Drug-inducing gynaecomastia--a critical review.

Gynaecomastia has been associated with a large variety of drugs in the literature. However, a causal relation of the incidence of gynaecomastia to a certain drug should be considered only if sufficient and significant evidence can be obtained from the studies published. In this review, studies quoted in Medline were evaluated according to the Scottish Intercollegiate Guidelines Network (SIGN) grading system for clinical studies. Reports on 92 drugs were found in Medline in combination with gynaecomastia. An imbalance of the oestrogen/androgen ratio causes gynaecomastia. Also, prolactin has gynaecomastia-inducing properties. In 14 of the drugs quoted, the studies lead to a level of recommendation 'A'. All these drugs have been designed to interfere with the production and action of sexual hormones or of prolactin. In 25 of the drugs, the level of recommendation was 'B'. Besides those drugs in this group that have been designed for interference with the metabolism of steroid hormones or of prolactin, in drugs for acid-related disorders, diuretics, antiretroviral drugs, antimycotics, psychoanaleptics, alcohol gynaecomastia was described as an unexpected adverse effect. Studies on the association of drugs and gynaecomastia do not share a generally accepted definition of gynaecomastia; in this way, the informational value is limited.

["Die grosse Barb" in the museum of the University of Marburg. An early documentation of acromegaly]. / Die grosse Barb im Marburger Universitätsmuseum. Eine frühe Dokumentation der Akromegalie.

The university museum for cultural history in the castle of Marburg has a portrait "Die grosse Barb", which represents a women suffering from acromegaly. She shows the typical pathologic alterations: thickening of the skin folds, thickening of the lips and the eyelids, growth of bones and cartilages, lengthening of the nose, enlargement of the ears, protrusion of the zygoma, mandible and the chin. Acromegaly is a consequence of enhanced secretion of growth hormone, which occurs also as a symptom of several syndromes, such as multiple endocrine neoplasia type 1, McCune-Albright-syndrome, and NAME syndrome (Carney complex type I). The most remarkable symptom of acromegaly is the gigantism. This occurs also in androgen-deficient states, such as the Klinefelter syndrome and some more genetic syndromes, of which the Simpson-Golabi-Behmel syndrome, the Sotos syndrome, the Marfan syndrome, the homocystinuria, and the fragile X-syndrome may be mentioned. Nothing is known on the further fate of the patient shown in the portrait. It is also unknown, whether she owes her position as a chambermaid to her gigantism, for it was a common use in courts to have people with abnormal body shapes in attendance.

Azoospermia in a renal transplant recipient during sirolimus (rapamycin) treatment.

Sirolimus is used as a powerful immunosuppressant drug in patients after organ transplantation. It was shown to block spermatogenesis by interrupting the stem cell factor/c-kit system. Oligozoospermia was shown in single patients. In addition, a decrease of testosterone and an increase of gonadotropin levels were observed. We report on a young patient who showed azoospermia during the treatment with sirolimus after renal transplantation. After changing the immunosuppression to tacrolimus, spermatogenesis of the patient recovered. Five months after cessation of the treatment with sirolimus, a sperm concentration of 8 x 10(6) ml(-1) was found. Depression of spermatogenesis is an important side effect in younger men who aspire paternity, so that waiving of sirolimus is advisable in these patients.

[Urogenital chlamydial infections in women and men]. / Urogenitale Chlamydieninfektionen bei Frau und Mann.

Genital infections with Chlamydia trachomatis occur in all social groups in Germany. About 100,000 German women are sterile because of tubal scarring due to chlamydiae. Genital chlamydial infections are asymptomatic in 70% of patients, even if salpingitis occurs. Typical symptoms of chlamydial infection are purulent cervicitis with vaginal discharge, painful cervical bleeding because of endometritis, lower abdominal pain with dyspareunia, and upper abdominal pain because of perihepatitis. DNA amplification tests on first voided urine or cervical swab are the most sensitive routine tests. Specific serum antibodies to C. trachomatis indicate a previous infection in sterile women. For treatment, a 10-14 day course of doxycycline 200 mg daily or a macrolide antibiotic in the patient as well as in the sexual partner is recommended. In the male, C. trachomatis causes urethritis and epididymitis. Opinions differ about involvement of the prostate gland and seminal vesicles. Identification of C. trachomatis antigen or DNA in the accessory gland secretions is not sufficiently reproducible. The two vectors are easily diagnosed in urethral swabs or in urine. The occurrence of chlamydial antibodies in serum or in seminal fluid is not a sign of current infection. Reliable studies which indicate a reduced fertility of men infected with C. trachomatis are not available.

Male breast cancer--an andrological disease: risk factors and diagnosis.

Gynaecomastia, the enlargement of the male breast, is considered as an andrological disease. To date, a review on male breast cancer (MBC) has not been published in an andrological journal. The papers underlying this review were published from authors of different institutions: Clinical Genetics, Dermatology, Gynaecology, Internal Medicine, Oncology, Pathology, Psychiatry, Radiology and Surgery. MBC accounts for approximately 1% of breast cancer patients. A total of 182 men died of breast cancer in 1999, in Germany. In the US, 1500 new cases per year occur. MBC accounts for <5% of surgically removed breast lumps. Diseases with increased oestrogen action increase the risk of MBC. Mutations of distinct genes are estimated to account for up to roughly 10% of MBC. BRCA1 and BRCA2 gene mutations are responsible for approximately 80% of the families with hereditary breast cancer. The diagnosis of MBC is not possible without histological examination. Different diagnostic procedures such as clinical diagnosis, sonography, mammography, fine-needle biopsy and core needle facilitate the decision whether a biopsy is necessary.

[Testosterone substitution in aging males. Which questions are answered?]. / Testosteronsubstitution beim alternden Mann. Welche Fragen sind beantwortet?

Testosterone effects different organs. Thus, a substitution of testosterone in the case of hormone deficiency seems plausible. By analysing 61 randomized studies, we demonstrated that in men older than 65 years there is an increase in bone mass (but not a decrease in fracture risk), an increase in lean body mass, and an increase in erythropoiesis. Changes in cardiovascular parameters, serum lipids, muscle mass, sexual functions, cognition and mood, however, are not clearly proven. The prostate is not negatively influenced. The lack of clear hazards from testosterone substitution in the aging male does not indicate unrestricted treatment safety. Until all doubts are cleared, each treatment should be carefully documented and monitored.

Levels of interleukin-6 and interleukin-8 in seminal fluid of men attending an andrological clinic.

The presence of interleukins (IL) and other cytokines in seminal plasma was demonstrated in the literature. In particular, the levels of IL-6 were found to be related to male accessory gland inflammation. The close correlation to leucocyte count indicates a production of interleukins from the leucocytes and by the prostate gland. No relation of IL-6 levels to spermatogenic activity was quoted in the literature. We measured IL-6 and IL-8 in 454 men and compared the values with seminal parameters. The mean values of IL-6 30.7 +/- 101.2 pg ml-1 and IL-8 2023 +/- 1721 pg ml-1. The correlation analysis revealed a significant correlation of IL-6 and/or IL-8 to age, total fructose, immunoglobulin G (IgG) concentration and leucocyte count. The significant correlation of IL-6 and fructose levels indicates that also the seminal vesicles take part in the production of seminal IL-6. No correlation of the two interleukins measured to sperm parameters occurred. The calculation of a single harmonic trend revealed a significant trend over the year of the levels of IL-6 with a maximum in December and a peak-to-trough variation of 33% of the mean. It may be the consequence of a higher frequency of seminal tract inflammations in autumn and winter.

Measurement of steroid levels in saliva in a population-based survey of lifestyle, medical conditions, marriage, sex life and hormone status in aging men: a feasibility study.

Some population-based studies on male aging measure testosterone and cortisol in saliva instead of serum, but very few measure estradiol and dehydroepiandrosterone sulfate (DHEA-S), suggesting further testing is needed for reliability and comparative validity. In addition, the effects of interview stress and circadian hormone secretion need to be checked. In a pilot study on the overall sexual capacity of aging men, 48 randomly selected, healthy, heterosexual, cohabiting men aged 50-80 years, from Mannheim, Germany, and 50 from the State College, Pennsylvania, USA, were administered a standardized interview covering medical biography, present and previous life and work, marriage and emotional status. Two saliva samples were collected from each subject for measurement of testosterone, cortisol, estradiol and DHEA-S levels before and after the interview, and each subject completed a confidential self-administered questionnaire on intercourse, masturbation, orgasm, fantasies, libido and arousal. Questionnaires, hormone measurement techniques and the survey protocol had been extensively pretested. Prior to the pilot study, the kits for measuring testosterone and DHEA-S in saliva were checked for comparative validity against established measuring techniques in serum in 31 cases for testosterone and in 24 different cases for DHEA-S. These 55 cases underwent clinical diagnosis and were not otherwise involved in this study. The cases had been referred to the Andrology Unit of the University Hospital, Marburg, for reasons unrelated to this study. Given the biological differences for both steroids between their presence in blood and in saliva, a perfect correspondence between the two values was not expected and was not observed. The correlations obtained, however, support the assumption that all statistical relationships between testosterone and DHEA-S values in serum and clinical, as well as behavioral, variables reported to date may be replicated for testosterone and DHEA-S values in saliva.

Dy-EOB-DTPA: tolerance and pharmacokinetics in healthy volunteers and preliminary liver imaging in patients.

RATIONALE AND OBJECTIVES: To investigate the tolerance and pharmacokinetics of the new liver-specific x-ray contrast agent Dy-EOB-DTPA [(4S)-4-(4-ethoxybenzyl)-3,6,9-tris(carboxylatomethyl)-3,6,9-triazaundecanedioic acid, dysprosium (Dy) complex, disodium salt] in healthy volunteers and to obtain preliminary imaging data by abdominal spiral computed tomography (CT) in tumor patients with liver metastases. METHODS: A total of 40 healthy male volunteers received 10-minute intravenous infusions of 0.05, 0.1, 0.25, 0.375, or 0.5 mmol/kg Dy-EOB-DTPA (n = 6 per dose group) or placebo (n = 10). Blood, urine, and feces were sampled for Dy measurements by inductively coupled plasma atomic emission spectrometry (ICP-AES) and for the detection of possible metabolites by high-performance liquid chromatography analysis with ICP-AES detection. Safety parameters were determined before, during, and after the study. Two patients with suspected liver metastases first received 120 mL of iopromide (300 mg iodine/mL; approximately 0.6 mmol/kg) and, 24 or 72 hours later, Dy-EOB-DTPA at a dose of 0.25 mmol/kg. Computed tomography images were obtained 50 seconds after iopromide administration and before and 90 minutes after Dy-EOB-DTPA administration. RESULTS: Dysprosium-EOB-DTPA was well tolerated. At the higher doses (0.375 and 0.5 mmol/kg), there was a slight increase in side effect intensity. In general, nausea, headache, and paresthesia mainly were reported as mild to moderate adverse events. Laboratory parameters did not exceed the normal range. Electrocardiographic, vital sign, or hemodynamic parameters were not affected by contrast agent administration. The terminal half-life of elimination of Dy-EOB-DTPA was approximately 1.5 hours, total clearance was 2 to 3 mL x min(-1) x kg(-1), and the renal clearance was approximately 1.5 mL x min(-1) x kg(-1). There was a significant dose dependence for the following parameters: maximal concentration in blood, terminal half-life, mean residence time, total clearance, urinary excretion, and fecal excretion. The volume of distribution in the steady state and renal clearance were not dependent on dose. In the blood and urine, no metabolites of Dy-EOB-DTPA could be detected. In the tumor patients, CT scanning after Dy-EOB-DTPA injection increased the number of detected metastases from 27 (plain scan) to 40 (iopromide) and then to 41 (Dy-EOB-DTPA) in patient No. 1 and from 1 (plain scan and iopromide) to 3 (Dy-EOB-DTPA) in patient No. 2. CONCLUSIONS: Dysprosium-EOB-DTPA was shown to be a well-tolerated liver-specific contrast agent. Its pharmacokinetic profile is characterized by a terminal half-life of approximately 1.5 hours. There are indications of saturation of liver uptake at the highest dose level of 0.5 mmol/kg. In comparison with plain scans and scans performed after iodinated contrast agent administration, Dy-EOB-DTPA seems to increase the number of detectable liver lesions.

Comparison of normal sperm morphology outcomes from two different computer-assisted semen analysis systems.

By eliminating the human evaluation variable, it was possible to carry out an investigation into the 'true' association between normal sperm morphology outcomes assessed according to the World Health Organization guidelines and strict criteria. Two computer-assisted semen analysis systems were used, IVOS and Mika, to evaluate Diff-Quik and Papanicolaou stained slides. As expected, the mean normal sperm morphology outcomes for the World Health Organization classification evaluations were markedly higher for both the Diff-Quik (mean difference = 40.13%) and the Papanicolaou (mean difference = 32.55%) stained slides. The association between the outcomes were low for the Diff-Quik stained slides (r = 0.379) and poor for the Papanicolaou stained slides (r = 0.110). While the association achieved with the computer-assisted semen analysis systems using Diff-Quik stained slides was comparable to the association between the manual evaluations (r = 0.386), the manual evaluation of Papanicolaou stained slides produced a relatively good association (r = 0.690). Although the numbers were small, the results show the probability of poor class correlations. Approximately 40% of outcomes were incorrectly classed at a 14% (strict criteria) and 50% (World Health Organization guidelines) cut-off point for both staining methods. This study confirms the fundamental differences between the two classification systems. The results also indicate that, of the two stains used, Diff-Quik should be the preferred staining method for computer-assisted sperm morphology evaluations.

Isolation and identification of sperm membrane antigens recognized by antisperm antibodies, and their possible role in immunological infertility disease.

Antisperm antibodies (ASA) are the main cause of immunological infertility, as they impair sperm function by binding to the sperm membrane. In this study, we isolated highly enriched sperm membrane proteins by two-dimensional (2D) gel electrophoresis. Isoelectric focusing, as a first dimension, was performed on precast DryStrip IPG 4-7. The second dimension was carried out on 12% sodium dodecyl sulphate-polyacrylamide gels. A total of 18 antigens were identified by the subsequent 2D Western blotting using ASA from seminal plasma samples of infertile patients. Six of the recognized proteins were isolated and analysed by means of mass spectrometry and peptide matching. They were identified as heat shock proteins HSP70 and HSP70-2, the disulphide isomerase ER60, the inactive form of caspase-3 and two subunits of the proteasome (component 2 and zeta chain). The biochemical identification of these proteins will be helpful in understanding the mechanisms by which ASA impair both sperm function and fertilization. Thus, these proteins may also be useful in the development of reliable methods for ASA detection.

The molecular basis for prevention of colorectal cancer.

Colorectal cancer is the second leading cause of cancer death in the United States. Despite aggressive treatment and early screening strategies, the prognosis for patients with advanced disease remains poor. Extensive research examining familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC), two common forms of inherited colorectal cancer, have provided invaluable insights into some of the molecular mechanisms underlying both familial, as well as nonfamilial, colorectal cancer. The molecules involved in these pathways may provide effective targets for prevention and/or treatment of colorectal cancer. These targets include cyclooxygenase-2 (COX-2), peroxisome proliferator-activated receptor (PPAR)-delta, PPAR-gamma, transforming growth factor-beta receptor type II, epidermal growth factor receptor, and inducible-nitrous oxide synthase.

Prostacyclin-mediated activation of peroxisome proliferator-activated receptor delta in colorectal cancer.

There is evidence from both genetic and pharmacologic studies to suggest that the cyclooxygenase-2 (COX-2) enzyme plays a causal role in the development of colorectal cancer. However, little is known about the identity or role of the eicosanoid receptor pathways activated by COX-derived prostaglandins (PG). We previously have reported that COX-2-derived prostacyclin promotes embryo implantation in the mouse uterus via activation of the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR) delta. In light of the recent finding that PPARdelta is a target of beta-catenin transactivation, it is important to determine whether this signaling pathway is operative during the development of colorectal cancer. Analysis of PPARdelta mRNA in matched normal and tumor samples revealed that expression of PPARdelta, similar to COX-2, is up-regulated in colorectal carcinomas. In situ hybridization studies demonstrate that PPARdelta is expressed in normal colon and localized to the epithelial cells at the very tips of the mucosal glands. In contrast, expression of PPARdelta mRNA in colorectal tumors was more widespread with increased levels in transformed epithelial cells. Analysis of PPARdelta and COX-2 mRNA in serial sections suggested they were colocalized to the same region within a tumor. Finally, transient transfection assays established that endogenously synthesized prostacyclin (PGI(2)) could serve as a ligand for PPARdelta. In addition, the stable PGI(2) analog, carbaprostacyclin, and a synthetic PPARdelta agonist induced transactivation of endogenous PPARdelta in human colon carcinoma cells. We conclude from these observations that PPARdelta, similar to COX-2, is aberrantly expressed in colorectal tumors and that endogenous PPARdelta is transcriptionally responsive to PGI(2). However, the functional consequence of PPARdelta activation in colon carcinogenesis still needs to be determined.

Bone marrow transplantation for infantile ceramidase deficiency (Farber disease).

Infantile ceramidase deficiency (Farber disease) is an uncommon, progressive lysosomal storage disease characterized by multiple ceramide-containing nodules (lipogranulomata) in the subcutaneous tissue and upper aerodigestive tract, painful periarticular swelling, psychomotor retardation, and varying degrees of ocular, pulmonary or hepatic involvement. Management of Farber disease has been limited to symptomatic supportive care, and few affected infants survive beyond 5 years of age. We performed an allogeneic bone marrow transplant (BMT) from an HLA-identical heterozygous sister in a 9.5-month-old female with minimally symptomatic Farber disease who received a pre-transplant regimen of busulfan and cyclophosphamide. Ceramidase activity in peripheral blood leukocytes increased from 6% before transplant to 44% (donor heterozygote level) by 6 weeks after BMT. By 2 months after transplant, the patient's subcutaneous lipogranulomata, pain on joint motion, and hoarseness had resolved. Despite modest gains in cognitive and language development, hypotonia and delayed motor skills persisted. Gradual loss of circulating donor cells with autologous hematopoietic recovery occurred; VNTR analyses showed 50% donor DNA in peripheral blood cells at 8.5 months after BMT and only 1% at 21 months after transplant. Interestingly, leukocyte ceramidase activity consistently remained in the heterozygous range despite attrition of donor cells in peripheral blood. This novel observation indicates ongoing hydrolase production by non-circulating donor cells, possibly in the mononuclear phagocytic system, and uptake by recipient leukocytes. Although lipogranulomata and hoarseness did not recur, the patient's neurological and neurocognitive status progressively declined. She died 28 months after BMT (age 37.5 months) with pulmonary insufficiency caused by recurrent aspiration pneumonias. Allogeneic BMT improves the peripheral manifestations of infantile ceramidase deficiency, but may not prevent the progressive neurological deterioration, even when carried out in minimally symptomatic patients.

Eicosanoids and the large intestine.

During the past three decades, many studies have been conducted to determine the precise role of eicosanoids in colorectal physiology and pathophysiology. This research has increased our understanding of bioactive lipid signaling, and may contribute to the development of more effective therapeutic modalities for digestive diseases in the future. The purpose of this report is to provide a brief overview of the role of eicosanoids in the colon and rectum. This information has been organized according to both functional and disease-related categories. The role of eicosanoids in colonic secretion, motility, inflammatory bowel disease, and colorectal neoplasia will be discussed.

Mechanisms of guanylin action via cyclic GMP in the kidney.

Guanylin, uroguanylin, and lymphoguanylin are small peptides that activate cell-surface guanylate cyclase receptors and influence cellular function via intracellular cGMP. Guanylins activate two receptors, GC-C and OK-GC, which are expressed in intestine and/or kidney. Elevation of cGMP in the intestine elicits an increase in electrolyte and water secretion. Activation of renal receptors by uroguanylin stimulates urine flow and excretion of sodium, chloride, and potassium. Intracellular cGMP pathways for guanylins include activation of PKG-II and/or indirect stimulation of PKA-II. The result is activation of CFTR and/or C1C-2 channel proteins to enhance the electrogenic secretion of chloride and bicarbonate. Similar cellular mechanisms may be involved in the renal responses to guanylin peptides. Uroguanylin serves as an intestinal natriuretic hormone in postprandial states, thus linking the digestive and renal organ systems in a novel endocrine axis. Therefore, uroguanylin participates in the complex physiological processes underlying the saliuresis that is elicited by a salty meal.

Relation of sexual dysfunction to hormone levels, diseases and drugs used in andrological patients.

In 169 patients visiting our department complaining of sexual dysfunction, the medical history was taken using a semistructured interview. A clinical investigation and a hormone analysis were added. The age of patients, hormone values, and items of the interview were collected into a common database. The items were categorized as either dichotomous (yes/no) or ordinal. Statistical analysis was performed using regression analysis with the aim to generate hypotheses of relations. An increase of FSH levels and a decrease of testosterone levels with age occurred. None of the relations of hormone levels or diseases to symptoms of sexual dysfunction produced odds ratios (OR) statistically significant different from 1. However, the risk of having a reduced libido and reduced morning erections was lower in psychoneurological diseases, the risk of reduced arousal and libido was lower in men with diabetes mellitus, but the risk of reduced morning erections was higher in these men. The testosterone levels were not associated with the risk of having reduced penile rigidity, duration of erection, arousal and sexual libido, reduced morning erections and the ability to masturbate. Smoking was not associated with reduced arousal, libido and morning erections. However, a significant increase of testosterone levels with number of cigarettes used was observed. We conclude that sexual dysfunction in patients visiting an andrological department for diagnosis and treatment is mostly not associated to any single evaluable factor.

Neutral endopeptidase and alcohol consumption, experiments in neutral endopeptidase-deficient mice.

Alcohol consumption was investigated in mice which were rendered deficient in the peptide-degrading enzyme neutral endopeptidase (EC 3.4.24.11) (NEP-/-) by gene targeting and compared to alcohol consumption in corresponding wild type mice (NEP+/+). Mice were offered a free choice to drink tap water or 10% alcohol. The NEP-/- mice consumed significantly more alcohol ( approximately 42%) than the NEP+/+ mice, whereas no significant differences were observed in the total fluid consumption. The daily food consumption of alcohol naive NEP-/- animals was elevated ( approximately 29%). Furthermore, the activities of peptidases closely related to neutral endopeptidase were analysed ex vivo in several brain regions from NEP-/- and NEP+/+ mice not treated with alcohol. There was no obvious compensation for the total loss of neutral endopeptidase by the functionally related peptidases angiotensin-converting enzyme and aminopeptidase N. In vitro, the degradation of exogenously applied [Leu(5)]enkephalin was not reduced in membrane preparations of those brain regions assayed in NEP-/- mice. A small reduction in [Leu(5)]enkephalin degradation was detected in striatal membrane preparations of NEP-/- mice, if aminopeptidase N was additionally blocked by bestatin or amastatin.