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Aims: Familial partial lipodystrophy (FPLD) is a rare autosomal dominant disorder, mostly due to mutations in lamin A (LMNA) or in peroxisome proliferator-activated receptor gamma (PPARG) genes. In the present study, we aimed to identify and functionally characterize the genetic defect underlying FPLD in an Italian family presenting with several affected individuals in three consecutive generations., Methods: Mutational screening by direct Sanger sequencing has been carried out on both LMNA and PPARG genes. In silico analyses and functional in vitro studies on transfected cell lines have been also performed to evaluate the biological impact of the identified mutation., Results: We identified a novel PPARG missense mutation (i.e., PPARγ2 Ile354Val) segregating with FPLD in the study family. In silico analyses and in vitro experiments showed that probably altering the PPARγ2 ligand binding domain conformation, the Ile354Val aminoacid change leads to a significant reduction (i.e., ~ 30-35%) of transcriptional activity in the mutant receptor, with no evidences of a dominant negative effect on the wild-type receptor., Conclusions: Our present data extend the spectrum of PPARG mutations responsible for FPLD3 and reinforce the notion that even loss of function mutations affecting transcriptional activity to an extent lower than that observed in the case of haploinsufficiency are able to cause a severe FPLD3 phenotype.

Purpose: The aim of this randomized study was to examine the efficacy of two high intensity educational programs: the conversation maps-based (CM™) education and the individual education (IE), compared to usual care (UC) in a cohort of type 2 diabetic (T2DM) patients., Methods: Ninety T2DM outpatients (30 per group) were randomized and 79 finished the study and were analyzed. The CM™ and IE groups received four educational sessions at 0, 4, 8 and 12 weeks, while the UC group received two brief individual sessions at 0 and 12 weeks. We evaluated glycemic control (HbA1c), diabetes treatment, body mass index (BMI) and carried out a questionnaire survey at three time points (before intervention, at 12 and at 32 weeks) to assess patients' satisfaction, attitudes toward diabetes and dietary knowledge., Results: All the three groups showed a significant and comparable reduction of both HbA1c and BMI. Diabetes therapy needed to be reinforced in a higher percentage of cases (39.3%) among UC patients compared to the IE (14.8%; p = 0.04) and the CM™ (8.3%; p = 0.01) groups. At 32 weeks Diabetes Treatment Satisfaction (DTSQ Q1 + Q4-8) significantly improved in the CM™ group (25.8 ± 4.5 vs. 22.4 ± 6.0; p < 0.01) and attitudes toward diabetes (ATT19) significantly improved in the IE group (58.0 ± 4.7 vs. 55.3 ± 5.1; p = 0.02)., Conclusions: Our trial provides preliminary data regarding the efficacy of structured group and individual education on achieving better glyco-metabolic control without drug therapy reinforcement and with positive effects on patients' attitude and treatment satisfaction.

Background: Hirsutism in females can be a source of considerable psychological distress and a threat to female identity. The aim of our study was to evaluate a possible relationship between facial, total body hair involvement and physical, mental and social well-being during 12 months of follow-up and treatment. Both objective and subjective methods of evaluating hirsutism were used: the Ferriman-Gallwey (FG) scoring method and the questionnaires General Health Questionnaire (GHQ)-12, Polycystic Ovary Syndrome Questionnaire (PCOSQ) and SF-12., Methods: The total of 469 female patients (mean age 27.61±7.63 years) was enrolled in 27 Italian centers participating in this study. Higher total body score was correlated to significant emotional discomfort. The correlation between the FG total body score, the facial score and physical/mental health was found to be significant in all the patients assessed by SF-12 questionnaire. The ongoing reduction of GHQ-12 score was found for the facial FG score at the first follow-up (T0-T1 period) and at the second one (T0-T2). No relationship was found between T1 and T2. At both 6 (T1) and 12 months (T2) follow-up an increase of PCOSQ Score (psychological improvement) was accompanied by a concomitant reduction of the FG Score (reduction of hirsutism). Physical health assessed by SF-12 questionnaire does not change at both 6- and 12-month follow-up, but mental health decreased at both T1 and T2., Results: The clinical improvement was achieved at 6 months regardless on treatment used and it was maintained for the next six-month follow-up. The clinical outcome could be assessed both by FG Score both through questionnaires administrated to each patient with hirsutism., Conclusions: For the evaluation of psychopathological discomfort the most appropriate questionnaire was GHQ-12, because of it major sensitivity to identify the psychological discomfort in the hirsutism.

The prevalence of very severe obesity has increased progressively and faster than other classes of obesity over the last years. It is unclear whether the prevalence of obesity-related complications and health risks increases progressively or reaches a plateau above a certain degree of obesity. The aim of our study was to investigate whether the severity of obesity was correlated with the prevalence of type 2 diabetes mellitus (T2DM), impaired fasting glucose, impaired glucose tolerance (IGT), metabolic syndrome (MS), and cardiovascular diseases (CVDs) in a large cohort of patients with different degrees of obesity. A cross-sectional study was conducted in 938 obese patients without a previous diagnosis of diabetes. Patients were assigned to different categories of obesity: mild-moderate obesity (BMI 30-39.9 kg/m(2)), morbid obesity (BMI 40-49.9 kg/m(2)), and super-obesity (SO, BMI ≥50 kg/m(2)). The prevalence of IGF, IGT, screen-detected T2DM, MS, and CVD was higher in SO patients than in the other groups. Interestingly, the association between SO and either MS or CVD was independent of glucose tolerance status, indicating that factors other than glucose metabolism also favor cardio-metabolic complications in obese patients. In patients without screen-detected T2DM (n = 807), insulin sensitivity and secretion OGTT-derived indexes indicated that SO patients had the worst glucose homeostasis relative to the other categories of obesity, which was indicated by the most reduced disposition index in these patients, a predictor of future T2DM. In conclusion, SO patients have an extremely high prevalence of glucose metabolism deterioration, and cardio-metabolic complications are more prevalent in these patients compared to less obese patients.

Growth Hormone (GH) and Insulin-like Growth Factor (IGF-1) stimulate proliferation, differentiation and extracellular matrix production in osteoblastic cells. GH and IGF-1 also stimulate recruitment and bone resorption activity in osteoclastic cells. A chronic systemic GH and IGF-1 excess produces an increased bone turn over in acromegalic patients (pts). Osteoporosis, joint alterations and bone deformities have a great clinical relevance in acromegalic pts and favour mortality and morbility. In the present study we evaluate the still unclear GH/IGF-1 activity on bone, Bone Mineral Density (BMD) and risk of osteoporotic Vertebral Fractures (VF), in relation to gender and gonadal status in acromegalic pts.Twenty acromegalic pts (12 F, 8 M) ranging 26-64 years were studied. Four pts were hypogonadic (1 F, 3 M), seven women were in post-menopause (PM) and four women eugonadic. The disease was active in twelve pts and inactive in eight pts. Serum and urinary 24/hrs calcium and phosphate and serum PTH, bone formation (P1NP) and resorption (beta-CTX) markers were assayed. BMD was measured using dual energy X ray absorptiometry (DXA) at the lumbar spine and femoral neck and bone quantitative ultrasonography (QUS) at phalanges. Osteoporotic VF were assessed by antero-posterior and lateral x-ray examinations of the thoracic and lumbar spine.Serum IGF-1, calcium and phosphate and 24-hours urinary calcium were significantly higher in pts with active disease in respect to pts with inactive disease. BMD was reduced in more of 50% of pts, in each skeletal sites measured. Z-score values were lower in males than in females. VF prevalence was 39% (43% in women, 57% in men). Fractured and non-fractured pts were not significantly different for BMD, T-score and Z-score.In conclusion, VF are frequent in acromegaly and, even mild and asymptomatic, play an important role on life quality and survival, already decreased in acromegalic pts. DXA and QUS methods are not sufficient for identifying pts at risk for fracture, due to the many possible interferences (bone deformities, osteoarthritis, joint rigidity and soft tissue tickening), since BMD is just one determinant of bone fracture. In the screening of acromegalic complications, it is necessary to perform a radiographic study of the spine at the time of diagnosis and during follow up.

Missense mutations of the lamin A/C gene, LMNA, have been recently identified in Dunnigan-type familial partial lipodystrophy (FPLD), which belongs to a heterogeneous group of rare disorders affecting adipose tissue distribution and metabolism. In this study, we sequenced the LMNA coding region from patients presenting with FPLD or other forms of lipodystrophy. We identified two heterozygous mutations in exon 8, R482W and R482Q, in FPLD patients (six families and one individual) with various clinical presentations. In addition, we found a novel heterozygous mutation (R584H) in exon 11, encoding specifically the lamin A isoform, in a patient with typical FPLD. Clinical and biochemical investigations in FPLD patients revealed that the expression and the severity of the phenotype were markedly dependent on sex, with female patients being more markedly affected. In subjects with generalized lipoatrophy, either congenital (13 case subjects) or acquired (14 case subjects), or Barraquer-Simon syndrome (2 case subjects), the entire LMNA coding sequence was normal. Although FPLD mutations are predominantly localized in exon 8 of LMNA, the finding of a novel mutation at codon 584, together with the R582H heterozygous substitution recently described, confirms that the C-terminal region specific to the lamin A isoform is a second susceptibility region for mutations in FPLD.

We report a case of a 34-year-old woman affected with ovarian arrhenoblastoma characterized by very high testosterone (T) levels (34.0-60.0 ng/ml; n.v.0.2-0.9) and suppressed gonadotropin levels. The physical examination revealed: severe hirsutism, acne, amenorrhea and other virilization signs. Basal hormonal evaluation also showed a markedly elevated 17-hydroxyprogesterone (17-OHP) and a mild delta 4 Androstenedione (A) and dehydroepiandrosterone sulfate (DHEAs) increase. ACTH test induced only slight changes in androgen secretion. By contrast, dexamethasone test greatly decreased A and DHEAs whereas T levels were only partially suppressed. Moreover, hCG test was clearly stimulatory for T and A. Suppressed gonadotropin levels did not respond to LHRH stimulation. The removal of the neoplasia was followed by normalization of T levels and increase of serum gonadotropins with subsequent restoration of a normal responsiveness to LHRH and resumption of an ovulatory menstrual cycle. This observation suggests that the high T levels played a primary role in the pathogenesis of the gonadotropin suppression and anovulation. Recovery of acne was complete whereas hirsutism score was reduced but still elevated after one year. This may be due to postoperative A and DHEAs levels slightly above the normal range, indicating the presence of adrenal hyperandrogenism.

Objective: To evaluate the efficacy and safety of T therapy in the induction of pubic hair growth in women with congenital panhypopituitarism., Design: Prospective clinical study., Setting: Patients followed at the University Endocrinology Clinic., Patients: Four women with congenital panhypopituitarism, showing no pubic hair development, currently treated with substitutive therapy with L-thyroxine, cortisone acetate, and estrogen-progestin combination., Interventions: A long-acting T preparation (25 to 50 mg) was given IM each month; serum T levels were determined before and after 12 and 24 months of therapy., Main Outcome Measure: Evaluation of pubarche stages (according to Tanner classification of stages)., Results: Patients developed pubarche (Tanner stage 3 to 5) after 3 to 18 months of T therapy. Testosterone levels were within the normal range during treatment. No hirsutism or other side effects were recorded., Conclusion: A cautious T treatment represents an effective and safe approach to the problem of pubarche induction in women with congenital panhypopituitarism.

Obesity is known to adversely affect breast cancer prognosis. Since obesity is associated with increased oestrogen levels, and oestrogens are growth stimulators of oestrogen receptor (ER)-positive breast carcinomas, we evaluated the relationship between the ER and progesterone receptor (PR) status of the neoplastic tissue and obesity in a series of 615 breast cancer patients. Both ER and PR concentrations were significantly and positively correlated with obesity by multiple regression analysis. Furthermore, the estimated probability of having an ER+/PR+carcinoma was significantly higher in obese patients (odds ratio 2.65, 95% confidence interval 1.56-4.48). This association between receptor-positive status and obesity was observed both in premenopausal and postmenopausal patients. Our data suggest, therefore, that obesity plays a role in determining the ER status of breast cancer and raise the possibility that ER presence in breast carcinomas occurring in obese patients is not indicative of a favourable prognosis.

Unexpectedly high LH and FSH serum levels, measured by conventional RIA methods employing a rabbit antibody, were observed in eight women 18 to 34 years of age who came to our observation for acne and/or hirsutism and with no sign of premature ovarian failure. Reinvestigation of patient histories revealed that all of them had previously received multiple injections of a multimicrobial vaccine containing rabbit proteins. Luteinizing hormone and FSH were remeasured by IRMA and ELISA. These techniques revealed that serum levels of both gonadotropins were within the normal range in all subjects. We believe that falsely elevated gonadotropin levels were induced by the presence of heterophilic antibodies against rabbit serum interfering in the conventional RIA.

Mexiprostil is a new gastroprotective 16-methoxy-16-methyl-PGE1 methyl ester. To assign the absolute configuration at C-15, a crystalline high-melting C-1 ester analog 5 11,15-dihydroxy-16-methoxy-16-methyl-9-oxoprost-13-en-1-oic acid 4-(4-bromobenzamide)phenyl ester (15R, 16R) was prepared and submitted to single crystal X-ray analysis. Since C-8, C-11, C-12 and C-16 are shown to have R configurations, the X-ray diffraction results established that the configuration at C-15 is also R.

In order to study the influence of sexual abstinence on sperm concentration and semen volume, we have evaluated 195 semen samples of healthy individuals, grouped as follows according to abstinence length: A) 2-4 days; B) 5-7 days; C) more than 7 days. Differences between semen samples collected at home or at the laboratory were also studied. Semen volume was smaller in group A than in group B and C (p less than 0.01), while no significant difference was found in sperm concentration among the three groups. The place of collection did not affect semen characteristics. These results suggest that while a shorter abstinence is associated with a smaller semen volume the length of abstinence does not affect sperm concentration.

The reproductive hormone function was investigated in three subjects, two brothers and one unrelated patient, with a Robertsonian translocation, who had come to us because of infertility. Basal levels of LH, FSH, testosterone, 17-beta-estradiol and prolactin were repeatedly measured by radioimmunoassays. In addition, clomiphene citrate, synthetic LH-RH, hCG and TRH tests were carried out. Karyotypes complemented by G-banding and C-banding, repeated semen analyses, and testicular biopsies were also obtained. The karyotype of all three subjects was 45, XY-13, -14, +t(13; 14) (p11; q11). Semen analyses showed oligozoospermia, and reduced or reduced/normal sperm motility. In addition, a high percentage of atypical forms was present in all three subjects. Reproductive hormone measurements in our three patients were substantially normal. Only one of the two brothers exhibited slightly low LH and testosterone levels. Both brothers also had elevated estradiol levels. Gonadotropin and testosterone responses to respective provocative stimuli, as well as prolactin elevation following TRH, were normal. In conclusion, the semen abnormalities observed in these three subjects with Robertsonian translocation appear to be responsible for their impaired fertility. However, the reason why some carriers of the same translocation are fertile and some others are subfertile or infertile remains unclear. It might be speculated that an individual genetic variability is responsible for different degrees of spermatogenic failure, accompanied, in more severe cases, also by reproductive hormone disorders.

The synthesis of 1-[(2-mercaptocyclopentyl)carbonyl]-L-prolines, 1-[(2-mercaptocyclobutyl)carbonyl]-L-prolines and related benzoyl derivatives as pure isomers is described. The abilities of all the compounds to inhibit angiotensin converting enzyme (ACE) in vitro and in vivo and to lower the systolic blood pressure in renal hypertensive dogs were determined. Three of them, namely 1-[[2-(benzoylthio)cyclopentyl]carbonyl]-L-proline (10f(R,S], 1-[(2-mercaptocyclopentyl)carbonyl]-L-proline (10g(R,S], and 1-[[2-(benzoylthio)cyclobutyl]carbonyl]-L-proline (16f(R,S], were found to be as potent as captopril in reducing blood pressure. The influence of chirality and ring size on the ACE inhibition is described.

The synthesis of the pure diastereoisomer of 16-methoxy-16-methyl-PGF2 alpha, -PGE2, and -PGE1 is described. The absolute configuration of C-16 was established by chemical methods, while the absolute C-15 configurations of the diastereoisomers were assigned tentatively on the basis of their chromatographic behavior and NMR spectra. The synthetic prostaglandin analogues were evaluated for antisecretory, antifertility, and diarrheogenic effects. Both the C-15 and C-16 configurations were found to be critical for the biological activities. These studies indicate that the introduction of the methyl and methoxy groups at C-16 into the prostaglandin analogues markedly increases the ratio of antisecretory to diarrheogenic action. One of the PGE1 derivatives, 9f(15 alpha, 16R) (MDL 646, mexiprostil), was selected for further pharmacological evaluation and is currently under clinical investigation.

An analysis of thyroid cancer morbidity was carried out in two adjacent areas of Sicily differing in iodine intake. A consecutive series of 911 patients with "cold" nodules from an iodine-deficient area (IDA) and 2537 from a control area (CA) were examined by fine needle aspiration and selected for surgery and pathologic examination. Malignancies were found in 27 of the patients (2.96%) from the IDA and in 139 patients (5.48%) from the CA. Based on a population survey indicating that "cold" thyroid nodules were 2.5 times more frequent in the IDA with respect to the CA, we calculated a prevalence of 127 thyroid cancers per 10(5) inhabitants in the IDA versus 93 in the CA (P less than 0.001). Moreover, follicular and anaplastic carcinomas were three times more frequent in the IDA than in the CA (75 versus 24 cases per 10(5) inhabitants, respectively). These studies indicate that iodine deficiency may be one factor in the development of certain thyroid malignancies in man.

Ovulation induction with human gonadotropins (hMG or pFSH and hCG) was simultaneously monitored with daily serum 17 beta-estradiol measurements and ultrasound in 38 infertile women. They were subgrouped as follows: A, hypogonadotropic hypogonadism (n. 7); B, polycystic ovary syndrome (n. 13); C, non-PCO chronic anovulation (n. 6); D, unexplained infertility (n. 12). The dose of hMG and the duration of therapy were assessed individually depending on the results of the monitoring when serum estradiol concentration was 500-1500 pg/ml and/or ultrasound showed of a follicle of at least 18 mm, hMG was stopped and hCG was administered 36 hours later. Ovulation was obtained in 61 cases and pregnancy occurred in 12 women out of 64 monitored cycles. The highest pregnancy rate was observed in hypogonadotropic hypogonadism; this group also required the greatest total dose of hMG to obtain ovulation. We confirm that women with PCOS are at increased risk with this therapy, since 5 subjects in our series showed signs of ovarian hyperstimulation in spite of the lowest total dose of FSH administered to this group. We conclude that anovulatory states of various origin are associated with different ovarian sensitivity.