Effectiveness of gonadotropin administration for spermatogenesis induction in hypogonadotropic hypogonadism: a possible role of androgen receptor CAG repeat polymorphism and therapeutic measures.

Prepuberal-onset (PRHH) and postpuberal-onset (PSHH) Hypogonadotropic Hypogondism (HH) refer to a heterogeneous group of patients, showing a broad spectrum of clinical signs and symptoms of androgen deficiency in consideration of the different possible aetiologies and the age at onset. These patients, though, required Gonadotropin treatment (GnTh) by means of administration of both the ß Human Chorionic Gonodadotropin (ß HCG) and the Follicle Stimulating Hormone (FSH) to obtain mature sperms in the ejaculate aiming to reach fertility levels. However, the response to GnTh is always unpredictable concerning either the effectiveness or the duration of the therapy. Consequently, different studies have been carried out to identify clinical (i.e. cryptorchidism, gynecomastia, testis size, etc) and biochemical markers [serum Testosterone (T) and Inhibin B (IB)] that can be useful to predict the effectiveness of GnTh. Given that the actions of T, even those directed at inducing and maintaining spermatogenesis, are mediated by its interaction with the Androgen Receptor (AR), we measured the AR CAG repeat polymorphism in men with HH, in order to examine whether the CAG polymorphism extensions could co-regulate the GnTh effectiveness. Twenty-three HH subjects were subdivided according to the age at onset (pre- and postpubertal) and treated with the same scheme and doses of GnTh, extending the period of treatment up to 30 months. Thirty-five healthy and fertile men served as a control group (CG). Twelve HH subjects (3 PRHH and 9 PSHH), who reached complete spermatogenesis within 12 months, showed the length of AR CAG repeat number [20 (19-23) = median (interquartile range 25th - 75th percentile)] not statistically different from our CG [20 (19-22)], while CAG repeat number [23 (20-25)] of 11 HH patients (9 PRHH and 2 PSHH) who obtained mature sperms in their ejaculate beyond a year to within 30 months, was significantly higher. Our results suggest that the length of AR CAG repeat polymorphism might affect the response to GnTh in men suffering from HH, in particular in those patients with prepubertal-onset hypogonadism.

Difference in growth hormone response to growth hormone-releasing hormone (GHRH) testing following GHRH subacute treatment in normal aging and growth hormone-deficient adults: possible perspectives for therapeutic use of GHRH or its analogs in elderly subjects?

The somatotroph axis function shows a decline in the elderly (somatopause). In particular growth hormone (GH) response to GH-releasing hormone (GHRH) is reduced in aged man but less than that observed in GH-deficient adults (GHDAs). Plasma GH response to GHRH (1 µg/kg BW) was significantly lower in four GHDAs than in seven healthy aged men 30, 60, and 90 min after acute GHRH administration. To verify whether a priming regimen might be able to increase the reduced GH response to GHRH, both healthy aged men and GHDA patients underwent repetitive administration of GHRH (100 µg GHRH intravenously as a single morning dose, every 2 days for 12 days). After the GHRH-priming regimen, plasma GH values 30, 60, and 90 min after the acute GHRH test were significantly higher than values at the corresponding time points before priming regimen in healthy aged men but not in GHDA patients. These findings confirmed that somatotroph cells become less sensitive to GHRH with normal aging and demonstrate that repetitive administration of GHRH restores the attenuated response only in healthy aged men but not in GHDA patients. This could support the possible use of GHRH or its analogs instead of recombinant human GH in elderly patients with the advantage of preserving the endogenous pulses of GH with the secretion of the different isoforms of GH. However, concerns arise about the possible role of these molecules in tumorigenesis and tumor growth promotion.

Evolution of a prolactin-secreting pituitary microadenoma into a fatal carcinoma: a case report.

Pituitary carcinomas are very rare tumors, nearly always presenting as widely invasive masses, although the hallmark of these lesions is the finding of distant metastases. One third of reported cases are prolactin (PRL)-secreting tumors. We report the case of a fatal pituitary carcinoma evolving within 4 years from a PRL-secreting microadenoma. A 22-year-old woman presented because of galactorrhea. Evaluation of the patient disclosed slight hyperprolactinemia and magnetic resonance imaging (MRI) showed a 7-mm intrapituitary lesion, which responded to treatment with cabergoline. About 4 years after the first evaluation she developed sudden headache, ptosis, and diplopia in the right eye. MRI disclosed the growth of a large pituitary mass, invading the right cavernous sinus. Despite two trans-sphenoidal surgical procedures followed by gamma-knife radiosurgery, the patient showed rapid local progression of the tumor and the occurrence of new lung lesions, probably of metastatic nature. The patient died 7 months after the development of her first neurological symptoms because of tumor apoplexy and subsequent subarachnoid hemorrhage. This case represents the first documented rapid evolution from a microprolactinoma initially responding to dopamine agonists to a fatal pituitary carcinoma.

Involvement of the transforming growth factor beta in the pathogenesis of hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is characterized by vessel alterations such as dilatation of postcapillary venules and arterio-venous communications, which account for the major clinical manifestations of the disease. Two types of HHT have been characterized HHT-1 and HHT-2, respectively, depending the former on endoglin mutations and the latter on activin receptor-like kinase 1 (ALK-1) mutations. Both endoglin and ALK-1 bind to the transforming growth factor (TGF) superfamily which, physiologically, regulates the activities of endothelial cells and also those related to the extracellular matrix. In this review, the salient features of TGF-beta will be outlined with special reference to its activity on the immune system and on tumorigenesis. Furthermore, the involvement of TGF-beta in the pathogenesis of some gastrointestinal diseases will be discussed and, in particular, in the course of liver disease, Helicobacter pylori infection and inflammatory bowel disease. In the light of these data and of animal model of HHT, the potential risk of developing other diseases in HHT patients will be discussed.

The impact of body mass index and type 2 diabetes on breast cancer: current therapeutic measures of prevention.

Epidemiological data have suggested a possible relationship between obesity, diabetes mellitus and cancer risk, particularly breast cancer. We set out to investigate the effect of body mass index and diabetes mellitus on the presence of breast cancer in the Apulian population. We selected 1,663 women affected with primary breast cancer and 4,702 control patients. All patients with breast cancer underwent surgical excision of the tumor and their tumors were histologically confirmed. The prevalence of type 2 diabetes (8%) in the women affected by breast cancer was significantly higher than in the control group (5%) (p<0.05). The majority of the diabetic women affected by breast cancer had a BMI value >25, both in premenopause and in postmenopause. With respect to BMI, the non-diabetic patients with breast cancer in postmenopause showed the same pattern as the diabetic ones. Instead, among the women in premenopause a higher percentage (55%) of patients with a BMI <24.9 was found (p<0.01). In the Apulian population, the presence of both type 2 diabetes and elevated values of BMI (that is in a condition of hyperinsulinemia) were found to enhance the frequency of breast cancer.

Evidence for a putative relationship between type 2 diabetes and neoplasia with particular reference to breast cancer: role of hormones, growth factors and specific receptors.

The issue of a possible relationship between type 2 diabetes and cancer is still debated. Such chronic diseases show a high incidence in the general population. In their pathophysiology both genetic and environmental factors are involved, inducing important modifications of metabolism. Diabetes is associated to profound metabolic alterations, such as hyperinsulinemia and insulin resistance, which are common in various diseases, i.e. obesity, hypertension, dyslipidemia and hyperuricemia. Those illnesses form the so-called metabolic syndrome. Insulin resistance, hyperestrinism and the associated hyperandrogenism may play a role in the onset of some malignancies, such as endometrium cancer, breast cancer and prostate cancer. Low plasma levels of IGF-1 are able to reduce the risk of cancer in type 2 diabetes patients. This goal can be obtained with preventive measures, as physical activity, diet and drugs that can reduce insulin resistance (metformin and thiazolidinediones).

Breast cancer: biological characteristics in postmenopausal type 2 diabetic women. Identification of therapeutic targets.

HYPOTHESIS: Epidemiological data have suggested a possible relationship between diabetes mellitus and cancer risk, particularly breast cancer. We set out to investigate the effect of diabetes mellitus on the expression of estrogen and progesteron receptors and on the proliferative activity of primary breast cancer. METHODS: We selected 77 diabetic women and 578 control patients all in post-menopause and diagnosed with primary breast cancer. All patients underwent surgical excision of the tumor and on the specimens were performed an assessment of estrogen receptor and progesteron receptor and proliferative activity assay by (3)H-Thymidine incorporation. RESULTS: Diabetic women showed a decreased proliferative activity, while having the same estrogen receptor and progesteron receptor status and mean cytoplasmic concentration of their receptors than control group. Insulin treated women had a lower proliferative activity than non-insulin treated ones. CONCLUSION: Hyperinsulinemia and hyperglicemia influence in negative way the proliferative activity of diabetic women, likely inducing the expression of transforming growth factor beta, despite the high serum levels of Insulin-like growth factor and estrogen.

Modifications of the immune responsiveness in patients with autoimmune thyroiditis: evidence for a systemic immune alteration.

Hashimoto's thyroiditis, the most common form of autoimmune thyroid disease, is characterised by lymphocytic infiltration of the thyroid gland, gradual destruction of the organ and production of thyroid specific auto antibodies (antithyroid peroxidase and antithyroglobulin antibodies). There are evidences that cast doubt on the pathogenetic role of these antibodies in thyroid autoimmunity. It is very likely that cellular destruction is mediated by other cellular mechanisms, such as auto reactive T-lymphocytes, natural killer and cytokines. However, other studies performed in animal models have led to the conclusion that organ specific autoimmune thyroiditis should be regarded as a polygenic disease with a penetrance that is strongly influenced by environmental factors. According to our recent results, patients affected by autoimmune thyroiditis exhibited a decreased percentage of NK and CD25 + bearing cells significantly in comparison to normal controls. Altogether these data indicated that in the patients with autoimmune thyroid disease a certain degree of peripheral immune deficiency was present.