Drug-induced gynecomastia: an evidence-based review.

INTRODUCTION: Drugs are estimated to cause about 10 - 25% of all cases of gynecomastia. Over the course of several decades, multiple medications have been implicated in the development of gynecomastia mostly in the form of case reports and case series. However, these reports suffer from a multitude of deficiencies, including poor quality of evidence. AREAS COVERED: Studies were selected for this review by performing an extensive electronic and hand-search using BIOSIS, EMBASE and Medline, from 1940 to present, for all reported drug associations of gynecomastia and their possible pathophysiology. Quality of evidence was assessed on a three-point scale: good, fair and poor, and each of the drugs reported to cause gynecomastia was assigned a level of strength. The pathophysiology of gynecomastia is also discussed in detail for each of the drugs found to have a good or fair evidence of association with gynecomastia. EXPERT OPINION: Most of the reported drug-gynecomastia associations were based on poor quality evidence. The drugs definitely associated with the onset of gynecomastia are spironolactone, cimetidine, ketoconazole, hGH, estrogens, hCG, anti-androgens, GnRH analogs and 5-α reductase inhibitors. Medications probably associated with gynecomastia include risperidone, verapamil, nifedipine, omeprazole, alkylating agents, HIV medications (efavirenz), anabolic steroids, alcohol and opioids.

Methanobrevibacter smithii is the predominant methanogen in patients with constipation-predominant IBS and methane on breath.

PURPOSE: Among irritable bowel syndrome (IBS) patients, breath methane producers overwhelmingly have constipation predominance (C-IBS). Although the most common methanogen in humans is Methanobrevibacter smithii, incidence and type of methanogenic bacteria in C-IBS patients are unknown. METHODS: By use of a questionnaire and lactulose breath testing, subjects with Rome II C-IBS and methane (>3 ppm) were selected (n = 9). The control group included subjects with IBS who had no breath methane (n = 10). Presence of bacterial DNA was assessed in a stool sample of each subject by quantitative-PCR using universal 16S rDNA primer. M. smithii was quantified by use of a specific rpoB gene primer. RESULTS: M. smithii was detected in both methane and non-methane subjects. However, counts and relative proportion of M. smithii were significantly higher for methane-positive than for methane-negative subjects (1.8 × 10(7) ± 3.0 × 10(7) vs 3.2 × 10(5) ± 7.6 × 10(5) copies/g wet stool, P < 0.001; and 7.1 ± 6.3 % vs 0.24 ± 0.47 %, P = 0.02 respectively). The minimum threshold of M. smithii resulting in positive lactulose breath testing for methane was 4.2 × 10(5) copies/g wet stool or 1.2 % of total stool bacteria. Finally, area-under-curve for breath methane correlated significantly with both absolute quantity and percentage of M. smithii in stool (R = 0.76; P < 0.001 and R = 0.77; P < 0.001 respectively). CONCLUSIONS: M. smithii is the predominant methanogen in C-IBS patients with methane on breath testing. The number and proportion of M. smithii in stool correlate well with amount of breath methane.

Factors affecting the yield of brush cytology for the diagnosis of pancreatic and biliary cancers.

OBJECTIVE: Pancreatobiliary malignancies often present as biliary strictures. Biliary brush cytology is an established diagnostic technique in the investigation of such strictures. The main shortcoming of the test, however, is its low sensitivity. The aim of this was to identify factors associated with a positive yield on biliary brush cytology. METHODS: Consecutive patients who had brush cytology for investigation of biliary strictures from 2005 to 2007 were included. Association of several factors with a positive result on brush cytology was studied using univariable and multivariable logistic regression analyses. RESULTS: Two hundred eighty patients were evaluated. One hundred nineteen (42.5%) patients had a final diagnosis of malignancy; of whom, 55 had a positive brush cytology (sensitivity, 46%; specificity, 100%). On multivariable analysis, age (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.06-10.4 per 5-year increase), total serum bilirubin levels (OR, 1.3; 95% CI, 1.01-1.6 per 5-unit increase), and presence of a mass on cross-sectional imaging (OR, 11.7; 95% CI 5.1-27.2) were independent predictors of a positive brush cytology result. CONCLUSIONS: Increasing age, higher serum bilirubin levels, and presence of a mass on cross-sectional imaging are independent factors associated with a positive result on biliary brush cytology. These findings suggest use of complementary tissue acquisition techniques in selected cases.

Gynecomastia: incidence, causes and treatment.

Gynecomastia is a benign proliferation of glandular tissue of the breast in males. It is common during three phases in the age distribution curve: the neonatal period, puberty and senescence. An imbalance between estrogen and androgen action at the level of breast tissue is believed to be the underlying pathophysiology. Initial steps in the clinical evaluation involve differentiating it from pseudogynecomastia and ruling out male breast carcinoma. A selective laboratory and radiological work-up should follow to identify the underlying cause. Pubertal gynecomastia resolves spontaneously in the majority of adolescents, and hence reassurance and observation is regarded as the best approach. In adults with persistent painful gynecomastia, a short-term trial of medical therapy is an option that has shown good results. For chronic, bothersome gynecomastia, removal by plastic surgery is the treatment of choice.

Growth and development of male external genitalia: a cross-sectional study of 6200 males aged 0 to 19 years.

OBJECTIVE: To provide estimates of normal variations in penile measurements and testicular volumes, and to establish reference ranges for clinical use. DESIGN: Cross-sectional, population-based study. SETTING: Schools, kindergartens, and child care centers in different parts of Bulgaria. PARTICIPANTS: A population of 6200 clinically healthy white males aged 0 to 19 years. INTERVENTIONS: The study physician chose schools, kindergartens, and child care centers randomly and examined children at random until he reached the required number. Each of the 20 age groups (age range, 0-19 years) had an equal number of males (ie, 310). MAIN OUTCOME MEASURES: The mean (SD) values and fifth, 50th, and 95th percentiles of height (Siber Hegner anthropometer), weight (beam balance), testicular volume (Prader orchidometer), penile length (rigid tape), and penile circumference (measuring tape) from birth to 19 years of age. RESULTS: Testes did not show any increase in size until the onset of puberty at age 11 years, whereas penile growth was gradual after birth. However, both penile and testicular development demonstrated peak growth from 12 to 16 years of age, which coincided with the maximal male pubertal growth spurt. Data indicate an earlier pubertal development for this study population than that for a similar population several decades ago. Significant differences between urban and rural populations regarding penile length were also noticed. CONCLUSIONS: Our study provides the contemporary reference range values for height, weight, testicular volume, and penile length and circumference of males aged 0 to 19 years. Our data show that, even by the end of 20th century, there is still some acceleration of male pubertal development. For the first time are reported somatic differences in genitalia within a population between urban and rural representatives.

Adenomas are detected more often in morning than in afternoon colonoscopy.

OBJECTIVES: The effectiveness of colonoscopy in preventing colon cancer depends on adenoma detection and removal. Adequacy of bowel preparation, careful mucosal visualization, and adequate withdrawal time are known to affect adenoma detection rate (ADR). Physician fatigue, which usually increases as the day progresses, might impair ADR. The aim of this study is to assess the effect of timing of colonoscopy, morning vs. afternoon, on ADR. METHODS: Medical records of 9,063 colonoscopies performed in 2006 were reviewed for patient demographics, indications, timing, and findings of colonoscopy. Asymptomatic outpatients who had adequate bowel preparation and complete colonoscopy were included. Morning colonoscopies were defined as those that started before 12 noon and afternoon colonoscopies as those that started after 12 noon. ADR is defined as the detection of at least one adenoma per colonoscopy. RESULTS: A total of 3,619 colonoscopies were included, of which 1,748 (48.3%) were done in the morning and 1,871 (51.7%) were done in the afternoon. ADR was 29.3% in the morning group compared with 25.3% in the afternoon group (P=0.008). There was a trend toward declining ADR for each subsequent hour of the day (P=0.01). In multivariable analysis, colonoscopy in the morning was significantly associated with increased ADR (odds ratio (OR) 1.2 (1.06, 1.4) P=0.006). CONCLUSIONS: Time of performance of colonoscopy seems to be an independent predictor for adenoma detection. ADR was significantly higher in morning colonoscopies than in afternoon colonoscopies. The reasons and implications of this finding should be studied further.

Technical and ethical challenges of fertility preservation in young cancer patients.

As cancer treatment improves, more young men and women survive, but they suffer from infertility as a major sequel of cancer treatment. Gamete and embryo cryopreservation are the only options available to these patients for preserving their fertility. Although cryopreservation of spermatozoa and embryos are already established, oocyte banking is still experimental. The advent of testicular tissue cryopreservation and spermatogonial stem cell transplantation in men, and ovarian tissue cryopreservation and in-vitro follicular maturation in women, has started a frenzy of experiments worldwide trying to demonstrate their potential use in fertility preservation. Although major improvements have been made in tissue cryobanking in the past decade, there are still many unresolved technical issues related to these procedures. Furthermore, the intersection of cancer and fertility preservation in young patients raises ethical, legal and policy issues for oncologists and cancer survivors. Informed consent of minor patients, legal parentage and medical negligence claims are some of the potential legal challenges faced by society and healthcare providers. This review summarizes the technical and ethical challenges of gamete cryopreservation in young cancer patients.

Should seminal oxidative stress measurement be offered routinely to men presenting for infertility evaluation?

OBJECTIVE: To determine if seminal oxidative stress measurement should be offered routinely to men presenting for infertility evaluation. METHODS: We performed an extensive review of the English-language literature by searching MEDLINE for studies published between 1980 and 2007. RESULTS: Research conducted during the last decade has provided growing support for the concept that excessive production of reactive oxygen species (ROS) is related to abnormal semen parameters and sperm damage. Routine semen analysis remains the backbone of clinical evaluation in male infertility, but determining the levels and sources of excessive ROS generation in semen is currently not included in the routine evaluation of subfertile men. However, the diagnostic and prognostic capabilities of seminal oxidative stress measurement exceed the capabilities of conventional sperm quality tests. An oxidative stress test may accurately discriminate between fertile and infertile men and identify those with a clinical diagnosis of male factor infertility who are likely to initiate a pregnancy if they are followed over a period of time. In addition, such a test can help select subgroups of patients with infertility in which oxidative stress is an important factor and those who may benefit from antioxidant supplementation. Although consensus is still required about the type and dosage of antioxidants to be used, rationale and evidence exist supporting their use in infertile men with elevated oxidative stress. CONCLUSION: Consensus is growing about the clinical utility of seminal oxidative stress testing in infertility clinics, but standardization of protocols to measure ROS is crucial before introducing these tests into routine clinical practice.

Effect of vaginal lubricants on sperm motility and chromatin integrity: a prospective comparative study.

OBJECTIVE: To evaluate the effect of vaginal lubricants Pre-Seed, FemGlide, Astroglide, and Replens on human sperm motility and chromatin integrity. DESIGN: Prospective, comparative, in vitro study. SETTING: Andrology laboratory at tertiary care hospital. PATIENT(S): Thirteen normozoospermic donors. INTERVENTION(S): Semen samples from 13 subjects were incubated in human tubal fluid media (HTF) controls and 10% (vol/vol) of Pre-Seed, FemGlide, Astroglide, and Replens lubricants. After 30 minutes, progressive sperm motility was assessed by light microscopy. Semen samples of 12 patients were placed in positive control (HTF), negative control (10% K-Y Jelly lubricant), and 10% vol/vol Pre-Seed and FemGlide lubricants. After 4 hours culture, spermatozoa were analyzed for percent DNA fragmentation index with use of the acridine orange-based sperm chromatin structure assay. MAIN OUTCOME MEASURE(S): Sperm motility and percent DNA fragmentation index. RESULTS: Percent motility did not differ significantly between HTF controls and Pre-Seed, whereas FemGlide, Replens, and Astroglide lubricants demonstrated a significant decrease in motility. There was no significant difference in percent DNA fragmentation index between the HTF controls and Pre-Seed, but a significant decline in sperm chromatin quality occurred with FemGlide and K-Y Jelly. CONCLUSION: Pre-Seed does not cause a significant decrease in progressive sperm motility or chromatin integrity in contrast to other lubricants used by couples.

Effect of cell phone usage on semen analysis in men attending infertility clinic: an observational study.

OBJECTIVE: To investigate the effect of cell phone use on various markers of semen quality. DESIGN: Observational study. SETTING: Infertility clinic. PATIENT(S): Three hundred sixty-one men undergoing infertility evaluation were divided into four groups according to their active cell phone use: group A: no use; group B: <2 h/day; group C: 2-4 h/day; and group D: >4 h/day. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Sperm parameters (volume, liquefaction time, pH, viscosity, sperm count, motility, viability, and morphology). RESULT(S): The comparisons of mean sperm count, motility, viability, and normal morphology among four different cell phone user groups were statistically significant. Mean sperm motility, viability, and normal morphology were significantly different in cell phone user groups within two sperm count groups. The laboratory values of the above four sperm parameters decreased in all four cell phone user groups as the duration of daily exposure to cell phones increased. CONCLUSION(S): Use of cell phones decrease the semen quality in men by decreasing the sperm count, motility, viability, and normal morphology. The decrease in sperm parameters was dependent on the duration of daily exposure to cell phones and independent of the initial semen quality.

Efficacy of varicocelectomy in improving semen parameters: new meta-analytical approach.

OBJECTIVES: To determine the efficacy of varicocelectomy in improving semen parameters. METHODS: A meta-analysis was performed to evaluate both randomized controlled trials and observational studies using a new scoring system. This scoring system was developed to adjust and quantify for various potential sources of bias, including selection bias, follow-up bias, confounding bias, information or detection bias, and other types of bias, such as misclassification. Of 136 studies identified through the electronic and hand search of references, only 17 studies met our inclusion criteria. The study population was infertile men with clinically palpable unilateral or bilateral varicocele and at least one abnormal semen parameter who had undergone surgical varicocelectomy (high ligation or inguinal microsurgery). Only those studies that had at least three semen analyses (ie, sperm count, motility, and morphology) per patient, before and after surgical varicocelectomy, were included. RESULTS: The combined analysis demonstrated that the sperm concentration increased by 9.71 x 10(6)/mL (95% confidence interval [CI] 7.34 to 12.08, P <0.00001) and motility increased by 9.92% (95% CI 4.90 to 14.95, P = 0.0001) after microsurgical varicocelectomy. Similarly, the sperm concentration increased by 12.03 x 10(6)/mL (95% CI 5.71 to 18.35, P = 0.0002) and motility increased by 11.72% (95% CI 4.33 to 19.12, P = 0.002) after high ligation varicocelectomy. The improvement in World Health Organization sperm morphology was 3.16% (95% CI 0.72 to 5.60, P = 0.01) after both microsurgery and high ligation varicocelectomy. CONCLUSIONS: Surgical varicocelectomy significantly improves semen parameters in infertile men with palpable varicocele and abnormal semen parameters.

Cell phones and male infertility: dissecting the relationship.

There has been a tremendous increase in the use of mobile phones in the past decade and concerns are growing about the possible hazardous effects of radio-frequency electromagnetic waves (EMW) emitted by these devices on human health. Preliminary studies, though with limitations in study design, suggest a possible link between cell phone use and infertility. A recent study found that use of cell phones adversely affects the quality of semen by decreasing the sperm counts, motility, viability and morphology. Evidence of detrimental effect of mobile phones on male fertility is still equivocal as studies have revealed a wide spectrum of possible effects ranging from insignificant effects to variable degrees of testicular damage. Although previous studies suggested a role of cell phone use in male infertility, the mode of action of EMW emitted from cell phones on the male reproductive system is still unclear. EMW can affect the reproductive system via an EMW-specific effect, thermal molecular effect or combination of both. Studies performed on human males are scarce and therefore further studies with a careful design are needed to determine the effect of cell phone use on male-fertilizing potential.

Role of metabolomic analysis of biomarkers in the management of male infertility.

Metabolomics is the systematic study of metabolites as small-molecule biomarkers that represent the functional phenotype in a cell, tissue or organism. Detection of crucial disturbances in the concentration of metabolites by metabolomic profiling of key biomarkers can be beneficial in the management of various medical conditions, including male-factor infertility. Recent studies have demonstrated the potential role of this rapid, noninvasive analysis in the investigation of infertile men. Differences in the concentration of oxidative stress biomarkers (-CH, -NH, -OH and ROH) have been found to be uniquely associated with semen plasma of healthy men compared with patients with idiopathic infertility, varicocele and vasectomy reversal. Furthermore, NMR spectra have shown significant differences in citrate, lactate, glycerylphosphorylcholine and glycerylphosphorylethanolamine among semen samples of men with spermatogenesis failure, obstructive azoospermia, oligoasthenoteratozoospermia and healthy donors. Evidence has also shown the value of (31)P-magnetic resonance spectroscopy in differentiating patients with testicular failure and ductal obstruction by utilizing phosphomonoester and beta-adenosine triphosphate as biomarkers. In addition, metabolomics has shown promise in assisted reproductive techniques. Recent studies involving spectroscopic measurements of follicular fluid and embryo culture media have revealed an association between biomarkers of oxidative stress and pregnancy outcome of oocytes and embryos.

Relationship of adolescent gynecomastia with varicocele and somatometric parameters: a cross-sectional study in 6200 healthy boys.

PURPOSE: To evaluate the relationship of gynecomastia with varicocele and somatometric parameters in otherwise clinically healthy boys. METHODS: The relationship between gynecomastia and somatometric parameters was examined with 6200 clinically healthy boys aged 0-19 years of different socioeconomic backgrounds in various schools, kindergartens, and childcare centers. Multivariable logistic regression analysis was used to model the prevalence of gynecomastia (>or=1cm) in relation to height, weight, testicular volume, penile length and circumference, age, pubic hair Tanner stage, and residential status. RESULTS: Pubic hair Tanner stages 3 and 4 had the highest incidence of gynecomastia. Gynecomastia was found only in boys more than 10 years old and its prevalence in the age group of 10-19 years (n = 3082) was 3.93 %. In boys 10-13 years old, gynecomastia was positively correlated with varicocele, the adjusted odds ratio (OR) was 2.1 (95% confidence interval [CI] = 1.1-4.1). For the age at which gynecomastia was most prevalent (group aged 12-14 years), the adjusted OR of gynecomastia occurring in boys with varicocele, using the Cochran-Mantel-Hasenzel method of adjusting for age was 1.9 (95% CI = 1.1-3.4). Gynecomastia was negatively correlated with body mass index (BMI). In addition, it was weakly correlated with testicular volume, positively in age group 10-13 years and negatively in those 14-19 years. However no relationship was found between gynecomastia and penis size, urban/rural status, and sea level of residence. CONCLUSIONS: Adolescent gynecomastia is a mid-puberty event. It is significantly associated with varicocele and somatometric parameters including BMI and testicular volume.