A. Bellastella

Serum and follicular fluid cytokines in polycystic ovary syndrome during stimulated cycles

OBJECTIVE To investigate the serum and intrafollicular tumor necrosis factor–α and interleukin-6 concentrations in infertile women with polycystic ovary syndrome (PCOS) undergoing in vitro fertilization (IVF). METHODS Thirty-one patients with PCOS undergoing IVF were studied. Thirty-nine normally ovulating women matched for age and body mass index and undergoing IVF for male infertility were the control group. Serum tumor necrosis factor–α, interleukin-6, and estradiol levels were assayed before recombinant follicle-stimulating hormone stimulation under gonadotropin-releasing hormone analogue suppression and 34–36 hours after human chorionic gonadotropin (hCG) administration at the time of the oocyte retrieval. Cytokine and estradiol concentrations were also evaluated in the follicular fluids obtained at the time of oocyte retrieval. RESULTS The patients with PCOS had higher serum and follicular fluid tumor necrosis factor–α and interleukin-6 concentrations (P < .001) and lower follicular fluid estradiol levels (P < .05) than control women. In both groups, the serum tumor necrosis factor–α, interleukin-6, and estradiol values increased significantly after hCG stimulation. In both groups, the follicular fluid cytokine concentrations were higher than those found in the serum. In the PCOS women the follicular fluid tumor necrosis factor–α values were significantly and inversely correlated to the follicular fluid estradiol values (ρ = −0.79; P < .001); this correlation was not found in the control subjects. CONCLUSION In infertile women with PCOS, 1) serum and follicular fluid interleukin-6 and tumor necrosis factor–α values were higher than those found in control women, 2) the cytokine concentrations were higher in the follicular fluid than in the serum, and 3) the intrafollicular tumor necrosis factor–α concentrations were significantly and inversely correlated to the estradiol levels. These results suggest an involvement of the immune system in PCOS.

Occurrence of thyroid autoimmunity and dysfunction throughout a nine-month follow-up in patients undergoing interferon-β therapy for multiple sclerosis

Thyroid autoimmunity and dysfunction are a well known side effect of IFN α therapy for viral hepatitis and tumors, while the IFN β effects on the thyroid gland in neurological patients have not been studied. The aim of this longitudinal study was to look for the appearance of thyroid autoimmunity as well as for the occurrence of overt thyroid disease in the patients affected by multiple sclerosis (MS) treated with IFN β 1b. Eight patients (4 males, 4 females) undergoing r-IFN β 1b treatment (8 M.U. every other day for 9 months) for relapsing remitting multiple sclerosis entered the study. We have analyzed thyroid function parameters and auto antibody levels before and after 1, 2, 3, 6 and 9 months of therapy. None of them referred to familiar thyroid pathology or presented clinically overt thyroid disease except for one patient (case 4) who showed TPO-Ab pretreatment positivity and another (case 8) who was in therapy with Levothy-roxine 100 μg/die for multinodular goiter. The number of patients with appearance of thyroid antibodies has slowly increased, until the third month of therapy with 3 patients out of 7 positive for TPO-Ab. The only case of overt thyroid dysfunction reported by us appeared after nine months of therapy and consisted of a hypothyroidism. Our data suggest that short-term interferon β treatment is able to induce thyroid autoimmunity (42.8%) and dysfunction (12.5%).

Idiopathic central diabetes insipidus in children and young adults is commonly associated with vasopressin‐cell antibodies and markers of autoimmunity

Objectives  Autoimmune targeting of hypothalamic‐neurohypophyseal structures in children and young adults with posterior pituitary and anterior pituitary dysfunction, as well as pituitary stalk involvement, are not yet completely understood.

CIRCANNUAL RHYTHMS OF PLASMA LUTEINIZING HORMONE, FOLLICLE‐STIMULATING HORMONE, TESTOSTERONE, PROLACTIN AND CORTISOL IN PREPUBERTY

For a period of four years we have been studying 106 healthy males and 66 healthy females, aged 6–10, by cross‐sectional design, to look for evidence of a circannual rhythm in LH, FSH, testosterone, PRL, and cortisol secretion. Plasma samples were taken at 0800 h and all hormones were measured by RIA. A cosine function was fitted to the single data to indicate any significant circannual (about 1 year) rhythm and to estimate its parameters: mesor, amplitude, and acrophase. Annual changes were validated in the secretion of: LH (annual crest time in January in both sexes), testosterone (studied only in males, annual crest time in July), and PRL (significant rhythm only in females with annual crest time in March). FSH and cortisol did not show an annual rhythm in both sexes. Our data suggest that sex influences the circannual hormonal rhythms from prepuberty onwards.

Effects of lithium treatment on hypothalamic-pituitary-thyroid axis: A longitudinal study

Lithium carbonate, widely used in the treatment of bipolar patients, is well known to induce thyroid alterations. In this longitudinal study the thyroid function was investigated during lithium treatment over a period of 12 months in 12 euthymic bipolar patients with a normal thyroid function and absence of thyroid antibodies. Nine of the 12 patients were further studied on the 15th month, 5 of these 9 on the 18th month and 4 of the last-mentioned 5 on the 24th month. The mean basal and TRH-stimulated TSH values during lithium therapy were significantly higher as compared to those at the beginning of the treatment. More particularly, during lithium therapy, a significant increase of basal TSH over the normal range was found in 10 out of the 12 patients. A rise of TRH-stimulated TSH was found in 11 out of the 12 patients. The impairment of the hypothalamic-pituitary-thyroid (HPT) axis was transitory in the majority of cases. Two patients developed a nodular goiter during the treatment. Plasma T3, T4, FT3 and FT4 levels did not change during the treatment. Thyroid antibodies remained undetectable. The conclusions of the study are twofold: 1) Subclinical hypothyroidism during lithium therapy is much more frequent than previous cross-sectional studies suggest; 2) Thyroxine replacement in lithium-treated patients is advisable in order to prevent subclinical hypothyroidism and the risk of a subsequent goiter.

Detection of vasopressin cell antibodies in some patients with autoimmune endocrine diseases without overt diabetes insipidus

OBJECTIVE Cytoplasmic autoantibodies to vasopressin cells (AVP) have been detected in patients with idiopathic central diabetes insipidus and only in one patient with endocrine autoimmune diseases without clinical diabetes insipidus. The aim of this study was to look for AVP cell antibodies (AVP‐cell‐Ab) in human sera of a large population of autoimmune endocrine disease patients without diabetes insipidus and to test whether an occurrence of these antibodies in some patients can be associated with partial impairment of posterior pituitary function.

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.

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.

DYSGERMINOMA IN 45,X TURNER SYNDROME: REPORT OF A CASE

Here we report the fourth case of dysgerminoma in a patient with the syndrome of gonadal dysgenesis and 45,X karyotype. Typical Turners syndrome features were unusually associated with breast development, menarche and secondary amenorrhoea. Exaggerated basal and GnRH stimulated gonadotrophin and low oestradiol levels were typical of post‐pubertal Turners syndrome. Detailed (standard) chromosome and banding analysis excluded the presence of Y chromosome material. This case suggests that the presence of a Y chromosome is not necessary for abnormal differentiation of germ cells and the occurrence of a gonadoblastoma.