Treating varicocele in 2018: current knowledge and treatment options.

PURPOSE: Varicocele is defined as a state of varicosity and tortuosity of the pampiniform plexus around the testis caused by retrograde blood flow through the internal spermatic vein. The prevalence of clinically relevant varicocele ranges from 5 to 20% in the male population and is often associated with infertility and reduction of sperm quality. In this review, the pathophysiology and clinical aspects of varicocele are reviewed along with therapeutic options and treatment effects on sperm parameters and fertility both in adult and in pediatric/adolescent subjects. METHODS: We conducted a Medline and a PubMed search from 1965 to 2018 to identify publications related to varicocele clinical aspects, treatment procedures and treatment outcomes. Keywords used for the search were: "varicocele", "varicocelectomy", "sclerotherapy", "male infertility", "subfertility", and "semen abnormalities". RESULTS: Data from a large number of studies in adolescent and adult males indicate that varicocele correction improves semen parameters in the majority of patients, reducing oxidative stress and improving sperm nuclear DNA integrity either with surgical or percutaneous approach. CONCLUSIONS: Varicocele repair seems to represent a cost-effective therapeutic option for all males (both adolescent and adults) with a clinical varicocele in the presence of testicular hypotrophy, worsening sperm alterations or infertility. On the other hand, some investigators questioned the role of varicocelectomy in the era of assisted reproduction. Thus, a better understanding of the pathophysiology of varicocele-associated male subfertility is of paramount importance to elucidating the deleterious effects of varicocele on spermatogenesis and possibly formulating new treatment strategies.

Male sexual disturbances in liver diseases: what do we know?

The alterations of sexual function known as the erectile dysfunction are quite frequent among patients affected by liver diseases and they tend to increase in advanced liver failure. This process is directly linked to cirrhosis or its treatments, such as liver transplantation, or to certain drugs (e.g. beta-blockers). Independent of cirrhosis, other factors may cause sexual problems in these patients. Alcohol itself seems to worsen sexual function in the absence of cirrhosis. Viral hepatitis has an uncertain influence on male gonadic function and even antiviral therapy itself can worsen some seminal and hormonal parameters, although it is reversible. Quality of life may be greatly decreased in cases of cirrhosis where these alterations are present, so it is important to value and care for them, if possible. This review investigates the major male sexual disturbances in liver diseases of various origins.

Exogenous platelet-activating factor improves the motility of human spermatozoa evaluated with C.A.S.A.: optimal concentration and incubation time.

The objective of this study is to determine the optimal conditions for human semen incubation treated with exogenous platelet activating factor (ePAF) for intra-uterine insemination (IUI). This prospective study was carried out on 32 infertile men and each semen sample was processed with the ISolate Sperm Separation Medium, washed with sperm washing medium (SWM) and resuspended either in SWM alone (control samples), or with ePAF 0.1, 0.5, and 1.0 µM. Each concentration was subsequently incubated and evaluated at 5, 15, 30, and 60 min. The motility parameters were evaluated by the computer-aided sperm analysis (C.A.S.A.) system. Curvilinear velocity, straight line velocity, average path velocity, rapid and progressive motility significantly increased compared to control samples at an ePAF concentration of 0.1 µM (with at least 15 min of incubation). The best results were obtained with ePAF concentrations of: 0.1 µM (60 min of incubation) and 0.5 µM (30-60 min of incubation). In conclusion, results are enhanced when ePAF is added to standard semen preparation for IUI. An ePAF concentration of 0.1 µM, with an incubation time of 15 min, can be used for semen samples with normal motility. Whilst, for semen samples with poor motility, the ePAF concentration is best increased to 0.5 µM and/or the incubation time prolonged to 60 min.

Radiological treatment of male varicocele: technical, clinical, seminal and dosimetric aspects.

PURPOSE: The purpose of this study was to present our experience with percutaneous treatment of male varicocele considering technical, clinical, seminal and dosimetric aspects. MATERIALS AND METHODS: At baseline and at 6 months' follow-up, 290 male patients aged between 18 and 37 (average age 27.3 years) with left (266 cases) or bilateral (24 cases) varicocele underwent clinical assessment, Doppler ultrasonography (US), laboratory testing of free and total serum testosterone, leutenising hormone (LH) and follicle stimulating hormone (FSH) gonadotropins, inhibin B and spermiogram. In 223 cases, selective catheterisation of the spermatic vein was performed with a right transfemoral approach. Two hundred and six out of 223 underwent radiological treatment of varicocele; in 194, hydroxy-poliethoxydocanol (Aetoxysclerol) was used only whereas in 12 cases (5.8%), 5 ml of absolute alcohol and a Gianturco coil (0.038-in. Cook coil, 10 mmx50 mm) were also used. In 17/223 patients (7.6%), sclerotherapy was contraindicated or not technically feasible. Sixty-seven patients refused radiological treatment and were used as a control group. In 20 patients, the following parameters were measured: dose area product, entrance surface dose, effective dose and gonad dose. RESULTS: Technical success was achieved in 206/223 cases; two phlebographic examinations (immediately following administration of the sclerosing agent and after 15-20 min) showed prethrombotic endoluminal alterations of the internal spermatic vein. At 6 months' follow-up, 172/206 patients (83.49%) showed complete resolution of the varicocele whereas 34/206 (16.5%) had only partial disengorgement of the pampiniform plexus. In these 206 patients, the spermogram showed a significant increase in sperm concentration (52.1+/-4.1 vs. 44.2+/-3.6 million/ml, p=0.002) and motility (40.5+/-2.2 vs. 33.3+/-2.0%, p=0.0001), with negligible morphological changes. In the control group and in the other 17 untreated patients, no variations in seminal parameters were observed. The following minor procedural complications were recorded: two cases of acute abdominal pain, three of vagal crisis during administration of sclerosing agent that resolved spontaneously and two of spermatic cord inflammation that resolved within days after medical therapy. We recorded no statistically significant differences with regard to testicular volume or serum hormone levels between the treated and untreated groups. Maximum effective dose and maximum gonad dose equivalent were 6.9 mSv and 0.69 mSv, respectively. DISCUSSION AND CONCLUSIONS: Percutaneous radiological treatment of varicocele is a minimally invasive technique, which is well tolerated by patients and able to significantly improve seminal parameters. The principal technical limitation to percutaneous treatment is related to difficult selective catheterisation of the spermatic vein due to anatomic alterations, spasms and intimal dissection of the vein. Moreover, when the cremasteric vein is incontinent, inguinal surgical ligation provides better results. In the majority of cases, administration of at least 3 ml sclerosing agent at 3% ensures occlusion of the gonadic vein above the abdominal collaterals, which are responsible for long-term recurrence if not treated. In the remaining cases, absolute alcohol and metallic coils can be used to complete the treatment. The positive results in seminal parameters do not, however, allow for reliable assessment of patients' fertility. Finally, we believe that radiological procedures are not indicated or justified when prolonged catheterisation with elevated gonadic irradiation is needed.

Glutathione levels in patients with erectile dysfunction, with or without diabetes mellitus.

The reduced form of glutathione (GSH) is the most important cell antioxidant and is also an essential cofactor for nitric oxide (NO) synthase that synthesizes NO from l-arginine. Reduced levels of GSH, due both to a hyperglycaemia-induced increase of free radical production and to a decrease of NADPH levels [like in diabetes mellitus (DM)], can hamper the endothelial cell functions. This condition may play an important role in the aetiology of some clinical signs, like erectile dysfunction (ED). The aim of this study was to test the hypothesis that GSH concentration is reduced in patients with ED and type 2 diabetes mellitus. We studied 111 male patients with ED: 64 with diabetes (ED/DM) and 47 without diabetes (ED/wDM); 20 patients with diabetes but without ED (DM) and 26 male normal subjects as a control group (C). The GSH red blood cell concentration was significantly lower in ED than in C (X +/- SD; 1782.12 +/- 518.02 vs. 2269.20 +/- 231.56 mumol/L, p < 0.001). In particular, GSH was significantly reduced in ED/DM vs. ED/wDM (1670.74 +/- 437.68 vs. 1930.63 +/- 581.01 micromol/L, p < 0.01). In DM, GSH was significantly lower than in C and significantly higher than in ED/DM (2084.20 +/- 118.14 vs. 2269.20 +/- 231.56 and vs. 1670.74 +/- 437.68 micromol/L, p < 0.002 and p < 0.001 respectively). GSH showed a negative correlation with fasting glucose concentrations (r = -0.34, p < 0.01) and with the duration of DM (r = -0.25, p < 0.05). A GSH depletion can lead to a reduction of NO synthesis, thus impairing vasodilation in the corpora cavernosa.

Acute goserelin administration inhibits gonadotropin and androgen secretion in post-menopausal women with ovarian hyperandrogenism.

The aim of this study was to verify the effect of goserelin, a GnRH agonist, in women with post-menopausal virilization. Six patients with post-menopausal virilization and increase in 17-hydroxyprogesterone (17-OHP), total (TT) and free testosterone (FT) levels underwent single subcutaneous administration of goserelin, 3.6 mg. Serum 17-OHP, TT, FT, LH, FSH, E2, delta4 and 3alpha-andro-stanediol glucuronide levels were measured before and 4, 8 and 18 days after goserelin administration. Goserelin administration was followed by progressive inhibition of FSH and LH, which fell to premenopausal levels on day 18, and progressive normalization of androgen parameters. The low E2 levels recorded at baseline were further reduced by goserelin administration. Four patients then underwent ovariectomy while in two patients, rejecting surgical treatment, goserelin treatment was protracted up to 6 and 12 months, respectively, with remission of hyperandrogenism. This study shows that in post-menopausal patients with virilization GnRH agonist allows to confirm the diagnosis of gonadotropin-dependent ovarian hyperandrogenism: its administration induces inhibition of gonadotropin levels, normalization of androgen parameters, and remission of virilization when the treatment is protracted in patients waiting for surgery.

Follow-up of varicocele treated with percutaneous retrograde sclerotherapy: technical, clinical and seminal aspects.

Varicocele is a common cause of male infertility; it can be treated by percutaneous retrograde embolization of the internal spermatic vein in order to improve sperm parameters and male fertility. The aim of this study was to verify the improvement of semen parameters after varicocele retrograde sclerotherapy. We evaluated 223 patients with left (206) or bilateral (17) varicocele (mean age +/- SD, 27.3 +/- 4.7 yr, range 18-37) by clinical, Doppler and seminal examinations; all the patients underwent phlebography, using 5F Cobra catheter from the right femoral vein access to the internal spermatic vein and varicocele sclerosing with Hydroxy-polyaethoxydodecanol. Doppler and seminal examinations 6 months after sclerotherapy were requested for the follow-up. Sixty-seven patients with left or bilateral varicocele who did not undergo sclerotherapy were studied as controls. Six months after sclerotherapy, a complete resolution of left varicocele was present in 172 patients (77.1%), while a partial improvement was obtained in 34 patients (15.3%). In these 206 patients seminal examination showed a significant improvement of sperm concentration (mean +/- SEM, 52.1 +/- 4.1 vs 44.2 +/- 3.6 million/ml, p = 0.002) and progressive motility (40.5 +/- 2.2 vs 33.3 +/- 2.0%, p = 0.0001), but not of normal sperm morphology (38.9 +/- 2.3 vs 37.4 +/- 2.1%, ns). In the control group no significant variations of seminal parameters were observed 6 months after the basal examination. In conclusion, varicocele retrograde sclerotherapy is a well-tolerated technique with a low cost-benefit ratio, able to improve semen parameters.

Gonadotroph cell pituitary adenomas in males.

BACKGROUND: Considered exceptional in the past, gonadotroph cell pituitary adenomas account for 3.5-6.4% of total surgically excised pituitary adenomas when examined with immunospecific staining. The aim of this study was to describe the clinical, hormonal, radiological and immunohistochemical features, the management and the follow-up of our patients with gonadotroph adenoma. METHODS: In this retrospective study we describe 14 male subjects aged 19-70 yrs affected by gonadotroph cell pituitary adenomas; the patients were studied by hormonal, radiological and immunohistochemical investigations and followed up for 3-13 yrs by ambulatory and/or hospitalized care. RESULTS: Visual impairment and/or decreased libido and erectile dysfunction were the symptoms at presentation. Increased serum gonadotropin concentrations were shown in 3 patients. Reduced levels of testosterone were present in 9 patients, and normal in the remainder. At diagnosis all patients had pituitary macroadenomas, with wide extrasellar extension in 12. All patients underwent trans-sphenoidal surgery and immunohistochemical staining of surgically excised specimens showed the presence of gonadotroph and alpha-subunit cells in all pituitary adenomas. After surgery 3 patients had clear radiological evidence of normal pituitary; in the others a doubtful MRI picture or a residual adenomatous tissue were present. In the patients who did not undergo radiotherapy immediately after surgery, a regrowth of tumoral tissue was shown in 1-10 yrs. CONCLUSIONS: We stress the importance of a close follow-up of patients with gonadotroph adenomas after surgery, and we raise the question of whether radiotherapy may be useful for avoiding any further adenomatous regrowth.

Postmenopausal virilization in a woman with gonadotropin dependent ovarian hyperthecosis.

We report a case of a 66-yr-old woman with progressive hair balding, hirsutism and virilization. Gonadotropins and estradiol levels were in the postmenopausal range; total testosterone (TT), free testosterone (FT) and 17-hydroxyprogesterone (17-OHP) were elevated with dehydroepiandrosterone sulphate, androstendione and cortisol serum levels in the normal range, as 24-hr free urinary cortisol. TT, FT and 17-OHP were normalized, and FSH and LH fell to premenopausal levels on 18th day after a single i.m. injection of the GnRH analogue (GnRHa), triptorelin. Then, a diagnosis of hyperandrogenism of ovarian origin was made and bilateral ovariectomy was performed. Histological study of gonadal tissue revealed diffuse stromal hyperplasia of both ovaries with occasional nests of luteinized cells. With immunoperoxidase techniques these cells stained positively for testosterone and progesterone. One month after surgery, androgen levels were normalized together with regression of most of the clinical signs of virilization. In conclusion, our patient showed a severe virilization developed after menopause; hormonal investigations suggested a gonadotropin dependent ovarian hyperandrogenism, confirmed by histological examination; the presence of luteinized cells in the ovarian stroma was responsible for hyperandrogenism, as confirmed by the immunoperoxidase technique.

Platelet cNOS activity is reduced in patients with IDDM and NIDDM.

Several studies in vitro and in vivo suggest that the nitric oxide (NO) production is impaired in diabetes mellitus. Reduced levels of NO could contribute to vascular alteration facilitating platelet-vascular wall interaction, adhesion of monocytes to endothelium, vascular smooth muscle proliferation and by decreasing endothelium-dependent vasodilation. In this study we evaluated the activity of the constitutive nitric oxide synthase (cNOS) in platelets of patients with insulin-dependent diabetes mellitus (IDDM) and with non-insulin-dependent diabetes mellitus (NIDDM). When compared to that of normal subjects, cNOS activity is significantly lower in patients with IDDM and with NIDDM (1.57 +/- 0.25 vs. 0.66 +/- 0.10 fmol/min/10(9) PLTs and 1.57 +/- 0.25 vs. 0.67 +/- 0.08, respectively; p<0.005). These data demonstrate that the platelet cNOS activity is decreased in diabetes mellitus.

[Hormonal control of sexual behavior in males and endocrinologic causes of sexual dysfunction]. / Il controllo ormonale del comportamento sessuale nel maschio e cause endocrinologiche di disfunzione sessuale.

The role of androgens in the male sex differentiation, in the genesis and preservation of the erectile function is summarized. In sex differentiation, testosterone acts on genitalia and central nervous system (CNS). In CNS sexual steroids exert a morphogenetic action during neuronal development. At the pubertal age, the increase of testosterone leads to the development of sex characteristics, the onset of libido and the beginning of the nocturnal spontaneous erectile function. Spontaneous erections are androgen-dependent, and they are impaired in androgen deficiency. Normal androgen levels lead to make voluntary erections. However, in the human species, cortical influences may greatly affect what could be possible to occur in relation to the hormonal situation. Endocrine causes of sexual dysfunction are responsible for about 20-25% of the total; among these primary and secondary hypogonadisms are the most frequent and they are to be managed with causal treatments and androgen replacement therapy. Therefore, androgen treatments are not useful in functional sex disorders and they may be at risk on prostatic tissue. Andropause is related to a progressive reduction of testicular function, principally due to vascular disorders, with low-normal androgen levels. On the basis of these observations it is underlined that in the human species the androgen presence is a necessary but not sufficient condition for a correct sex function.

Clinical and genetic variability in XX sex-reversed patients.

Three 46, XX hypogonadal subjects are described who exhibited different clinical and genetic characteristics. Two patients, with complete sex-reversal, are sterile males with hypogonadal features; the third patient, with partial sex-reversal, presented with a eunuchoid appearance and with ambiguous genitalia. Polymerase chain reaction (PCR) amplification of DNA from these patients showed the presence of a translocation of the sex-determining region of the Y chromosome (Sry) only in the first two patients described.

A new approach in the evaluation of gonadotropins for the diagnosis of polycystic ovary syndrome.

The new immunometric methods using monoclonal antibodies to detect gonadotropins revealed a reduction in the absolute values of these hormones, especially LH, due to a decrease in cross-reaction between gonadotropin subunits. Therefore, reference values of the LH/FSH ratio and their diagnostic significance in the polycystic ovary syndrome (PCOS) need to be defined again. We evaluated the LH/-FSH ratio in basal conditions and after administration of GnRH (100 micrograms as i.v. bolus) in seventy patients with PCOS employing an immunoenzymatic method. In PCOS patients the LH/FSH ratio was greater than 1 in 70% when evaluated on a single sample and in 88% when evaluated on a pooled serum from four samples every 30 minutes; in the control group the ratio was always lower than 1. The LH/-FSH ratio evaluated on the peak values in response to GnRH was greater than 2 in all patients and lower than 2 in the control group. Our results indicate that the LH/FSH ratio is still an important diagnostic tool in PCOS, especially when evaluated on the peak values in response to GnRH, even if its reference values are lower using these new monoclonal methods.