Alexander W. Pastuszak

The use of genomics, proteomics, and metabolomics in identifying biomarkers of male infertility.

Although male factors account for approximately 50% of all infertility, the mechanisms underlying their origin are unknown. Currently, clinicians rely primarily on semen analyses to predict male reproductive potential and chart treatment success. Even when invasive procedures are performed, the causes of male factor infertility frequently remain elusive. Recently, the advent of new technologies has spurred the search for novel male infertility biomarkers, and the detection of genes, proteins, or metabolites unique to the infertile male holds much promise. The concept that a cost-effective, noninvasive, and accurate set of biomarkers can be identified to diagnose male factor infertility is tantalizing. This review focuses on the various methodologies used in the discovery of novel biomarkers along with their findings. Specific attention is paid to recent advances in the fields of genetics, proteomics, and metabolomics.

Testosterone Replacement Therapy in Patients with Prostate Cancer After Radical Prostatectomy

PURPOSE Testosterone replacement therapy in men with prostate cancer is controversial, with concern that testosterone can stimulate cancer growth. We evaluated the safety and efficacy of testosterone in hypogonadal men with prostate cancer treated with radical prostatectomy. MATERIALS AND METHODS We performed a review of 103 hypogonadal men with prostate cancer treated with testosterone after prostatectomy (treatment group) and 49 nonhypogonadal men with cancer treated with prostatectomy (reference group). There were 77 men with low/intermediate (nonhigh) risk cancer and 26 with high risk cancer included in the analysis. All men were treated with transdermal testosterone, and serum hormone, hemoglobin, hematocrit and prostate specific antigen were evaluated for more than 36 months. RESULTS Median (IQR) patient age in the treatment group was 61.0 years (55.0-67.0), and initial laboratory results included testosterone 261.0 ng/dl (213.0-302.0), prostate specific antigen 0.004 ng/ml (0.002-0.007), hemoglobin 14.7 gm/dl (13.3-15.5) and hematocrit 45.2% (40.4-46.1). Median followup was 27.5 months, at which time a significant increase in testosterone was observed in the treatment group. A significant increase in prostate specific antigen was observed in the high risk and nonhigh risk treatment groups with no increase in the reference group. Overall 4 and 8 cases of cancer recurrence were observed in treatment and reference groups, respectively. CONCLUSIONS Thus, testosterone therapy is effective and, while followed by an increase in prostate specific antigen, does not appear to increase cancer recurrence rates, even in men with high risk prostate cancer. However, given the retrospective nature of this and prior studies, testosterone therapy in men with history of prostate cancer should be performed with a vigorous surveillance protocol.

Testosterone Replacement Therapy in the Setting of Prostate Cancer Treated With Radiation

A lack of consensus and few data support testosterone replacement therapy (TRT) in hypogonadal men who have been treated for prostate cancer (CaP), particularly those who have received radiation therapy. We performed retrospective review of 13 hypogonadal men with CaP, treated with brachytherapy or external beam radiotherapy who were subsequently treated with testosterone (T) between 2006 and 2011. Serum T, free T (FT), estrogen (E), sex hormone-binding globulin (SHBG), prostate-specific antigen (PSA), hemoglobin (Hgb) and hematocrit (Hct) values were evaluated approximately every 3 months after TRT initiation up to 67 months of follow-up. Prostate biopsies demonstrated four men with Gleason (Gl) 6, 7 with Gl 7 and 2 with Gl 8 disease. Median (interquartile range) age at TRT initiation was 68.0 (62.0–77.0) years, initial T 178.0 (88.0–263.5) ng dl−1, FT 10.1 (5.7–15.0) pg ml−1 and PSA 0.30 (0.06–0.95) ng ml−1. Median follow-up after TRT initiation was 29.7 months (range 2.3–67.3 months). At median follow-up, a significant increase in mean T (368.0 (281.3–591.0) ng dl−1, P=0.012) and SHBG were observed, with no significant increases in Hgb, Hct, E, FT, or PSA (0.66 (0.16–1.35) ng ml−1, P=0.345). No significant increases in PSA or CaP recurrences were observed at any follow-up interval. TRT in the setting of CaP after treatment with radiation therapy results in a rise in serum T levels and improvement in hypogonadal symptoms without evidence of CaP recurrence or progression.

Anabolic steroid induced hypogonadism in young men.

PURPOSE The use of anabolic androgenic steroids has not been traditionally discussed in mainstream medicine. With the increased diagnosis of hypogonadism a heterogeneous population of men is now being evaluated. In this larger patient population the existence of anabolic steroid induced hypogonadism, whether transient or permanent, should now be considered. MATERIALS AND METHODS We performed an initial retrospective database analysis of all 6,033 patients who sought treatment for hypogonadism from 2005 to 2010. An anonymous survey was subsequently distributed in 2012 to established patients undergoing testosterone replacement therapy. RESULTS Profound hypogonadism, defined as testosterone 50 ng/dl or less, was identified in 97 men (1.6%) in the large retrospective cohort initially reviewed. The most common etiology was prior anabolic androgenic steroid exposure, which was identified in 42 men (43%). Because of this surprising data, we performed an anonymous followup survey of our current hypogonadal population of 382 men with a mean±SD age of 49.2±13.0 years. This identified 80 patients (20.9%) with a mean age of 40.4±8.4 years who had prior anabolic androgenic steroid exposure. Hypogonadal men younger than 50 years were greater than 10 times more likely to have prior anabolic androgenic steroid exposure than men older than 50 years (OR 10.16, 95% CI 4.90-21.08). Prior anabolic androgenic steroid use significantly correlated negatively with education level (ρ=-0.160, p=0.002) and number of children (ρ=-0.281, p<0.0001). CONCLUSIONS Prior anabolic androgenic steroid use is common in young men who seek treatment for symptomatic hypogonadism and anabolic steroid induced hypogonadism is the most common etiology of profound hypogonadism. These findings suggest that it is necessary to refocus the approach to evaluation and treatment paradigms in young hypogonadal men.

Concomitant Intramuscular Human Chorionic Gonadotropin Preserves Spermatogenesis in Men Undergoing Testosterone Replacement Therapy

PURPOSE Testosterone replacement therapy results in decreased serum gonadotropins and intratesticular testosterone, and impairs spermatogenesis, leading to azoospermia in 40% of patients. However, intratesticular testosterone can be maintained during testosterone replacement therapy with co-administration of low dose human chorionic gonadotropin, which may support continued spermatogenesis in patients on testosterone replacement therapy. MATERIALS AND METHODS We retrospectively reviewed the records of hypogonadal men treated with testosterone replacement therapy and concomitant low dose human chorionic gonadotropin. Testosterone replacement consisted of daily topical gel or weekly intramuscular injection with intramuscular human chorionic gonadotropin (500 IU) every other day. Serum and free testosterone, estradiol, semen parameters and pregnancy rates were evaluated before and during therapy. RESULTS A total of 26 men with a mean age of 35.9 years were included in the study. Mean followup was 6.2 months. Of the men 19 were treated with injectable testosterone and 7 were treated with transdermal gel. Mean serum hormone levels before vs during treatment were testosterone 207.2 vs 1,055.5 ng/dl (p <0.0001), free testosterone 8.1 vs 20.4 pg/ml (p = 0.02) and estradiol 2.2 vs 3.7 pg/ml (p = 0.11). Pretreatment semen parameters were volume 2.9 ml, density 35.2 million per ml, motility 49.0% and forward progression 2.3. No differences in semen parameters were observed during greater than 1 year of followup. No impact on semen parameters was observed as a function of testosterone formulation. No patient became azoospermic during concomitant testosterone replacement and human chorionic gonadotropin therapy. Nine of 26 men contributed to pregnancy with the partner during followup. CONCLUSIONS Low dose human chorionic gonadotropin appears to maintain semen parameters in hypogonadal men on testosterone replacement therapy. Concurrent testosterone replacement and human chorionic gonadotropin use may preserve fertility in hypogonadal males who desire fertility preservation while on testosterone replacement therapy.

Depression is correlated with the psychological and physical aspects of sexual dysfunction in men.

Few studies have objectively examined the relationship between depression and various stages of sexual function. Here we associate depression and sexual function using validated questionnaires. A retrospective review of 186 men was performed; demographics and serum hormone levels were obtained. Responses to questionnaires evaluating depressive symptoms (Patient Health Questionnaire (PHQ-9)), sexual function (International Index of Erectile Function (IIEF)) and hypogonadal symptoms (quantitative Androgen Decline in the Aging Male (qADAM)) completed by each patient were correlated using Spearman’s rank correlation. Mean±s.d. subject age: 52.6±12.7 years; mean serum hormone levels: TT 429.8±239.2 ng dl−1, free testosterone 9.72±7.5 pg ml−1 and estradiol 34.4±22.8 pg ml−1. Negative correlations were observed between total PHQ-9 score and the sexual desire (ρ=−0.210, P=0.006), intercourse satisfaction (ρ=−0.293, P<0.0001) and overall satisfaction (ρ=−0.413, P<0.0001) domains of the IIEF and individual IIEF questions pertaining to erectile function. Men with a PHQ-9 score ⩾10 (mild depression or worse), had lower sexual desire and sex life satisfaction. A negative correlation between PHQ-9 score and qADAM score (ρ=−0.634, P<0.0001) was observed and men with higher PHQ-9 score had lower qADAM scores. Depressive symptoms in men correlate with both psychological as well as physical aspects of sexual function.

The Genetics of Male Fertility—From Basic Science to Clinical Evaluation

Our understanding of male fertility has increased dramatically over the past several decades, in large part because of advances in technology and the ability to rapidly analyze large quantities of high-resolution genetic data. These research efforts have led to an understanding of some of the genes involved in male fertility and have enabled us to test for defects in these genes that result in infertility in men. However, our understanding of male fertility remains far from comprehensive, and many genes involved in male fertility likely remain to be identified and their mechanisms of action elucidated. This can only be accomplished through continued, persistent investigations using cutting-edge technologies. In this review, we discuss the history of genetic testing and how it applies to male fertility, from the identification of the sex chromosomes at the turn of the century to classification of single-nucleotide polymorphisms that may result in infertility and are the crux of modern genetic analysis. We discuss the genetic testing methodologies traditionally used for genetic assessment of infertile males, including karyotype analysis, sperm fluorescence in situ hybridization, and polymerase chain reaction-based testing for Y chromosomal evaluation, as well as cutting-edge genetic testing methodologies using microarrays and whole-genome sequencing, permitting analysis at a nucleotide-level resolution. Finally, we describe our vision of the future of genetic testing in the setting of male infertility, culminating in truly personalized medicine for each affected infertile male.

Erectile Dysfunction as a Marker for Cardiovascular Disease Diagnosis and Intervention: A Cost Analysis

INTRODUCTION Erectile dysfunction (ED) is a risk factor for cardiovascular disease (CVD). We examine the costs of screening men with ED for CVD risk factors and the cost savings of treating these at risk men. AIM This study aims to evaluate the effect of screening men presenting with ED for CVD risk factors and to determine the cost effectiveness of this screening protocol. METHODS The known incidence and prevalence of ED and CVD, the rate of undiagnosed CVD, and the effects of CVD treatment were used to model the change in prevalence of acute CVD events and ED as a function of the number of men with ED and CVD. The cost savings associated with reduction in acute cardiovascular (CV) events and ED prevalence was estimated over 20 years. MAIN OUTCOME MEASURES Acute CVD event rate reduction and associated cost savings were modeled over 20 years. RESULTS The relative risk of ED in men with CVD is 1.47 and the coprevalence of both ED and CVD was estimated at 1,991,520 men. Approximately 44% of men with CVD risk factors are unaware of their risk. If all men presenting with ED were screened for CVD, 5.8 million men with previously unknown CVD risk factors would be identified over 20 years, costing

Varicocele and testicular function.

2.7 billion to screen. Assuming a 20% decrease in CV events as a result of screening and treatment, 1.1 million cardiovascular events would be avoided, saving

The Genetic Basis of Peyronie Disease: A Review

21.3 billion over 20 years. Similarly, 1.1 million cases of ED would be treated, saving