S. Zarrilli

Hyperprolactinemia in men: clinical and biochemical features and response to treatment.

Hyperprolactinemia induces hypogonadism by inhibiting gonadotropin-releasing hormone pulsatile secretion and, consequently, follicle-stimulating hormone, luteinizing hormone, and testosterone pulsatility. This leads to spermatogenic arrest, impaired motility, and sperm quality and results in morphologic alterations of the testes similar to those observed in prepubertal testes. Men with hyperprolactinemia present more frequently with a macroadenoma than a microadenoma. Symptoms directly related to hypogonadism are prevalent. In men hypogonadism leads to impaired libido, erectile dysfunction, diminished ejaculate volume, and oligospermia. It is present in 16% of patients with erectile dysfunction and in approx 11% of men with oligospermia. Treatment with bromocriptine or cabergoline (CAB) is effective in men with prolactinomas, with a response that is in general comparable to treatment in women. Seminal fluid abnormalities rapidly improve with CAB treatment, while other dopaminergic compounds require longer periods of treatment. Moreover, to improve gonadal function in men, the integrity of the hypothalamic-pituitary-gonadal axis is necessary. New promising data indicate that a substantial proportion of patients with either micro- or macroprolactinoma do not present hyperprolactinemia after long-term withdrawal from CAB. Whether this corresponds to a definitive cure is still unknown, but treat-ment withdrawal should be attempted in patients achieving normalization of prolactin levels and disappearance of tumor mass to investigate this issue.

Estrogens and health in males

Estrogen receptor concentrations are higher in the male reproductive tract than in other organs. Brain structure, neuronal organization and behavioral sex differences result from brain conversion of testosterone into estradiol within the brain. Estrogens modulate hormonal secretion at pituitary level and immune function at thymus level. Estrogens promote vasodilatatory and protective effects on the cardiovascular system by acting on the vascular smooth muscle and endothelium. Adult men with mutations in genes for estrogen receptor or aromatase are affected by osteopenia and tall stature, open epiphysis, which is corrected by estrogen treatment. Over the past few years there has seen a decline in sperm concentration, which has been attributed to exposure of fetal testes to estrogens. Many substances have estrogen-like properties and inhibit the action of estradiol or testosterone action. In conclusion, estrogens play a pivotal role in men also. In particular, taking in account their prevalent origin from testosterone aromatization at tissue and peripheral levels the presence and the distribution of the two receptors (ERalpha and ERbeta) are responsible for different responses in physiological and pathological conditions.

PRL Secreting Adenomas in Male Patients

Prolactinomas are the most frequent pituitary tumors and their frequency varies with age and sex, occurring most frequently in females between 20–50 yr-old. In men, hyperprolactinaemia is often present for many years without symptoms, as generally the most important symptoms are the decrease in libido and/or sexual potency both underestimated by the majority of the patients. Prolactin (PRL) plays a role in the process of spermatogenesis, and normal serum PRL levels are required for normal testicular function. On the other hand, hyperprolactinaemia has multiple negative effects on the gonadal axis. As a consequences hyperprolactinemic males show alteration of sexual potency and seminal fluid quality. Cabergoline treatments is able to induce normalization of PRL levels and a reduction of tumor mass in the majority of patients and consequently restoring the normal semen quality and ameliorating the quality of life of men with pituitary PRL-secreting adenoma.

Correlation between Seminal Carnitine and Functional Spermatozoal Characteristics in Men with Semen Dysfunction of Various Origins

AbstractBackground and objective: L-carnitine is an essential molecule involved in mitochondrial metabolism, controlling the transport of acetyl and acyl groups across the mitochondrial inner membrane. Carnitine and acetylated carnitine (L-acetylcarnitine) are found in high concentrations in the epididymis, where they also act as antioxidants, protecting spermatozoa against damage caused by reactive oxygen species. In this open study we investigated the correlation between seminal carnitine levels and spermatozoal function, and the effect of combined L-carnitine + L-acetylcarnitine therapy, in infertile men. Patients and methods: 170 infertile men were enrolled in this study. Patients were divided into those with a total sperm motility below the normal WHO range (<50% motility, group 1 [n = 102]) and those with total sperm motility within the normal range (>=50% motility, group 2 [n = 68]). Patients in group 1 were further divided into two groups: those with primary or secondary azoospermia (1B [n = 36]), and those without (1A [n = 66]). Patients in group 1A received L-carnitine 1 g/day and L-acetylcarnitine 500mg twice daily for 6 months. Seminal carnitine levels were measured and correlated with sperm count and motility, eosin test, hypo-osmotic swelling test, acridine orange test for sperm nuclear DNA integrity and sperm kinetics evaluated by computer-assisted sperm analysis in all patients. Results: There was a significant correlation between seminal carnitine concentration and sperm concentration, total sperm count, sperm total motility, rapid forward progression, live sperm count, membrane function, nuclear DNA integrity, capacity for cervical mucus penetration, linearity of spermatic movement, and amplitude of lateral sperm head movement (all p < 0.0001) in the entire study population. In group 1A, there was a significant increase in total motility, live sperm count, membrane integrity and linearity of spermatic movement after 3 and 6 months of L-carnitine/L-acetylcarnitine treatment, and in capacity for cervical mucus penetration after 6 months of treatment, compared with baseline. Conclusion: Seminal carnitine concentration may be an appropriate marker of sperm and epididymal function. L-carnitine/L-acetylcarnitine treatment may be an effective therapy to improve mainly functional seminal parameters.

Glutathione peroxidase (GPX) activity in seminal plasma of healthy and infertile males

Human spermatozoa are more dependent on glutathione peroxidase/glutathione reductase (GPX/GR) system, via reduced glutathione (GSH), to inactivate reactive oxygen metabolites (ROMs) such as hydrogen peroxide and organic hydroperoxides. To demonstrate whether there is a substantial difference in GPX activity between normal and pathological seminal plasma, we decided to evaluate the activity of this enzyme in healthy subjects and infertile males with normal hormonal patterns. Our results demonstrate that in healthy subjects the seminal plasma contains a GPX activity that is about 10 times greater than the GPX activity detected in the seminal plasma of infertile males. By using specific antibodies against plasmatic GPX (GPX3), we also demonstrate that enzymatic activity, detected in the seminal plasma of both healthy and infertile males is GPX3. Therefore, the evaluation of GPX activity in human seminal plasma could be a new useful marker of gonadal function in men.

Bone mineral density and bone markers in hypogonadotropic and hypergonadotropic hypogonadal men after prolonged testosterone treatment.

After prolonged treatment (76.4±10 and 70.1±12.3 months, respectively) (mean± SE) with testosterone enanthate (250 mg im every 3 weeks), bone mineral density (BMD) and bone metabolism were evaluated in 12 patients (aged 29.3±1.4 yr) affected by idiopathic hypogonadotropic hypogonadism (IHH), in 8 patients (29.6±2.6 yr) affected by Klinefelter’s syndrome (KS), and in 10 healthy men (30.6±1.7 yr) matched according to age and BMI. Spinal BMD in IHH was significantly lower than in controls (0.804±0.04 vs 1.080±0.01 g/cm2; p<0.001), while there was no difference in neck BMD (0.850±0.01 vs 0.948±0.02 g/cm2). Neither spinal (0.978±0.05 g/cm2) nor neck (0.892±0.03 g/cm2) BMD in KS were significantly different from controls. Six IHH and one KS subjects were osteoporotic, while 6 IHH and 2 KS subjects were osteopenic. A significant inverse correlation was found between spinal BMD and age at the treatment onset in IHH (r=−0.726, p=0.007). In IHH there were significant increases in bone formation (alkaline phosphatase=318.3±33.9 vs 205.4±20.0 IU/l; osteocalcin=13.44±1.44 vs 8.57±0.94 ng/ml; p<0.05) and in bone resorption (urinary cross-linked N-telopeptides of type I collagen= 149.1± 32.3 vs 47.07±8.4 nmol bone collagen equivalents/mmol creatinine; p<0.05) compared to controls, while such differences were not present in KS. Our results outline the importance of BMD evaluation in all hypogonadal males. Nevertheless, bone loss is a minor characteristic of KS, while it is a distinctive feature of IHH. Therefore, early diagnosis and age-related replacement therapy coupled with a specific treatment for osteoporosis could be useful in preventing future severe bone loss and associated skeletal morbidity.

The treatment with cabergoline for 24 month normalizes the quality of seminal fluid in hyperprolactinaemic males

Background  Alterations of sperm number and motility are found in hyperprolactinaemic men. Cabergoline treatment reverses alterations in semen. No information is currently available on the quality of seminal tests in hyperprolactinemia in response to cabergoline treatment.

Hormonal and seminal evaluation of Leydig cell tumour patients before and after orchiectomy.

Seven patients (aged 25–38 years) were admitted because of mono‐ or bilateral gynaecomastia. Plasma levels of follicle‐stimulating hormone (FSH), luteinizing hormone (LH), prolactin, testosterone, 17‐β‐estradiol, Δ4‐androstenedione, dehydropiandrosterone sulphate (DHEA‐S) and 17‐OH‐progesterone were determined and semen analysis was carried out. FSH and LH levels were also measured after acute LH‐RH administration (100 μg intravenously), and testosterone and 17‐β‐estradiol were also evaluated after acute human chorionic gonadotrophin (hCG) administration (5000 IU intramuscularly). Testicular echography demonstrated the presence of a solid hypoechoic tumour. Therefore all patients were submitted to hemicastration by orchidofuniculotomy and a benign Leydig cell tumour was diagnosed in the removed testes. Hormonal and semen evaluations were repeated 3, 6, 9 and 12 months after surgery. The data before and after surgery were compared with a control group of 10 age‐matched males. Before surgery, patients showed low FSH basal plasma levels; high levels of 17‐β‐estradiol and low testosterone levels similar to those after hCG administration. A dyspermia was observed. Unilateral orchidectomy eliminated the autonomous secretion of oestrogen(s) so an increase of LH, FSH and testosterone levels, together with an improvement of spermatogenesis, were obtained.

RNA expression Bcl-W, a new related protein Bcl-2 family, and caspase-3 in isolated Sertoli cells from pre-pubertal rat testes

Apoptosis has a major role in molding the embryo, in the maintenance of tissue homeostasis, and in the defense against pathogens, while its disgregulation is strongly implicated in cancer as well as in autoimmune and degenerative diseases. The opposite action of anti-apoptotic proteins (Bcl-2 family) and pro-apoptotic proteins (p53, Bax, Bak) regulates the activation of caspases that are the effectors proteases of the cell suicide. Bcl-W is a pro-survival protein, recently discovered, related to the Bcl-2 family. The presence of Bcl-W is fundamental for spermatogenesis in rats. Caspases are cysteine-dependent aspartate-specific proteases, and their over-expression can result in apoptotic cell death. Normally, caspases exist in cells as inactive pro-enzymes and can be activated by 2 distinct mechanisms: the FADD/caspase 8 cascade, and the Apaf-1/caspase 9 cascade. These 2 mechanisms are used extensively by cells for the activation of the effectors caspases: caspase 3, caspase 6, and/or caspase 7. Bcl-W and caspases might have a pivotal role in maintenance of Sertoli cells integrity. In this study, we demonstrate that both Bcl-W mRNA and caspase 3 mRNA are expressed in isolated Sertoli cells of pre-puberal rat testes. This finding might be crucial in clarifying whether Sertoli cells die by an apoptotic mechanism. Further studies are required to understand whether the expression of Bcl-W and caspases is different before and after puberty in rat testis and/or in pathological conditions, that lead to an increased cell apoptosis.

Congenital bilateral anorchia: clinical, hormonal and imaging study in 12 cases

Summary. Twelve anorchid pre‐pubertal and post‐pubertal patients, aged between 8.5 and 41 years, were studied. The FSH and LH basal levels as well as their responses to Gn‐RH (100 μg i.v.) were increased and prolonged in the post‐pubertal patients. The testosterone levels were in the prepubertal range and failed to increase after HCG administration (1500 I.U. t.i.d. for 3 days).