Objective: It has been suggested that both endogenous reproductive hormones and hormone therapy may play a protective role against coronary artery disease (CAD). However, recent clinical trials have failed to demonstrate the benefit of a variety of forms of hormone therapy. The observational data on the role of endogenous reproductive hormones, using surrogate measures such as number of birth, age at menarche, and age at menopause are inconsistent. In addition, the longer-term associations have not been evaluated. The aim of this study was to evaluate the relationships between detailed measurements of endogenous and exogenous estrogen exposure time with angiographic CAD and major adverse cardiovascular events.

Methods: We assessed total estrogen exposure time, quantitative CAD by a core angiography laboratory, and prospectively measured major adverse cardiovascular events in 646 postmenopausal women undergoing coronary angiography for evaluation for suspected ischemia in the Women’s Ischemia Syndrome Evaluation (WISE) study.

Results: Timing of postmenopausal exogenous hormone therapy (HT) use was associated with reduced CAD. Two summarized total estrogen time scores (TET and sTET) were not related to angiographic CAD after accounting for HT use. In addition, these scores were not related to cardiovascular events over a median of 6.0 years of follow-up.

Conclusions: There was no independent relation of estrogen exposure time to angiographic CAD or major adverse cardiovascular events in a contemporary cohort of postmenopausal women evaluated for suspected ischemia. Our results suggest that the paradigm of estrogen protection from CAD in women may be more complex than estrogen exposure duration alone.

Objective To determine the prevalence of depressive symptoms and associated risk factors among climacteric women.
Methods In this cross-sectional study, women aged 40-59 years, visiting inpatients at the Enrique C. Sotomayor Obstetrics and Gynecology Hospital, Guayaquil, Ecuador, were surveyed with the 17-item Hamilton Depression Rating Scale (HDRS), the Menopause Rating Scale (MRS) and a questionnaire seeking personal and partner data.
Results A total of 404 women filled out the HDRS and the MRS. The mean age was 48.2 ± 5.7 years; 85.1% had 12 or less years of schooling and 44.8% were postmenopausal. None were on hormonal therapy for the menopause or on psychotropic drugs. The mean total HDRS score was 13.7 ± 7 (median 13); this was higher among perimenopausal women. Of all the respondents, 78.7% had some degree of depressive symptoms (HDRS total score ≥8), which was mild in 32.2% and ranged from moderate to very severe in 46.5%. Logistic regression analysis determined that the severity of the menopausal symptoms related to the somatic and psychological domains of the MRS and the partner profile (low education and alcohol abuse) were the main determinants for women having higher depressive scores (total HDRS ≥8).
Conclusion In this specific climacteric population, depressive symptoms were very prevalent and were associated with the severity of menopausal symptoms (somatic and psychological) and partner’s problems.

Aim To investigate the association of different clinical parameters with the histological diagnosis and the prevalence of premalignant and malignant endometrial polyps.
Method The study included 516 cases from January 2002 to December 2006. Possible risk factors such as age, menopause status, abnormal bleeding, obesity, hypertension, diabetes mellitus, hormone therapy, use of tamoxifen and size of polyp were investigated in relation to their association with the malignant potential of endometrial polyps.
Results All cases of endometrial polyps underwent hysteroscopic resection; 96.9% of the cases were benign, 1.2% premalignant and 1.9% malignant. Premalignant and malignant endometrial polyps were significantly associated with advanced age (460 years), menopause, obesity and diabetes. The malignant polyps were analyzed to eight endometrioid, one serous and one clear cell carcinoma.
Conclusion The prevalence of premalignant and malignant endometrial polyps is very low. Advanced age, menopause, obesity and diabetes increase the risk of endometrial polyp malignancy.

Objective To evaluate the clinical value of basal anti-Müllerian hormone (AMH) measurements compared with other available determinants, apart from chronologic age, in the prediction of ovarian response to gonadotrophin stimulation.
Design Prospective cohort study.
Setting Tertiary referral center for reproductive medicine and an IVF unit.
Patient(s) Women undergoing their first cycle of controlled ovarian hyperstimulation (COH) for in vitro fertilization (IVF).
Materials and methods Basal levels of FSH and AMH as well as antral follicle count (AFC) were measured in 165 subjects. All patients were followed prospectively and their cycle outcomes recorded.
Main Outcome Measure(s) Predictive value of FSH, AMH, and AFC for extremes of ovarian response to stimulation.
Result(s) Out of the 165 women, 134 were defined as normal responders, 15 as poor responders, and 16 as high responders. Subjects in the poor response group were significantly older then those in the other two groups. Anti-Müllerian hormone levels and AFC were markedly raised in the high responders and decreased in the poor responders. Compared with FSH and AFC, AMH performed better in the prediction of excessive response to ovarian stimulation–AMH area under receiver operating characteristic curve (ROCAUC) 0.81, FSH ROCAUC 0.66, AFC ROCAUC 0.69. For poor response, AMH (ROCAUC 0.88) was a significantly better predictor than FSH (ROCAUC 0.63) but not AFC (ROCAUC 0.81). AMH prediction of ovarian response was independent of age and PCOS. Anti-Müllerian hormone cutoffs of >3.75 ng/mL and <1.0 ng/mL would have modest sensitivity and specificity in predicting the extremes of response.
Conclusion(s) Circulating AMH has the ability to predict excessive and poor response to stimulation with exogenous gonadotrophins. Overall, this biomarker is superior to basal FSH and AFC, and has the potential to be incorporated in to work-up protocols to predict patient’s ovarian response to treatment and to individualize strategies aiming at reducing the cancellation rate and the iatrogenic complications of COH.

Objective: To evaluate the effect of pregestational metformin administration on abortion risk in polycystic ovary syndrome (PCOS) patients.
Design: Systematic review and meta-analysis.
Setting: Academic Department of Obstetrics and Gynecology in Italy.
Patient(s): Women affected by PCOS receiving pregestational metformin.
Intervention(s): Systematic review of randomized controlled trials (RCTs) published up to June 2008 and subsequent meta-analysis.
Main Outcome Measure(s): Abortion rate.
Result(s): Seventeen RCTs were included in the final analysis. Overall, no effect of the metformin administration was detected on the abortion risk. No statistically significant effect of metformin on the abortion risk was observed in any comparison when subgrouping the RCTs according to received treatment.
Conclusion(s): Metformin has no effect on the abortion risk in PCOS patients when administered before pregnancy.

The relevance of the progestagen component in combined hormone replacement therapy (HRT) for breast cancer risk has been long debated. In vitro studies have shown that progestins exert both genomic transcriptional and non-genomic effects that can enhance the proliferation, invasiveness and spread of breast cancer cells. According to a novel hypothesis, progestins can still activate cancer stem cells in patients with pre-existing, clinically undetected breast cancer. However, some experimental and clinical data suggest that different progestins may have a different impact on the pathophysiology of malignant breast cells. In vitro studies on estrogen receptor (ER)+ breast cancer cells have shown that the addition of medroxyprogesterone acetate (MPA) to estradiol (E2) produces a significantly higher increase of the mRNA levels and activities of estrogen-activating enzymes aromatase, 17β hydroxysteroid dehydrogenase type-1 and sulfatase when compared with progesterone plus E2. In randomised trial performed on ovariectomised adult female monkeys, oral E2 plus MPA have resulted in a significantly greater proliferation of breast lobular and ductal epithelium when compared with placebo, whereas E2 plus micronised progesterone have not. In the same experimental model, oral E2 plus MPA have been found to induce the expression of genes encoding epidermal growth factor receptor (EGFR) ligands and downstream targets, whereas E2 alone or E2 plus micronised progesterone had no or modest effects on EGFR-related genes. In last years, some clinical studies on HRT users have shown that androgenic progestin- or MPA-based formulations are associated with an increased breast cancer incidence, whereas micronised progesterone- or dydrogesterone-based formulations are not. Further basic and clinical investigations on this topic are strongly warranted to elucidate whether the choice of the progestagen component in combined HRT could be of clinical relevance as for breast cancer risk.

Objective: To assess the thrombotic risk associated with oral contraceptive use with a focus on dose of oestrogen and type of progestogen of oral contraceptives available in the Netherlands.

Design: Population based case-control study. Setting: Six participating anticoagulation clinics in the Netherlands (Amersfoort, Amsterdam, The Hague, Leiden, Rotterdam, and Utrecht).
Participants: Premenopausal women < 50 years old who were not pregnant, not within four weeks postpartum, and not using a hormone excreting intrauterine device or depot contraceptive. Analysis included 1524 patients and 1760 controls.
Main Outcome Measures: First objectively diagnosed episodes of deep venous thrombosis of the leg or pulmonary embolism. Odds ratios calculated by cross-tabulation with a 95% confidence interval according to Woolf’s method; adjusted odds ratios estimated by unconditional logistic regression, standard errors derived from the model.

Results: Currently available oral contraceptives increased the risk of venous thrombosis fivefold compared with non-use (odds ratio 5.0, 95% CI 4.2 to 5.8). The risk clearly differed by type of progestogen and dose of oestrogen. The use of oral contraceptives containing levonorgestrel was associated with an almost fourfold increased risk of venous thrombosis (odds ratio 3.6, 2.9 to 4.6) relative to non-users, whereas the risk of venous thrombosis compared with non-use was increased 5.6-fold for gestodene (5.6, 3.7 to 8.4), 7.3-fold for desogestrel (7.3, 5.3 to 10.0), 6.8-fold for cyproterone acetate (6.8, 4.7 to 10.0), and 6.3-fold for drospirenone (6.3, 2.9 to 13.7). The risk of venous thrombosis was positively associated with oestrogen dose. We confirmed a high risk of venous thrombosis during the first months of oral contraceptive use irrespective of the type of oral contraceptives.

Conclusions: Currently available oral contraceptives still have a major impact on thrombosis occurrence and many women do not use the safest brands with regard to risk of venous thrombosis.

Context and objective: The metabolic syndrome (MetS) indicates an increased cardiovascular risk. The objective of the present study was to determine the impact of the MetS and its individual traits on subclinical atherosclerosis, as measured with six noninvasive measurements of atherosclerosis (NIMA) in a 50- to 70-yr-old Dutch population-based cohort. Furthermore, we determined the impact of three different definitions of the MetS.

Design:Weperformed NIMA in 1517 participants of the Nijmegen Biomedical Study. The MetS was defined by definitions of the National Cholesterol Education Program, International Diabetes Federation, and the World Health Organization.

Results: Participants with the MetS (National Cholesterol Education Program) were characterized by increased subclinical atherosclerosis compared with participants without any trait of the MetS, as reflected by lower ankle-brachial index at rest [percent change (95% confidence interval), M: –5.2% (–9; –1), F: –3.1% (–6; –1)] and after exercise [M: –7.7% (–17;+2), F: –6.6% (–11; –2)], higher augmentation index [M: +4.8% (+3; +7), F: +1.9% (+4; +18)], increased pulse wave velocity [M: +22.8% (+15;+32), F: +20.5% (+14; +28)], increased intima-media thickness [M: +9.3% (+5; +13), F: +6.9% (+3; +11)], and thicker plaques [M: +17.6% (–2; +41), F: +26.6% (+5; +53)]. Most intriguingly, the number of traits was strongly associated with the severity of subclinical atherosclerosis because all NIMA gradually deteriorated with increasing number of traits present; NIMA were already deteriorated when one or two traits were present and further deteriorated when four or five traits of the MetS were present. Similar result were found when International Diabetes Federation and World Health Organization definitions of the MetS were used. Conclusions: For cardiovascular risk prediction, it is more important to take into account the presence of each individual traitandthenumberof traits of theMetSthan to diagnose the presence of the MetS.

Objective: To compare the effects of anastrozole (1 mg) and clomiphene citrate (CC; 100 mg) used for ovulation induction in women with polycystic ovary syndrome. Design: Prospective controlled trial.

Setting: University teaching hospital and private-practice setting.

Patient(s): The study comprised a total of 216 infertile women (469 cycles) with polycystic ovary syndrome.

Intervention(s): Patients received anastrozole (1 mg/d; 115 patients, 243 cycles) for 5 days, starting on day 3 of menses. A matched historical group of patients with polycystic ovary syndrome who were treated with CC (100 mg/d; 101 patients, 226 cycles) was used as a control group. Timed intercourse was advised 24–36 hours after hCG injection.

Main Outcome Measure(s): Number of follicles, serum E2, serum P, endometrial thickness, and pregnancy and miscarriage rates.

Result(s): The mean age, parity, and duration of infertility in both groups were similar, but statistically significantly more polycystic ovaries were found in the anastrozole group (odds ratio ¼ 2.44; 95% confidence interval ¼ 1.19–5.02). The total numbers of follicles were significantly higher in the CC group (3.8 ± 0.6 vs. 3.4 ± 0.5). Endometrial thickness at the time of hCG administration was significantly greater in the anastrozole group (10.1 ± 0.22 mm vs. 8.2 ± 0.69 mm). The duration of stimulation was similar in the two groups. Ovulation occurred in 165 (67.9%) of 243 cycles in the anastrozole group and in 150 (68.6%) of 226 cycles in the CC group without significant difference. Serum P was significantly higher in the CC group (7.1 1.11 vs. 8.1 ± 0.88 ng/mL). The pregnancy and miscarriage rates were similar in the two groups.

Conclusion(s): Anastrozole was associated with significantly fewer mature and growing follicles, thicker endometrium, and slightly higher pregnancy rate. Anastrozole may be helpful in situations in which multiple pregnancy is not desirable or the risk of ovarian hyperstimulation syndrome is high.

Aim. To study the impact of family history (FH) of type 2 diabetes mellitus on β-cell compensatory mechanism in women with polycystic ovary syndrome (PCOS).

Subjects and methods. A total of 70 women with PCOS, 14 with first-degree relative with type 2 diabetes mellitus (T2DM) (FH+), 56 with negative FH of T2DM (FH-) and 72 age and BMI matched control healthy women (CNT) underwent oral glucose tolerance test (OGTT). Insulin resistance was evaluated as oral glucose index (OGIS); insulin and C-peptide secretion as the insulinogenic index in 30th min of OGTT.

Results. Fasting blood glucose levels were significantly higher in FH+ than in FH- (p < 0.05). Fasting insulin was higher in FH+ than in CNT (p < 0.05). Fasting C-peptide was significantly higher in both FH- and FH+ than in CNT (p < 0.05 and p < 0.01, respectively). OGIS was lower in FH+ than in FH- or in CNT (p < 0.05). Insulinogenic index calculated from C-peptide values (II-Cp) was lower in FH+ than in CNT (p < 0.05). Adaptation index calculated from the values of OGIS and insulinogenic index was significantly lower in FH+ than in CNT or in FH- (p < 0.0001 and p < 0.01, respectively).

Conclusions. Insulin resistance and defective early-phase insulin secretion is present only in those PCOS-affected subjects who had positive FH of T2DM.

The polycystic ovary syndrome (PCOS), mainly characterized by clinical and/or biochemical hyperandrogenism, ovarian dysfunction and/or polycystic morphology as well as associated metabolic disorders, is the most common endocrine disorder in women of reproductive age. The familial clustering of PCOS cases and the accumulating evidence that the interaction between multiple genetic and environmental factors is necessary for the development of the syndrome, has triggered the conduct of genetic studies on PCOS. These studies have focused on many genetic polymorphisms, investigating their possible positive or negative correlation with the syndrome. The related genes can be grouped in four categories: those related with insulin resistance, those that interfere with the biosynthesis and the action of androgens, those that encode inflammatory cytokines and other candidate genes. Despite the progress that has been made in the elucidation of the genetic mechanisms of the PCOS, the genetic studies on the syndrome still face many obstacles and challenges. Further studies are needed, in order to shed new light in the pathogenesis of the syndrome, which will allow for new approaches in the diagnostics and therapeutics of PCOS.

BACKGROUND: There is preliminary evidence to suggest an impact of stress on chances of achieving a pregnancy with in-vitro fertilization (IVF). The majority of the available research has focused on stress related to infertility and going through IVF-treatment, and it is still unclear whether non-fertility-related, naturally occurring stressors may influence IVF pregnancy chances. Our aim was to explore the association between IVF-outcome and negative, i.e. stressful, life-events during the previous 12 months.

METHODS: Prior to IVF, 809 women (mean age: 31.2 years) completed the List of Recent Events (LRE) and questionnaires measuring perceived stress and depressive symptoms.
RESULTS: Women who became pregnant reported fewer non-fertility-related negative life-events prior to IVF (Mean: 2.5; SD: 2.5) than women who did not obtain a pregnancy (Mean: 3.0; SD: 3.0) (t(465.28) = 2.390, P = 0.017). Logistic regression analyses revealed that the number of negative life-events remained a significant predictor of pregnancy (OR: 0.889; P = 0.02), when controlling for age, total number of life-events, perceived stress within the previous month, depressive symptoms, and relevant medical factors related to the patient or treatment procedure, including duration of infertility, number of oocytes retrieved and infertility etiology. Mediation analyses indicated that the association between negative life events and IVF pregnancy was partly mediated by the number of oocytes harvested during oocyte retrieval.
CONCLUSION: A large number of life-events perceived as having a negative impact on quality of life may indicate chronic stress, and the results of our study indicate that stress may reduce the chances of a successful outcome following IVF, possibly through psychobiological mechanisms affecting medical end-points such as oocyte retrieval outcome.

Objective: To determine the prevalence of histologically proven endometriosis in a subset of infertile women.

Design: Retrospective case series with electronic file search and multivariable logistic regression analysis.

Settings: Tertiary academic fertility center.

Patients: Two hundred twenty-one infertile women without previous surgical diagnosis for infertility with regular cycles (variation, 21–35 days) whose partners have a normal semen analysis.

Interventions: Diagnostic laparoscopy and, if necessary, operative laparoscopy with CO2 laser excision.

Main Outcome Measurements: The prevalence of endometriosis and of fertility–reducing nonendometriotic tubal and/or uterine pathology.

RESULTS: The prevalence of endometriosis was 47% (104/221), including stage I (39%, 41/104), stage II (24%, 25/104), stage III (14%, 15/104), and stage IV (23%, 23/104) endometriosis, and was comparable in patients with (54%, 61/113) and without (40%, 43/108) pelvic pain. The prevalence of fertility-reducing nonendometriotic tubal and/or uterine pathology was 29% in all patients (15% in women with and 40% in women without endometriosis). A multivariate logistic regression model including pain, ultrasound data, age, duration of infertility, and type of fertility was not or not sufficiently reliable for the prediction of endometriosis according to the revised American Fertility Society (rAFS) classifications I–II and rAFS III–IV, respectively.

CONCLUSIONS: Reproductive surgery is indicated in infertile women belonging to the study population, regardless of pain symptoms or transvaginal ultrasound results, since half of them have endometriosis and 40% of those without endometriosis have fertility-reducing pelvic pathology.

Objective: To summarize the role of melatonin in the physiology and pathophysiology of the ovary.

Design: Review of literature.

Setting: University Health Science Center.

RESULTS:Patients in the tertile with the greatest decrease in each of the BTMs had the greatest mean increase in BMD and the lowest percentage of BMD nonresponders at 24 months. Several characteristics were independently associated with BMD nonresponse, including smaller 3-month reductions from baseline in serum C-terminal telopeptide of type 1 collagen, bone-specific alkaline phosphatase, and N-terminal propeptide of type 1 procollagen; younger age of menopause; a family history of osteoporosis; and higher baseline trochanteric BMD. Baseline BTMs were not predictive of 24-month BMD response to therapy. The strongest associations were for changes in BTMs with treatment.

CONCLUSIONS: In groups of patients, short-term changes in markers of bone turnover appear to be predictors of longer term BMD response and nonresponse to bisphosphonate therapy.

Aim: To elucidate the dynamics of FSH, LH, prolactin (PRL), TSH and insulin secretion in women with polycystic ovarian syndrome (PCOS) treated with metformin (MET).

Patients and methods: In a prospective, controlled and randomised trial, 32 women with PCOS and 32 with normal cycle were recruited to receive MET (850 mg b.i.d.) or placebo (n: 16 for each subgroup) for an average of 40 days. Pituitary function and insulin secretion were assessed before and after intervention by GnRH-TRH tests and oral glucose tolerance test induced insulin response.

RESULTS:Basal and area under the response curve (AURC) LH values were higher in PCOS than in normal controls before MET and declined following treatment in the former group (P < 0.05). Ovulatory PCOS responders had lower basal LH, AURCLH and AURCPRL values during MET than anovulatory cases (P < 0.05 for all) and AURCins was lower in ovulatory than anovulatory PCOS before and on MET (P < 0.02-P < 0.05), with a rise of QUICKY index in the former group during MET treatment (P < 0.05). FSH and TSH were similar.

CONCLUSIONS: MET administration lowered LH activity in all PCOS women and in ovulatory responders and also compromised PRL stimulated secretion in the latter cases. These findings were indicative of an effect of MET on pituitary activity.

Hot flush is one of the most commonly reported symptoms during menopause; however, it is not experienced by all menopausal women, for reasons that remain unclear. In this review, we present current evidence that link hot flushes with cardiovascular disease, suggesting that the persistence of hot flushes many years after the menopause may represent a marker of an underlying disorder that increases the risk for cardiovascular disease.

Context:Osteoporosis primarily affects postmenopausal women. However, young women with estrogen deficiency also are at increased risk for low bone density.

Objective:The aim of the study was to assess bone density and associated risk factors for reduced bone density in young, estrogen-deficient women using primary ovarian insufficiency (POI) as the disease model.

Design and Setting: We conducted a cross-sectional study at a tertiary care research center. Participants: We studied women with POI (n = 442), concurrent controls (n = 70), and matched controls from NHANES III (n = 353).

Participants:We studied women with POI (n = 442), concurrent controls (n = 70), and matched controls from NHANES III (n = 353).

Primary Outcome Measure: We measured bone mineral density (BMD) using dual-energy x-ray absorptiometry.

RESULTS:Patients on average had 2–3% lower BMD at L1–L4, femoral neck, and total hip (P < 0.01 at all sites). The modifiable risk factors for BMD below the expected range for age (Z-score <–2) were: more than 1-yr delay in diagnosis of estrogen deficiency (P = 0.018), low (<32 ng/ml) vitamin D levels (P = 0.002), estrogen replacement nonadherence (P = 0.002), low calcium intake (P = 0.005), and lack of exercise (P = 0.005). As compared to Caucasians, African-American and Asian women with POI were 3.18 and 4.34 times more likely, respectively, to have Z-scores below –2 (P = < 0.0001 for both). Race was an overall risk factor, but on regression modeling, not an independent predictor of low bone density.

CONCLUSIONS: Women with POI have lower bone density compared to regularly menstruating women. Compared to Caucasians, minority women with estrogen deficiency are more likely to have BMD below the expected range for age. This racial disparity appears to be related to a combined effect of several modifiable risk factors. Delay in diagnosis of POI also contributes to reduced bone density by delaying proper therapy.

Context: Adult women with polycystic ovary syndrome (PCOS) have decreased GnRH pulse generator sensitivity to progesterone (P)-mediated slowing. This defect is androgen mediated because it is reversed with androgen receptor blockade. Adolescent hyperandrogenism often precedes PCOS.

Objective: The aim of the study was to evaluate GnRH pulse generator sensitivity to P-mediated slowing in normal and hyperandrogenic girls.

Design: We conducted a controlled interventional study.

Setting: The study was conducted in a general clinical research center.

Participants: A total of 26 normal control (NC) and 26 hyperandrogenic (HA) girls were studied.

Intervention: Frequent blood sampling was performed for 11 h to assess LH pulse frequency before and after 7 d of oral estradiol and P.

Main Outcome Measure: We measured the slope of the percentage reduction in LH pulse frequency as a function of d 7 P (slope).

RESULTS:Overall, Tanner 3-5 HA subjects were less sensitive to P-mediated slowing than Tanner 3-5 NC (slope, 4.7 ± 3.4 vs. 10.3 ± 7.7; P = 0.006). However, there was variability in the responses of HA subjects; 15 had P sensitivities within the range seen in NC, whereas nine were relatively P insensitive. The two groups had similar testosterone levels. Fasting insulin levels were higher in P-insensitive HA girls (39.6 ± 30.6 vs. 22.2 ± 13.9 µIU/ml; P = 0.02), and there was an inverse relationship between fasting insulin and P sensitivity in HA girls (P = 0.02). Tanner 1-2 NC had lower testosterone levels and were more P sensitive than Tanner 3-5 NC (slope, 19.3 ± 5.8; P = 0.04).

CONCLUSIONS: Hyperandrogenism is variably associated with reduced GnRH pulse generator sensitivity to P-mediated slowing during adolescence. In addition to androgen levels, insulin resistance may modulate P sensitivity.

BACKGROUND: In clinical practice, bone mineral density (BMD) determined by dual-energy x-ray absorptiometry is used to monitor response to osteoporosis therapy. However, 1 to 2 yr are usually required to assess patients’ BMD responses. The possibility of earlier indicators of a response or nonresponse to treatment, such as changes in bone turnover markers (BTMs), is of interest to physicians and patients.

METHODS: In this post hoc analysis of women treated with once-weekly bisphosphonates, we examined the association of tertile percentage change from baseline in BTMs at 3 or 6 months and association of several baseline clinical characteristics with 24-month percentage change from baseline in BMD and with percentage of patients showing BMD nonresponse (defined as BMD loss at two or more of four sites) at 24 months. Multivariable analysis was performed to determine which factors were independently associated with BMD nonresponse.

RESULTS:Patients in the tertile with the greatest decrease in each of the BTMs had the greatest mean increase in BMD and the lowest percentage of BMD nonresponders at 24 months. Several characteristics were independently associated with BMD nonresponse, including smaller 3-month reductions from baseline in serum C-terminal telopeptide of type 1 collagen, bone-specific alkaline phosphatase, and N-terminal propeptide of type 1 procollagen; younger age of menopause; a family history of osteoporosis; and higher baseline trochanteric BMD. Baseline BTMs were not predictive of 24-month BMD response to therapy. The strongest associations were for changes in BTMs with treatment.

CONCLUSIONS: In groups of patients, short-term changes in markers of bone turnover appear to be predictors of longer term BMD response and nonresponse to bisphosphonate therapy.

CONTEXT: Postmenopausal women have greater visceral adiposity compared with premenopausal women. Adipokines are associated with increased adiposity, insulin resistance, and atherosclerosis. OBJECTIVE: The objective of the study was to assess changes in adipokines and inflammatory markers through the menopausal transition and correlate them with changes in visceral adiposity.

DESIGN AND SETTING: This was a prospective cohort study of women through the menopausal transition conducted at the University of Washington.

PARTICIPANTS: Sixty-nine healthy women were followed up longitudinally from premenopausal (aged 45–55 yr) to postmenopausal status (aged 49–60 yr).

OUTCOME: On premenopausal and postmenopausal visits, fasting blood was drawn for adiponectin, leptin, serum amyloid A (SAA), C-reactive protein (CRP), monocyte-chemotactic protein-1, tissue plasminogen activator antigen (tPA), IL-6, and TNF-. Body composition measures were assessed by body mass index, whole-body dual x-ray absorptiometry scan, and computed tomography scan of the abdomen at the lumbar 4–5 level.

RESULTS: Women had a statistically significant increase in SAA, tPA, monocyte-chemotactic protein-1, and adiponectin between the two measurement occasions (P = 0.04, P = 0.02, P = 0.001, and P < 0.001, respectively). The increase in intraabdominal fat was correlated positively with the change in SAA (r = 0.31, P = 0.02), CRP (r = 0.56, P < 0.001), tPA (r = 0.40, P = 0.002), and leptin (r = 0.41, P = 0.002) and negatively correlated with the change in adiponectin (r = –0.37, P = 0.005). After adjustment for change in sc abdominal fat, the correlation between change in CRP, tPA, leptin, and adiponectin remained significantly associated with change in intraabdominal fat. CONCLUSIONS: Women going through the menopausal transition have deleterious changes in inflammatory markers and adipokines that correlate with increased visceral adiposity.

CONTEXT: Autoimmune thyroid disease develops in genetic susceptible subjects, provoked by environmental factors. Little is known of the environment in the early stages of autoimmunity. OBJECTIVE: We evaluated environmental factors contributing to de novo occurrence of thyroid antibodies.

DESIGN: We conducted a prospective cohort study of 521 euthyroid women without thyroid antibodies in serum who were relatives of autoimmune thyroid disease patients. Follow-up was 5 yr. Baseline characteristics were related to the occurrence of thyroid peroxidase (TPO) and/or thyroglobulin (Tg) antibodies. Exposure to environmental factors in the year prior to the occurrence of antibodies was investigated in a nested case-control study.

RESULTS: The 5-yr probability for conversion to TPO antibodies (TPO-Ab) and/or Tg antibodies (Tg-Ab) was 20.1%, and for TPO-Ab alone the probability was 14.5%. None of the baseline characteristics except TSH contributed to the risk of seroconversion. Each case (occurrence of antibodies) was matched for age and duration of follow-up with two controls (no seroconversion). Exposure to environmental stimuli was similar between cases and controls except for smoking. At study entrance, current smokers among cases and controls were 31.3 and 35.5%, respectively (nonsignificant). Current smoking decreased in cases during follow-up. Consequently, the odds ratios (OR) of smoking for developing TPO-Ab and/or Tg-Ab were 0.62 [95% confidence interval (CI), 0.37–1.04] 1 yr before seroconversion and 0.59 (95% CI, 0.35–0.99) at seroconversion; for conversion to TPO-Ab, these figures are 0.58 (95% CI, 0.31–1.09) and 0.54 (95% CI, 0.29–1.02), respectively.

CONCLUSION: Discontinuation of smoking is associated with an increased risk for occurrence of TPO-Ab and/or Tg-Ab in serum. The observation is in line with the decreased risk of hypothyroidism in smokers.

Androgens are critical steroid hormones that determine the expression of the male phenotype, including the outward development of secondary sex characteristics as well as the initiation and maintenance of spermatogenesis. Their actions are mediated by the androgen receptor (AR), a member of the nuclear receptor superfamily. AR functions as a ligand-dependent transcription factor, regulating expression of an array of androgen-responsive genes. Androgen and the AR play important roles in male spermatogenesis and fertility. The recent generation and characterization of male total and conditional AR knockout mice from different laboratories demonstrated the necessity of AR signaling for both external and internal male phenotype development. As expected, the male total AR knockout mice exhibited female-typical external appearance (including a vagina with a blind end and a clitoris-like phallus), the testis was located abdominally, and germ cell development was severely disrupted, which was similar to a human complete androgen insensitivity syndrome or testicular feminization mouse. However, the process of spermatogenesis is highly dependent on autocrine and paracrine communication among testicular cell types, and the disruption of AR throughout an experimental animal cannot answer the question about how AR in each type of testicular cell can play roles in the process of spermatogenesis. In this review, we provide new insights by comparing the results of cell-specific AR knockout in germ cells, peritubular myoid cells, Leydig cells, and Sertoli cells mouse models that were generated by different laboratories to see the consequent defects in spermatogenesis due to AR loss in different testicular cell types in spermatogenesis. Briefly, this review summarizes these results as follows: 1) the impact of lacking AR in Sertoli cells mainly affects Sertoli cell functions to support and nurture germ cells, leading to spermatogenesis arrest at the diplotene primary spermatocyte stage prior to the accomplishment of first meiotic division; 2) the impact of lacking AR in Leydig cells mainly affects steroidogenic functions leading to arrest of spermatogenesis at the round spermatid stage; 3) the impact of lacking AR in the smooth muscle cells and peritubular myoid cells in mice results in similar fertility despite decreased sperm output as compared to wild-type controls; and 4) the deletion of AR gene in mouse germ cells does not affect spermatogenesis and male fertility. This review tries to clarify the useful information regarding how androgen/AR functions in individual cells of the testis. The future studies of detailed molecular mechanisms in these in vivo animals with cell-specific AR knockout could possibly lead to useful insights for improvements in the treatment of male infertility, hypogonadism, and testicular dysgenesis syndrome, and in attempts to create safe as well as effective male contraceptive methods.

Objective: To evaluate the return to fertility among women planning to become pregnant after the use of a continuous regimen of levonorgestrel 90 mg and ethinyl E2 20 mg.

Design: Descriptive analysis of pregnancy outcomes after participation in a contraceptive trial.

Setting: Multicenter trial.

Subject(s): Participants in a phase 3 contraceptive trial who discontinued to become pregnant.

Intervention(s): Eligible subjects were contacted at 3 and 12 months after treatment discontinuation to determine if and when they had conceived.

Main Outcome Measure(s): Kaplan-Meier analysis displaying the time until conception after oral contraceptive discontinuation.

Result(s): In the phase 3 trial, 34 of 2,134 subjects cited a desire for pregnancy as a reason for discontinuation. Of these, 4 were already pregnant before stopping treatment, 4 initiated other contraception, and 5 were lost to followup. Of the remaining 21 subjects at risk of pregnancy, the pregnancy rate was 57% at 3 months, 81% at 12 months, and 86% (18 of 21) (95% confidence interval 64% to 97%) at 13 months after discontinuation of treatment.

Conclusion(s): These findings suggest that a continuous oral contraceptive with levonorgestrel 90 mg and ethinyl E2 20 mg does not delay the return to fertility.

Objective: To review the impacts of obesity on women’s reproductive health and fertility.

Design: Literature review.

Setting: Academic medical center.

Patient(s): Forty articles are referenced. The number of patients evaluated in each of the studies varies from 33 to 213,208.

Intervention(s): Articles were identified from an Ovid/Medline search using the search terms obesity, dysfunctional uterine bleeding, contraception, miscarriage, infertility, and weight loss.

Main Outcome Measure(s): The impacts of obesity on reproductive health and fertility.

Result(s): Obesity is associated with early puberty, aberrant menstrual patterns, decreased contraceptive efficacy, ovulatory disorders, an increased miscarriage rate, and worse assisted reproductive technology outcomes. Losing weight can ameliorate many of these problems.

Conclusion(s): Obesity is one of the most significant causes of morbidity and mortality in the U.S. Providers must educate patients about the impacts of obesity on reproductive health and fertility.

Objective: To determine the effects of myo-inositol on oocyte quality in polycystic ovary syndrome (PCOS) patients undergoing intracytoplasmic sperm injection (ICSI) cycles.

Design: A prospective, controlled, randomized trial.

Setting: Assisted reproduction centers.

Patient(s): Sixty infertile PCO patients undergoing ovulation induction for ICSI.

Intervention(s):All participants underwent standard long protocol. Starting on the day of GnRH administration, 30 participants received myo-inositol combined with folic acid (Inofolic) 2 g twice a day and 30 control women received folic acid alone, administrated continuously.

Main Outcome Measure(s): Primary end points were number of morphologically mature oocytes retrieved, embryo quality, and pregnancy and implantation rates. Secondary end points were total number of days of FSH stimulation, total dose of gonadotropin administered, E2 level on the day of hCG administration, fertilization rate per number of retrieved oocytes, embryo cleavage rate, live birth and miscarriage rates, cancellation rate, and incidence of moderate or severe ovarian hyperstimulation syndrome.

Result(s): Total r-FSH units (1,958 ± 695 vs. 2,383 ± 578) and number of days of stimulation (11.4 ± 0.9 vs. 12.4 ± 1.4) were significantly reduced in the myo-inositol group. Furthermore, peak E2 levels (2,232 ± 510 vs. 2,713 ± 595 pg/mL) at hCG administration were significantly lower in patients receiving myo-inositol. The mean number of
oocytes retrieved did not differ in the two groups, whereas in the group cotreated with myo-inositol the mean number of germinal vesicles and degenerated oocytes was significantly reduced (1.0 ± 0.9 vs. 1.6 ± 1.0), with a trend for increased percentage of oocytes in metaphase II (0.82 ± 0.11% vs. 0.75 ± 0.15%).

Conclusion(s): These data show that in patients with PCOS, treatment with myo-inositol and folic acid, but not folic acid alone, reduces germinal vesicles and degenerated oocytes at ovum pick-up without compromising total number of retrieved oocytes. This approach, reducing E2 levels at hGC administration, could be adopted to decrease the risk of hyperstimulation in such patients.

Objective: To test the hypothesis that day 5 ET (D5ET) is superior to day 3 ET (D3ET) in pregnancy outcome and that it also reduces multiple gestations.

Design: Retrospective cohort study.

Setting: Assisted reproductive technologies program at Wilford Hall Medical Center.

Patient(s): Patients electing for either D3ET or D5ET.

Intervention(s): Participants meeting inclusion criteria for D5ET elected either D3ET or D5ET.

Main Outcome Measure(s):Cycles were compared by day of transfer and further stratified by patient age (<35 years and 35–40 years). The number of oocytes retrieved, embryos on day 3, embryos transferred, pregnancy rate, implantation rate, and twin and high order multiples (Rtriplets) rates were compared.

Result(s):Of the 274 patients who met our inclusion criteria, 153 underwent a D3ET and 121 underwent a D5ET. The D5ET group had a significantly lower mean age and number of embryos transferred and a higher implantation rate (56% vs. 42%) than the D3ET group. Patients who were 35–40 years old had a significantly higher live-birth rate (68% vs. 40%). Although not statistically significant, the D5ET groups had higher clinical pregnancy (73% vs. 65%) and twin pregnancy (33% vs. 25%) rates.

Conclusion(s): Blastocyst transfer resulted in fewer embryos transferred, with a trend toward improved clinical pregnancy and higher twin pregnancy rates. Live-birth rates were improved in patients 35–40 years of age. Younger patients opting for D5ET should do so with a commitment toward single ET.

Objective: To evaluate the long-term effects on bone mineral density (BMD) in women diagnosed with menstrual disorders in their adolescence.

Design: Prospective follow-up study six years after the initial investigation.

Setting: A youth clinic that is part of the school health system in Stockholm.

Population: Eighty-seven women diagnosed with secondary amenorrhea or oligomenorrhea in adolescence.

Methods:Subjects underwent gynecological examination, evaluation of eating behavior and physical activity. Whole body Dual Energy X-ray Absorptiometry was used for measurement of BMD.

Main Outcome Measure(s): BMD.

Result(s):The overall frequency of osteopenia/osteoporosis was 52%, and three girls had osteoporosis. Women with previous secondary amenorrhea had significantly lower BMD in the pelvis and lumbar spine than those with previous oligomenorrhea. The strongest predictor of low BMD was a restrictive eating disorder in adolescence and the most important counteraction was high physical activity at follow-up and a body mass index (BMI) ? 22. Persistent menstrual dysfunction at follow-up was associated with polycystic ovary syndrome and lower frequency of osteopenia.
Conclusions. This clinical follow-up study has demonstrated a high frequency of osteopenia in women diagnosed with menstrual disorders in adolescence. Previous anorectic behavior was the strongest negative predictor of BMD. It is important to pay attention to an underlying eating disorder in young women with menstrual dysfunction in order to promote bone health.

Objective: To evaluate the effect of metformin addition during ovarian hyperstimulation on cycle parameters and outcome of in vitro fertilization (IVF) treatment in polycystic ovary syndrome (PCOS) patients with a body mass index (BMI) <28 kg/m2.

Design: Retrospective review of patients’ records.

Setting: Istanbul Memorial Hospital Assisted Reproductive Treatment Unit.

Population: A total of 339 non-obese PCOS patients undergoing IVF were evaluated according to the supplementation of metformin.

Methods: Cycle parameters and IVF outcomes of 220 patients given metformin were compared to those of 119 patients treated without metformin.

Main outcome measures: Implantation and pregnancy rates.

Results:Metformin co-treatment led to significantly lower peak E2 levels (3,481 pg/ml vs. 4,192 pg/ml; p <0.0001). However, gonadotropin consumption, stimulation duration, numbers of total and mature oocytes retrieved, fertilization rate, and ratio of grade I embryos developed were similar in both groups. In the metformin administered group, significantly higher implantation (25% vs. 18%; p=0.003) and pregnancy rates (58% vs. 45%; p=0.04) were achieved. Abortion and moderate-severe ovarian hyperstimulation syndrome rates were found to be similar in both groups.

Conclusions: Although metformin use was especially and strongly recommended in obese PCOS cases, its supplementation during IVF in PCOS patients with a BMI <28 kg/m2 was observed to be beneficial and efficacious.

Background and aim:. Because of a growing demand for alternative treatments of the psychological and somatic/vasomotor symptoms related to menopausal transition, in this study we aimed to investigate the effect of a 2-month supplementation period with the Klamath algae extract (Klamin®, Nutratec Srl, Urbino, Italy) on the general and psychological well-being of a group of 21 menopausal women not treated with hormonal therapy, as well as on their oxidative stress status and level of antioxidants. Klamin is an extract naturally rich in powerful algal antioxidant molecules (AFA-phycocyanins) and concentrated with Klamath algae’s natural neuromodulators (phenylethylamine as well as natural selective MAO-B inhibitors).

CONCLUSIONS: At the end of the Klamin supplementation period, plasma lipid peroxidation significantly decreased (as proven by a significant lowering of plasma MDA levels), while the overall antioxidant system improved thanks to the significant increase in the plasma levels of carotenoids, tocopherols and retinol. Furthermore, the average Green Scale score, which evaluates menopausal symptoms and thus by contrast the overall and psychological well-being of menopausal women, was significantly reduced. As it did not show the steroid-like effects on the hormonal parameters, Klamin could be proposed both as a valid natural remedy for women seeking an alternative to hormonal therapy, as well as as a complementary treatment for many climacteric symptoms

BACKGROUND: The purpose of the present study was to examine long-term reproductive outcome and ovarian reserve in an unselected population of women with polycystic ovary syndrome (PCOS).

METHODS: A total of 91 patients with confirmed PCOS and 87 healthy controls were included in the study. Patients had been diagnosed between 1987 and 1995 and at the time of the follow-up, subjects were 35 years of age or older.

RESULTS: Among women who had attempted a pregnancy, 86.7% of PCOS patients and 91.6% of controls had given birth to at least one child. Among PCOS patients who had given birth, 73.6% had done so following a spontaneous conception. Mean ovarian volume and the number of antral follicles in PCOS patients were significantly greater than in control women (P < 0.001, respectively). PCOS patients also had higher serum concentrations of anti-Müllerian hormone and lower follicle-stimulating hormone levels.
CONCLUSIONS: Most women with PCOS had given birth, and the rate of spontaneous pregnancies was relatively high. Together with the ultrasound findings and the hormonal analyses, this finding could imply that PCOS patients have a good fecundity, and an ovarian reserve possibly superior to women with normal ovaries.

BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with metabolic abnormalities. It is debated whether all women with PCOS should be screened for metabolic abnormalities as these may vary with PCOS phenotype, age and ethnicity. The aims of this study were to assess the prevalence of metabolic abnormalities in Dutch anovulatory PCOS women and to define criteria for metabolic screening.

METHODS: Anovulatory patients, diagnosed with PCOS according to the Rotterdam consensus criteria, underwent metabolic screening. Through stepwise multivariate analysis patient characteristics associated with metabolic syndrome (MetS) and insulin resistance (IR) were evaluated for their use as selection parameters for metabolic screening.

RESULTS: Overall, prevalence of MetS and IR was 15.9% (n = 25) and 14% (n = 22), respectively, in 157 PCOS women (age 29.0 ± 4.8 years, BMI 26.1 ± 6.7 kg/m2). Anovulatory hyperandrogenic women (with or without polycystic ovaries) had more often MetS and IR (with, 20.8 and 19.8%; without, 100 and 40%, respectively) than non-hyperandrogenic PCOS women (0 and 1.8%; P < 0.001). Waist circumference >83.5 cm along with increased free androgen index (FAI) had the most powerful association with the presence of MetS and IR (area under the receiver operating characteristic curve 0.912) and offered a reduction in the necessity of screening for metabolic derailments of about 50%.

CONCLUSIONS: The hyperandrogenic PCOS phenotypes are highly linked to the presence of MetS and IR in Dutch PCOS women. Waist circumference combined with FAI was identified as an efficient combination test to select those PCOS women who should be screened for the presence of MetS and/or IR

Objective: To compare the efficacy and safety of dienogest (DNG) with intranasal buserelin acetate (BA) in patients with endometriosis.

Design: Phase III, randomized, double-blind, multicenter, controlled trial.

Setting: Twenty-four study centers in Japan.

Patient(s): Two hundred seventy-one patients with endometriosis.

Intervention(s): Dienogest (2 mg/day, orally) or BA (900 mg/day, intranasally) for 24 weeks.

Main Outcome Measure(s): The pre- to posttreatment changes in the scores of five subjective symptoms during nonmenstruation (lower abdominal pain, lumbago, defecation pain, dyspareunia, and pain on internal examination) and two objective findings (induration in the pouch of Douglas and limited uterine mobility).

Result(s): Dienogest reduced the scores of all symptoms and findings at the end of treatment, and the mean changes in the scores of all symptoms and findings except induration in the pouch of Douglas were comparable to those obtained with BA. Compared with BA, DNG was associated with irregular genital bleeding more frequently and with fewer hot flushes. The reduction in bone mineral density (BMD) during DNG treatment was significantly lower than that during BA treatment.

Conclusion(s): DNGis as effective as intranasal BA in alleviating endometriosis, and causes lessBMDloss

Objectives: To provide an overview of the studies that have evaluated the return to fertility following cessation of oral contraceptives (OCs), including recent evidence in women discontinuing extended-cycle and continuous-use regimens.

Design: Comprehensive review.

Patient(s): None.

Intervention(s): Relevant articles were identified through a PubMed literature search (1960–2007) and a crossreference of published data.

Main Outcome Measure(s): Time to fertility following contraceptive use.

Result(s): Numerous studies have demonstrated some delay in the time to conception in previous users of Ocs who discontinued use in order to conceive, but this impairment appears to be temporary and typically limited to the early months following cessation of OC use. Reported 12-month conception rates in former cyclic OC users range from 72%–94% and are similar to those observed in women discontinuing intrauterine devices (71%–92%), progestin-only contraceptives (70%–95%), condoms (91%), and natural family planning (92%). There is a limited amount of data on the time to conception in women stopping extended-cycle and continuous-use OCs, but the data suggest that subsequent return to fertility is generally comparable to that of cyclic OCs.

Conclusion(s): A comprehensive survey of reported data indicates that the return of fertility in former OC users (both cyclic and extended/continuous regimens) in women who stop use in order to conceive is comparable to that observed with other contraceptive methods.

Endometrial carcinoma is the most common genital cancer in women. While patients usually present with vaginal bleeding, in 10–20% this characteristic symptom is absent. Endometrial thickness (double layer) is measured by transvaginal sonography and thickening indicates an increased risk of malignancy or other pathology (hyperplasia or polyps). Objective: We sought to correlate hysteroscopic and pathological findings in asymptomatic postmenopausal women with sonographically thickened endometrium (>6mm). Study design: A prospective observational study in a university hospital of 304 postmenopausal women referred between 1996 and 2006 because of a sonographically thickened endometrium in the absence of abnormal bleeding, who underwent continuous flow hysteroscopy (4.5mm Storz hysteroscope) and fractionated curettage of the uterine cervix and corpus (D & C) in addition to vaginal sonography (5MHz probe). Results: The mean age of the women was 64.8 (range 57.7–71.9) years. Average endometrial thickness measured by ultrasound was 12mm±6.7mm. Hysteroscopy suggested the presence of endometrial polyps in 226 women (74.3%), simple endometrial hyperplasia in 34 (11.2%), atrophic endometrium in 18 (5.9%), complex endometrial hyperplasia in 2 (0.7%), atypical hyperplasia in 3 (1%) and leiomyoma in 9 (3.0%). In 12 women (3.9%), the hysteroscopic appearance suggested malignancy and histology revealed endometrial adenocarcinoma. All hysteroscopic results were confirmed by histological examination. Conclusion: Hysteroscopy represents an easy, safe and effective method for the investigation of asymptomatic women with a thickened endometrium found with transvaginal ultrasound. The commonest pathology was endometrial polyps.

Objectives: Relatively few studies have evaluated relationships between stress, psychological distress, psychosocial factors and menopause symptoms, and none have evaluated emotional intelligence (EI) in relation to menopause. In this study, direct and indirect relationships were evaluated between stress, psychological distress, psychosocial factors (e.g. social support, coping, EI), menopause symptom severity and physical health in middle-aged women.

Methods: One hundred and sixteen women aged 45–55 years were recruited through women’s health centres and community organizations. They completed a short questionnaire asking about stress, psychological distress (i.e. anxiety, depression), EI, attitude to menopause, menopause symptoms and physical health.

Results: Low emotional intelligence was found to be related to worse menopause symptoms and physical health, and these associations were partly mediated by high stress, anxiety and depression, a negative attitude to menopause and low proactive coping

Conclusions: Women with high EI appear to hold more positive attitudes to menopause and experience less severe stress, psychological distress and menopause symptoms and better physical health. These results suggest that women who expect menopause to be a negative experience or are highly stressed or distressed may be more likely to experience a more negative menopause.

Metformin is an insulin sensitizer widely used for the treatment of patients affected by type 2 diabetes mellitus. Because many women with polycystic ovary syndrome (PCOS) are insulin resistant, metformin was introduced in clinical practice to treat these patients also. Moreover, metformin’s effect has other targets beside its insulin-sensitizing action. The present review was aimed at describing all evidence-based and potential uses of metformin in PCOS patients. In particular, we will analyze the uses of metformin not only for the treatment of all PCOS-related disturbances such as menstrual disorders, anovulatory infertility, increased abortion, or complicated pregnancy risk, hyperandrogenism, endometrial, metabolic and cardiovascular abnormalities, but also for the prevention of the syndrome

Context: Ovarian dysfunction is classically categorized on the basis of cycle history, FSH, and estradiol levels. Novel ovarian markers may provide a more direct insight into follicular quantity in hypergonadotropic women.

Objective: The objective of the study was to investigate the distribution of novel ovarian markers in young hypergonadotropic women as compared with normogonadotropic regularly menstruating women.

Design: This was a nationwide prospective cohort study.

Setting: The study was conducted at 10 hospitals in The Netherlands.

Patients: Women below age 40 yr with regular menses and normal FSH (controls; n = 83), regular menstrual cycles and elevated FSH [incipient ovarian failure (IOF); n = 68]; oligomenorrhea and elevated FSH [referred to as transitional ovarian failure (TOF); n = 79]; or at least 4 months amenorrhea together with FSH levels exceeding 40 IU/liter [premature ovarian failure (POF); n = 112].

Main Outcome Measures: Serum levels of anti-Müllerian hormone (AMH), inhibin B, and antral follicle count (AFC) was measured.

Results: All POF patients showed AMH levels below the fifth percentile (p5) of normoovulatory women. Normal AMH levels (>p5) could be identified in 75% of IOF, 33% of TOF patients, and 98% of controls. AFC and AMH levels changed with increasing age (P < 0.0001), whereas inhibin B did not (P = 0.26). AMH levels were significantly different between TOF and IOF over the entire age range, whereas AFC became similar for TOF and IOF at higher ages.

Conclusions: Compared with inhibin B and AFC, AMH was more consistently correlated with the clinical degree of follicle pool depletion in young women presenting with elevated FSH levels. AMH may provide a more accurate assessment of the follicle pool in young hypergonadotropic patients, especially in the clinically challenging subgroups of patients with elevated FSH and regular menses (i.e. IOF) and in hypergonadotropic women with cycle disturbances not fulfilling the POF diagnostic criteria (i.e. TOF).

Gynecological Endocrinology 24: 631 – 636, 2008

Eighty-three women were classified into two groups according to the 2003 Rotterdam consensus criteria. The NO group comprised women (n = 45) with regular menstrual cycles and proven fertility, whereas the PCO group comprised women (n = 38) with oligo-anovulation, clinical and/or biochemical features of hyperandrogenism, and polycystic ovary morphology at two-dimensional ultrasound. All women were evaluated by means of 3D-PDA. The parameters studied in both groups were follicle number per ovary (FNPO), ovarian volume (OV), mean gray value (MG) and three vascular indices: vascularization index (VI), flow index (FI) and vascularization flow index (VFI).

The PCO group showed a higher mean OV as well as FNPO. No differences in MG, VI, FI and VFI were found between the groups.

3D-PDA indices are not useful for discriminating between normal and polycystic ovaries.

Testosterone therapy during menopause has a wide range of benefits that reach beyond the realm of human sexuality. This is a consequence not only of the widespread distribution of androgen receptors in various extragonadal tissues but also of the conversion of androgens to estrogens in the tissues in which aromatase expression is present. For this reason, testosterone therapy during the climacteric years will not only supply androgens but will also stimulate estrogen production in tissues that express aromatase. Furthermore, the bioavailability of androgens to the tissues depends not only on the rate of their production by the postmenopausal ovaries and adrenals but also on the circulating levels of sex hormone-binding globulin (SHBG). Tibolone inhibits SHBG production in the liver, thus increasing free testosterone levels. The association of tibolone with testosterone as a form of androgen replacement therapy during the climacteric is discussed, as is the use of low-dose testosterone, tibolone or the association of both in perimenopausal patients with signs of androgen deficiency. Testosterone treatment has a boosting effect not only on human sexuality but also on the sensation of well-being, a stimulatory effect conferred by the increase in β-endorphins.

Evaluate the efficacy of catch-up HPV vaccination in sexually active young women and the potential impact of HPV vaccines on the practice of organized screening.

Women enrolled in the Future II study and (2) from a separate population-based study in Iceland.

Analysis of cytological and histological results and colposcopic examinations among 710 women, aged 18-23, with less than five sexual partners, irrespectively of baseline HPV status at enrolment. The impact on screening practice as determined by evaluating the distribution of 12 oncogenic HPV types in 582 cervical intraepithelial lesions (CIN 2-3) and cancer cases.

Distribution of evaluated parameters according to age at enrolment. Age distribution of four HPV groups, within age classes and HPV groups: mean time to development of lesions, mean time to development of CIN 2-3+, cumulative frequency for CIN 2-3+ lesions after the last normal smear.

Fifty out of 99 postmenopausal women seen previously were re-assessed after 24 months. Levels of BMD, bone markers, serum estradiol (E2) and total testosterone were determined.

BMD decreased in the femoral neck (∼2%) (p < 0.008), but remained stable in the other skeletal areas; E2 and serum Crosslaps (sCTX) decreased by 34% (p < 0.001) and 21% (p < 0.003), respectively. Women aged ≤ 65 years exhibited decreased BMD only in the femoral neck (2%, p < 0.01), without changes in bone markers. Women aged > 65 years exhibited a decrease in sCTX levels and stable BMD values at all skeletal sites. E2 levels decreased similarly in both groups (∼35%). Women with baseline E2 levels ≥ 10 pg/ml showed stable BMD in spite of their E2 levels decreasing by 42% (p < 0.001); sCTX decreased by 21% (p < 0.01). Women with baseline E2 levels < 10 pg/ml showed a 2% decrease (p < 0.001) in femoral neck BMD and a 19% decrease (p < 0.002) in E2 levels, without changes in bone markers.

Although endogenous E2 decreased to around 7 pg/ml in these menopausal women, this level would seem to be sufficient to maintain BMD in almost all skeletal areas, and to be more effective in older women.

Preterm delivery is the leading cause of perinatal morbidity and mortality in the United States, and its incidence is increasing. The present manuscript reviews the literature on the relationship of hypothyroidism and/or autoimmune thyroid disease to preterm delivery.

A PubMed search was used to identify all relevant articles. A reference search of all retrieved articles was undertaken. All articles identified in the search were included in the review.

Uncontrolled case series were discussed in the manuscript but not included in drawing conclusions from the literature.

Peripubertal obesity (body mass index-for-age_95%) in girls is associated with hyperandrogenemia. LH likely contributes to this relationship, but overnight LH secretion in obese girls is poorly characterized.

The aim of the study was to evaluate LH pulse characteristics in obese girls throughout pubertal maturation.

We conducted a cross-sectional analysis.

The study was performed in a general clinical research center.

Eight nonobese and five obese Tanner 1–2 girls participated, as well as 32 nonobese and 12 obese Tanner 3–5 girls.

LH pulse frequency, amplitude, and mean LH were measured in three 4-h time blocks (block 1, 1900–2300 h; block 2, 2300–0300 h; and block 3, 0300–0700 h).

Tanner stage 1–2 nonobese girls demonstrated nocturnal increases of LH frequency (P <0.01, block 1 vs. 2) and mean LH (P< 0.05, block 1 vs. 2 and 3). Obese Tanner 1–2 girls had lower 12-h LH frequency and LH amplitude (P< 0.05 for both), with no overnight changes of LH pulse parameters. Compared to normal, LH frequency was elevated in Tanner 3–5 obese girls (P<0.01 in all blocks), whereas LH amplitude was low (P _ 0.05 in all blocks). Overnight increases of LH amplitude were observed in nonobese Tanner 3–5 girls (P _ 0.0001), but not in obese Tanner 3–5 girls.

Obesity in prepubertal and early pubertal girls is associated with reduced LH secretion and reduced nocturnal changes of LH. In later pubertal girls, obesity is linked with reduced LH amplitude, but elevated LH frequency; the latter may reflect effects of  hyperandrogenemia.

The “metabolic syndrome” (MetS) is a clustering of components that reflect overnutrition, sedentary lifestyles, and resultant excess adiposity. The MetS includes the clustering of abdominal obesity, insulin resistance, dyslipidemia, and elevated blood pressure and is associated with other comorbidities including the prothrombotic state, proinflammatory state, nonalcoholic fatty liver disease, and reproductive disorders. Because the MetS is a cluster of different conditions, and not a single disease, the development of multiple concurrent definitions has resulted. The prevalence of the MetS is increasing to epidemic proportions not only in the United States and the remainder of the urbanized world but also in developing nations. Most studies show that the MetS is associated with an approximate doubling of cardiovascular disease risk and a 5-fold increased risk for incident type 2 diabetes mellitus. Although it is unclear whether there is a unifying pathophysiological mechanism resulting in the MetS, abdominal adiposity and insulin resistance appear to be central to the MetS and its individual components. Lifestyle modification and weight loss should, therefore, be at the core
of treating or preventing the MetS and its components. In addition, there is a general consensus that other cardiac risk factors should be aggressively managed in individuals with the MetS. Finally, in 2008 the MetS is an evolving concept that continues to be data driven and evidence based with revisions forthcoming.