Role of thyroid stimulating hormone in the maintenance and functioning of the human corpus luteum.

PURPOSE: To evaluate the impact of high thyroid stimulating hormone (TSH) levels on human granulosa-luteal (hGL) cells. METHODS: hGL cells were isolated from follicular aspirates derived from patients undergoing IVF treatment without any thyroid disorder (serum TSH 0.5-2 mU/L). Cells were cultured at 37 °C in DMEM, supplemented with 5% FBS. The cells were treated with 1 nM LH and increasing concentrations of TSH. At the end of culture, conditioned medium and cells were collected to analyze progesterone production, cell viability, and mRNA levels of genes involved in the steroidogenesis process. Human ovarian tissues were analyzed for TSH receptor (TSHR) expression by IHC. RESULTS: The expression of TSHR was detected in human corpus luteum by IHC and in hGL by RT-PCR. In hGL cells, TSH treatment did not modulate progesterone production nor the expression of steroidogenic genes, such as p450scc and HSD3b 1/2. However, TSH induced a dose-dependent increase in cell death. Finally, TSH did not affect LH-induced p450scc and HSD3b1/2 expression while LH partially reverted TSH negative effect on cell death in hGL. CONCLUSIONS: Elevated TSH levels in hypothyroid women may be associated with impaired CL functioning and maintenance. These findings open a new line of research for the importance of the treatment of women with thyroid dysfunction that could contribute to the onset of infertility.

Prevalence of elevated pulmonary artery systolic pressure in Down Syndrome young patients with and without congenital heart disease.

This study examined the prevalence and distribution of elevated systolic pulmonary arterial pressure, measured by echocardiography, in young patients with down syndrome associated or not with congenital heart disease and surgical correction during childhood. Pulmonary artery systolic pressure, computed by regurgitant tricuspid flow velocity evaluation, is the most frequently used parameter for the screening of pulmonary hypertension. Down syndrome and congenital heart disease often coexist and the probability to detect elevated systolic pulmonary arterial pressure in this setting is high. However, little is known about the evaluation of pulmonary arterial pressure during growth of patients with down syndrome with or without congenital heart disease. We enrolled 47 young patients (55% of male sex; mean age: 18.4 ± 6.0 years), 40 with congenital heart disease and 7 without a cardiac defect. Systolic pulmonary arterial pressure was assessed by echocardiography. No difference was found in the population dichotomized by presence or absence of CHD. Only male sex (p=0.000), highly sensitive troponin-T (P=0.027), tricuspid annular plane systolic excursion (TAPSE, p=0.045) and sPAP (p=0.004) were elevated in surgical group. The ASD was found as, the most common structural abnormality in our patients (50%), followed by VSD (27.5%) and complex CHD (such as complete atrioventricular canal defect, CAVC = 25% and Fallot disease = 15%). Furthermore, about 45% of patients had the combined defect. Only 37.5% of patients underwent to corrective surgery during the first months of life. We observed a significantly increase of sPAP values in patients with complex CHD, such as CAVC (p=0.019) and Fallot disease (p=0.001) but, in the following multivariate analysis performed in the patients with CHD, only Fallot disease remains as independent predictors of elevated values of sPAP (p=0.022). An elevated systolic pulmonary arterial pressure may represent the key screening tool in the diagnostic assessment of suspect pulmonary arterial hypertension in high risk population with down syndrome regardless the presence of congenital heart disease.

"Hormone of darkness" and human reproductive process: direct regulatory role of melatonin in human corpus luteum.

PURPOSE: To investigate the possible role of melatonin on human luteal cell function. METHODS: Corpora lutea were obtained from normally menstruating women (25-38 years old) in the midluteal phase (days 5-6 from ovulation) at the time of surgery for non-endocrine gynecologic diseases. The protocol was approved by the institutional review board of Università Cattolica del Sacro Cuore in Rome and all patients provided written informed consent. The corpora lutea were dated on the basis of the presumptive day of ovulation (day 0) , determined by urinary luteinizing hormone (LH) peak, ultrasound detection of corpus luteum or disappearance of the dominant follicle, and a rise in the plasma P concentration. ELISA or EIA kit and immunohistochemistry were performed. RESULTS: Melatonin was able to increase progesterone release and to influence the balance between luteotrophic and luteolityc factors. In addition, melatonin expression and MT2 receptor were detected, confirming the direct action of this indoleamine on CL. CONCLUSIONS: Melatonin may play an intriguing role in direct regulation of CL function and in establishing and maintaining of initial pregnancy. In conclusion, melatonin could become a relevant medication for improving ovarian and luteal function and in the early stages of pregnancy, opening new opportunities for the management of several ovarian-luteal and pregnancy diseases.

The resting metabolic rate in women with polycystic ovary syndrome and its relation to the hormonal milieu, insulin metabolism, and body fat distribution: a cohort study.

PURPOSE: To evaluate possible alterations of a major determinant of energy expenditure, the resting metabolic rate (RMR), in women with polycystic ovary syndrome (PCOS) compared with age-BMI similar controls. To assess whether the hormonal milieu, the body fat distribution and the insulin metabolism may affect energy consumption in these patients. METHODS: This is a monocentric observational prospective cohort study, including 109 Caucasian PCOS subjects and 31 healthy control women. (Median age PCOS 26.0 ± 9.2 years, controls 25.5 ± 8.5 years; median BMI-body mass index PCOS 26.4 ± 9.4 kg/m2, controls 27.2 ± 12.8 kg/m2). RMR was evaluated by the SenseWear Armband (SWA), a reliable and validated metabolic holter, never previously used in the PCOS population to this purpose. Hormonal assessment, insulin metabolism evaluated by HOMA-IR and OGTT, anthropometric features (BMI and WHR) were also assessed. RESULTS: Median RMR resulted similar in PCOS and control women: 1520.0 ± 248.00 kcal/day vs 1464.0 ± 332.70 kcal/day (p = 0.472), even after adjusting for BMI, fat distribution, insulin metabolism parameters. RMR resulted significantly correlated with BMI, WHR, estradiol levels, SHBG, total cholesterol, triglycerides, basal glycaemia, basal insulinemia, AUC insulin 240', and HOMA. In the subgroup of patients with WHR > 0.85, PCOS women showed a significantly lower RMR compared with controls. CONCLUSIONS: The higher prevalence of obesity, which negatively influences the reproductive and general health of PCOS women, could be related to factors other than an intrinsic alteration of the RMR. Further studies are needed to clarify the possible role of the visceral fat in modulating the energy balance in PCOS. TRIAL REGISTRATION NUMBER: clinicaltrials.gov Identifier NCT03132545.

Increased fibulin-1 plasma levels in polycystic ovary syndrome (PCOS) patients: possible contribution to the link between PCOS and cardiovascular risk.

PURPOSE: To investigate a possible relation between fibulin-1 plasma levels and PCOS. DESIGN: ELISA quantitative determination of human fibulin-1. METHODS: 50 women with PCOS and 40 control patients who attended the Unit of Human Reproductive Pathophysiology, Università Cattolica del Sacro Cuore, Rome, were enrolled. Ultrasonographic pelvic examinations, hormonal profile assays, oral tolerance test OGTT, lipid profile and ELISA quantitative determination of human fibulin-1 were performed. RESULTS: Fibulin-1 levels were found to be statistically significantly higher in PCOS patients than in matched control women. No statistically significant positive correlation was found between fibulin-1 and AUCi, HOMA-IR, total cholesterol, LDL, AMH, androstenedione and FAI, whereas a statistically significant positive correlation was found between fibulin-1 and 17OHP (p = 0.016) in the PCOS group. However, multivariable linear regression analysis showed that 17 OH P did not independently predict fibulin-1 levels (p = 0.089). CONCLUSIONS: Our data could contribute to explain the hypothesized increased cardiovascular risk and vascular damage in patients with PCOS. A better understanding of the cellular and molecular mechanisms involved in cardiometabolic disorders associated with PCOS is mandatory to identify new therapeutic strategies to eventually prevent the progression of cardiovascular diseases in these patients.

Genetics and Gene Therapy in Hunter Disease.

Mucopolysaccharidosis type II or Hunter syndrome is an X-linked lysosomal storage disease caused by a mutation in the gene encoding the lysosomal enzyme iduronate-2-sulfatase. The consequent enzyme deficiency causes a progressive, multisystem accumulation of glycosaminoglycans, which is the cause of the clinical manifestations involving also Central Nervous System for patients with the severe form of disease. The limits of the currently available therapies for Hunter syndrome, hematopoietic stem cell transplantation and recombinant enzyme replacement therapy, mainly regarding brain achievement, have encouraged several studies which recognized gene therapy as a potential therapeutic option for this condition. In vitro studies firstly aimed at the demonstration that viral vector- mediated IDS gene expression could lead to high levels of enzyme activity in transduced cells. The encouraging results obtained allowed the realization of many preclinical studies investigating the utilization of gene therapy vectors in animal models of Mucopolysaccharidosis II, together with a phase I clinical trial approved for Hunter patients affected by the mild form of the disease. Together to in vivo studies in which recombinant vectors are directly administered, systematically or by direct injection into Central Nervous System, also ex vivo gene therapy, consisting in transplantation of autologous hematopoietic stem cells, modified in vitro, into the animal or patient, has been tested. A wider clinical application of the results obtained so far is essential to ensure that gene therapy can be definitively validated as a therapeutic option available and usable for this rare but life-threatening disorder.

The 312N variant of the luteinizing hormone/choriogonadotropin receptor gene (LHCGR) confers up to 2·7-fold increased risk of polycystic ovary syndrome in a Sardinian population.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is a frequent condition, affecting about 15% of women of reproductive age. Because of its familial occurrence, a multifactorial model of susceptibility, including both genetic and environmental factors, has been proposed. However, the identification of genetic factors has been elusive. DESIGN: Case-control study aimed at evaluating possible associations between functionally relevant variants of the luteinizing hormone/choriogonadotrophin receptor gene (LHCGR) and PCOS phenotype. PATIENTS: A total of 198 PCOS and 187 non-PCOS women, aged 14-35 years, of Sardinian origin, were referred to the outpatient clinic of the Department of Obstetrics and Gynaecology of the University of Cagliari (Sardinia). PCOS diagnosis was based on the Rotterdam criteria. MEASUREMENTS: We determined the genotype of ins18LQ, S291N and S312N variants at the LHCGR locus. Genotype was related to the presence or absence of PCOS and to several clinical and biochemical characteristics. RESULTS: The presence of at least one 312N allele was strongly associated with PCOS risk (OR, 2·04; 95% CI, 1·32-3·14; χ(2) , 10·47; P = 0·001). 312N homozygosity was associated with a further risk increase (OR, 2·73; 95% CI, 1·25-5·95; χ(2) , 6·65; P = 0·01). The number of ins18LQ alleles was associated with LH serum levels in controls (χ(2) , 8·04, P = 0·017). CONCLUSIONS: For the first time, we have identified a genetic variant that is strongly associated with PCOS in an isolated population. These results, if confirmed in other cohorts, may provide the opportunity to test the S312N genotype at the LHCGR locus in fertile women to assess the risk of PCOS. The avoidance of triggering factors like weight increase may improve the reproductive outcome of potentially at-risk subjects.

Could antispasmodic drug reduce pain during hysterosalpingo-contrast sonography (HyCoSy) in infertile patients? A randomized double-blind clinical trial.

OBJECTIVE: To assess the effectiveness of an antispasmodic drug, hyoscine-N-butylbromide, in reducing pain during hysterosalpingo-contrast sonography (HyCoSy). METHODS: Eight hundred and sixteen patients undergoing HyCoSy were randomized to receive 10 mg hyoscine-N-butylbromide (n = 408) or placebo (n = 408) per os, 30 min before the procedure, in a double-blind randomized controlled trial. Immediately after the procedure, the patient was asked to describe any pain experienced in comparison with pain usually suffered during the menstrual cycle, and the operator assigned a pain score between 0 and 4 as follows: 0 (no reaction or discomfort), 1 (slight pain, less than menstrual pain), 2 (moderate pain, exceeding menstrual cramps but no vasovagal reaction), 3 (vasovagal reaction or pain requiring observation in a hospital) and 4 (vasovagal reaction or pain requiring resuscitation). The primary aim was to estimate the difference in pain score, considered as a categorical value, between the active arm of the trial and the control group. The secondary aim was to evaluate if pain is related to tubal patency. RESULTS: There was no difference in pain score between the hyoscine-N-butylbromide group and the placebo group (P = 0.807). There was a negative correlation between pain and tubal patency, regardless of treatment group (P < 0.0001). CONCLUSIONS: Administration of 10 mg antispasmodic drug hyoscine-N-butylbromide does not reduce pain in patients undergoing HyCoSy.

Nicotine and cotinine affect the release of vasoactive factors by trophoblast cells and human umbilical vein endothelial cells.

OBJECTIVE: To examine nicotine (N) and cotinine (C) effects on trophoblast cells (TCs) and human umbilical vein endothelial cells (HUVEC) secretion of soluble fms-like tyrosine kinase (sFlt-1), soluble endoglin (sENG), placental growth factor (PlGF), transforming growth factor-beta (TGF-beta) and vascular endothelial growth factor (VEGF). STUDY DESIGN: Human placentas and umbilical cords were collected from uncomplicated pregnancies at term from a total of 24 non-smoking women with a history of normal blood pressure. TCs and HUVEC were cultured for 24 h with C or N (from 10(-12) to 10(-7) M). MAIN OUTCOME MEASURES: sFlt-1, sENG, PlGF, TGF-beta and VEGF release and messenger RNA (mRNA) expression were evaluated by ELISA and real-time polymerase chain reaction (PCR), respectively. RESULTS: N and C reduced sFlt-1, sENG and PlGF release by TCs and TGF-beta release by HUVEC. Conversely, N and C increased PlGF secretion, while N alone increased sFlt-1 release by HUVEC. N and C were able to modulate VEGF mRNA expression in HUVEC. CONCLUSIONS: Our results suggest that N and C affect the balance of some important vasoactive factors released by TCs and HUVEC. This might be one of the possible mechanism through which smoke reduces the risk of hypertensive disorders during pregnancy as well as contributes to the well known detrimental effects of smoking on fetal development.

Ultrasound in polycystic ovary syndrome--the measuring of ovarian stroma and relationship with circulating androgens: results of a multicentric study.

BACKGROUND: The introduction of transvaginal approach in ultrasound (US) has enabled the accurate evaluation of the structure of the ovary and stroma. Stroma represents an acknowledged US marker for polycystic ovary syndrome (PCOS). The proportion revealed between the stroma and the ovary surface in the median section (S/A ratio) had been indicated as a reliable marker for hyperandrogenism. In order to verify the feasibility of this determination in routine use and to confirm the efficacy of S/A ratio in predicting hyperandrogenism in PCOS, a multicentric study was performed in association with five Italian research groups. METHODS: A total of 418 subjects of fertile age presenting oligomenorrhoea or secondary amenorrhoea, enlarged ovaries measuring >10 cm(3) and/or >12 follicles measuring 2-9 mm in diameter took part in the study. Clinical, US and hormonal evaluations were performed in the early follicular phase or on random days in amenorrhoeic subjects. US assessment included ovarian volume, follicle number, ovarian and stroma area in median section. The hormonal study included a baseline plasma determination of LH, FSH, estradiol (E(2)), androstenedione (A), testosterone (T), dehydroepiandrosteronesulphate, 17-hydroxy-progesterone, sex hormone-binding globulin and prolactin. Correlations and receiver operator curves were used in statistical analysis of data. RESULTS: S/A was found to be the best significant predictor of elevated A and T levels. In order to ascertain significant cut-off values in relation to A and T levels Youden indexes were calculated and indicated 0.32 as the best cut-off for the S/A ratio. CONCLUSIONS: This work underlines the importance of stroma measure in improving US diagnosis of PCOS and suggest that this parameter may be used in routine clinical practice. In fact, multicentre study demonstrated the easy feasibility of such procedure without need of sophisticated machines or intensive training for operators.

Is the PCOS diagnosis solved by ESHRE/ASRM 2003 consensus or could it include ultrasound examination of the ovarian stroma?

BACKGROUND: The clinical heterogeneity of polycystic ovary syndrome (PCOS) is mirrored by the unceasing debate on the most appropriate diagnostic criteria. METHODS AND RESULTS: To highlight differences and inconsistencies between NIH and ESHRE/ASRM criteria, we applied them to 375 patients with oligo/amenorrhoea and signs of hyperandrogenism. Among them, we identified 273 women with PCOS according to NIH, whereas up to 345 patients fulfilled ESHRE/ASRM criteria. The 72 patients, constituting the gap between the two classifications, exhibited a lower expression of clinical signs compared with the 273 patients matching both criteria. To the whole group, we then applied the ESHRE/ASRM criteria modified to include an easily reproducible ultrasound examination of the ovarian stroma (UCSC criteria). In this way, we identified 30 women who were healthy according to all criteria, 37 affected by PCOS according only to the ESHRE/ASRM Consensus, 35 affected according only to the UCSC and ESHRE/ASRM criteria and 273 who were considered to have PCOS by all criteria. These groups showed a progressively increasing expression of PCOS features. CONCLUSION: In the grey area between NIH and ESHRE/ASRM classifications, UCSC criteria could identify a subgroup of women, missed by NIH criteria, with more pronounced stigmas than those identified by ESHRE/ASRM criteria alone, and who may profit more from a targeted therapy.

Pituitary-ovarian response to the gonadotrophin-releasing hormone-agonist test in anovulatory patients with polycystic ovary syndrome: predictive role of ovarian stroma.

OBJECTIVE: To evaluate the influence of ovarian stroma on basal and poststimulus androgen secretion in patients affected by secondary amenorrhoea and polycystic ovaries (PCO) at ultrasound (US). DESIGN: Prospective study. PATIENTS: Fifty-one patients with PCO selected from a group of 72 normal weight women aged 20-25 years affected by secondary amenorrhoea and 10 normal ovulatory controls. METHODS: All subjects underwent US to evaluate volume, area, stromal area and stromal/total area ratio of both ovaries. Plasma levels of gonadotrophins, oestradiol (E2) and androgens were measured before and 24 h after GnRH-a injection. 60 min after stimulus LH and FSH were also assayed. RESULTS: Thirty patients had increased ovarian stroma (IS) and 21 patients normal ovarian stroma (NS). Significantly higher LH levels characterized the IS group, both basally and after GnRH-a stimulation compared with NS and controls (P < 0.01). Baseline levels of androstenedione, testosterone and 17-OHprogesterone (17-OHP) were significantly higher in IS group. Moreover, 17-OHP hyper-response to GnRH-a was demonstrated in IS group in comparison to NS and control groups (P < 0.005). CONCLUSIONS: Stroma evaluation may be of use in discriminating between different pathogenic factors in secondary amenorrhoea. This criterion may be applied to support the correct diagnosis of polycystic ovary syndrome (PCOS). Indeed, in line with the most recently proposed guidelines, patients affected by multifollicular ovaries could be classified as PCOS. The possibility of taking into account more than one US criterion or of carefully reanalysing the significance of increased stroma volume should be considered.

Drospirenone for the treatment of hirsute women with polycystic ovary syndrome: a clinical, endocrinological, metabolic pilot study.

The aim of this study was to investigate the effects of the new estro-progestinic containing the antimineralcorticoid progestogen drospirenone (DRSP) in women with polycystic ovary syndrome (PCOS). Fifteen hirsute PCOS patients were treated with 30 microg ethinyl estradiol plus 3 mg DRSP for 12 cycles. Ultrasonographic pelvic exams, evaluation of hirsutism scores, and hormonal and lipid profile assays were performed at baseline and after three, six, and 12 cycles of treatment. An oral glucose tolerance test and euglycemic hyperinsulinemic clamp were also performed, except at the third cycle. The treatment was well tolerated, and all women attained satisfactory cycle control. Hirsutism significantly improved from the sixth cycle onward. Body weight and fat distribution as well as blood pressure remained stable throughout the treatment. Plasma levels of LH, testosterone, SHBG, and, consequently, the free androgen index significantly fell from the third cycle on. Dehydroepiandrosterone sulfate and 17-hydroxyprogesterone significantly decreased after six cycles. The treatment did not affect glycoinsulinemic homeostasis. A trend toward an increase was seen for total cholesterol, triglycerides, and high- and low-density lipoproteins (HDL and LDL) plasma concentrations, although all parameters remained within the normal range. No modifications in total cholesterol/HDL and HDL/LDL ratios were induced by the therapy. The ethinyl estradiol/DRSP combination seems to be effective in ameliorating clinical and hormonal features of PCOS.

Effect of pioglitazone treatment on the adrenal androgen response to corticotrophin in obese patients with polycystic ovary syndrome.

BACKGROUND: To investigate the effect of pioglitazone on adrenal steroidogenesis in polycystic ovary syndrome (PCOS), we studied 11 obese (two with BMI >25 kg/m(2); nine with BMI >27 kg/m(2)) PCOS women before and after 6 months of treatment at a dose of 45 mg/day. METHODS: During the early follicular phase, ultrasonography and hormonal assays were performed. On separate days, all women underwent an oral glucose tolerance test (OGTT), a euglycaemic hyperinsulinaemic clamp and an adrenocorticotrophin hormone (ACTH) test. The same protocol was repeated after therapy. RESULTS: Pioglitazone treatment significantly reduced the insulin response to OGTT and improved the insulin sensitivity indices (P < 0.01 and P = 0.03 respectively). A significant decrease was found in LH (P < 0.05) and androstenedione (P < 0.01) levels after therapy, whereas the other hormonal parameters improved but not significantly. Pioglitazone administration reduced the response of 17alpha-hydroxyprogesterone (17OHP) and androstenedione to ACTH (P < 0.01 and P < 0.02 respectively), most likely through an inhibition of cytochrome P450. The same treatment was able to rebalance the relative activity of 17,20-lyase, as documented by an increase in the androstenedione:17OHP ratio (P < 0.05) after ACTH stimulation. CONCLUSIONS: Our data support the contention that insulin enhances ACTH-stimulated steroidogenesis, while inducing a relative impairment of 17,20-lyase activity. Whether the beneficial effects of pioglitazone on this imbalance could be related to the ameliorated glyco-insulinaemic metabolism or to a direct effect on the adrenal glands remains to be determined.

The effect of age on the ovarian response to gonadotropin and on pregnancy rate in polycystic ovary syndrome.

Recent studies have proposed that, in women affected by the polycystic ovary syndrome (PCOS), aging is able to regularize the menstrual cyclicity. To evaluate the ovarian response in PCOS patients according to their age, we studied 33 PCOS patients, 20 of whom with an age ranging from 28 to 34 years (younger PCOS) and 13 ranging from 35 to 45 years (older PCOS). All patients underwent an ovulation induction therapeutic protocol with low-dose recombinant follicle stimulating hormone, for a total of 80 cycles (44 cycles for the younger PCOS group and 36 cycles for the older PCOS group). No significant difference was found between the days of therapy (12.3 +/- 5.4 vs. 13.5 +/- 5.6 days), total amount of drugs (980.7 +/- 568.9 IU vs. 1063.9 +/- 469.5 IU) or ovulation rate (93% vs. 89%) in the two groups. The two groups showed a significant difference in the maximum estradiol level (2053.5 +/- 1497.2 vs. 1269.0 +/- 911.5 pmol/l, p < 0.01), the number of the recruited and preovulatory follicles (1.7 +/- 2.5 vs. 0.64 +/- 0.9, p < 0.05 and 1.7 +/- 1.1 vs. 1.2 +/- 0.5, p < 0.01, respectively) and the pregnancy rate (36% vs. 14%, p < 0.05). In conclusion, our data clearly showed that, also in PCOS, advanced age is a negative prognostic factor in the ovarian response to ovulation induction therapies.

Insulin and GH secretion in adolescent girls with irregular cycles: polycystic vs multifollicular ovaries.

In the present study insulin (I) and GH secretion was studied in a group of twenty-five young adolescent girls (mean age: 15 +/- 0.23 yr) with cycle irregularity associated to clinical signs of hyperandrogenism in comparison with that observed in eleven normal matched subjects with regular menses. All patients underwent basal hormone measurements and, on two consecutive days, an oral glucose tolerance test (OGTT) and a GHRH iv test. Therefore, all subjects had a transabdominal US scan for the measurement of ovarian volume and the characterization of ovarian morphology. On the basis of the US examination we found patients with polycystic ovaries (PCO-like group) and subjects with multifollicular ovaries (MFO group). PCO-like group exhibited T (p<0.01) and LH (p<0.05) plasma levels higher than control group and the highest free androgen index (FAI) values (13 +/- 0.87). All patients with irregular menses showed plasma concentrations of AUC for I (AUC-I) significantly higher in respect to control group (7359.4 +/- 709 vs 5447 +/- 431 microIU/ml x 180 min, p<0.01) as well as both PCO-like group and MFO group did (p<0.001 and p<0.01) respectively. MFO group showed higher values of the AUC for GH (AUC-GH) (2809 +/- 432 ng/ml x 120 min) in respect to controls (1708 +/- 208 ng/ml x 120 min, p<0.05) and PCO-like subjects (p<0.001), who on the contrary showed the lowest AUC-GH values (618 +/- 119 ng/ml x 120 min). In conclusion, PCO-like patients associated hyperinsulinemia with a blunted GH secretion while MFO patients had higher GH secretion associated with higher AUC-I values in a way suggesting an immature and still developing reproductive system.

A pilot study of the long-term effects of acipimox in polycystic ovarian syndrome.

BACKGROUND: To evaluate the effects of long-term acipimox administration on glucose-induced insulin secretion and peripheral insulin sensitivity in polycystic ovarian syndrome (PCOS), 20 PCOS subjects (eight lean and 12 obese) and 14 body mass index-matched controls (seven lean and seven obese) were investigated. METHODS: Fasting blood samples were collected for basal hormone and lipoprotein assays, after which patients underwent an oral glucose tolerance test (OGTT). The following day a euglycaemic-hyperinsulinaemic clamp was performed. After 4-6 weeks of treatment with acipimox at a dose of 250 mg given orally three times a day, the patients repeated the study protocol. RESULTS: No significant differences were found in the glucose, insulin or C-peptide responses to OGTT before and after anti-lipolytic drug administration in any group, nor was there any effect on insulin sensitivity. Concerning the lipid profile, acipimox administration led to a significant decrease of cholesterol and low-density lipoprotein levels in obese PCOS patients as well as in obese and lean controls. Lower triglycerides were found after the drug administration in both obese groups. Post-treatment free fatty acid levels were not significantly different when compared with basal values. CONCLUSIONS: Acipimox does not appear to be an effective insulin-lowering drug in PCOS, even if it can be used in obese women with PCOS as an additional therapeutic agent to ameliorate the atherogenic lipid profile of the syndrome.

Recombinant versus urinary follicle-stimulating hormone in the low-dose regimen in anovulatory patients with polycystic ovary syndrome: a safer and more effective treatment.

BACKGROUND: We studied polycystic ovarian syndrome (PCOS) in fifty 25- to 37-year-old women who failed to conceive with clomiphene citrate treatment. METHODS: Twenty patients were submitted to treatment with low-dose (75 IU) urinary FSH (uFSH) in order to achieve ovulation and 30 patients were treated with recombinant FSH (rFSH) according to the same protocol. RESULTS: Ovulation was achieved in 75 and 97% of the cycles after uFSH and rFSH, respectively (p < 0.02). The length of treatment needed to achieve ovulation, the number of ampules given and dose per kilogram were significantly lower in the rFSH group. Mild ovarian hyperstimulation syndrome (OHSS) was observed in 9 uFSH cycles, whereas only 1 of the women treated with rFSH developed an OHSS (1/38 vs. 9/36; p < 0.01). CONCLUSION: rFSH is more efficient than uFSH in inducing ovulation in PCOS patients. The high prevalence of ovulatory cycles using a lower dose guaranteed greater safety of treatment and significantly reduced the incidence of OHSS.

Naltrexone effect on pulsatile GnRH therapy for ovulation induction in polycystic ovary syndrome: a pilot prospective study.

The aim of the present study was to analyze the opioid influence on LH pulsatility in polycystic ovary syndrome (PCOS) patients and to evaluate the effectiveness of a long-term opioid antagonist (naltrexone) treatment in improving the pulsatile GnRH therapy which is successful in this syndrome. Ten obese women affected by PCOS participated in the study. Patients were hospitalized during the early follicular phase and underwent an oral glucose tolerance test (OGTT) with 75 g of glucose and a pulse pattern study followed by a GnRH test (100 pg i.v.). All patients were then treated for ovulation induction with pulsatile administration of GnRH (5 microg/bolus every 90 min). Since pregnancies did not occurr in any patient, after spontaneous or progestin-induced menstrual cycles, all patients received naltrexone at a dose of 50 mg/day orally for 8 weeks and during treatment repeated the basal protocol study and the ovulation induction cycle with the same modalities. The naltrexone treatment significantly reduced the insulin response to OGTT and the LH response to GnRH bolus, whereas it did not affect the FSH and LH pulsatility patterns. Concerning the ovulation induction by pulsatile GnRH, naltrexone treatment was able to improve, although not significantly, the ovulation rate (60% pre-treatment vs 90% post-treatment). Furthermore, the maximum diameter of the dominant follicle and the pre-ovulatory estradiol concentration were higher after long-term opioid blockade (follicular diameter 19.5+/-1.76 mm pre-treatment vs 21.6+/-2.19 mm post-treatment, p<0.001; maximum estradiol level 728.7+/-288.5 pmol/l pre-treatment vs 986.4+/-382.1 pmol/l post-treatment, p<0.05). During the naltrexone-pulsatile GnRH co-treatment two pregnancies occurred. In conclusion, our data show that naltrexone-pulsatile GnRH co-treatment is able to improve the ovarian responsiveness to ovulation induction in obese PCOS patients when compared to pulsatile GnRH alone. This action seems to be related to a decrease of insulin secretion. Further randomized studies should be performed in order to obtain significant conclusions on the possible clinical application.

A new ultrasound criterion for the diagnosis of polycystic ovary syndrome: the ovarian stroma/total area ratio.

OBJECTIVE: To evaluate whether some ultrasound parameters of ovarian morphology can discriminate between control women and patients with polycystic ovary syndrome (PCOS). DESIGN: Retrospective data analysis. SETTING: Volunteers women in an academic research environment. PATIENT(S): Eighty amenorrheic or oligomenorrheic women and 30 normal ovulatory control participants. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): We evaluated ovarian volume, area, stroma, and the stroma/total area (S/A) ratio by use of transvaginal pelvic ultrasound; and we assayed serum levels of gonadotropin, androgen, and estradiol during the early follicular phase (days 2 to 5) of the menstrual cycle in regularly cycling controls and on a random day in amenorrheic patients. RESULT(S): Patients with PCOS showed significantly higher ovarian volume, area, stroma, and mean S/A ratio when compared to multifollicular and control groups. Cut-off values have been defined for ovarian volume (13.21 mL), area (7.00 cm2), stroma (1.95 cm2), and S/A ratio (0.34). The sensitivity for PCOS diagnosis was 21%, 4%, 62%, and 100%, respectively. The S/A ratio showed the most significant correlation with the androgen levels. CONCLUSION(S): The evaluation of the S/A ratio can differentiate between PCOS and control or multifollicular women with both a sensitivity and a specificity of 100%. Furthermore, this ultrasound parameter is strictly related to hormonal milieu and to anthropometric characteristics.