Jon L. Pryor

Microdeletions in the Y Chromosome of Infertile Men

Background Some infertile men with azoospermia or severe oligospermia have small deletions in regions of the Y chromosome. However, the frequency of such microdeletions among men with infertility in general is unknown. We sought to determine the prevalence of Y-chromosome microdeletions among infertile men and to correlate the clinical presentation of the men with specific deletions. Methods We studied 200 consecutive infertile men. Each man was evaluated comprehensively for known causes of infertility, and Y-chromosome microdeletions were studied with use of the polymerase chain reaction to amplify specific regions of the chromosome. The Y chromosomes of 200 normal men were also analyzed. Results Fourteen infertile men (7 percent) and four normal men (2 percent) had microdeletions of the Y chromosome. Nine of the infertile men had azoospermia or severe oligospermia (sperm concentration, <5 million per milliliter), four had oligospermia (sperm concentration, 5 million to <20 million per milliliter), and one had normospermia (sperm concentration, ≥20 million per milliliter). The size and location of the deletions varied and did not correlate with the severity of spermatogenic failure. The fathers of six infertile men with microdeletions were studied; two had the same deletions as their sons, and four had no deletions. Conclusions A small proportion of men with infertility have Y-chromosome microdeletions, but the size and position of the deletions correlate poorly with the severity of spermatogenic failure, and a deletion does not preclude the presence of viable sperm and possible conception.

Efficacy and tolerability of dapoxetine in treatment of premature ejaculation: an integrated analysis of two double-blind, randomised controlled trials

BACKGROUND No drugs are approved for treatment of premature ejaculation. Our aim was to determine the efficacy and tolerability of on-demand dapoxetine in patients with severe premature ejaculation. METHODS We determined the efficacy of dapoxetine in a prospectively predefined integrated analysis of two 12-week randomised, double-blind, placebo-controlled, phase III trials of identical design done independently, in parallel, at 121 sites in the USA. Men with moderate-to-severe premature ejaculation in stable, heterosexual relationships took placebo (n=870), 30 mg dapoxetine (874), or 60 mg dapoxetine (870) on-demand (as needed, 1-3 h before anticipated sexual activity). The primary endpoint was intravaginal ejaculatory latency time (IELT) measured by stopwatch. Safety and tolerability were assessed. All analyses were done on an intention-to-treat basis. The trials are registered at ClinicalTrials.gov, numbers NCT00211107 and NCT00211094. FINDINGS 672, 676, and 610 patients completed in the placebo, 30 mg dapoxetine, and 60 mg dapoxetine groups, respectively. Dapoxetine significantly prolonged IELT (p<0.0001, all doses vs placebo). Mean IELT at baseline was 0.90 (SD 0.47) minute, 0.92 (0.50) minute, and 0.91 (0.48) minute, and at study endpoint (week 12 or final visit) was 1.75 (2.21) minutes for placebo, 2.78 (3.48) minutes for 30 mg dapoxetine, and 3.32 (3.68) minutes for 60 mg dapoxetine. Both dapoxetine doses were effective on the first dose. Common adverse events (30 mg and 60 mg dapoxetine, respectively) were nausea (8.7%, 20.1%), diarrhoea (3.9%, 6.8%), headache (5.9%, 6.8%), and dizziness (3.0%, 6.2%). INTERPRETATION On-demand dapoxetine is an effective and generally well tolerated treatment for men with moderate-to-severe premature ejaculation.

Defining regions of the Y‐chromosome responsible for male infertility and identification of a fourth AZF region (AZFd) by Y‐chromosome microdeletion detection

Cytogenetic and molecular deletion analyses of azoospermic and oligozoospermic males have suggested the existence of AZoospermia Factor(s) (AZF) residing in deletion intervals 5 and 6 of the human Y‐chromosome and coinciding with three functional regions associated with spermatogenic failure. Nonpolymorphic microdeletions in AZF are associated with a broad spectrum of testicular phenotypes. Unfortunately, Sequence Tagged Sites (STSs) employed in screening protocols range broadly in number and mapsite and may be polymorphic. To thoroughly analyze the AZF region(s) and any correlations that may be drawn between genotype and phenotype, we describe the design of nine multiplex PCR reactions derived from analysis of 136 loci. Each multiplex contains 4–8 STS primer pairs, amplifying a total of 48 Y‐linked STSs. Each multiplex consists of one positive control: either SMCX or MIC2. We screened four populations of males with these STSs. Population I consisted of 278 patients diagnosed as having significant male factor infertility: either azoospermia, severe oligozoospermia associated with hypogonadism and spermatogenic arrest or normal sperm counts associated with abnormal sperm morphology. population II consisted of 200 unselected infertile patients. population III consisted of 36 patients who had previously been shown to have aneuploidy, cytological deletions or translocations involving the Y‐chromosome or normal karyotypes associated with severe phenotype abnormalities. Population IV consisted of 920 fertile (control) males.

Single-Blind, Multicenter, Placebo Controlled, Parallel Study to Assess the Safety and Efficacy of Intralesional Interferon α-2b for Minimally Invasive Treatment for Peyronie’s Disease

PURPOSE We investigated the efficacy and safety of intralesional interferon alpha-2b for the treatment of Peyronies disease. MATERIALS AND METHODS A total of 117 consecutive patients with a mean age of 55.1 years who had Peyronies disease were enrolled in a single-blind, multicenter, placebo controlled, parallel study to determine the efficacy and safety of intralesional interferon alpha-2b therapy (Schering, Kenilworth, New Jersey), including 62 who received placebo and 55 who received interferon alpha-2b. Saline (10 ml) in controls and interferon alpha-2b (5 x 10(6) U) were administered biweekly for 12 weeks. Each patient was evaluated for penile curvature, plaque size and density, penile pain, erectile function and penile hemodynamics before and after study completion. Improvement in these parameters was statistically compared between the groups. RESULTS A total of 53 patients in the control arm and 50 in the interferon alpha-2b arm completed the study. Improvement in penile curvature, plaque size and density, and pain resolution was significantly greater in patients treated with interferon alpha-2b vs placebo. The increase in mean International Index of Erectile Function scores was not significantly different between the groups. Penile blood flow improvement was observed in interferon alpha-2b treated patients but not in those who received placebo. The decrease in the number of penile vascular pathologies was significantly higher in interferon alpha-2b cases. Side effects, mostly flu-like symptoms, which were frequently noted in patients on interferon alpha-2b, were mild to moderate in degree and of short duration. CONCLUSIONS This single-blind, multicenter, placebo controlled, parallel study demonstrates that intralesional interferon alpha-2b at a dose of 5 x 10(6) units biweekly for 12 weeks is effective and safe as minimally invasive therapy for Peyronies disease.

Rapid Accumulation of Human Immunodeficiency Virus (HIV) in Lymphatic Tissue Reservoirs during Acute and Early HIV Infection: Implications for Timing of Antiretroviral Therapy

The follicular dendritic cell network (FDC) in lymphoid tissues (LTs) is the major site of human immunodeficiency virus (HIV) storage in presymptomatic and late stages of disease. However, little is known about the rate of virus accumulation during the acute and early stages. In situ hybridization and quantitative image analysis were used to determine the amount of virus bound to the FDC network during the first year of infection. The FDC pool was already >7.0 log10 copies of HIV RNA/g LT in the first year, and 2 patients biopsied within 2-4 days of symptom onset had 7.3 and 8.2 log10 copies of HIV RNA/g LT, respectively. There was no correlation between duration of infection and accumulation of HIV into the FDC network. These data suggest that a large pool of infectious virus is established soon after infection and that initiation of antiretroviral therapy when symptoms of primary HIV infection are recognized is unlikely to prevent substantial accumulation of virus in the FDC network.

Productive Infection of T Cells in Lymphoid Tissues during Primary and Early Human Immunodeficiency Virus Infection

Current models suggest that during human immunodeficiency virus type 1 (HIV-1) transmission virions are selected that use the CCR5 chemokine receptor on macrophages and/or dendritic cells. A gradual evolution to CXCR4 chemokine receptor use causes a shift in the proportion of productively infected cells to the CD4 cell population. Productively infected cells during acute and early infection in lymphoid tissue were assessed, as well as the impact of productive infection on the T cell population in 21 persons who had biopsies performed on days 2-280 after symptoms of acute HIV-1 seroconversion. Even in the earliest stages of infection, most productively infected cells were T lymphocytes. There were sufficient infected cells in lymphoid tissue (LT) to account for virus production and virus load in plasma. Despite the relatively high frequency of productively infected cells in LT, the impact on the size of the T cell population in LT at this stage was minor.

Premature Ejaculation: A psychophysiological review

This review examines the most common male sexual dysfunction, premature ejaculation (PE). The prevalence, classification, neurophysiology, neuropharmacology, and psychological studies that offer evidence useful for understanding and clinically evaluating PE are reviewed. It is proposed that there are two basic kinds of PE: biogenic and psychogenic. Studies reporting pharmacological aspects of ejaculation offer some suggestions regarding the mechanisms of ejaculation as well as possible pharmacologic aid for some premature ejaculators. The traditional assumption among sex therapists that PE is almost universally caused by psychological features, and easily treated with sex therapy behavioral techniques, is drawn into question. Based on the limited available results from systematic investigations, behavioral treatments for PE remain beneficial to only a minority of men three years after treatment ends, suggesting that this male dysfunction is difficult to treat effectively. The mediocre results reported in treatment outcome studies may be due, in part, to reports on heterogeneous groups of premature ejaculators, for whom treatment has been generalized rather than targeted to the specific type of PE. We propose a biological and psychological etiology. With more discriminating assessment and more specific diagnosis of PE, and with treatment designed to address the particular type of PE, long-term outcome should improve for this common sexual dysfunction.

Premature Ejaculation: A Psychophysiological Approach for Assessment and Management

This article distinguishes several subtypes of biogenic and psychogenic premature ejaculation (PE) according to their etiologic features: the physiological PE types of (a) neurologic constitution, (b) acute physical illness, (c) physical injury, and (d) pharmacologic side effect; and the psychological PE types of (a) psychological constitution, (b) acute psychological distress, (c) relationship distress, and (d) psychosexual skills deficit. Attention is given to assessment and differential diagnosis, and to specific treatment of the types of PE, such as the pharmacologic management of difficult neurologic cases. Effective psychosexual treatment combines multiple strategies such as physiological relaxation, pubococcygeal muscle training, cognitive and behavioral pacing strategies, and the involvement of the partner in the therapy. Treatment should determine the specific type of PE and comprehensively address its particular features in order to improve long-term treatment effectiveness.This article distinguishes several subtypes of biogenic and psychogenic premature ejaculation (PE) according to their etiologic features: the physiological PE types of (a) neurologic constitution, (b) acute physical illness, (c) physical injury, and (d) pharmacologic side effect; and the psychological PE types of (a) psychological constitution, (b) acute psychological distress, (c) relationship distress, and (d) psychosexual skills deficit. Attention is given to assessment and differential diagnosis, and to specific treatment of the types of PE, such as the pharmacologic management of difficult neurologic cases. Effective psychosexual treatment combines multiple strategies such as physiological relaxation, pubococcygeal muscle training, cognitive and behavioral pacing strategies, and the involvement of the partner in the therapy. Treatment should determine the specific type of PE and comprehensively address its particular features in order to improve long-term treatment effectiveness.

Long-term follow-up of patients receiving injection therapy for erectile dysfunction

OBJECTIVES During the last decade, vasoactive intracavernosal pharmacotherapy (VIP) has been used extensively for the treatment of erectile dysfunction. However, there is concern about high discontinuation rates and the possibility of long-term complications. Because of few long-term studies on VIP, we investigated efficacy, side effects, satisfaction index, and drop-out rate for injection therapy in patients who started treatment more than 5 years ago. METHODS Questionnaires were mailed to 108 patients who were started on VIP more than 5 years ago, between November 1984 and July 1989. The hospital records and data from the 100 responders (93%) were reviewed. RESULTS Only 32% of the patients continue to use VIP. Most (56%) of those who discontinued did so during the first year. The patients cited one or more of the following reasons for discontinuation: desire for a permanent modality of therapy (29%), lack of a suitable partner (26%), fear of needles (23%), poor response (23%), fear of complications (22%), and lack of sexual spontaneity (21%). This study, which has one of the longest follow-up periods in the literature, has significant new findings in three areas: discontinuation rates fall after 2 years, long-term complications are relatively minor, and patients who discontinue therapy are significantly older or have a poor initial impression of VIP. Paradoxically, discontinuing VIP was apparently unrelated to side effects or etiology of erectile dysfunction, and 82% of patients would still recommend VIP to a friend. CONCLUSIONS This study conclusively shows that because of high initial satisfaction and relatively minor side effects, VIP should remain as one of the initial options for long-term treatment of erectile dysfunction. However, despite seemingly doing well, patients often discontinue therapy, and therefore should be followed closely so that alternative therapy can be offered.

Prevalence and effect of varicoceles in an elderly population

OBJECTIVES The prevalence of a varicocele in the adolescent and young adult populations is approximately 15%. Because other varicose veins increase in prevalence with advanced age, we hypothesized that the incidence of varicoceles in the elderly population would be greater and might affect testicular size, consistency, and function. METHODS As part of a prostate cancer screening program, we prospectively evaluated 354 men (mean age 60.7 years) by physical examination for the presence of a varicocele, testicular size, and consistency, and measured the serum testosterone level. RESULTS A varicocele was present bilaterally in 19.8% (70 of 354), left sided only in 22.0% (78 of 354), and right sided only in 1.1% (4 of 354) of patients. Decreased testosterone levels correlated with older age (P = 0.001) and the presence of bilaterally soft testes (P = 0.02) but not the presence of a varicocele. Testes in men with bilateral varicoceles were significantly smaller (P = 0.001) and softer (P = 0.001) than in men without varicoceles. Higher grade varicoceles were more likely to be associated with soft testes (P = 0.001) than were lower grade varicoceles. CONCLUSIONS The 42% prevalence of varicoceles in our elderly population was greater than that for historic control younger populations, suggesting either an increase with age or examiner sensitivity bias. Varicoceles in the elderly, especially when bilateral, significantly affect testicular consistency (softer) and testicular size (smaller), but do not directly decrease serum testosterone levels. The presence of bilaterally soft testes in elderly men indicates bilateral gonadal dysfunction and may be a physical examination finding associated with decreased serum testosterone.