Ahmed Mahmoud

Endogenous testosterone and cardiovascular disease in healthy men: a meta-analysis

Context The literature provides no clear answer as to whether low endogenous testosterone increases risk of cardiovascular disease (CVD) in healthy men. Objective Our purpose was to estimate the predictive value of testosterone for CVD and to identify study features explaining conflicting results. Data Sources Articles were identified by a Medline and Embase search and citation tracking. Study Selection Eligible were prospective population-based cohort and nested case-control studies of testosterone and atherosclerosis, stroke, myocardial infarction, ischaemic heart disease, death from coronary heart disease or mortality. Data extraction Two independent researchers re-expressed associations of testosterone and CVD in a uniform manner to be used in meta-regression analyses for identification of study features explaining conflicting results, and to estimate the predictive value of testosterone for CVD. Results and Conclusions 19 potentially eligible articles were identified. Overall, a weak independent association was found with an estimated summary RR of 0.89 for a change of one standard deviation in total testosterone level (95% CI 0.83 to 0.96). Age of study population and year of publication modified the relationship between testosterone and CVD. The estimated summary RR was 1.01 (0.95 to 1.08) for studies of men younger than 70 years of age, and 0.84 (0.76 to 0.92) for studies including men over 70 years of age. The latter studies showed a particular pronounced association if published after 1 January 2007. Results were largely confirmed by separate analyses of free- and bioavailable testosterone. The systematic review displayed no association between endogenous testosterone and risk for CVD in middle-aged men. In elderly men, testosterone may weakly protect against CVD. Alternatively, low testosterone may indicate a poor general health.

The role of food supplements in the treatment of the infertile man

Recently, concerns have been raised about the presumptive increased risk of serious undesirable side effects in children born after IVF and intracytoplasmic sperm injection (ICSI). These treatments must, therefore, be reserved as the ultimate option after evidence-based and cause-directed treatment of the male patient with deficient semen has been exhausted. The present authors found that sperm quality and function improved with the intake of complementary food supplementation using a combination of zinc and folic acid, or the antioxidant astaxanthin (Astacarox), or an energy-providing combination containing (actyl)-carnitine (Proxeed). Also, double blind trials showed that the latter two substances increase spontaneous or intrauterine insemination- (IUI-) assisted conception rates. Extracts of Pinus maritima bark (Pycnogenol), which inhibits the cyclo-oxygenase enzyme, reducing prostaglandin production and inflammatory reaction, and extracts of the Peruvian plant Lepidium meyenii were shown to improve sperm morphology and concentration, respectively, in uncontrolled trials. Linseed (flaxseed) oil contains alfa-linolenic acid and lignans. The former corrects the deficient intake of omega-3 essential fatty acids, which is correlated with impaired sperm motility among subfertile men. Lignans are precursors of enterolacton, which inhibits aromatase and reduces the ratio of 16-OH over 2-OH oestrogen metabolites. The resulting reduction in oestrogen load may favourably influence Sertoli cell function.

Chronic prostatitis and male accessory gland infection--is there an impact on male infertility (diagnosis and therapy)?

The aim of this article was to discuss by means of a review of the literature and own study material the multifactorial aetiology of male infertility, extrapolate this hypothesis to male accessory gland infection (MAGI) and relate it to chronic prostatitis and its treatment. Infertility is a multifactorial disease and diagnosis and therapy must be oriented as such. Although the relationship between prostatitis and infertility remains unclear, bacteria, viruses, leucocytes, reactive oxygen species, cytokines, obstruction and immunological abnormalities must be seen as cofactors in the development of infertility in patients with MAGI and prostatitis. Infection, trauma, allergy, neurogenic damage, chemical or mechanical factors can lead to a long‐lasting inflammation of the prostate or pelvic organs even after eradication of the aetiological agent, and is potentially related to infertility through cytokines. In relation to treatment of infertility, antibiotics play a role in bacterial prostatitis whereas in abacterial prostatitis other treatments like antioxidants, sacral nerve stimulation and anti‐inflammatory treatment are worth to be studied in the future.

Short-term aromatase inhibition: effects on glucose metabolism and serum leptin levels in young and elderly men.

OBJECTIVE To assess and compare the effects of short-term aromatase inhibition on glucose metabolism, lipid profile, and adipocytokine levels in young and elderly men. DESIGN AND METHODS Ten elderly and nine young healthy men were randomized to receive letrozole 2.5 mg daily or placebo for 28 days in a crossover design. RESULTS Both in young and elderly men, active treatment significantly increased serum testosterone (+128 and +99%, respectively) and decreased estradiol levels (-41 and -62%, respectively). Fasting glucose and insulin levels decreased in young men after active intervention (-7 and -37%, respectively) compared with placebo. Leptin levels fell markedly in both age groups (-24 and -25%, respectively), while adiponectin levels were not affected by the intervention. Lipid profile was slightly impaired in both groups, with increasing low density lipoprotein-cholesterol levels (+14%) in the younger age group and 10% lower levels of APOA1 in the elderly. A decline in IGF1 levels (-15%) was observed in the younger age group. No changes in weight or body mass index were observed in either young or old men. CONCLUSIONS Short-term aromatase inhibition appears to affect glucose metabolism in young men, and lipid metabolism, including leptin secretion, in young and elderly men. Furthermore, the short period of exposure suggests that these changes might be mediated by direct effects of sex steroids rather than by changes in body composition.

Long term effects of micro-surgical testicular sperm extraction on androgen status in patients with non obstructive azoospermia

BackgroundThe aim of our study was to review the results of microsurgically performed testicular sperm extraction (TESE) and to evaluate its possible long term effects on serum testosterone (T).MethodsWe operated on 48 men (35 +/- 8 years) with non-obstructive azoospermia (NOA). If no spermatozoa were found following a micro epididymal sperm extraction (Silber et al., 1994) and testicular biopsy, testicular microdissection was performed or multiple microsurgical testicular biopsies were taken. The mean follow-up of the serum T was 2.4 +/- 1.1 years.ResultsSperm was retrieved in 17/48 (35%) of the men. The per couple take home baby rate if sperm was retrieved was 4/17 (24%). Serum T decreased significantly at follow-up (p < 0.05) and 5/31 (16%) de novo androgen deficiencies developedConclusionIn patients with non-obstructive azoospermia in whom no spermatozoa were found following a micro epididymal sperm aspiration and a simple testicular biopsy, we were able to retrieve spermatozoa in 35% of the men. The take home baby rate was 24% among couples with spermatozoa present upon TESE. De novo androgen deficiency occurred in 16% of the male patients following TESE indicating that, in men with NOA, long term hormonal follow up is recommended after TESE.

Preventing diseases of the prostate in the elderly using hormones and nutriceuticals.

The prostate has only one function, namely to secrete fluid containing substances that are needed for reproduction. This requires an extremely high concentration of androgens in the tissues. Benign prostatic hypertrophy (BPH) seems to be related to the long-term exposure of the prostate to the strong androgen 5α-dihydrotestosterone (DHT) and, possibly, to estrogens. The relation between prostate cancer and androgens is suggested to be U-shaped, with both extremes of androgen concentrations being associated with increased risk of invasive cancer. In the treatment of patients with BPH, the lipidic liposterolic extracts of Serenoa repens were as effective as the pharmaceutical inhibitors of the 5α-reductase enzyme or α1-adrenergic blockers in relieving urinary symptoms. In addition to moderately inhibiting the 5α-reductase activity, Serenoa seems to exert anti-inflammatory and complementary cellular actions with beneficial effects on the prostate. Unlike the pharmaceutical 5α-reductase inhibitors, finasteride and dutasteride, Serenoa does not suppress serum PSA, facilitating the follow-up and the early detection of prostate cancer. We suggest a strategy to prevent prostate cancer that aims at providing men with partial androgen deficiency correct testosterone substitution with a sustained release buccal bio-adhesive tablet. In addition, food supplementation with extracts of Serenoa repens and a combination of the antioxidants selenium, (cis)-lycopene and natural vitamin E, together with fish oil rich in long-chain polyunsaturated essential fatty acids of the omega-3 group seems warranted. Clearly, a holistic approach including careful clinical and biological monitoring of the aging man and his prostate remains mandatory.

Mechanisms of Disease: late-onset hypogonadism

Late-onset hypogonadism (formerly called the andropause) is a clinical and biochemical syndrome associated with advancing age, which is characterized by typical signs and symptoms and a deficiency in serum testosterone levels. Age-related hypoandrogenism in the male is a result of the interaction of hypothalamopituitary and testicular factors. The hypothalamic pulsatile secretion of gonadotropin-releasing hormone is blunted, due to increased hypothalamic sensitivity to inhibition by steroids, but the responsiveness of the pituitary gonadotrophs seems to be intact. In addition, testicular volume as well as Leydig cell mass and reserve function are diminished. Taken together, these mechanisms result in reduced testosterone secretion and the loss of nycthemeral variability.

Fifteen years of Belgian experience with external quality assessment of semen analysis

Semen analysis is difficult to standardize, quality control and quality assurance are necessary to ensure that results are accurate and precise. This Belgian EQA survey over a 15‐year period, involving 121 laboratories, attempted to reduce interlaboratory variability and at the same time, encouraged participating laboratories to implement correct techniques as advised by the WHO. Over the total period, the median coefficient of variation (CV) for sperm count, irrespective of the method used was 19.2%, while using improved Neubauer chamber resulted in a significantly (p < 0.001) lower median CV (14.4%). The overall median CV for rapid progressive motility was high (37.1%), but progressive motility (15.1%) and total motility (13.8%) were acceptable. Sperm morphology revealed a large variability in 79.4% irrespective of the staining procedures or evaluation criteria used. Participation in the Belgian EQA is on voluntary basis. Both, participation and implementation of the correct techniques should be made mandatory for accreditation and benefit of patient treatment. The existing Belgian EQA program should now be harmonized with other existing EQA schemes in Europe.

Which efforts towards conservative treatment of male infertility will be successful? Reactive oxygen species, antioxidants, and sperm phospholipids

Polymorphonuclear white blood cells in semen and, to a lesser extent, incompletely matured spermatozoa generate excess reactive oxygen species (ROS), mostly hydrogen peroxide and nitric oxide. Due to their paucity in cytoplasm and antioxidant mechanisms, spermatozoa have little defence against these ROS, which damage their membrane and DNA (Fig. 1). The former results in a lower proportion of polyunsaturated fatty acids, mainly docosohexaenoic acid (2256v3), with increased mean melting point and decreased fluidity of the membrane, particularly of the sperm head (Zalata et al., 1998). As a consequence, sperm acrosome reaction and fusogenic capacity are inhibited, causing decreased probability of conception, lower success rate of Figure 1. Overview of the effects of ROS and the alleged protective influence of antioxidants. intra-uterine insemination (IUI) (Milingos et al., 1996) and of conventional IVF (Aitken, 1989). included antibiotics in case of documented infection Damage to sperm DNA may result in transition of the accessory sex glands, spermatic venous mutagenesis whereby the oxidized product of embolization in case of varicocele, or Tamoxifen the nucleotide guanine (8-OH-2-deoxyguanosine) (Zambon) for idiopathic oligozoospermia. binds to thymine instead of cytosine (C5G conSperm concentration increased significantly verting to A5T). When spermatozoa with damaged in cases with initial oligozoospermia (<20 DNA are introduced into oocytes during ICSI, million ml−1, P<0.01), and the concentration of genetic disturbance may occur in the offspring if peroxidase-positive round cells (polymorphonuthe repair mechanisms are insufficient. clear white blood cells) remained unchanged. In Antioxidant treatment may reduce the oxidative 21 out of 22 cases ROS was decreased during damage and it may increase the in vivo and in vitro treatment to 16% of the initial value (P<0.001). fertility of spermatozoa, as well as their relative In parallel, the concentration of 8-OH-2-deoxysafety for use in ICSI. We have performed a pilot guanosine was decreased to 37% of the value study treating subfertile patients with either oral before treatment (P<0.001) and, in addition, the acetyl-cysteine (gift of Zambon, Brussels, Belgium) calcium–ionophore-induced acrosome reaction and/or a mixture of essential fatty acids (rich in increased significantly (P<0.01). docosohexaenoic acid) and natural vitamins A and Five couples out of 22 with adequate follow-up E (gift of Scotia, Stirling, Scotland) as a complement of 5.4 months (median) achieved pregnancy, correto conventional medical treatment. The latter sponding to a fecundability of 3.5% per cycle, as compared with 1.2% per cycle in historically Correspondence: F. Comhaire, Department of Endocrinology and Centre for Andrology, University Hospital Gent, Belgium. untreated or placebo-treated controls.

Male Reproductive Status and Its Relationship With Man-Made, Hormone-Disrupting Substances: Studies in Flanders, Belgium

Sperm quality seems to have declined over time in certain regions in the world. This regional trend coincides with the progressive increase in the incidence of male genital tract anomalies including testicular maldescent, hypospadias and testicular cancer. The association of these pathologies has been called the ‘testicular dysgenesis syndrome’ (TDS). The possible implications of decreased male fertility cannot be underestimated. Couples attending fertility clinics have a higher chance of multiple pregnancies, preterm delivery and consequently also of low birth weight, which is a known risk factor for a number of pathological conditions at adulthood. Many studies suggest TDS to be caused by man-made endocrine disrupters, mostly chemicals initiating estrogen actions (xenoestrogens) or inhibiting the effects of endogenous androgens (anti-androgens). Thousands of man-made chemicals have been released into the environment in vast quantities since the chemical industry began to boom in the 1950’s. Humans and wildlife are exposed to these chemicals through their nutrition, the air, the water and, more importantly, through the placenta during foetal development. In order to reliably estimate the reproductive health risks posed by these chemicals, scientific programmes should pursue the identification of the routes via which humans and wildlife are exposed to these xenobiotics using biomarkers of internal and external exposure. These are new and important tools, complementary to the traditional chemical analytical techniques as they reflect the integrated response of an individual or test organism to multiple compounds, accounting for possible additive, antagonistic or synergistic effects.