[Male infertility: non-surgical therapy]. / Infertilità maschile: terapia non chirurgica.

Infertility is defined as the inability of a couple to conceive after 12 months of unprotected intercourse and affects 15% of couples with male component of 50%. The failure of spermatogenesis can result from hypothalamic, pituitary or testicular disorders although in the majority of cases it remains idiopathic. The diagnostic process includes medical history, semen analysis, hormonal studies, genetic studies and radiological evaluation.Targeted hormonal therapies are available for patients whose infertility is caused by altered levels of androgens, prolactin, or TSH. Main treatments aim to restore normal sexual function by administering testosterone and to increase spermatogenesis with pulsatile GnRH.Fertility in men suffering from hypogonadotrophic hypogonadism can be restored through hormone therapy using GnRH or with the use of gonadotropins when there is hypothalamic failure. In the past, treatment options for the factors of idiopathic male infertility were mainly based on the use of anti-estrogens that cause an increased secretion of FSH and LH and therefore of testosterone.Oxytocin promotes the progression of the sperm and increases the conversion of testosterone into dihydrotestosterone. The aromatase's inhibitors decrease the conversion of androgens to estrogens, increasing serum levels of androgens, resulting in an increased release of gonadotropins.Two areas showed interesting future perspectives for the treatment of infertility: gene therapy and transplantation of spermatogonial stem cells.

[Modern management of cryptorchidism: which evidences?]. / Approccio moderno al criptorchidismo: quali evidenze?

The term cryptorchidism is related to the failure of the migration of the testis to the scrotum. In most cases, testis are retained along the physiological route through the inguinal canal. In 1% of cases the gubernaculum testis is abnormally fixed (testicular ectopy).In 20% of cases, one testis is not clinically palpable. The US has a sensitivity of 45% and a specificity of 78% in detecting intra-abdominal testis. Consequently, laparoscopy should be considered the gold-standard in these cases.Hormonal therapy has been considered in order to aid testicular descent, without or before surgery. Recent data suggest that these strategies seem to have a success rate 10% higher than placebo, while surgery alone is effective in 33-100% of cases.Several histological studies showed microscopic damages due to cryptorchidism since age of 6-9 months. Some Authors suggest that up to 40% retained testis completely lose their own germinal cells pool at the age of two years. Consequently guide-lines suggest that surgery should be proposed at the age of 6-18 months.Cancer relative risk associated to cryptorchidism is calculated to be 1.5-7.5% higher than in general population and lower than what is traditionally estimated (15-33%). Moreover, this risk increases 2.9-32.0 times when surgery is performed after the age of 10-11 years.

Are human male patients with DAX1/NR0B1 mutations infertile?

DAX-1 stands for Dosage sensitive sex-reversal, Adrenal hypoplasia congenital (AHC), on the X chromosome. DAX-1 mutations usually cause primary adrenal insufficiency or congenital adrenal hypoplasia in early childhood and hypogonadotropic hypogonadism (MIM # 300200). DAX-1 protein is necessary to maintain normal spermatogenesis. In humans, male fertility has been studied in few patients carrying DAX-1 mutations. Cases of azoospermia have been reported, as well as unsuccessful gonadotropin treatments. The clinician should be informed that TESE-ICSI technique carries a potential hope to father non-affected children, as shown in this review.

Neonatal gonadotropin therapy in male congenital hypogonadotropic hypogonadism.

Congenital hypogonadotropic hypogonadism (CHH) causes pubertal failure and infertility in both women and men due to partial or total secretory failure of the two pituitary gonadotropins lutropin (LH) and follitropin (FSH) during periods of physiological activation of the gonadotropic axis. Men and women with CHH frequently seek treatment for infertility after hypogonadism therapy. Some etiologies, such as autosomal dominant or X-linked Kallmann syndrome, raise the question of hereditary transmission, leading to increasing demands for genetic counseling and monitoring of medically assisted pregnancies. Diagnosis and treatment of newborn boys is, therefore, becoming an increasingly important issue. In male individuals with complete forms of CHH, the antenatal and neonatal gonadotropin deficit leads to formation of a micropenis and cryptorchidism, which could undermine future sexual and reproductive functions. Standard treatments, usually started after the age of puberty, often only partially correct the genital abnormalities and spermatogenesis. The aim of this Review is to examine the possible additional benefits of neonatal gonadotropin therapy in male patients with CHH. Encouraging results of neonatal therapy, together with a few reports of prepubertal treatment, support the use of this novel therapeutic strategy aimed at improving sexual and reproductive functions in adulthood.

Polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common female endocrinopathy, affecting 5-10% of the female population. It involves overproduction of ovarian androgens leading to a heterogeneous range of symptoms including hirsutism, acne, anovulation and infertility. Hyperinsulinaemia, exacerbated by obesity, is often a key feature. Treatment depends on the presenting symptoms, which may often be ameliorated by weight loss where relevant. Anti-androgen preparations are used for hyperandrogenic symptoms, and clomiphene citrate (CC) is the first-line treatment for anovulation and infertility. Aromatase inhibitors are being investigated as an alternative to CC. Failure to conceive with CC can be treated in a number of ways, including the addition of insulin-lowering agents (mainly metformin), low-dose gonadotrophin therapy or surgically by laparoscopic ovarian drilling. Although the exact aetiology of PCOS is not known, the therapeutic alternatives provide reasonably successful symptomatic treatment.

Gonadotropin treatment restores in vitro interleukin-1beta and tumour necrosis factor-alpha production by stimulated peripheral blood mononuclear cells from patients with idiopathic hypogonadotropic hypogonadism.

In the present study, we aimed to investigate the effects of testosterone deficiency and gonadotropin therapy on the in vitro production of tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) by peripheral blood mononuclear cells (PBMCs) from patients with idiopathic hypogonadotropic hypogonadism (IHH) in order to elucidate the modulatory role of androgen in cytokine production. Fifteen male patients with untreated IHH and 15 age-matched healthy male subjects were enrolled in the study. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), free testosterone (FT), sex hormone binding globulin (SHBG), prolactin, and IL-2 and IL-4 levels were also measured. In unstimulated cultures, IL-1beta and TNF-alpha secretion were not significantly different between patient and control groups. However, after stimulation with lipopolysaccharide (LPS), secretion of IL-1beta and TNF-alpha was significantly higher in cultures from untreated patients with IHH than in control subjects. Mean FSH, LH and FT levels were significantly lower, whereas SHBG, IL-2 and IL-4 levels were significantly higher in patients with IHH compared than in controls. In patients with IHH, FT negatively affected the serum levels of IL-4 and in vitro secretion of IL-1beta and TNF-alpha. In addition, IL-2 and IL-4 affected the in vitro secretion of IL-1beta in a positive manner. Gonadotropin therapy decreased both TNF-alpha and IL-1beta in PBMCs from patients with IHH. The levels of serum IL-2 and IL-4 were also decreased by therapy. In conclusion, in the present study, gonadotropin treatment restored the in vitro production of IL-1beta and TNF-alpha by PBMCs from patients with IHH, suggesting that androgen modulates proinflammatory cytokine production, at least directly through its effects on PBMCs. It seems probable that this effect plays an important role in the immunosuppressive action of androgens.

The Parkes lecture: controlled ovarian stimulation in women.

Recent advances in knowledge of the endocrine and paracrine mechanisms that regulate human ovarian folliculogenesis have been parallelled by the introduction into clinical practice of new drugs that can be used safely and effectively to stimulate ovarian function in infertile women. Most notably, recombinant DNA technology has been applied to the production of molecularly pure forms of the gonadotrophins, FSH and LH, opening the way to the development of improved strategies for manipulating the ovarian paracrine system. The clinical objectives of controlled ovarian stimulation fall into two categories, depending on patient needs: (1) induction of multiple follicles from which mature oocytes can be harvested for use in assisted reproduction protocols such as in vitro fertilization and embryo transfer; or (2) induction of spontaneous ovulation of a single mature follicle so that conception might occur in vivo. This review summarizes the physiological principles upon which the use of gonadotrophins for clinical purposes is based, highlighting new opportunities for improved treatment as a result of the availability of recombinant FSH and LH.

Effect of gonadotrophin-releasing hormone agonist treatment on growth hormone secretion in women with polycystic ovarian syndrome.

The suppression of the pituitary-gonadal axis by the administration of gonadotrophin-releasing hormone agonists (GnRH-a) is used occasionally as an adjunct therapy with gonadotrophins for ovulation induction in women with polycystic ovarian syndrome (PCOS). A number of recent clinical studies have suggested that women with polycystic ovaries (PCO) may have disturbances of normal growth hormone (GH) kinetics and alterations in the GH/insulin-like growth factor (IGF)-I system. The purpose of this study was to determine the effect of GnRH-a administration on GH-releasing hormone (GHRH)-stimulated GH release in women with PCOS. Eight women with PCO and six control women were studied before and after 2 months of treatment with the long acting GnRH-a triptoreline (3.75 mg monthly injections). GHRH was given as a single i.v. injection and blood samples for GH measurements were obtained at -15, 0, 30, 60, 90 and 120 min. The GH responses were expressed as the area under the curve (AUC) or the differences from the basal value (delta(max)). The GH response to GHRH (mean +/- SEM) was lower in women with PCO (AUC 114.9 +/- 43.1 versus 206.2 +/- 28.7 ng/ml/120 min, P < 0.05 and delta(max) 31.6 +/- 8.2 versus 49.4 +/- 5.8 ng/ml, P < 0.05). After treatment with the GnRH-a, the GH response to GHRH was significantly smaller than before treatment in both groups (PCO AUC 34.6 +/- 9.0 ng/ml/120 min and delta(max) 12.4 +/- 3.1 ng/ml; controls AUC 148.8 +/- 28.4 ng/ml/120 min and delta(max) 31.2 +/- 6.1 ng/ml), but the PCO group had a significantly smaller response. These data demonstrate that women with PCO have a reduced GH response to GHRH compared with normal controls and that GnRH-a administration causes a further GH reduction in both groups. Women with PCO have a greater suppression of GH response to GHRH during treatment with GnRH-a. This suggests that a different level of sensitivity in the somatotrophic axis exists in PCOS.

Short- and long-term effects of ovulation induction.

Ovulation induction using clomiphene citrate, gonadotropins, and gonadotropin-releasing hormone is reviewed. The short- and long-term consequences of these therapies are discussed in detail.

Current and future status of ovulation induction in polycystic ovary syndrome.

Great progress had been achieved during the last 20 years in the field of ovulation induction in patients with polycystic ovary syndrome (PCOS). Clomiphene citrate remains the first line of treatment for all anovulatory women with PCOS, since in properly selected patients the cumulative pregnancy rate approaches that in normal women. Human urinary gonadotrophins have been used extensively for ovulation induction, but the development of low-dose regimens has opened a new era in the management of anovulation related to PCOS. This article discusses the main advantages and disadvantages of the principal methods and regimens currently used for ovulation induction in patients with PCOS including clomiphene citrate, gonadotrophins, pulsatile gonadotrophin-releasing hormone (GnRH) and GnRH agonists. It also discusses new drugs discovered recently, particularly recombinant gonadotrophins and GnRH antagonists, and provides some thoughts regarding their use in future protocols. Finally, based on the discovery of new ovarian substances which specifically control luteinizing hormone (LH) secretion, this article develops assumptions on possible implications of these substances in the pathophysiology of PCOS and their potential use in the management of the syndrome.

Ovulation induction in the ovulatory woman.

Controlled ovarian hyperstimulation is frequently employed as empiric therapy for the treatment of unexplained infertility, mild male factor, cervical factor, and treated endometriosis. Prescribed in the form of either clomiphene citrate or gonadotropins, it is often combined with intrauterine insemination and offered to patients as a less expensive and less invasive alternative to the assisted reproductive technologies. Efficacy studies for these regimens are very important, as patients who would appear to be ideal candidates for this empiric therapy frequently do not suffer from absolute infertility; rather they are often subfertile, and may conceive spontaneously given enough time. Although there are few well-designed, controlled trials that assess the effectiveness of this form of therapy, the majority of the published data do suggest an improvement in pregnancy rates when compared to expectant management.