A. A. Sinisi

Loss of oestrogen receptor β, high PCNA and p53 expression and aneuploidy as markers of worse prognosis in ovarian granulosa cell tumours

Aims:  Ovarian granulosa cell tumour (OGCT) is a sex‐cord stromal tumour with a general trend toward late relapse and/or metastasis. However, mortality rate corrected for long‐term follow‐up shows that about 50% of patients die within 20 years of diagnosis. Classical clinicopathological parameters are unable to predict the biological behaviour of OGCT. The involvement of a recently characterized subtype of oestrogen receptor, ERβ, in ovarian carcinogenesis has been hypothesized.

Epidemiology, diagnosis, and treatment of male hypogonadotropic hypogonadism

Hypogonadotropic hypogonadism (HH), or secondary hypogonadism, is a clinical condition due to an impairment of the pituitary function, characterized by low testosterone plasma levels associated with normal or low FSH and LH plasma levels. An impairment of gonadotropin secretion and, therefore, a reduced efficiency of spermatogenesis was reported to be frequently associated to conditions different from the classical causes of secondary hypogonadism. These conditions (metabolic, endocrine and eating disorders, physical exercise etc.) have been associated with a non-classical form of HH that could be called “functional” HH (FHH). FHH differs from the classical one by the evidence that gonadotropin levels are in the low-normal range, but are inadequate for the testosterone levels, that often are also in the low-normal range. This commentary aims at reviewing knowledge on the forms of male HH in order to indicate and discuss clinical context, diagnostic and therapeutic approach in the less known non-classical form, i.e. FHH.

Raloxifene induces cell death and inhibits proliferation through multiple signaling pathways in prostate cancer cells expressing different levels of estrogen receptorα and β

Raloxifene (RAL), a selective estrogen receptor (ER) modulator (SERM) seems to induce apoptosis in both androgen‐dependent and ‐independent prostate cell (PC) lines via activation of ERβ and an antagonistic effect on ERα. In this study, we evaluated the effects of RAL on epithelial PC growth using the two following in vitro models: the androgen‐dependent cell line EPN which expressed both ERs; and a stabilized epithelial cell line derived from a prostate cancer specimen (CPEC), which expressed low levels of ERβ and lacked ERα. In EPN cells, there was an increase in the pre‐G1 apoptotic peak and a reduction in the S phase of the cell cycle with G0/G1 arrest after E2 or RAL treatment; bcl‐2 mRNA and Bcl‐2 protein levels were significantly reduced, while activated caspase‐3 and Par‐4 levels increased significantly after either E2 or RAL treatment; in addition, c‐myc transcript was inhibited after 10−6 M RAL treatment. A dose‐dependent increase of metallothionein II gene RNA level was also induced by RAL in EPN. In CPEC, there was only a weak apoptotic peak associated with caspase‐3 activation and Par‐4 increase after either E2 or RAL treatment; while c‐myc transcript level increased. RAL induced a rapid but transient phosphorylation of ERK 1/2 in EPN cells but generated a sustained effect in CPEC. These findings suggest that RAL effects on PC growth control in vitro are cell‐specific, depending on ERβ or ERβ/ERα relative expression levels. Moreover, this study demonstrated that RAL affected both transcriptional regulation and non‐genomic signals, which resulted in the modulation of multiple signaling pathways of apoptosis and of cell cycle progression. J. Cell. Physiol. 226: 1334–1339, 2011.

Involvement of Hypothalamus Autoimmunity in Patients with Autoimmune Hypopituitarism: Role of Antibodies to Hypothalamic Cells

CONTEXT Antipituitary antibodies (APA) but not antihypothalamus antibodies (AHA) are usually searched for in autoimmune hypopituitarism. OBJECTIVE Our objective was to search for AHA and characterize their hypothalamic target in patients with autoimmune hypopituitarism to clarify, on the basis of the cells stained by these antibodies, the occurrence of autoimmune subclinical/clinical central diabetes insipidus (CDI) and/or possible joint hypothalamic contribution to their hypopituitarism. DESIGN We conducted a cross-sectional cohort study. PATIENTS Ninety-five APA-positive patients with autoimmune hypopituitarism, 60 without (group 1) and 35 with (group 2) lymphocytic hypophysitis, were studied in comparison with 20 patients with postsurgical hypopituitarism and 50 normal subjects. MAIN OUTCOME MEASURES AHA by immunofluorescence and posterior pituitary function were evaluated; then AHA-positive sera were retested by double immunofluorescence to identify the hypothalamic cells targeted by AHA. RESULTS AHA were detected at high titer in 12 patients in group 1 and in eight patients in group 2. They immunostained arginine vasopressin (AVP)-secreting cells in nine of 12 in group 1 and in four of eight in group 2. All AVP cell antibody-positive patients presented with subclinical/clinical CDI; in contrast, four patients with GH/ACTH deficiency but with APA staining only GH-secreting cells showed AHA targeting CRH- secreting cells. CONCLUSION The occurrence of CDI in patients with lymphocytic hypophysitis seems due to an autoimmune hypothalamic involvement rather than an expansion of the pituitary inflammatory process. To search for AVP antibody in these patients may help to identify those of them prone to develop an autoimmune CDI. The detection of AHA targeting CRH-secreting cells in some patients with GH/ACTH deficiency but with APA targeting only GH-secreting cells indicates that an autoimmune aggression to hypothalamus is jointly responsible for their hypopituitarism.

Total parathyroidectomy without autotransplantation in the surgical treatment of secondary hyperparathyroidism of chronic kidney disease

Background: Subtotal parathyroidectomy (SP) and total parathyroidectomy (TP) with autotransplantation (TPai) are the most commonly adopted operations for the treatment of secondary hyperparathyroidism (2HPT). TP without autotransplantation had previously been confined to patients with advanced dialytic vintage, not eligible for kidney transplantation. Over the years, the procedure has gained more widespread use, but there is no precise knowledge on the immediate and long-term effects. Methods: The authors analyzed the immediate and long-term results of TP without autotransplantation, that is after the systematic removal of at least four glands in 20 patients operated for 2HPT, which were compared with results from TPai in an equal number of cases. Results: An improvement of the typical clinical symptoms was found in every patient undergoing surgery, and a significant reduction in intact PTH (iPTH) serum levels was achieved. Immediate normalization of iPTH level was observed in 11/20 TP cases, hypoparathyroidism in 4/20 and persistent HPT in 5/20 cases. One year of follow-up showed a slight increase in hypoparathyroidism, with 1/20 (5%) recurrence of the disease. One-year TPai results showed a similar percentage of euparathyroidism, as well as a higher long-term recurrence rate (4/20, 20%), although values do not reach statistical significance. Conclusions: TP may still be considered the operation of choice in patients with aggressive forms of 2HPT or of advanced dialytic vintage, with no access to renal transplantation, because of its low recurrence rate (5%). Post-operative aparathyroidism is rare, while hypoparathyroidism and hypocalcemia can be well controled by medical treatment.

Seminal anti-Müllerian hormone level is a marker of spermatogenic response during long-term gonadotropin therapy in male hypogonadotropic hypogonadism

BACKGROUND In adult men, anti-Müllerian hormone (AMH) levels are higher in semen than in serum, but the significance and control of its seminal secretion are still unknown. This study evaluated seminal and serum AMH levels during long-term gonadotropin therapy in men with hypogonadotropic hypogonadism (HH). METHODS A total of 20 men with never treated prepubertal-onset HH received i.m. hCG to normalize testosterone (T) and induce puberty. Afterwards, 11 of them, requiring fertility, were treated with HCG plus recombinant FSH (rFSH) (75 IU) twice a week, whereas 9 continued to receive hCG alone for 12 months. Before and during therapy, serum AMH, inhibin B and T levels were assessed. Semen samples were also collected during therapy for sperm count and seminal AMH assay. RESULTS HCG alone decreased basal high serum AMH and stimulated T and inhibin B levels. rFSH plus hCG increased seminal AMH levels, which were consequently significantly higher than with hCG alone, and positively correlated to sperm densities and testicular volumes at 3 and 12 months (P < 0.001). CONCLUSIONS Our data demonstrate that rFSH, added to hCG, stimulates seminal AMH and spermatogenesis in HH. Thus, seminal AMH levels are under T and FSH control and are closely related to progression of spermatogenesis. Our results also suggest that an early seminal AMH increase may be a marker of good future response to gonadotropin therapy in HH.

Recent advances in the biology of germ cell tumors: implications for the diagnosis and treatment

Testicular germ cell tumors (TGCT), are the most frequent solid malignant tumors in men 20–40 yr of age, and the most frequent cause of death from solid tumors in this age group. TGCT can be subdivided into seminoma and non-seminoma germ cell tumors (NSGCT), including embryonal cell carcinoma, choriocarcinoma, yolk sac tumor, and teratoma. Seminomas and NSGCT do not only present distinctive clinical features, but they also show significant differences as far as therapy and prognosis are concerned. Many novel markers have given further advantages to discriminate between histological subgroups. In addition, therapeutic approaches for the treatment of TGCT have been proposed: humanized antibodies against receptors/surface molecules on cancer cells, inhibitors of serine-threonine, and tyrosine kinases, and others. The review will focus on the recent advances in the research of molecular alterations identified in TGCT and on novel targeted anti-neoplastic strategies that might help to treat chemotherapy-resistant TGCT.

Effect of long‐term cabergoline therapy on the immunological pattern and pituitary function of patients with idiopathic hyperprolactinaemia positive for antipituitary antibodies

Objective  The occurrence of antipituitary antibodies (APA) in patients with idiopathic hyperprolactinaemia (IH) and the effects of dopamine agonists on these antibodies and long‐term pituitary function outcome have been so far not evaluated. This longitudinal study was aimed at investigating, in patients with IH the occurrence of APA and the effect of cabergoline on the pituitary function and behaviour of APA.

Genetic prenatal RET testing and pregnancy management of multiple endocrine neoplasia Type II A (MEN2A): A case report

Multiple endocrine neoplasia 2A (MEN 2A) is an inherited dominant syndrome characterised by medullary thyroid carcinoma, adrenal pheochromocytoma and hyperparathyroidism due to specific RET proto-oncogene mutations. Fertile MEN 2A women are at risk of complicated pregnancy because of unrecognised pheochromocytoma and transmission of RET mutation to the progeny. This condition may cause psychological distress in affected pregnant patients and their families. Here we describe the genetic prenatal testing, the pregnancy management and obstetric outcome in a MEN 2A patient with a right side adrenal hyperplasia and elevated calcitonin levels, a condition suspicious for possible recurrence of pheochromocytoma. We confirm that maternal or fetal complications are rare when MEN 2A diagnosis is made before pregnancy and an accurate monitoring is instituted. Furthermore, our results indicate that prenatal testing for RET mutations is highly recommended in making decisions and assuring parents on the lifelong risk of tumors. This will avoid the psychological distress that can further complicate the pregnancy of affected women.

Efficacy of recombinant human follicle stimulating hormone at low doses in inducing spermatogenesis and fertility in hypogonadotropic hypogonadism

Background: Recombinant-FSH (rFSH) added to hCG at dose of 450 IU weekly is effective in inducing spermatogenesis in patients with hypogonadotropic hypogonadism (HH), but there are no data on the use of lower doses. Aim: This observational retrospective study evaluated whether 150–225 IU of rFSH weekly were able to induce spermatogenesis in HH men who failed to start it with hCG alone. Subjects and methods: Thirty-four patients with pre-pubertal onset HH (20–44 yr old) without adverse fertility factors were considered for this study. After hCG pre-treatment they received also either rFSH (Group 1) or highly purified urinary FSH (hpFSH) (Group 2) 75 IU sc 2 or 3 times weekly. Semen analysis was performed every 3 months during pre-treatment and the 1st yr of combined therapy. Patients were also invited to refer pregnancies in their partners during the subsequent 12 months. Results: Total sperm count/ejaculate did not show significant difference between 2 groups, while a significantly higher forward motility was observed in Group 1 (p<0.05). The median times to achieve sperm output thresholds (first sperm appearance, sperm concentration >1.5 or >5 mil/ml) were significantly lower in Group 1 (p<0.04, 0.03, and 0.001, respectively). A tendency to a shorter time to pregnancy was shown in partners of Group 1. Conclusions: Our data indicate that lower rFSH week dose than that so far used was able to induce potentially fertilizing sperm output in HH men previously treated with hCG. The rFSH effects are comparable to those of hpFSH but with a trend to a faster outcome achievement.