A novel SNP at exon 17 of INSR is associated with decreased insulin sensitivity in Chinese women with PCOS

To investigate the association of single-nucleotide polymorphisms (SNPs) in exon 17 of the insulin receptor (INSR) gene with insulin resistance and INSR beta-subunit expression in polycystic ovary syndrome (PCOS) patients, a case-control study was carried out in an academic endocrinology clinic of China. One hundred and nine Chinese patients with PCOS and 107 healthy Chinese women as control were recruited. Their leukocytes and red blood cells were separated from blood samples, for SNP analysis with single-stranded conformation polymorphism and for the INSR beta-subunit expression detection by western blot analysis, respectively. A novel T/C SNP at codon Cys1008 (position 3128 of NM_000208) of INSR was found in two allele genotypes, i.e. the homozygous CC and the heterozygous TC. A higher frequency of the mutant homozygous CC was observed in the PCOS women with PCOS than that in the controls (21.1 versus 5.6%, P < 0.01). In contrast with the women with wild-type genotype, a significantly lower insulin sensitivity index in the women with each of the two mutant genotypes was revealed (CC: 0.335 +/- 0.026/TC: 0.346 +/- 0.027 versus TT: 0.367 +/- 0.029, P < 0.05). No relationship was found between the novel SNP and the INSR beta-subunit expression. We concluded that the novel T/C SNP at codon Cys1008 of INSR is associated with decreased insulin sensitivity in Chinese women with PCOS and that the association is not by the change of synthesis or secretion of INSR beta-subunit, but most possibly by the effects of this novel SNP on the function of INSR beta-subunit.     

Aortic function is compromised in a rat model of polycystic ovary syndrome

BACKGROUND: Arterial mechanical parameters are modified in women with polycystic ovary syndrome (PCOS), before and during pregnancy. This study tested the hypothesis that aortic mechanics and endothelial function are modified in the mifepristone-treated rat model of PCOS. METHODS: Female rats injected daily with mifepristone or vehicle for 7-9 days were assessed by ultrasound to allow estimation of aortic stiffness index and compliance. The influence of acetylcholine (ACh) and sodium nitroprusside (SNP) on dissected phenylephrine-contracted aortic rings was assessed. RESULTS: Aortic compliance was reduced by 67% in mifepristone-treated rats versus controls (P<0.05), while stiffness index was increased 2.3-fold (P<0.02). ACh-induced dilation was less in aortic rings from mifepristone-treated rats (P=0.022) and was less sensitive to the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) (P<0.001), while SNP-induced dilation was greater (P=0.001). CONCLUSIONS: Aortic mechanics in vivo and endothelial function in vitro were consistently perturbed in mifepristone-treated rats. Aortic ring behaviour suggested that NO release was depressed or degradation elevated, with a compensatory increase in NO sensitivity and/or activation of a non-NO-mediated relaxation mechanism. The mifepristone-treated rat is a valid model for investigation of the vascular deficits seen in PCOS.     

Effect of postmenopausal hormone replacement on atherosclerosis in femoral arteries.

OBJECTIVES: On the basis of epidemiological and experimental data, it has been supposed that hormone replacement therapy (HRT) inhibits atherosclerosis in postmenopausal women. This randomized controlled trial examined whether 1 mg 17beta-estradiol daily, combined cyclically with 0.025 mg gestodene in every month (HRT 1), or in every third month (HRT 2) slows the increase of intima-media thickness in femoral arteries compared with no HRT. METHODS: Healthy postmenopausal women (n=321) with an increased risk for future vascular disease as indicated by >1 mm of intima-media thickness in the carotid arteries were equally randomized to one of the three groups for 48 weeks. Ultrasound scans of femoral arteries were recorded at study start and study end, together with a thorough clinical examination and laboratory work-up. RESULTS: Complete scans were obtained in 260 of the 264 subjects who participated until study end. Mean maximum intima-media thickness of four femoral artery segments (common and superficial, both sides) was 0.93+/-0.37 mm (mean+/-S.D.) at study start. It increased by 0.02+/-0.05, 0.02+/-0.05, and 0.03+/-0.05 mm in the HRT 1, HRT 2 and no HRT groups, respectively (HRT 1 versus no HRT, HRT 2 versus no HRT; both P>0.2). Compared with no HRT, HRT significantly lowered follicle stimulating hormone, low-density lipoprotein cholesterol, and fibrinogen. CONCLUSIONS: In this 1-year trial, irrespective of the progestogen dose used, HRT with 1 mg 17 beta-estradiol did not inhibit progression of femoral artery atheroslerosis in postmenopausal women with subclinical vascular disease.     

Height, weight, and motor-social development during the first 18 months of life in 126 infants born to 109 mothers with polycystic ovary syndrome who conceived on and continued metformin through pregnancy

BACKGROUND: We prospectively assessed growth and motor-social development during the first 18 months of life in 126 live births (122 pregnancies) to 109 women with polycystic ovary syndrome (PCOS) who conceived on and continued metformin (1.5-2.55 g/day) through pregnancy. METHODS: The lengths and weights of PCOS neonates were compared with gender-specific Centers for Disease Control and Prevention (CDC) infant data. Gestational diabetes (GD) and pre-eclampsia in women with PCOS were compared with 252 healthy women without PCOS who had >or=1 live birth (262 live births). RESULTS: There were 101 out of 126 (80%) term (>or=37 gestational weeks) PCOS births, which was not significantly different (P = 0.7) from controls, 206 out of 252 (81.7%). There were two (1.6%) birth defects. GD occurred in nine out of 119 PCOS pregnancies (7.6%) versus 40 out of 251 (15.9%) controls, P = 0.027. The prevalence of pre-eclampsia did not differ in PCOS versus control pregnancies (4.1 versus 3.6%, P = 0.8). The birth length and weight of the 52 male neonates did not differ (P > 0.05) from those of CDC males; the 74 female neonates were shorter than CDC females (48.9 +/- 5.4 versus 50.6 +/- 2.7 cm, P = 0.006) and weighed less (3.09 +/- 0.85 versus 3.29 +/- 0.52 kg, P = 0.04). There were no systematic differences in growth between PCOS and CDC infants over 18 months. At 3, 6, 9, 12 and 18 months, of a potential 100% motor-social development score, scores (+/-SD) were 95 +/- 13, 98 +/- 8%, 95 +/- 10, 97 +/- 8 and 94 +/- 16%; no infants had motor-social developmental delays. CONCLUSIONS: Metformin reduced development of GD, was not teratogenic and did not adversely affect birth length and weight, growth or motor-social development in the first 18 months of life.     

Microvascular dysfunction in women with polycystic ovary syndrome

BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with multiple cardiovascular risk factors and an increased prevalence of arterial dysfunction. However, microvascular dysfunction in PCOS has not been assessed. METHODS: Subjects comprised 12 women with PCOS and 12 age-matched controls with normal ovaries. Microvascular function was assessed by observing forearm skin microvascular erythrocyte flux responses, to cumulative iontophoretic doses of 1% (w/v) acetylcholine (ACh) and 1% (w/v) sodium nitroprusside (SNP), using laser Doppler imaging. RESULTS: Basal microvascular perfusion was comparable in PCOS and controls. The increase in skin microvascular perfusion in response to ACh was however generally blunted in PCOS women (P = 0.018). Peak ACh-induced erythrocyte flux was also less (p < 0.04) in PCOS women (125.1 +/- 21.7, i.e. 5.3-fold basal flux) than in controls (200.8 +/- 28.5, i.e. 8.3-fold basal flux). Analysis of covariance indicated this effect was unrelated to differences in body mass index or serum testosterone but serum insulin may be a weak confounder. No differences were noted between the PCOS and control groups in their response to SNP. CONCLUSION: Despite its limited sample size studied, this is the first demonstration that women with PCOS exhibit microvascular endothelial dysfunction, indicated by an inhibited vasodilatory response to ACh.     

The effects of hormone replacement therapy on echocardiographic basic cardiac functions in postmenopausal women

This prospective study was designed to investigate the effects of hormone replacement therapy (HRT) on systolic and diastolic functions. Twenty-eight non-smoking, healthy postmenopausal women who had not received any kind of HRT for at least three years within the onset of menopause were included in the study. All patients received 0.625 mg conjugated oestrogens and 2.5 mg medroxyprogesterone acetate as daily HRT regimen. Their basic systolic and diastolic functions were investigated echocardiographically using standard positions and windows before and 6 months after initiation of HRT. The means of age, weight and length of postmenopausal period were 49.3 +/- 5.8 years, 63.5 +/- 8.7 kg and 46.3 +/- 7.1 months, respectively. Heart rate and systolic and diastolic pressures were similar during the pre- and post-treatment periods. After 6 months of HRT, the mean left ventricular end-systolic and end-diastolic volumes were decreased significantly (71.3 +/- 16.4 versus 56.3 +/- 22.8 ml, 144.5 +/- 26.1 versus 111.7 +/- 24.0 ml, respectively, P < 0.05). Left ventricular ejection fraction was increased (45.1 +/- 6.2% versus 54.8 +/- 4.1%, P < 0.05). Improvement in diastolic function was significant compared with the pretreatment period (E/A 0.90 +/- 0.2 versus 1.10 +/- 0.4, deceleration time 238 +/- 36.8 versus 201 +/- 24.2 ms, respectively, P < 0.05). Based on our preliminary results, we conclude that besides the known favourable effects on women's lives, HRT may also improve cardiac performance and age-related dysfunctions. The present results further suggest that oestrogens exert many direct effects on the cardiovascular system, other than the metabolic changes related to lipoproteins.      

A prospective,randomized, controlled trial comparing highly purified hMG with recombinant FSH in women undergoing ICSI: ovarian response and clinical outcomes

BACKGROUND: To assess the clinical profile and efficacy in assisted reproductive treatment of a new human-derived highly purified (HP) menotropin, we compared HP hMG and recombinant (r) FSHalpha use in ICSI within a prospective, randomized, controlled study. METHODS: 100 infertile women were treated with HP hMG (50 patients) or rFSHalpha (50 patients). All patients received the same daily gonadotrophin dose (150 IU) following GnRH agonist suppression (long regimen) until more than three follicles >17 mm and estradiol (E(2)) levels >600 pg/ml were reached. Patients were monitored with daily LH, FSH, hCG, estradiol (E(2)), progesterone, and testosterone measurements; and alternate day pelvic ultrasound. RESULTS: Treatment duration (11.1 +/- 0.4 versus 12.9 +/- 0.5 days, P < 0.05) and gonadotrophin dose (22.4 +/- 1.0 versus 27.0 +/- 1.5 ampoules, P < 0.05) were lower in the HP hMG group. Conversely, peak pre-ovulatory E(2) (1342 +/- 127 versus 933 +/- 109 pg/ml, P < 0.005); and area under the curve of E(2) (3491 +/- 350 versus 2602 +/- 349 pg/ml.day, P < 0.05), immunoreactive serum FSH (65.9 +/- 2.1 versus 48.8 +/- 1.8 IU/l.day, P < 0.001). and hCG (1.7 +/- 0.3 versus 0.0 +/- 0.0 IU/l/day, P < 0.001) during treatment were higher in the HP hMG group. Cycle cancellation rates, transferred embryo number, pregnancy rates per started cycle (30 versus 28%) and per embryo transfer (35 versus 35%) and miscarriage rates (6 versus 6%) were not significantly different. CONCLUSIONS: HP hMG treatment was associated with: (i) a more efficient patient response, as reflected by reduced treatment duration and gonadotrophin requirements; (ii) increased serum levels of hCG, E(2), and immunoreactive FSH during treatment; (iii) an ICSI outcome indistinguishable from rFSHalpha.     

Venous endothelial function in postmenopausal women after six months of tibolone therapy.

STUDY OBJECTIVE: To test venous endothelial function in long-term climateric therapy with tibolone. DESIGN: Measurement of dorsal hand-vein diameter by venous occlusion plethysmography during infusion of norepinephrine (NE), bradykinin (BK), NG-monomethyl L-arginine (L-NMMA) and sodium nitroprusside (SNP). SETTING: Plethysmography and Menopause Units. University Hospital Valdecilla. Santander. Spain. PATIENTS: Eleven postmenopausal women having continuous treatment with oral tibolone (2.5 mg/day) for 6 months. INTERVENTIONS: Three plethysmography studies were made: at baseline, and at three and six months of treatment. Main outcome measures: Dorsal hand-vein diameter measured by venous occlusion plethysmography during infusion of NE, BK, L-NMMA and SNP. RESULTS: (a) Baseline study: maximum dilation with BK was 54.2+/-10.2%. (b) Three-month study: BK dilation of 71.5+/-11.9%, with a significant increase of 17.3% (P=0.019) compared with baseline. (c) Six-month study: BK dilation of 77.5+/-11.9%, with a significant increase 23.3% (P=0.002) compared with baseline. Maximal vasodilation was reached with SNP in the three studies and L-NMMA infusion has a similar vasoconstrictor response in the three studies. CONCLUSIONS: Long-term climateric therapy with tibolone improves vein endothelium-dependent vasodilation suggesting a positive impact of this drug on endothelial function.     

Effects of age,hypertension and HRT on serum aminopeptidase A activity

OBJECTIVES: It is conceivable that aminopeptidase A (APA)/angiotensinase is involved in the pathogenesis of hypertension. The aim of this study was to evaluate the influences of age, hypertension and hormone replacement therapy (HRT) on serum APA activity in middle-aged and elderly women. METHODS: Blood samples were collected from 117 women aged 40-69, 48 normotensive healthy women not receiving HRT, 57 normotensive women receiving HRT, and 12 hypertensive women (blood pressure >140/90 mmHg) with no medication. Serum APA activity was measured using alpha-glutamyl-p-nitroanilide as substrate spectrophotometrically. RESULTS: Serum APA activity increased along with age between 40 and 69 in healthy women not taking HRT (r=0.351, P<0.05). Hypertensive women had higher serum APA activity than age-matched normotensive women (25.4+/-4.2 versus 22.4+/-3.4 microM/min; P<0.05) Compared with non-users of HRT, APA activity was elevated in women receiving HRT (23.9+/-3.8 versus 20.4+/-3.2 microM/min; P<0.05). CONCLUSIONS: APA activity had a positive correlation with age in healthy women. Furthermore, hypertension and HRT up-regulated the serum APA activity significantly. The measurements of serum APA would be of value to elucidate the physiological and clinical roles of APA, although further studies are required.     

Differential effects of oral conjugated equine estrogen and transdermal estrogen on atherosclerotic vascular disease risk markers and endothelial function in healthy postmenopausal women

BACKGROUND: Recent studies have revealed that HRT may increase the risk for atherosclerotic vascular disease (ASVD). METHODS: We investigated the effects of HRT via different administration routes on the markers for ASVD and endothelial function in healthy postmenopausal women. The oral HRT group (n=18) received conjugated equine estrogen 0.625 mg/day; the transdermal HRT group (n=18) received 17beta-estradiol (E2) gel 0.6 mg/day for 6 months. The control group (n=30) had no treatment for 6 months. RESULTS: The C-reactive protein (CRP) rose from 0.129+/-0.116 to 0.752+/-0.794 mg/dl (P<0.01) in the oral HRT group but remained unchanged in the transdermal HRT and control groups. The flow-mediated vasodilation (FMD) in the brachial artery was increased significantly by HRT from 6.0% before oral HRT to 14.7% after oral HRT (P<0.001) and from 5.9% before transdermal HRT to 13.9% after transdermal HRT (P=0.001). CONCLUSIONS: These data suggest that oral estrogen induces ASVD risk by increasing acute inflammation; however, transdermal estrogen avoids this untoward effect. Additionally, transdermal estrogen exerts a positive effect on endothelial function similar to that of oral estrogen. Therefore, the transdermal route might be favourable in terms of ASVD risks.     

Differences in ovarian function parameters between Chinese and Caucasian oocyte donors: do they offer an explanation for lower IVF pregnancy rates in Chinese women?

BACKGROUND: IVF outcomes in Chinese women are inferior to those of Caucasian patients. Reflecting prematurely diminished ovarian function, women with elevated age-specific baseline (b-) FSH levels are designated to suffer from premature ovarian aging (POA). We investigated if the prevalence of POA differs between these two ethnic populations. METHODS: We compared patient characteristics and first IVF cycle outcomes in 29 consecutive, Caucasian and 17 Asian-Chinese oocyte donors. POA was diagnosed in a donor if her b-FSH levels exceeded the 95% confidence interval (CI) for her age group. RESULTS: There was no age difference between Chinese and Caucasian groups (26.2 +/- 4.9 versus 25.7 +/- 3.1 years, respectively). Chinese women demonstrated, however, a higher cycle cancellation rate (5/17, 29.4%), either before cycle start or during stimulation (0/29; relative risk 1.42, 95% CI 1.04-1.9; P < 0.01), fewer oocytes per initiated cycle (9.3 +/- 9.7 versus 15.3 +/- 7.1, respectively; P < 0.05) (difference disappeared for only cycles that reached retrieval) and higher b-FSH levels (7.5 +/- 1.9 versus 5.1 +/- 1.7 mIU/ml, respectively; P = 0.004). Nine out of 17 (53%) of Chinese and only 1/26 (4%) of Caucasian donors met b-FSH level criteria for a presumptive POA diagnosis. Their odds of meeting POA criteria were approximately 30-times greater (odds ratio 31.5; 95% CI 3.5-18.7; P < 0.0001). CONCLUSIONS: These data suggest a possible explanation for lower IVF pregnancy rates in Chinese women. Preceding treatment, Chinese women at all ages should be carefully investigated to detect occult POA. Ethnicity may have to be considered an additional outcome variable in fertility studies.     

Association between single nucleotide polymorphisms of estrogen receptor alpha gene and efficacy of HRT on bone mineral density in post-menopausal Japanese women

BACKGROUND: Although HRT for post-menopausal women can protect against bone loss, variations in bone responses exist. We studied whether single nucleotide polymorphisms (SNP) of the estrogen receptor-alpha (ERalpha) gene contribute to the effect of HRT on lumbar spine bone mineral density (BMD). METHODS: Subjects were 84 post-menopausal women who had been taking HRT for 3 years to treat osteopenia or osteoporosis. Eighteen SNP in the ERalpha gene were characterized by a single nucleotide primer extension assay. RESULTS: Genotyping of the 84 individuals revealed that all SNP were quite common, the minor allele frequency being > or = 20%. A SNP in intron 6 (IVS6+14144) was significantly associated with the response to HRT for the first 3 years after starting treatment (P = 0.043, 0.025 and 0.032 for the first, second and third years respectively). Haplotype analysis revealed that a combination of SNP IVS6+14144 and IVS4+4238 was significantly correlated with the response to HRT; women with haplotype G-G (IVS6 14144-IVS4 4238) showed a significantly higher response (P = 0.014, 0.043 and 0.010 for the first second and third year respectively). CONCLUSIONS: These results suggest that a specific SNP and the haplotype of the selected SNP could be used to predict the effect of HRT on lumbar BMD.     

The effect of oestrogen on cytokine and antioxidant levels in male to female transsexual patients

OBJECTIVE: Whilst hormone replacement therapy (HRT) can be beneficial, it can be associated with deep venous thrombosis (DVT) and stroke. As male to female transsexuals take much higher doses of oestrogen than women on HRT, they provide a unique opportunity to study the long-term effects of oestrogen in a group of relatively young individuals who are largely free of established vascular disease. METHODS: Thirty-eight male to female gender patients were enrolled into the study. Of these, 25 were receiving oestrogen treatment and 13 who were not on treatment served as a control group. Serum levels of cholesterol, HDL, triglycerides, Interleukin 6 (IL-6), nitric oxide (NO), glutathione, and superoxide dismutase (SOD) were measured in all patients. RESULTS: The results showed that compared to the control group, patients on oestrogen had significantly raised levels of NO (32.1+/-14.3 versus 20.3+/-10.0, P<0.05) and reduced levels of IL-6 (0.75+/-0.6 versus 1.37+/-0.7, P<0.05) and SOD (13.2+/-3.0 versus 24.0+/-10.0, P<0.05). These changes were not accompanied by any significant change in plasma lipid levels. CONCLUSION: It would appear that the very high levels of oestrogen taken by the gender patients produce similar beneficial effects to those seen in women on HRT. However, in this patient group it appears that these changes are independent of changes in cholesterol, triglyceride, and HLD.     

Hormone replacement in postmenopausal women: impact of progestogens on autonomic tone and blood pressure regulation

OBJECTIVE: Depressed heart rate variability (HRV) reflects an imbalance of autonomic tone and independently predicts increased cardiovascular risk in patients with congestive heart failure or after acute myocardial infarction. While hormone replacement therapy (HRT) with estrogens beneficially modulates autonomic tone and blood pressure (BP) regulation in postmenopausal women, the impact of concomitant treatment with progestogens remains unclear. DESIGN: In this cross-sectional study, HRV and BP were examined in 62 healthy women (ages 48-71 years) using digital beat-to-beat interval recordings of heart rate and 24-hour ambulatory BP measurements. RESULTS: Demographic parameters did not differ among women without HRT (n = 23), on estrogen (n = 17; ERT), or on progestogen-estrogen containing HRT (n = 22; PERT). Total power of HRV was significantly lower, whereas mean heart rate (HR) was significantly higher among women on PERT group versus controls and ERT (total power: 1611 +/- 146 vs. 2497 +/- 308 and 2472 +/- 348 ms(2); heart rate: 80.7 +/- 1.2 vs. 75.0 +/- 1.4 and 74.0 +/- 2.2 bpm; p < 0.05). In addition, low-frequency power and time-dependent parameters of HRV were lower among women on PERT group versus controls and ERT (p < 0.05). ERT use was associated with reduced systolic and diastolic daytime BP, whereas no significant differences were evident PERT users compared with controls. CONCLUSIONS: Progestogen-containing replacement therapy was associated with increased HR and an attenuation of HRV in postmenopausal women. BP was lower in women on ERT, whereas this effect was offset in the PERT group. These observations could at least partially explain the ambiguous results of progestogen-containing HRT on cardiovascular risk in the Heart and Estrogen/Progestin Replacement Study (HERS).     

Sublingual administration of micronized estradiol and progesterone, with and without micronized testosterone: effect on biochemical markers of bone metabolism and bone mineral density

OBJECTIVES: The purpose of this investigation was to evaluate the relative efficacy of the sublingual administration of micronized estradiol (E2), progesterone (P4), and testosterone (T) on bone mineral density and biochemical markers of bone metabolism. DESIGN: In this double-blind, prospective study, postmenopausal women were randomly assigned to one of four treatment groups: hysterectomized women were assigned to either 1) micronized E2 (0.5 mg) or 2) micronized E2 (0.5 mg) + micronized T (1.25 mg). Women with intact uteri were assigned to either 3) micronized E2 (0.5 mg) + micronized P4 (100 mg) or 4) micronized E2 (0.5 mg) + micronized P4 (100 mcg) + micronized T (1.25 mg). For the purpose of this study, the four treatment groups were combined into two groups for all comparisons. The E2 and E2+P4 groups were combined into the HRT alone group (n=30), and the E2+T and E2+P4+T groups were combined into the HRT + T group (n=27). Hormones were administered sublingually as a single tablet twice a day for 12 months. Bone mineral density was measured in the anterior-posterior lumbar spine and total left hip via dual energy x-ray absorptiometry. Bone metabolism was assessed via serum bone-specific alkaline phosphatase and urinary deoxypyridinoline and cross-linked N-telopeptide of type I collagen, both normalized to creatinine. Data were analyzed via a repeated measures analysis of variance and a Student's t test (alpha=0.05). RESULTS: The subjects were of similar age (54.0 +/- 0.8 years), height (64.0 +/- 0.3 in), weight (157.6 +/- 4.2 lb), and had similar baseline follicle-stimulating hormone (66.4 +/- 3.2 mIU/L), E2 (26.4 +/- 1.5 pg/ml), P4 (0.3 +/- 0.1 ng/ml), total T (19.0 +/- 1.5 ng/dL), and bioavailable T (3.7 +/- 0.3 ng/dL) levels. During therapy, serum levels increased (p < 0.05) for each hormone. Bone mineral density and bone markers at baseline were similar for each treatment group. Bone-specific alkaline phosphatase decreased (p < 0.05) by -14.3 +/- 4.1% in the HRT alone group and by -8.2 +/- 4.6% in the HRT + T group. Deoxypyridinoline levels decreased significantly in the HRT alone and HRT + T groups, - 14.4 +/- 6.8% and -26.9 +/- 7.6%, respectively. Significant reductions (p < 0.05) in cross-linked N-telopeptide of type I collagen were also observed in both groups, -24.4 +/- 6.5% and -39.5 +/- 8.6%, respectively. Bone mineral density in the lumbar spine increased (p < 0.05) by +2.2 +/- 0.5% the HRT alone group and by + 1.8 +/- 0.6% in the HRT + T group. Total hip bone mineral density was maintained in the HRT alone group (+0.4 +/- 0.4%) and increased (p < 0.05) in the HRT + T group (+ 1.8 +/- 0.5%). CONCLUSIONS: Sublingual micronized HRT favorably decreases serum and urine markers of bone metabolism, prevents bone loss, and results in a slight increase in spine and hip bone mineral density. Although the addition of testosterone to HRT for 1 year did not result in added benefit to the spine bone mineral density, it did result in a significant increase in hip bone mineral density. Longer duration of therapy may have further improved these outcomes.     

Early outcome of myomectomy by laparotomy, minilaparotomy and laparoscopically assisted minilaparotomy. A randomized prospective study

BACKGROUND: To compare in the first 7 days after surgery the outcome of myomectomy performed by three laparotomic approaches: laparotomy (LT), minilaparotomy (MLT) and laparoscopically assisted minilaparotomy (LA-MLT). METHODS: Fifty-one women with 5-15 cm total myoma diameter were randomized blindly using a computer randomization list, to LT (n = 17), MLT (n = 17) or LA-MLT (n = 17). RESULTS: Mean operation length was similar in the three groups. Mean (+/- SEM) time of paralytic ileus (55.0 +/- 4.5 versus 33.4 +/- 3.4 h; P < 0.01) and discharge (141.6 +/- 5.2 versus 81.5 +/- 8.2 h; P < 0.01) was longer in LT than LA-MLT or even MLT. In comparison with LA-MLT, LT induced a greater haemoglobin decline (-3.07 +/- 0.3 versus -1.8 +/- 0.15 mg/dl; P < 0.025), and a greater post-operative stress, as documented by increased prolactin (+15.1 +/- 3.8 versus +0.16 +/- 4.5 ng/ml; P < 0.03) and decreased insulin sensitivity (fasting glucose/insulin; -7.5 +/- 2.6 versus -0.7 +/- 2.1; P < 0.02). Seven days after surgery, abdominal pain (P < 0.05) was higher after LT (3.0 +/- 0.6) than MLT (0.5 +/- 0.2) and LA-MLT (0.9 +/- 0.4). CONCLUSIONS: In selected cases, myomectomy by LA-MLT offers some advantages versus LT and, to a smaller extent, MLT.     

Dilatory responses to acetylcholine, calcitonin gene-related peptide and substance P in the congestive heart failure rat

It was examined to what extent congestive heart failure (CHF) in rats, induced by ligation of the left coronary artery, affects the vascular responses to the vasodilatory substances acetylcholine (ACh), calcitonin gene-related peptide (CGRP), and substance P (SP). After induction of CHF status, the basilar, mesenteric and renal arteries and the iliac vein were studied in vitro. Dilatory responses were determined in relation to pre-contraction by the thromboxane mimetic U46619. Sham-operated animals (Sham) served as controls. U46619 induced stronger contraction in CHF basilar and renal arteries compared with the corresponding segments in Sham. ACh induced concentration-dependent dilations in all vessels examined with no difference of maximum relaxation or potency between CHF and Sham. SP induced weak dilations in all arteries examined while the response was markedly attenuated in CHF iliac veins compared with Sham (Emax% 12.2 +/- 3.4 vs. 32.3 +/- 4.8, P = 0.01). The CGRP induced dilation in the CHF basilar artery was weaker (Emax% 18.6 +/- 6.5 vs. 66.9 +/- 5.0, P < 0.001) and less potent (pEC50: 8.2 +/- 0.2 vs. 9.0 +/- 0.2, P = 0.01) compared with Sham. Further, CGRP was less potent in the renal artery of CHF rats compared with Sham (pEC50: 8.1 +/- 0.2 vs. 9.5 +/- 0.3, P < 0.01). In the CHF iliac vein, CGRP was more potent compared with Sham (pEC50: 9.7 +/- 0.4 vs. 8.3 +/- 0.4, P < 0.05). It can be concluded CHF is accompanied by alterations in the vascular response to the dilatory substances studied. The changes differ between vascular beds and between the different substances.     

Relationship of ovarian stimulation response with vascular endothelial growth factor and degree of granulosa cell apoptosis

BACKGROUND: The aim of this study was to evaluate the concentration of vascular endothelial growth factor (VEGF) in follicular fluid and in granulosa cell cultures in relation to the degree of apoptosis in granulosa cells from patients with different types of ovarian response to controlled ovarian hyperstimulation. METHODS: We studied 30 women who underwent controlled ovarian hyperstimulation and oocyte retrieval. Group A comprised patients with 1-4 follicles (n = 10), group B patients with 5-14 follicles (n = 10) and group C patients with >15 follicles (n = 10). RESULTS: Mean (+/-SD) VEGF concentrations in follicular fluid were 1232 +/- 209, 813 +/- 198 and 396 +/- 103 pg/ml for groups A, B and C respectively (P > 0.01). Concentrations of VEGF in granulosa cell supernatant were 684 +/- 316, 1101 +/- 295 and 1596 +/- 227 pg/ml respectively (P < 0.05). Percentages of apoptotic cells in granulosa cells culture was 55.02 +/- 7.5, 23.98 +/- 4.4 and 14.2 +/- 2.3% respectively (A versus B, P < 0.01, A versus C, P < 0.006, B versus C, NS). CONCLUSIONS: Our findings showed that in patients with decreased ovarian response to controlled ovarian hyperstimulation, follicular fluid VEGF concentration is elevated, the concentration from granulosa cells culture supernatant is decreased and the percentage of apoptotic granulosa cells is increased, while opposite findings occurred in patients with normal or hyper-responses.     

Exercise prevents age-related decline in nitric-oxide-mediated vasodilator function in cutaneous microvessels

Ageing is associated with impaired endothelium-derived nitric oxide (NO) function in human microvessels. We investigated the impact of cardiorespiratory fitness and exercise training on physiological and pharmacological NO-mediated microvascular responses in older subjects. NO-mediated vasodilatation was examined in young, older sedentary and older fit subjects who had two microdialysis fibres embedded into the skin on the ventral aspect of the forearm and laser Doppler probes placed over these sites. Both sites were then heated to 42 degrees C, with Ringer solution infused in one probe and N-nitro-L-arginine methyl ester (L-NAME) through the second. In another study, three doses of ACh were infused in the presence or absence of L-NAME in similar subjects. The older sedentary subjects then undertook exercise training, with repeat studies at 12 and 24 weeks. The NO component of the heat-induced rise in cutaneous vascular conductance (CVC) was diminished in the older sedentary subjects after 30 min of prolonged heating at 42 degrees C (26.9 +/- 3.9%CVC(max)), compared to older fit (46.2 +/- 7.0%CVC(max), P < 0.05) and young subjects (41.2 +/- 5.2%CVC(max), P < 0.05), whereas exercise training in the older sedentary group enhanced NO-vasodilator function in response to incremental heating (P < 0.05). Similarly, the NO contribution to ACh responses was impaired in the older sedentary versus older fit subjects (low dose 3.2 +/- 1.3 versus 6.6 +/- 1.3%CVC(max); mid dose 11.4 +/- 2.4 versus 21.6 +/- 4.5%CVC(max); high dose 35.2 +/- 6.0 versus 52.6 +/- 7.9%CVC(max), P < 0.05) and training reversed this (12 weeks: 13.7 +/- 3.6, 28.9 +/- 5.3, 56.1 +/- 3.9%CVC(max), P < 0.05). These findings indicate that maintaining a high level of fitness, or undertaking exercise training, prevents age-related decline in indices of physiological and pharmacological microvascular NO-mediated vasodilator function. Since higher levels of NO confer anti-atherogenic benefit, this study has potential implications for the prevention of microvascular dysfunction in humans.     

A real-life prospective health economic study of elective single embryo transfer versus two-embryo transfer in first IVF/ICSI cycles

BACKGROUND: We analysed the difference in maternal, neonatal and total costs after single (SET) versus double day 3 embryo transfer (DET). METHODS: We performed a two-centre prospective study of women in their first IVF/ICSI cycle choosing between SET or DET. Infertility treatment data were gathered from a database; maternal and neonatal outcome data from a case report form (CRF); health economic data from medical acts registered in the CRF for the outpatient part and from hospital bills. SET was performed in 206/367 (56.1%) and DET in 161/367 (43.9%) women. RESULTS: In all, 367 transfers yielded 186 positive pregnancy tests, 148 ongoing pregnancies and 136 live deliveries (50.7, 40.3 and 37.1% per embryo transfer) of which 15 (11.0%) were twins. Live birth rate was 37.4% for SET, 36.6% for DET. Intention-to-treat analysis showed differences for: duration of pregnancy (SET: 39.0 +/- 1.4 versus DET: 38.3 +/- 2.2 weeks; P = 0.055), percentage prematurity (8.5 versus 23.8%; P = 0.033), percentage of neonates hospitalized (5.7 versus 17.9%; P = 0.121) and duration of neonatal hospitalization (6.3 +/- 2.2 versus 10.3 +/- 10.1 days; P = 0.01). Total cost after DET was higher (SET: 4700 +/- 3239 versus DET: 8613 +/- 10 105; P = 0.105), due to significantly higher neonatal costs (451 +/- 957 versus 3453 +/- 8154; P < 0.001) and not to differences in maternal costs (4250 +/- 2882 versus 5160 +/- 4106; P = 0.152). CONCLUSIONS: This prospective health economic study shows that transfer of a single top quality embryo is equally effective as, but substantially cheaper than, double embryo transfer in women <38 years of age in their first IVF/ICSI cycle.