidogenesis, but the mechanisms of E2 signaling in human testis are poorly understood. GPER-1 (GPR30), a G protein-coupled membrane receptor, mediates rapid genomic and non-genomic response to estrogens. The aim of this study was to evaluate GPER-1 expression in the testis, and its role in estradiol dependent regulation of steroidogenesis in isolated rat Leydig cells and human testis. Materials and Methods Isolated Leydig cells (LC) from adult rats and human testicular tissue were used in this study. Expression and localization studies of GPER-1 were performed with qRT-PCR, immunofluorescence, immunohistochemistry and Western Blot. Luteinizing Hormone (LH) -stimulated, isolated LC were incubated with estradiol, G-1 (GPER-1-selective agonist), and estrogen receptor antagonist ICI 182,780. Testosterone production was measured with radioimmunoassay. LC viability after incubation with G-1 was measured using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay. Results GPER-1 mRNA is abundantly expressed in rat LC and human testis. Co-localization experiments showed high expression levels of GPER-1 protein in LC. E2-dependent activation of GPER-1 lowers testosterone production in isolated rats LCs and in human testis, with statistically and clinically significant drops in testosterone production by 20–30% as compared to estradiol-naïve LC. The exposure to G-1 does not affect viability of isolated LCs. Conclusions Our results indicate that activation of GPER-1 lowers testosterone levels in the rat and human testis. The expression of GPER-1 in human testis, which lack ERα, makes it an exciting target for developing new agents affecting testosterone production in men.

Higher pregnancy rates using testicular sperm in men with severe oligospermia

OBJECTIVE To evaluate assisted reproductive technology (ART) outcomes using testicular sperm in oligospermic men who previously failed to achieve paternity using TUNEL-positive ejaculated sperm. DESIGN Retrospective cohort. SETTING Academic medical center. PATIENT(S) Twenty-four oligospermic men who failed one or more ART cycles using ejaculated sperm with TUNEL-positive proportion >7%, and subsequently underwent microsurgical testicular sperm extraction (TESE). INTERVENTION(S) TESE followed by intracytoplasmic sperm injection (ICSI). MAIN OUTCOME MEASURE(S) TUNEL-positive level in ejaculated and testicular sperm; clinical pregnancy. RESULT(S) The mean TUNEL-positive level was 24.5% for ejaculated sperm, and 4.6% for testicular sperm. Clinical pregnancy was achieved in the first ART cycle with testicular sperm in 12 (50%) out of 24 couples. There was no statistically significant difference in maternal and paternal age, maternal gravity and parity, number of previous ART attempts, concentration or motility of retrieved sperm, number of oocytes retrieved, fertilization rate, or number of embryos transferred between couples who did and did not achieve pregnancy. No miscarriages occurred. All 12 pregnancies resulted in the delivery of healthy children. CONCLUSION(S) The percentage of TUNEL-positive cells is lower in testicular sperm for oligospermic men who have abnormal ejaculated sperm DNA fragmentation. The use of testicular sperm for ICSI was associated with a 50% pregnancy and live-birth rate for couples who had previously failed one or more IVF-ICSI cycles with ejaculated sperm. No other clinical predictors of successful pregnancies after the use of surgically retrieved sperm could be identified. In men with elevated TUNEL-positive ejaculated sperm and failed ART, TESE may be considered.

Effects of 12 weeks of tadalafil treatment on ejaculatory and orgasmic dysfunction and sexual satisfaction in patients with mild to severe erectile dysfunction: integrated analysis of 17 placebo‐controlled studies

Disorders of ejaculation and orgasm are common, even in men with only mild erectile dysfunction (ED). Treatment with the phosphodiesterase type‐5 inhibitor tadalafil was associated with improvements in ejaculatory and orgasmic function. Patients with residual ejaculatory or orgasmic dysfunction experience reduced sexual satisfaction. These findings need to be corroborated in further clinical trials involving men without ED.

Factors associated with ejaculatory and orgasmic dysfunction in men with erectile dysfunction: analysis of clinical trials involving the phosphodiesterase type 5 inhibitor tadalafil.

Study Type – Prognosis (cohort series)

Evolving techniques to evaluate ejaculatory function.

Purpose of review Recent findings in the physiology and neurobiology of ejaculation have expanded our understanding of male sexual function and have allowed the development of new instruments to investigate ejaculatory and orgasmic disorders. Recent findings The evidence-based definition of lifelong premature ejaculation has set a model in the evaluation and treatment outcome of sexual dysfunction. New instruments to objectively assess arousal, orgasm and the expulsion phase of ejaculation such as functional MRI, dynamic pelvic ultrasound, PET scans and validated questionnaires have lead to a better understanding of sexual dysfunction in men. Animal models, developments in neurobiology and clinical experience have transformed a purely psychoanalytical approach to ejaculatory and orgasmic function into a novel multidisciplinary, scientifically sound and evidence-based discipline of medicine. Summary Ejaculation is an integral part of normal sexual function. Ejaculatory dysfunction is common and may cause substantial disruption to the quality of a patients life. A better understanding of the epidemiology, pathophysiology, neuroscience and genetics of ejaculatory and orgasmic function will eventually lead to the development of new, effective methods of treatment of disorders of ejaculation and orgasm in men.

When to ask male adolescents to provide semen sample for fertility preservation

Background Fertility preservation in adolescents undergoing sterilizing radiation and/or chemotherapy is the standard of care in oncology. The opportunity for patients to provide a semen sample by ejaculation is a critical issue in adolescent fertility preservation. Methods Fifty males with no medical or sexual developmental abnormalities were evaluated. The subjects were screened for evidence of orgasmic, erectile, and ejaculatory dysfunction. A detailed sexual development history was obtained under an Institutional Review Board (IRB)-approved protocol. Results Fifty males, aged 18-65 years (mean 39±16.03 years) volunteered to be part of this study. The mean reported age for the onset of puberty was 12.39 years (95% CI, 11.99-12.80 years), 13.59 years (95% CI, 13.05-14.12 years) for the first ejaculation, 12.56 years (95% CI, 11.80-13.32 years) for the start of masturbation, and 17.26 years (95% CI, 16.18-18.33 years) for the first experienced intercourse. Seventy-five percent of the cohort reached puberty by the age of 13.33, experienced masturbation by 14.5, first ejaculated by the age of 14.83, and had intercourse at age of 19.15 years. The first experienced ejaculation fell 1.5 years after the onset of puberty in 80% present of the cohort, and 84% starts masturbation 1.5 years after the onset of puberty. The mean response between the younger and the older subject was not statistical significance. Conclusions It is appropriate to consider a request for semen specimens by masturbation from teenagers at one year and six months after the onset of puberty; the onset age of puberty plus 1.5 years is an important predictor of ejaculation and sample collection for cryopreservation.

Bulbocavernosus muscle area measurement: a novel method to assess androgenic activity

Serum testosterone does not correlate with androgen tissue activity, and it is critical to optimize tools to evaluate such activity in males. Ultrasound measurement of bulbocavernosus muscle (BCM) was used to assess the relationship between the number of CAG repeats (CAGn) in the androgen receptor (AR) and the BCM size; the changes in the number of CAGn over age were also evaluated. Transperineal ultrasound measurement of the BCM was also performed. AR CAGn were determined by high performance liquid chromatography, and morning hormone levels were determined using immunoassays. Forty-eight men had CAG repeat analysis. Twenty-five were <30 years of age, mean 23.7 years (s.d. = 3.24) and 23 were >45 years of age, mean 53 years (s.d. = 5.58). The median CAGn was 21 (13–29). BCM area was greater when the number of CAGn were <18 as compared to the number of CAGn >24 (P = 0.04). There was a linear correlation between the number of CAGn and the BCM area R2 = 16% (P = 0.01). In the 45 to 65-years-old group, a much stronger negative correlation (R2 = 29%, P = 0.01) was noticed. In the 19 to 29-years-old group, no such correlation was found (R2 = 4%, P = 0.36). In older men, the number of CAGn increased with age (R2 = 32%, P = 0.01). The number of CAGn in the AR correlates with the area of the BCM. Ultrasound assessment of the BCM is an effective surrogate to evaluate end-organ activity of androgens. The number of CAGn may increase with age.