[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.

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.

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.

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.

[Disappearance of migraine crises in two patients with male infertility treated with human chorionic gonadotropin/human menopausal gonadotrophin]. / Desaparición de crisis migrañosas en dos pacientes tratados con hCG/hMG por infertilidad masculina.

Two patients aged 52 and 31 respectively, treated for male infertility with gonadotrophins (LCG/LMG), showed marked improvement of their migraine crises associated with a typical aura which had been present since puberty. Changes in the number, motility and morphology of the spermatozoids were seen in the seminogram. The plasma concentrations of FSH, LH, testosterone an 17-beta oestrodiol were within normal limits. After three months of empirical treatment with LCG/ LMG (to stimulate spermatogenesis) the migraine crises ceased and the patients are still free of migraine after 32 and 26 months respectively. The relationship between migraine and the sex hormones is discussed, in the context of current knowledge of the psysiopathology of migraine and the beneficial effects obtained after treatment with LCG/LMG. We have not found any reference in the literature to the use of gonadotrophins in the treatment of migraine with a typical aura.

Adjuvant growth hormone for induction of ovulation with gonadotrophin-releasing hormone agonist and gonadotrophins in polycystic ovary syndrome: a randomized, double-blind, placebo controlled trial.

The objective of this study was to explore the effect of cotreatment with recombinant human growth hormone (GH), gonadotrophin-releasing hormone agonist (GnRHa) and human menopausal gonadotrophin (HMG) for induction of ovulation in women with clomiphene resistant polycystic ovary syndrome (PCOS). It was designed as a randomized, double-blind, placebo controlled trial in which 30 women with anovulation associated with PCOS who were resistant to clomiphene all received DTRP6-LHRH (Decapeptyl microcapsules, 3.75 mg, i.m.) and, 2 weeks later, HMG in a standard, conventional, individually adjusted dose regimen until human chorionic gonadotrophin (HCG) and then luteal phase support could be given. From day 1 of HMG therapy, patients were randomized to receive either human GH (Norditropin, 12 IU/day, i.m., for 7 days) or placebo. The number of ampoules, duration of treatment and daily effective dose of HMG required to achieve ovulation, serum oestradiol concentrations and number of follicles induced, ovulation and pregnancy rates, serum insulin and insulin-like growth factor-I (IGF-I) concentrations were measured. There were no significant differences between growth hormone and placebo groups in any of the outcomes measured, other than a growth hormone induced increase in serum insulin and IGF-I levels. We conclude that although GH kinetics are abnormal and GH pituitary reserves generally low in women with PCOS, adjuvant GH treatment to GnRHa/HMG does not influence follicular development or sensitivity in response to gonadotrophins and that it does not seem likely to be of any potential clinical benefit for the treatment of PCOS.

Pregnancy in women with Kallmann's syndrome.

OBJECTIVE: To induce of ovulation and pregnancy in women with Kallmann's syndrome. DESIGN: Retrospective study. PATIENTS: Three women with hypogonadotropic hypogonadism and anosmia with a desire for pregnancy. INTERVENTIONS: Investigation of hypothalamic-pituitary-ovarian function and induction of ovulation by pulsatile GnRH or intramuscular human pituitary gonadotropins (hPG) or hMG with hCG. MAIN OUTCOME MEASURES: Successful induction of ovulation as measured by serum P levels and successful pregnancy. RESULTS: Ovulation was induced successfully in all three patients on more than one occasion and nine pregnancies occurred. Gonadotropin-releasing hormone was given IV by an electronically timed syringe driver. A total of 12 pulsatile GnRH cycles resulted in two pregnancies, 6 of these cycles being in one patient who did not ovulate or conceive with this therapy. Ovulation occurred in 10 of 16 hMG or hPG cycles, with conception in 7 of these. Gonadotropin usage was higher in these women compared with women with hypogonadotropic hypogonadism without anosmia (2,850 compared with 2,100 IU per treatment cycle), and the follicular phase was longer. CONCLUSIONS: All three women conceived and had children after induction of ovulation. The success rate of these therapies in Kallmann's syndrome appears to be high in spite of very few reports in the literature.

Endocrine changes and follicular development in patients during ovulation induction using Goserelin and different gonadotropin treatments.

The aim of this study was to compare endocrine changes and the follicular development in patients receiving pure FSH alone or in association with LH after desensitization with an LH-RH agonist depot. Thirty four cycles were selected for this prospective randomized study. Desensitization was obtained using Goserelin the cycle before the stimulation. Induction of ovulation for IUI was carried out with 225 IU/day of pure FSH or with 225 IU/day of hMG. The number of days and ampules required for follicular maturation were equivalent in the two groups. The same number of follicles were developed, while different, but not significant, pregnancy rates were obtained. Estradiol values at the end of stimulation were significantly lower for FSH group. In conclusion the contemporary administration of LH with FSH does not exert any effect on follicular development, but it seems to facilitate E2 synthesis, probably providing more substrate for the aromatization process.

Human gonadotrophins.

Treatment with exogenous gonadotrophic hormones to overcome certain cases of female infertility has been used for more than 30 years. Children born after such treatment have not shown any increased incidence of abnormalities (genetic or otherwise) and their reproductive ability seems normal. Furthermore, no increase in malignant disease (breast, ovarian, endometrial) have been reported following such repetitive gonadotrophic stimulations. Thus it seems the treatment can be regarded as safe. Two categories of patients are treated today. Firstly, hypothalamic-hypophyseal insufficiencies (WHO group I), where treatment is compulsory for attaining fertility, and secondly (including anovulation WHO group II), more or less regularly cycling women, where gonadotrophic treatment is used to augment fertility. Especially in the latter group, caution must be taken not to induce adverse effects. To meet these demands, exogenous gonadotrophic stimulation needs to be combined with other drugs and regimens that take into consideration the problems created by the concomitant presence of endogenous gonadotrophins.

Levels of steroid and protein hormones in antral fluids of women treated with different combinations of gonadotropins, clomiphene citrate, and a gonadotropin-releasing hormone analog.

Levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, progesterone (P), and total protein in follicular fluids collected from 18 patients pretreated with a gonadotropin-releasing hormone analog (GnRHa), in association with human menopausal gonadotropin (hMG) and FSH, were compared with values for 69 patients treated with FSH, hMG, FSH/hMG, or clomiphene citrate (CC)/hMG in an in vitro fertilization (IVF) program. The authors have established a number of significant differences in chemical and physical properties of follicular fluids of patients treated by different regimen, and concur with earlier evidence that the volume of a follicle, and its P and total protein content, are related to the maturity of the oocyte nested within the follicle. Overall, however, differences in concentrations of gonadotropins in follicular fluids between groups were not consistent with differences in follicular fluid steroid levels, and levels of immunoactive gonadotropins in follicular fluids were not in accord with dosages of exogenous immunoactive gonadotropin administered during hyperstimulation. The most favorable outcomes of IVF (greater than 70% of oocytes fertilized) were established with oocytes collected from patients treated with FSH only or with CC/hMG, and patients treated with FSH only yielded the highest average number of oocytes which fertilized in vitro (6.2 per patient).