Increased androgen, anti-Müllerian hormone, and sporadic anovulation in healthy, eumenorrheic women: a mild PCOS-like phenotype?

Abstract:
Context: Hyperandrogenism is a hallmark of polycystic ovary syndrome (PCOS) in women with irregular menses, yet the relationship between androgens and ovarian dysfunction remains poorly understood in eumenorrheic women.

Objective: The objective of the study was to evaluate whether sporadic anovulation was associated with higher T and anti-müllerian hormone (AMH; marker of ovarian follicle count) concentrations in eumenorrheic women.
Design: This was a prospective cohort study from 2005 to 2007.
Setting: The study was conducted at the University of Buffalo in western New York state.

Participants: A total of 259 eumenorrheic women without a self-reported history of infertility, PCOS, or other endocrine disorder participated in the study.

Main Outcome Measures: Total T and AMH were measured five to eight times per cycle for one (n = 9) or two (n = 250) cycles per woman (n = 509 cycles) with timing of menstrual cycle phase assisted by fertility monitors. Anovulatory cycles were defined biochemically by progesterone and LH concentrations. Repeated-measures ANOVA was conducted on log-transformed data with adjustment for age.

Results: Compared with ovulatory cycles (n = 467), sporadic anovulatory cycles (n = 42) had marginally higher total and significantly higher free T [mean 23.7 ng/dL (95% confidence interval [CI] 21.4-26.3) vs 21.6 ng/dL (95% CI 20.9-22.3), P = .08, and 0.36 ng/dL (95% CI 0.33-0.40) vs 0.32 ng/dL (95% CI 0.31-0.33), P = .02, respectively] during menses and also throughout the luteal phase (P < .01 for all). Women with higher T had elevated AMH concentrations, increased reporting of a history of acne requiring medical treatment, but not increased hirsutism.

Conclusions: Mechanisms of androgen-related ovulatory dysfunction that characterize PCOS in women with menstrual disturbances may occur across a continuum of T concentrations, including in eumenorrheic women without clinical hyperandrogenism.

The Journal of clinical endocrinology and metabolism


Pharmacokinetics of two low-dose levonorgestrel-releasing intrauterine systems and effects on ovulation rate and cervical function: pooled analyses of phase II and III studies

Kristina Gemzell-Danielsson

Department of Women's and Children's Health, Karolinska institutet, SE-17177 Stockholm, Sweden.

Abstract:
OBJECTIVE: To assess the pharmacokinetics and pharmacodynamics of levonorgestrel intrauterine system (LNG-IUS) 13.5 mg and LNG-IUS 19.5 mg (total content).

DESIGN: Pooled pharmacokinetic and pharmacodynamic analyses of phase II and III studies.

SETTING: Randomized, open-label, multicenter studies.

PATIENT(S): Nulliparous and parous women.

INTERVENTION(S): Levonorgestrel intrauterine system 13.5 mg, LNG-IUS 19.5 mg, or LNG-IUS 20 μg/24 h (total content 52 mg).

MAIN OUTCOME MEASURE(S): Pharmacokinetics of LNG, ovulation rate, cervical function, and endometrium effects.

RESULT(S): The in vivo LNG release rate of LNG-IUS 13.5 mg was approximately 14 μg/24 h after 24 days, declining progressively to 5 μg/24 h after 3 years. The average LNG serum concentration over 3 years of use was 74.3 ng/L, 114 ng/L, and 218 ng/L for LNG-IUS 13.5 mg, LNG-IUS 19.5 mg, and LNG-IUS 20 μg/24 h, respectively. All treatments showed very similar progestogenic effects on cervical mucus, with low and similar cervical scores throughout treatment. Ovulation was observed in the majority of women in all groups where assessment was possible, although there was a lower incidence of anovulation with LNG-IUS 13.5 mg and LNG-IUS 19.5 mg compared with LNG-IUS 20 μg/24 h. The progestogenic effect on the endometrium was marked in all three LNG-IUS groups.

CONCLUSION(S): Levonorgestrel intrauterine system 13.5 mg and LNG-IUS 19.5 mg result in alower systemic exposure to LNG, lower incidence of anovulation, and similar progestin impact on the endometrium and cervical function compared with LNG-IUS 20 μg/24 h.


Zinc and homocysteine levels in polycystic ovarian syndrome patients with insulin resistance

Ahmet Erdem

Department of Obstetrics and Gynecology, Gazi University, Ankara, Turkey.

Abstract: In this study, our objective was to evaluating the value of serum zinc levels as an etiologic and prognostic marker in patients with polycystic ovarian syndrome. We conducted a prospective study, including 53 women with polycystic ovarian syndrome and 33 healthy controls. We compared serum zinc levels, as well as clinical and metabolic features, of the cases. We also compared serum zinc levels between patients with polycystic ovarian syndrome with insulin resistance. Mean zinc levels were found to be significantly lower in patients with polycystic ovarian syndrome than healthy controls. Multiple logistic regression analysis of significant metabolic variables between polycystic ovarian syndrome and control groups (serum zinc level, body mass index, the ratio of triglyceride/high-density lipoprotein cholesterol, and homocysteine) revealed that zinc level was the most significant variable to predict polycystic ovarian syndrome. Mean serum zinc levels tended to be lower in patients with polycystic ovarian syndrome with impaired glucose tolerance than patients with normal glucose tolerance, but the difference was not statistically significant. In conclusion, zinc deficiency may play a role in the pathogenesis of polycystic ovarian syndrome and may be related with its long-term metabolic complications.


Vitamin D alters genes involved in follicular development and steroidogenesis in human cumulus granulosa cells

Abstract:
CONTEXT: Vitamin D deficiency is common among reproductive-aged women and has a role in female reproduction.

OBJECTIVE: This study evaluated the role of 1,25-dihydroxyvitamin D3 (vit D3) in ovarian follicular development and steroidogenesis by using a human granulosa cell (GC) model.

DESIGN, SETTING, AND PARTICIPANTS: Fifty-four women who underwent in vitro fertilization were enrolled.

INTERVENTION: Follicular fluid (FF) and mural and cumulus GCs were collected from small and large follicles. In separate experiments, primary cumulus GCs were cultured with or without vit D3 followed by RT-PCR for mRNA expression levels. The effect of recombinant anti-Mullerian hormone (AMH) on nuclear localization of phospho-Smad 1/5/8 was evaluated in the presence or absence of vit D3 by using immunofluorescence. 25-Hydroxyvitamin D levels in FF as well as cell culture media AMH, progesterone, and estradiol (E2) concentrations were determined by ELISA and RIA.

MAIN OUTCOME MEASURES: The following were measured: 1) mRNA expression levels; 2) 3β-hydroxysteroid dehydrogenase (3β-HSD) enzyme activity; 3) FSH-induced aromatase mRNA and E2 production; and 4) nuclear localization of phospho-Smad 1/5/8.

RESULTS: In a multivariate analysis, 25 OH-D levels in FF negatively correlated with AMH and AMH receptor (AMHR)-II mRNA levels in cumulus GCs of small follicles. Compared with women with replete 25-hydroxyvitamin D levels in FF, those with insufficient/deficient levels had a 2-fold increase in AMHR-II mRNA levels in cumulus GCs of small follicles (P = .02). Treatment with vit D3 caused a decrease in AMHR-II and FSH receptor mRNA but an increase in 3-βHSD mRNA levels compared with control (P < .05). Vit D3 enhanced 3-βHSD enzyme activity as assessed by increasing progesterone release; however, vit D3 did not affect FSH-induced aromatase mRNA and E2 production, but it decreased the phosphorylation of Smad 1/5/8 and its nuclear localization.

CONCLUSION: These data suggest that vit D3 alters AMH signaling and steroidogenesis in human cumulus GCs, possibly reflecting a state of GC luteinization potentiation.


Selenium Supplementation for Hashimoto's Thyroiditis: Summary of a Cochrane Systematic Review

Zbys Fedorowicz

Department of UKCC (Bahrain Branch), The Cochrane Collaboration, Awali, Bahrain.

Ben Carter

Institute for Medical Informatics and Biostatistics

Amira Y Albusta

Department of College of Medicine, AMA International University of Bahrain, Manama, Awali, Bahrain.

Abstract: Selenium supplementation in people with Hashimoto's thyroiditis might reduce antibody levels and result in a decreased dosage of levothyroxine (LT4) and may provide other beneficial effects (e.g. on mood and health-related quality of life). The aim of our systematic review was to assess the effects of selenium supplementation on Hashimoto's thyroiditis. We searched The Cochrane Library, MEDLINE, EMBASE and Web of Science for randomized controlled trials. Study selection, data extraction, assessment of risk of bias and analyses were carried out by two independent review authors. We assessed the quality of the evidence of included studies using GRADE. Four studies rated at unclear to high risk of bias comprising 463 participants were included. One study at high risk of bias showed statistically significant improvement in subjective well-being with sodium selenite 200 μg plus titrated LT4 compared with placebo plus titrated LT4 (RR 4.67, 95% CI 1.61-13.50). Selenomethionine 200 μg as a single treatment or combined with LT4 reduced the serum levels of anti-thyroid peroxidase antibodies compared with placebo (or placebo plus LT4) in three studies (p < 0.001). Although the changes from baseline were statistically significant in these three studies, their clinical relevance is unclear. In conclusion, the results of these four studies, assessed at unclear to high risk of bias, show that evidence to support or refute the efficacy of selenium supplementation in people with Hashimoto's thyroiditis is incomplete and not reliable to help inform clinical decision making.


Injectable and oral contraceptives and risk of HIV acquisition in women: an  analysis of data from the MDP301 trial

Richard Hayes

London School of Hygiene & Tropical Medicine

Abstract:
STUDY Question: Do injectable and oral contraceptives increase the risk of human immunodeficiency virus (HIV) acquisition in women?

SUMMARY ANSWER: After adjusting for confounders, evidence of a significantly increased risk of HIV remained for women using injectable depo-medroxyprogesterone (DMPA) (hazard ratio = 1.49, 95% confidence interval (1.06-2.08)) but not for injectable norethisterone-enanthate (Net-En) or oral contraceptive pills (OC).

WHAT IS KNOWN ALREADY: An association between the use of some types of hormonal contraception (HC) methods and an increased risk of HIV, possibly through changes in the genital tract environment and alterations in the immune response, has been previously observed, although not consistently. A recent systematic review of these studies has highlighted the need for more definitive evidence.

STUDY DESIGN, SIZE, DURATION: A secondary data analysis of the MDP301 phase 3 microbicide trial was conducted to estimate the effects of use of different methods of HC on the risk of HIV acquisition in women. HIV-negative women (n = 8663) with a median age of 28 years were included in the analysis; 382 HIV seroconverted by 52 weeks follow-up; 10% of women-years were lost to follow-up before 52 weeks.

PARTICIPANTS/MATERIALS, SETTING, Methods: Contraceptive use was reported at each 4-weekly visit. Cox proportional hazards (PH) models were used to estimate the effects of baseline and current use of injectable DMPA, injectable Net-En and OC compared with no HC, on the risk of HIV, adjusting for baseline and time-updated covariates. Causal effects for 52 weeks of HC use compared with no HC were estimated in a weighted Cox model, censoring women at deviation from baseline HC use (or non-use) or pregnancy.

MAIN RESULTS AND THE ROLE OF CHANCE: At baseline, 2499 (29%) women were on DMPA, 1180 (14%) on Net-En, and 1410 (16%) on OC; 3574 (40%) not on HC, started HC in follow-up. Adjusted hazard ratios (HR) for baseline HC use, compared with no HC, were 1.38 (95% confidence interval (CI) 1.07-1.78) for DMPA; 1.18 (0.86-1.62) for Net-En and 0.97 (0.68-1.38) for OC. The estimated causal effects of DMPA and Net-En over 52 weeks were: HR = 1.49 (95% CI 1.06-2.08) and HR = 1.31 (95% CI 0.62-1.61), respectively.

LIMITATIONS, REASONS FOR CAUTION: A main limitation of the study was that it was a secondary analysis of data from a study that was not designed to investigate this question. Despite our best efforts, we cannot exclude residual confounding to explain the effect of DMPA.

WIDER IMPLICATIONS OF THE Findings: The results of this study should be reviewed by the World Health Organization to determine whether current recommendations on the use of DMPA in settings with high HIV prevalence require modification.

STUDY FUNDING/COMPETING INTERESTS: MDP is a partnership of African and European academic/government institutions with commercial organizations, which is funded by the UK Government (DFID and MRC), with support from IPM and EDCTP. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: None.


The injectable-only contraceptive medroxyprogesterone acetate, unlike norethisterone acetate and progesterone, regulates inflammatory genes in endocervical cells via the glucocorticoid receptor

Janet P Hapgood

Department of Molecular and Cell Biology University of Cape Town Rondebosch South Africa

Abstract: Clinical studies suggest that the injectable contraceptive medroxyprogesterone acetate (MPA) increases susceptibility to infections such as HIV-1, unlike the injectable contraceptive norethisterone enanthate (NET-EN). We investigated the differential effects, molecular mechanism of action and steroid receptor involvement in gene expression by MPA as compared to NET and progesterone (P4) in the End1/E6E7 cell line model for the endocervical epithelium, a key point of entry for pathogens in the female genital mucosa. MPA, unlike NET-acetate (NET-A) and P4, increases mRNA expression of the anti-inflammatory GILZ and IκBα genes. Similarly, MPA unlike NET-A, decreases mRNA expression of the pro-inflammatory IL-6, IL-8 and RANTES genes, and IL-6 and IL-8 protein levels. The predominant steroid receptor expressed in the End1/E6E7 and primary endocervical epithelial cells is the glucocorticoid receptor (GR), and GR knockdown experiments show that the anti-inflammatory effects of MPA are mediated by the GR. Chromatin-immunoprecipitation results suggest that MPA, unlike NET-A and P4, represses pro-inflammatory cytokine gene expression in cervical epithelial cells via a mechanism involving recruitment of the GR to cytokine gene promoters, like the GR agonist dexamethasone. This is at least in part consistent with direct effects on transcription, without a requirement for new protein synthesis. Dose response analysis shows that MPA has a potency of ∼ 24 nM for transactivation of the anti-inflammatory GILZ gene and ∼ 4-20 nM for repression of the pro-inflammatory genes, suggesting that these effects are likely to be relevant at injectable contraceptive doses of MPA. These findings suggest that in the context of the genital mucosa, these GR-mediated glucocorticoid-like effects of MPA in cervical epithelial cells are likely to play a critical role in discriminating between the effects on inflammation caused by different progestins and P4 and hence susceptibility to genital infections, given the predominant expression of the GR in primary endocervical epithelial cells.


Modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: systematic review  and meta-analysis

Abstract:
Background: There is substantial variability in cancer risk in women who have inherited a BRCA1 or BRCA2 (BRCA1/2) mutation. Numerous factors have been hypothesized to modify these risks, but studies are of variable quality, and it remains unclear which of these may be of value in clinical risk assessment.

Methods: PubMed and Web of Science databases were searched for articles published through September 2013. Fixed effects meta-analysis was done using the hazard ratios and/or odds ratios to estimate the pooled effect estimates (ES) and 95% confidence intervals (CIs) to identify factors that are associated with cancer risk modification in BRCA1/2 mutation carriers.

Results: We identified 44 nonoverlapping studies that met predefined quality criteria. Sufficient evidence is available to make clinically relevant inferences about a number of cancer risk modifiers. The only variable examined that produced a probable association was late age at first live birth, a meta-analysis showed a decrease in the risk of breast cancer in BRCA1 mutation carriers with women aged 30 years or older vs. women younger than 30 years (ES = 0.65; 95% CI =0.42 to 0.99). The same was shown for women aged 25 to 29 years versus those aged less than 25 years (ES = 0.69; 95% CI = 0.48 to 0.99). Breastfeeding and tubal ligation were associated with reduced ovarian cancer risk in BRCA1 mutation carriers; oral contraceptives were associated with reduced risk among BRCA1/2 mutation carriers. Smoking was associated with increased breast cancer risk in BRCA2 mutation carriers only.

Conclusions: Data assessing many potential risk modifiers are inadequate, and many have not been externally validated. Although additional studies are required to confirm some associations, sufficient information is available for some risk factors to be used in risk counseling or lifestyle modification to minimize cancer risk in BRCA1/2 mutation carriers

Journal of the National Cancer Institute


Effect of Anticholinergic Medications on Falls, Fracture Risk, and Bone Mineral Density Over a 10-Year Period

Lisa-Ann Fraser, Jonathan D Adachi, William D Leslie, David Goltzman, Robert Josse, Jerilynn Prior, Stephanie Kaiser, Nancy Kreiger, Christopher S Kovacs, Tassos P Anastassiades, Alexandra Papaioannou

Abstract:
Background: Many medications used in older adults have strong anticholinergic (ACH) properties, which may increase the risk of falls and fractures. Use of these medications was identified in a population-based Canadian cohort.

Objective: To identify the fall and fracture risk associated with ACH medication use.

Methods: Data collection and analysis were conducted at baseline, year 5, and year 10. Cross-sectional analyses were performed to examine associations between ACH medication use and falls. Time-dependent Cox regression was used to examine time to first nontraumatic fracture. Finally, change in bone mineral density (BMD) over 10 years was compared in ACH medication users versus nonusers.

Results: Strongly ACH medications were used by 618 of 7753 participants (8.0%) at study baseline, 592 (9.5%) at year 5, and 334 (7.7%) at year 10. Unadjusted ACH medication use was associated with falls at baseline (odds ratio = 1.50; 95% CI = 1.14-1.98; P = 0.004), but the association was no longer significant after covariate adjustment. Similar results occurred at years 5 and 10. ACH medication use was associated with increased incident fracture risk before (hazard ratio = 1.22; CI = 1.13-1.32; P < 0.001) but not after covariate adjustment. Mean (SD) change in femoral neck BMD T-score over 10 years, in those using ACH medications at both years 0 and 5, was -0.60 (0.63) in ACH users versus -0.49 (0.45) in nonusers (P = 0.041), but this was not significant after covariate adjustment.

Conclusions: ACH medications were not found to be independently associated with an increased risk of falling, fractures, or BMD loss. Rather, factors associated with ACH medication use explained the apparent associations.


Premenstrual spotting of ≥2 days is strongly associated with histologically confirmed endometriosis in women with infertility

Richard O Burney

Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Madigan Healthcare System, Tacoma, WA; Department of Clinical Investigation, Madigan Healthcare Syst...

Raywin R Huang

Department of Clinical Investigation, Madigan Healthcare System, Tacoma, WA.

Abstract:
OBJECTIVE: The purpose of this study was to assess the prevalence of endometriosis in women with premenstrual spotting and to determine the predictive value of this symptom in the diagnosis of endometriosis.

STUDY DESIGN: We conducted a retrospective cohort study of 80 consecutive women who presented to the infertility clinic for evaluation and who subsequently underwent laparoscopic assessment for infertility with or without pelvic pain. Our main outcome measure was the presence or absence of histologically confirmed endometriosis in women with and without premenstrual spotting.

RESULTS: Endometriosis was significantly more prevalent in subfertile women who reported premenstrual spotting for ≥2 days relative to women without this symptom (89% [34/38 women] vs 26% [11/42 women]; P < .0001). Multinomial logistic regression analysis demonstrated the presence of premenstrual spotting for ≥2 days to be associated significantly with the presence of endometriosis (odds ratio, 16; 95% confidence interval, 3.9-65.4; P < .01) and red vesicular lesion type (odds ratio, 52.6; 95% confidence interval, 8.6-323.1; P < .001).

CONCLUSION: In this cohort of women with infertility, premenstrual spotting of ≥2 days was associated strongly with histologically confirmed endometriosis and a better predictor than dysmenorrhea or dyspareunia of finding endometriosis at laparoscopy. Premenstrual spotting of at least 2 days was also associated strongly with both higher stage disease and the red vesicular peritoneal endometriosis phenotype.

American Journal of Obstetrics and Gynecology


Body weight and body composition of depot medroxyprogesterone acetate users

Natalia Dal’Ava

Universidade Estadual de Campinas (UNICAMP)

Natália Dal'Ava

Human Reproduction Unit, Department of Obstetrics and Gynecology, School of Medical Sciences, University of Campinas (UNICAMP), and the National Institute of Hormones and Women's Health, 13084-971,...

Abstract:
Objectives: Weight gain is a concern with the contraceptive depot-medroxyprogesterone acetate (DMPA); however, this issue remains controversial. The objective of this study was to compare body weight (BW) and body composition (BC) in DMPA and copper intrauterine device (IUD) users at baseline and after one year of use.

Study Design: We enrolled new DMPA users and age and weight matched new IUD users into this prospective study. Weight and height were measured, BC (fat and lean mass) was evaluated using dual-energy X-ray absorptiometry, and physical activity was assessed at baseline and at 12 months. Student's paired t test and the Wilcoxon paired test for matched samples were used.

Results: Ninety-seven women were enrolled for the study; 26 matched pairs continued using the initial method for at least one year, and completed the baseline and 12 month assessments. An increase of 1.9 kg occurred in BW (p=.02) in DMPA users at 12 months of use, resulting from an increase in fat mass of 1.6 kg (p=.03). Weight remained stable in IUD users; however, there was an increase in lean mass at 12 months of use (p=.001). The number of women practicing physical activity increased in this group. There was a significant difference between the groups regarding the variation in the percentage of central fat (p=.04).

Conclusion: Weight gain in the DMPA group after the first year of use resulted from an increase in fat mass. Weight remained stable in the IUD group; however, an increase in lean mass and a reduction in localized abdominal fat mass occurred, possibly because more users were practicing physical activity. IMPLICATIONS STATEMENT: There was a greater increase in body weight in DMPA users compared to TCu380A IUD users in the first year of use of the contraceptive method. Furthermore, the weight increase in users of DMPA occurred principally as the result of an increase in fat mass. Physical activity probably could increase the lean mass in the users of TCu380A IUD.


Use of ovulation predictor kits as adjuncts when using fertility awareness methods (FAMs): a pilot study

Abstract:
Purpose: Difficult clinical signs such as confusing cervical mucus or erratic basal body temperature can make the use of fertility awareness methods (FAMs) difficult in some cases. The goal of this study was to assess the feasibility of using a cheap urinary luteinizing hormone (LH)-surge identification kit as an adjunct to identify the infertile phase after ovulation when facing these scenarios.

Methods: The study used a block-allocation, crossover, 2-arm methodology (LH kit/FAM vs FAM only). Comparison of the 2 arms was done with regard to the accuracy of identification (yes/no) of the luteal phase in each cycle as confirmed by serum progesterone concentrations.

Results: We recruited 23 Canadian women currently using FAM, aged 18 to 48 years, who have had menstrual cycles 25 to 35 days long for the past 3 months and perceive themselves to have difficulty with identifying the infertile phase after ovulation. LH kits identified 100% of the luteal phases, whereas FAM indentified 87% (statistically significant). In those identified cycles, LH kits provided a mean of 10.3 days of infertility, and FAM only provided 10 days of infertility (not statistically significant).

Conclusions: Among this population, LH kits may offer an adjunct for women who may wish to have an additional double-check. However, there are still clinical circumstances when even an LH kit does not provide confirmation. More research in this area is encouraged.

Journal of the American Board of Family Medicine : JABFM


Oral contraceptives for functional ovarian cysts

David A Grimes

University of North Carolina at Chapel Hill

Abstract:
BACKGROUND: Functional ovarian cysts are a common gynecological problem among women of reproductive age worldwide. When large, persistent, or painful, these cysts may require operations, sometimes resulting in removal of the ovary. Since early oral contraceptives were associated with a reduced incidence of functional ovarian cysts, many clinicians inferred that birth control pills could be used to treat cysts as well. This became a common clinical practice in the early 1970s.

OBJECTIVES: This review examined all randomized controlled trials that studied oral contraceptives as therapy for functional ovarian cysts.

SEARCH METHODS: In March 2014, we searched the databases of CENTRAL, PubMed, EMBASE, and POPLINE, as well as clinical trials databases (ClinicalTrials.gov and ICTRP). We also examined the reference lists of articles. For the initial review, we wrote to authors of identified trials to seek articles we had missed.

SELECTION CRITERIA: We included randomized controlled trials in any language that included oral contraceptives used for treatment and not prevention of functional ovarian cysts. Criteria for diagnosis of cysts were those used by authors of trials.

DATA COLLECTION AND ANALYSIS: Two authors independently abstracted data from the articles. One entered the data into RevMan and a second verified accuracy of data entry. For dichotomous outcomes, we computed the Mantel-Haenszel odds ratio with 95% confidence interval (CI). For continuous outcomes, we calculated the mean difference with 95% CI.

MAIN RESULTS: We identified eight randomized controlled trials from four countries; the studies included a total of 686 women. Treatment with combined oral contraceptives did not hasten resolution of functional ovarian cysts in any trial. This held true for cysts that occurred spontaneously as well as those that developed after ovulation induction. Most cysts resolved without treatment within a few cycles; persistent cysts tended to be pathological (e.g., endometrioma or para-ovarian cyst) and not physiological.

AUTHORS' CONCLUSIONS: Although widely used for treating functional ovarian cysts, combined oral contraceptives appear to be of no benefit. Watchful waiting for two or three cycles is appropriate. Should cysts persist, surgical management is often indicated.

The Cochrane database of systematic reviews


Cohort efficacy study of natural family planning among perimenopause age women

Abstract:
Objective: To determine the efficacy of using natural family planning (NFP) methods to avoid unintended pregnancy among women of perimenopause age (i.e., age 40-55 years).
Design: A secondary analysis of subset data from two prospective observational cohort studies.
Setting: A university based in-person and online NFP service program.

Participants: One hundred and sixty couples who used either a website or an in-person NFP service to learn how to avoid pregnancy from January 2001 to November 2012.

Methods: A prospective 12-month effectiveness study among 160 women (between ages 40-55) who used NFP to avoid pregnancy. The women used either a hormonal fertility monitor, cervical mucus monitoring, or both to estimate the fertile phase of their menstrual cycles. Survival analysis was used to determine the pregnancy rate over 12 months of use.

Results: There were a total of five unintended pregnancies among the participants. The typical use pregnancy rate was six per 100 women over 12 months. The monitor alone participants (n = 35) had a 12-month pregnancy rate of three, the participants (n = 73) who used mucus alone had a pregnancy rate of four, and the participants (n = 42) who used the fertility monitor plus mucus had a pregnancy rate of six.

Conclusion: Natural family planning methods can be effective for older women to avoid an unintended pregnancy with correct use and adequate instructions. The pregnancy rate most likely was affected by diminished fertility and motivation to limit family size.

Journal of Obstetric, Gynecologic, and Neonatal Nursing : JOGNN


Inherited Thrombophilia

Inherited Thrombophilia

Abstract: Thrombophilia alters normal hemostasis, shifting the balance in favor of thrombus formation. Inherited conditions include factor V Leiden (FVL), prothrombin G20210A mutation, deficiencies in natural anticoagulants (antithrombin [AT], protein C, and protein S), hyperhomocysteinemia, and elevations in clotting factors (factors VIII and XI). Although FVL and prothrombin mutation are common disorders, deficiencies in the natural anticoagulants are rare. The risk of initial thrombosis conferred by inherited thrombophilia varies with the highest risk in those homozygous for either FVL or prothrombin mutation, or with AT deficiency. In the nonpregnant patient, the presence of a thrombophilia does not affect treatment of an acute event. Although vitamin B supplementation has been shown to decrease the levels of homocysteine, the treatment has failed to show a benefit in thrombus prevention and is therefore not recommended.


Interstitial cystitis associated with primary Sjögren's syndrome successfully treated with a combination of tacrolimus and corticosteroid: A case report and literature review

Yo Ueda

National Center for Global Health and Medicine

Hikaru Tomoe

Tokyo Women's Medical University Adachi Medical Center

Abstract: We report a case of interstitial cystitis (IC) associated with primary Sjögren's syndrome (SS) successfully controlled with combination therapy of tacrolimus and a corticosteroid. In 2011, a 69-year-old female, who had been diagnosed with primary SS 23 years ago, developed IC and was successfully treated with tacrolimus and prednisolone combination therapy. The mechanism of IC, including the involved autoimmunity, has not been elucidated. Clinical observation studies suggest a potential association between SS and IC. However, IC is currently thought to be underdiagnosed in patients with SS as well as in the general population. Based on our case and others reported previously, IC associated with SS responds well to immunosuppressive therapy. In particular, a combination of a calcineurin inhibitor (tacrolimus or cyclosporine) with a corticosteroid seems to be highly effective. The possibility of IC in patients with SS complaining of lower urinary tract symptoms without features of infection or other identifiable causes should be given attention.


Progesterone Within Ovulatory Menstrual Cycles Needed for Cardiovascular Protection: An Evidence-Based Hypothesis

Jerilynn C Prior

Vancouver Hospital and Health Sciences Centre


Chronic endometritis in women with recurrent early pregnancy loss and/or fetal demise

Dana B McQueen

Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois. Electronic address: dana.mcqueen@northwestern.edu.

Abstract:
OBJECTIVE: To assess the prevalence of chronic endometritis in women with a history of recurrent early pregnancy loss (REPL) and/or fetal demise (FD).

DESIGN: Observational cohort study using prospectively collected data.

SETTING: Recurrent pregnancy loss program in an academic medical center.

PATIENT(S): Three hundred ninety-five women with a history of two or more pregnancy losses of less than 10 weeks' size or a fetal demise of 10 or more weeks' size.

INTERVENTION(S): All women had an endometrial biopsy. Chronic endometritis was treated with antibiotics, and a second endometrial biopsy was recommended as a "test of cure."

MAIN OUTCOME MEASURE(S): Subsequent live-birth rate (LBR).

RESULT(S): The overall prevalence of chronic endometritis was 9% (35/395) in this cohort; 7% (21/285) in the REPL group, 14% (8/57) in the FD group, and 11% (6/53) in the combined REPL/FD group. The cure rate was 100% after a course(s) of antibiotics. The subsequent cumulative LBR was 88% (21/24) for the treated chronic endometritis group versus 74% (180/244) for the group without chronic endometritis. The per-pregnancy LBR for the treated chronic endometritis group was 7% (7/98) before treatment versus 56% (28/50) after treatment.

CONCLUSION(S): There was a high prevalence of chronic endometritis in this cohort. The test of cure was 100% with antibiotics. Subsequent LBRs after treatment were encouraging.


Oral contraceptives and breast cancer risk overall and by molecular subtype among  young women

William E Barlow

Division of Public Health Sciences, 2Division of Human Biology, Fred Hutchinson Cancer Research Center; Departments of 3Epidemiology, 4Biostatistics, and 5Pathology, University of Washington, Seatt...

Abstract:
Background: Evidence suggests that recent oral contraceptive (OC) use is associated with a small increased breast cancer risk; yet risks associated with contemporary OC preparations and by molecular subtype are not well characterized.

Methods: We conducted a population-based case-control study of invasive breast cancer among women ages 20 to 44 residing in the Seattle-Puget Sound area from 2004 to 2010 (985 cases and 882 controls). We collected information on contraceptive use and participant characteristics via an in-person interview. Multivariable-adjusted logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI).

Results: Lifetime duration of OC use for ≥ 15 years was associated with an increased breast cancer risk (OR, 1.5; 95% CI, 1.1-2.2). Current OC use (within 1 year of reference date) for ≥ 5 years was associated with an increased risk (OR, 1.6; 95% CI, 1.1-2.5) and there were no statistically significant differences in risk by OC preparation. Risk magnitudes were generally greater among women ages 20 to 39, and for estrogen receptor-negative (ER(-)) and triple-negative breast cancer (current use for ≥ 5 years among ages 20-39: ER(-) OR, 3.5; 95% CI, 1.3-9.0; triple-negative OR, 3.7; 95% CI, 1.2-11.8), although differences between groups were not statistically significant.

Conclusions: Long-term use of contemporary OCs and current use for ≥ 5 years was associated with an increased breast cancer risk among women ages 20 to 44. Risk may be greater among younger women and for ER(-) and triple-negative breast cancer, but these findings require confirmation. IMPACT: Continued surveillance and pooled analyses of OC use and breast cancer risk by molecular subtype are needed as OC preparations evolve.

Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American  Association for Cancer Research, Cosponsored by the American Society of  Preventive Oncology


Recommendations for the laboratory-based detection of Chlamydia trachomatis and Neisseria gonorrhoeae--2014

Abstract: This report updates CDC's 2002 recommendations regarding screening tests to detect Chlamydia trachomatis and Neisseria gonorrhoeae infections (CDC. Screening tests to detect Chlamydia trachomatis and Neisseria gonorrhoeae infections-2002. MMWR 2002;51[No. RR-15]) and provides new recommendations regarding optimal specimen types, the use of tests to detect rectal and oropharyngeal C. trachomatis and N. gonorrhoeae infections, and circumstances when supplemental testing is indicated. The recommendations in this report are intended for use by clinical laboratory directors, laboratory staff, clinicians, and disease control personnel who must choose among the multiple available tests, establish standard operating procedures for collecting and processing specimens, interpret test results for laboratory reporting, and counsel and treat patients. The performance of nucleic acid amplification tests (NAATs) with respect to overall sensitivity, specificity, and ease of specimen transport is better than that of any of the other tests available for the diagnosis of chlamydial and gonococcal infections. Laboratories should use NAATs to detect chlamydia and gonorrhea except in cases of child sexual assault involving boys and rectal and oropharyngeal infections in prepubescent girls and when evaluating a potential gonorrhea treatment failure, in which case culture and susceptibility testing might be required. NAATs that have been cleared by the Food and Drug Administration (FDA) for the detection of C. trachomatis and N. gonorrhoeae infections are recommended as screening or diagnostic tests because they have been evaluated in patients with and without symptoms. Maintaining the capability to culture for both N. gonorrhoeae and C. trachomatis in laboratories throughout the country is important because data are insufficient to recommend nonculture tests in cases of sexual assault in prepubescent boys and extragenital anatomic site exposure in prepubescent girls. N. gonorrhoeae culture is required to evaluate suspected cases of gonorrhea treatment failure and to monitor developing resistance to current treatment regimens. Chlamydia culture also should be maintained in some laboratories to monitor future changes in antibiotic susceptibility and to support surveillance and research activities such as detection of lymphogranuloma venereum or rare infections caused by variant or mutated C. trachomatis.

MMWR. Recommendations and Reports : Morbidity and Mortality Weekly Report.  Recommendations and Reports


Choice of lumbar spine bone density reference database for fracture prediction in  men and women: a population-based analysis

William D Leslie

University of Manitoba, Winnipeg, MB, Canada

Christopher S Kovacs

Memorial University of Newfoundland, St John’s, NL, Canada

Abstract: The diagnosis of osteoporosis in men is controversial, although most studies demonstrate similar fracture rates for men and women with the same level of hip bone mineral density (BMD). Whether this applies to the lumbar spine is currently uncertain and has important implications with respect to choice of reference population for T-score calculation and osteoporosis diagnosis. This question was specifically addressed in the population-based Canadian Multicentre Osteoporosis Study cohort of 4745 women and 1887 men ages 50+ yr at the time of baseline lumbar spine dual energy x-ray absorptiometry. In up to 10 yr of observation, incident clinical major osteoporotic fractures occurred in 110 men (5.8%) vs 543 women (11.4%) (p < 0.001). Mean lumbar spine BMD in men was greater than in women, both among those with and those without incident major osteoporotic fracture (p < 0.001). Men were at slightly lower risk for incident major osteoporotic fracture than women for an equivalent lumbar spine BMD (ageand BMD-adjusted rate ratio 0.75, 95% confidence interval 0.60-0.93, p = 0.008) with similar findings after adjustment for the World Health Organization fracture risk assessment clinical risk factors or competing mortality. No significant sex difference in the BMD relationship was seen for vertebral fractures (clinical or radiographic) or for all fractures. In summary, this large population-based longitudinal cohort study found similar or lower fracture risk for men vs women after adjustment for absolute lumbar spine BMD and additional covariates. The least complicated model for describing fracture risk is therefore to use the same reference lumbar spine data for generating T-scores in men and women.

Journal of Clinical Densitometry : the Official Journal of the International  Society for Clinical Densitometry


Luteal phase deficiency in regularly menstruating women: prevalence and overlap  in identification based on clinical and biochemical diagnostic criteria

Sunni L Mumford

Eunice Kennedy Shriver National Institute of Child Health and Human Development

Pauline Mendola

University at Buffalo, State University of New York

Jean Wactawski-Wende

Department of Epidemiology and Environmental Health, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY.

Abstract:
Context: Although adequate luteal hormone production is essential for establishing pregnancy, luteal phase deficiency (LPD) is poorly characterized among eumenorrheic women.

Objective: We assessed the prevalence and overlap of two established LPD diagnostic criteria: short luteal phase duration less than10 days (clinical LPD) and suboptimal luteal progesterone of 5 ng/mL or less (biochemical LPD) and their relationship with reproductive hormone concentrations.
Design, Setting, and

Participants: We conducted a prospective study in western New York (2005-2007) following 259 women, aged 18-44 years, for up to two menstrual cycles.

Results: Among ovulatory cycles with recorded cycle lengths (n = 463), there were 41 cycles (8.9%) with clinical LPD, 39 cycles (8.4%) with biochemical LPD, and 20 cycles (4.3%) meeting both criteria. Recurrent clinical and biochemical LPD was observed in eight (3.4%) and five (2.1%) women, respectively. Clinical and biochemical LPD were each associated with lower follicular estradiol (both P ≤ .001) and luteal estradiol (P = .03 and P = .02, respectively) after adjusting for age, race, and percentage body fat. Clinical, but not biochemical, LPD was associated with lower LH and FSH across all phases of the cycle (P ≤ .001).

Conclusions: Clinical and biochemical LPD were evident among regularly menstruating women. Estradiol was lower in LPD cycles under either criterion, but LH and FSH were lower only in association with shortened luteal phase (ie, clinical LPD), indicating that clinical and biochemical LPD may reflect different underlying mechanisms. Identifying ovulation in combination with a well-timed luteal progesterone measurement may serve as a cost-effective and specific tool for LPD assessment by clinicians and researchers.

The Journal of Clinical Endocrinology and Metabolism


Hormonal contraceptive use and breast cancer in Thai women

Abstract:
Background: Breast cancer is the most common cancer in women worldwide. We investigated the association of hormonal contraceptive use and breast cancer in Thai women.

Methods: A cohort study was conducted in Khon Kaen, Thailand. There were 70 cases of histologically confirmed breast cancer among 11 414 women aged 30 to 69 years who were recruited as participants in the cohort study during the period from 1990 through 2001. The study population was followed-up until December 31, 2011. To identify factors associated with incidence of breast cancer, hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using a Cox proportional hazards model.

Results: The 11 414 women provided a total observation time of 157 200 person-years. Breast cancer risk among women with a history of hormonal contraceptive use was 1.31 times that of women without such a history, but the difference was not statistically significant (95% CI, 0.65-2.65). No type of hormonal contraceptive was associated with a significant increase in breast cancer risk as compared with women who had never used hormonal contraceptives (oral contraception: HR = 1.35, 95% CI, 0.65-2.78; injection contraception: HR = 1.25, 95% CI, 0.56-2.80), and there was no relationship between duration of hormonal contraceptive use and breast cancer.

Conclusions: There was no association between hormonal contraceptive use and breast cancer; however, this finding should be viewed with caution due to the small number of cases.


Acceptability of prophylactic salpingectomy with delayed oophorectomy as  risk-reducing surgery among BRCA mutation carriers

Laura L Holman

The University of Texas MD Anderson Cancer Center

Abstract:
Objective: Given the emerging evidence for the fimbria as the site of origin for many serous carcinomas in BRCA mutation carriers, consideration is being given in studying prophylactic salpingectomy with delayed oophorectomy (PSDO) as a risk-reducing surgery. We aimed to determine the interest in a study of PSDO among these women.

Methods: We evaluated the results of an online survey conducted by Facing Our Risk of Cancer Empowered (FORCE), a patient advocacy group, from October 2010 to August 2012. Premenopausal BRCA mutation carriers with no history of ovarian cancer or prior bilateral salpingo-oophorectomy (BSO) were included.

Results: Of the 204 women meeting inclusion criteria, median age was 35 years, 92.5% were white, 25.7% were Jewish, and 16.7% had a history of breast cancer. Overall, 34.3% reported interest in a study of salpingectomy, 35.3% were unsure, and 30.4% were not interested in the study. Women noted the possibility of lowering ovarian cancer risk without menopause as a compelling reason to participate (83.8%). Reasons for not participating in a salpingectomy study included surgical complications (46.6%), potential ovarian damage (42.2%), planning BSO soon (32.4%), and surgical costs (32.8%). Acceptable study risks included the need for two surgeries (77.2%), possibility of not lowering ovarian cancer risk (68%), and disruption of ovarian blood supply (66.5%).

Conclusions: One-third of BRCA mutation carriers indicated definite interest in a PSDO study. Potential study risks were acceptable to most women. These findings suggest that patient accrual for a clinical trial of prophylactic salpingectomy with delayed oophorectomy is possible.


Occult microscopic endometriosis: undetectable by laparoscopy in normal peritoneum

Abstract:
STUDY QUESTION: Is there any occurrence of hidden (occult) endometriotic lesions in normal peritoneum of women with and without visible endometriosis?

SUMMARY ANSWER: We detected a slightly higher occurrence of occult microscopic endometriosis (OME) in normal peritoneum of women with visible endometriosis than in control women.

WHAT IS KNOWN ALREADY: Based on a small number of cases, the concept of invisible microscopic endometriosis in visually normal peritoneum has been reported for more than a decade but there is controversy regarding their tissue activity and clinical significance.

STUDY DESIGN, SIZE, DURATION: This case-controlled research study was conducted with prospectively collected normal peritoneal samples from 151 women with and 62 women without visible endometriosis.

PARTICIPANTS/MATERIALS, SETTING, METHODS: Normal peritoneal biopsy specimens from different pelvic sites of were collected during laparoscopy. A histological search of all peritoneal biopsy specimens for the detection of invisible endometriosis was done by immunoreaction to Ber-EP4 (epithelial cell marker), CD10 (stromal cell marker) and Calretinin (mesothelial cell marker). Tissue expression of estrogen/progesterone receptors (ER/PR) and cell proliferation marker, Ki-67, was performed by immunohistochemistry to identify tissue activity.

MAIN RESULTS AND THE ROLE OF CHANCE: Three different patterns of OME were detected based on (I) the presence of typical gland/stroma, (II) reactive hyperplastic change of endometrioid epithelial cells with surrounding stroma and (III) single-layered epithelium-lined cystic lesions with surrounding stroma. A higher tendency toward the occurrence of OME was found in women with visible endometriosis (15.2%, 23/151) compared with control women (6.4%, 4/62) (P = 0.06, χ(2) test). The epithelial cells and/or stromal cells of OME lesions were immunoreactive to Ber-EP4 and CD10 but not reactive to Calretinin. ER and PR expression was observed in all patterns of OME lesions. Ki-67 index was significantly higher in pattern I/II OME lesions than in pattern III OME lesions (P< 0.05 for each).

LIMITATIONS, REASONS FOR CAUTION: Bias in the incidence rate of OME lesions in this study cannot be ignored, because we could not analyze biopsy specimens from the Pouch of Douglas of women with revised classification of the American Society of Reproductive Medicine Stage III-IV endometriosis due to the presence of adhesions in the pelvis.

WIDER IMPLICATIONS OF THE FINDINGS: We re-confirmed a decade long old concept of invisible (occult) endometriosis in visually normal peritoneum of women with visible endometriosis. The existence of a variable amount of tissue activity in these occult lesions may contribute to the recurrence/occurrence of endometriosis or persistence/recurrence of pain manifestation in women even after successful ablation or excision of visible lesions by laparoscopy.

STUDY FUNDING/COMPETING INTEREST(S): This work was supported in part by Grants-in-aid for Scientific Research from the Japan Society for the Promotion of Science. There is no conflict of interest related to this study.

TRIAL REGISTRATION NUMBER: Not applicable.


Serum leptin levels and reproductive function during the menstrual cycle

Abstract:
Objective: The purpose of this study was to investigate the role of leptin on reproductive hormones and ovulation.

Study Design: The BioCycle Study (2005-2007) followed 259 healthy premenopausal women not using hormonal contraceptives for ≤2 menstrual cycles (n = 509 cycles). Serum leptin, estradiol, progesterone, luteinizing hormone (LH), follicle-stimulating hormone, and testosterone were measured ≤8 times per cycle. The association of time-varying leptin and reproductive hormones over the cycle was estimated with the use of linear mixed models that were adjusted for percent body fat and age with inverse probability weighting for time-varying physical activity, caloric intake, and other reproductive hormones. The odds ratio for sporadic anovulation (n = 42 cycles) was estimated with the use of generalized linear models that were adjusted for percent body fat and age.

Results: Geometric mean serum leptin levels increased from menses to the late luteal phase (16.7-20.4 ng/mL; P < .01), with a mid-cycle peak (21.7 ng/mL) at the time of the LH surge (P < .01). A 10% higher leptin level across the menstrual cycle was associated with higher estradiol levels (2.2%; 95% CI, 1.5-3.0), luteal progesterone levels (2.1%; 95% CI, 0.5-3.7), ovulatory LH levels (1.2%; 95% CI, 0-2.3), testosterone levels (0.6%; 95% CI, 0.3-0.9), and lower follicle-stimulating hormone levels (-0.7%; 95% CI, -1.1 to -0.4). Leptin at the time of the expected LH surge was moderately inversely associated with sporadic anovulation (per log increase in leptin; adjusted odds ratio, 0.58; 95% CI, 0.28-1.22).

Conclusion: The association that was observed between leptin level and reproductive function points to a possible relationship between serum leptin level and enhanced fertility.

American journal of obstetrics and gynecology


Relationship between ovarian cysts and infertility: what surgery and when?

Loïc Sentilhes

Department of Obstetrics and Gynecology, Bordeaux University Hospital, Bordeaux, France. Electronic address: loicsentilhes@hotmail.com.

Abstract: The relationship between ovarian cysts and infertility is a subject of debate, mainly because it is difficult to determine the real impact of the cyst and its treatment on later fertility. For a long time it was hoped that surgical treatment could prevent potential complications (such as rupture or malignancy). For presumed benign ovarian tumors, fertility sparing should be the main concern. The goal of this survey of current knowledge on the subject is to thoroughly explore the potential relationship between cysts, their treatment, and infertility. Our study is based on a review of the literature dealing with the epidemiology of ovarian cysts and the effects of their surgical management in relation to infertility. Analysis of the epidemiologic data, drawn mainly from comparative studies and cohorts, shows that the role of cysts in infertility is controversial and that the effects of surgical treatment are often more harmful than the cyst itself to the ovarian reserve. Surgery does not seem to improve pregnancy rates. When a surgical option is nonetheless chosen, a conservative laparoscopic approach is more suitable. Besides excision, sclerotherapy and plasma vaporization are promising, offering a greater preservation of the ovarian parenchyma, especially in endometriomas. These techniques must be better defined. The context of the infertility is essential, and surgeons and specialists in reproductive medicine should decide management jointly.


Cardiovascular and general safety of a 24-day regimen of drospirenone-containing  combined oral contraceptives: final results from the International Active  Surveillance Study of Women Taking Oral Contraceptives

Kristina Bardenheuer

Berlin Center for Epidemiology and Health Research

Abstract:
Objectives: The "International Active Surveillance Study of Women Taking Oral Contraceptives" investigated the risks of shortand long-term use of an extended 24-day regimen of drospirenone and ethinylestradiol (DRSP24d) compared to established oral contraceptives (OCs) in a routine clinical setting.

STUDY Design: Prospective, controlled, noninterventional cohort study conducted in the United States and six European countries with three main cohorts: new users of DRSP24d, DRSP21d (21-day regimens of DRSP-containing OCs), and non-DRSP (OCs without DRSP). All self-reported clinical outcomes of interest (OoI) were validated via attending physicians and relevant source documents. Main OoI were serious clinical outcomes, in particular venous thromboembolism (VTE). Comprehensive follow-up procedures were implemented. Statistical analyses were based on Cox regression models. Primary statistical variable was the VTE hazard ratio (HR) for DRSP24d vs. non-DRSP.

Results: A total of 2285 study centers enrolled 85,109 women. Study participants were followed for 2 to 6 years, which generated 206,296 woman-years (WY) of observation. A low loss to follow-up of 3.3% was achieved. DRSP24d, DRSP21d, non-DRSP and levonorgestrel-containing OCs (LNG) showed similar incidence rates of venous and arterial thromboembolism, fatal outcomes, cancer, severe depression and other serious adverse events. VTE incidence rates for DRSP24d, DRSP21d, non-DRSP and LNG were 7.2, 9.4, 9.6 and 9.8 VTE/10,000 WY, respectively. Adjusted HRs for DRSP24d vs. non-DRSP and DRSP24d vs. LNG were 0.8 [95% confidence interval (CI), 0.5-1.3] and 0.8 (95% CI, 0.4-1.5).

Conclusion: DRSP24d, DRSP21d, non-DRSP and LNG use was associated with similar risks of serious adverse events, and particularly VTE, during routine clinical use. IMPLICATION STATEMENT: The 24-day regimen of drospirenone-containing combined OCs is associated with similar risks of venous and arterial thromboembolism, fatal outcomes, cancer, severe depression and other serious adverse events compared to 21-day regimens of drospirenone-containing combined OCs, OCs without drospirenone and LNGs.


Glucocorticoids predict 10-year fragility fracture risk in a population-based ambulatory cohort of men and women: Canadian Multicentre Osteoporosis Study (CaMos)

Christopher S Kovacs

Memorial University of Newfoundland, St John’s, NL, Canada

Jerilynn C Prior

Vancouver Hospital and Health Sciences Centre

Jonathan D Adachi

McMaster University, Hamilton, ON, Canada

Abstract:
We determined the prospective 10-year association among incident fragility fractures and four glucocorticoid (GC) treatment groups (Never GC, Prior GC, Baseline GC, and Ever GC). Results showed that GC treatment is associated with increased 10-year incident fracture risk in ambulatory men and women across Canada.
Purpose: Using the Canadian Multicentre Osteoporosis Study dataset, we determined the prospective 10-year association between incident fragility fractures and GC treatment.

Methods: We conducted a 10-year prospective observational cohort study at nine sites across Canada. A total of 9,263 ambulatory men and women 25 years of age and older were included in the analysis. Multivariable Cox proportional hazards analyses were conducted to determine the relationship among GC treatment groups in four levels that included Never GC, Prior GC, Baseline GC, and Ever GC (combined baseline and prior groups) and time to fracture.

Results: In each of the Never GC, Prior GC, Baseline GC, and Ever GC treatment groups, the number of participants were 8,832 (95.4 %), 303 (3.3 %), 128 (1.4 %), and 431 (4.7 %), respectively. Of the 9,263 individuals enrolled, incident fragility non-spine, hip, spine, and any fractures were experienced by a total of 896 (9.67 %), 157 (1.69 %), 130 (1.40 %), and 1,102 (11.90 %) over 10-years, respectively. For men and women combined, prior GC treatment was associated with a higher hazard ratio (HR) for time to incident non-vertebral (HR = 1.5, 95 % confidence interval [CI] = 1.1, 2.0), hip (HR = 2.1, 95 % CI = 1.1, 4.0), and any fracture (HR = 1.4, 95 % CI = 1.0, 1.8) compared with never GC treatment.

Conclusions: GC treatment is associated with increased 10-year incident fracture risk; this highlights the importance of considering therapy to prevent GC-induced fractures for patients who are using GC for various medical conditions.


Effect of progestins on immunity: medroxyprogesterone but not norethisterone or levonorgestrel suppresses the function of T cells and pDCs

Abstract:
Objectives: The potential effect of hormonal contraception on HIV-1 acquisition and transmission represents an important public health issue. Several observational studies have suggested an association between the use of hormonal contraception, in particular injectable depot medroxyprogesterone acetate (DMPA), and an increased risk of HIV-1 acquisition and transmission. We and others have previously demonstrated that DMPA acts as a potent inhibitor of innate and adaptive immune mechanisms. The study presented here addresses the immunomodulatory properties of several common progestins with a potential to replace DMPA.

Study design: To identify safe alternatives to DMPA, we tested the effect of commonly used progestins on the function of human primary T cells and plasmacytoid dendritic cells (pDCs) obtained from the blood of healthy premenopausal women.

Results: Medroxyprogesterone acetate (MPA) inhibited the activation of T cells and pDCs in response to T cell receptorand Toll-like receptor-mediated activation at physiological concentrations. Etonogestrel exerted a partial suppressive activity at high concentrations. In sharp contrast, norethisterone (NET) and levonorgestrel (LNG) did not exhibit detectable immunosuppressive activity.

Conclusion: Evidence indicating the immunosuppressive properties of DMPA strongly suggests that DMPA should be discontinued and replaced with other forms of long-term contraception. Since NET and LNG do not exert immunosuppressive properties at physiological concentrations, these progestins should be considered as alternative contraceptives for women at high risk for HIV-1 infection.

Implications: The presented data suggest that, at physiological levels, the progestins NET and LNG do not suppress cytokine production by immune cells and should be considered as alternatives to DMPA; however, more in vivo testing is needed to confirm this data.


Antidepressant use and 10-year incident fracture risk: the population-based Canadian Multicentre Osteoporosis Study (CaMoS)

William D Leslie

University of Manitoba, Winnipeg, MB, Canada

Abstract:
We used data from a large, prospective Canadian cohort to assess the association between selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) and fracture. We found an increased risk of fractures in individuals who used SSRI or SNRI, even after controlling for multiple risk factors.
Introduction: Previous studies have suggested an association between SSRIs and increasing risk of fragility fractures. However, the majority of these studies were not long-term analyses or were performed using administrative data and, thus, could not fully control for potential confounders. We sought to determine whether the use of SSRIs and SNRIs is associated with increased risk of fragility fracture, in adults aged 50 + .

Methods: We used data from the Canadian Multicentre Osteoporosis Study (CaMos), a prospective randomly selected population-based community cohort; our analyses focused on subjects aged 50+. Time to event methodology was used to assess the association between SSRI/SNRI use, modeled time-dependently, and fragility fracture.

Results: Among 6,645 subjects, 192 (2.9%) were using SSRIs or/and SNRIs at baseline. During the 10-year study period, 978 (14.7%) participants experienced at least one fragility fracture. In our main analysis, SSRI/SNRI use was associated with increased risk of fragility fracture (hazard ratio (HR), 1.88; 95% confidence intervals (CI), 1.48-2.39). After controlling for multiple risk factors, including Charlson score, previous falls, and bone mineral density hip and lumbar bone density, the adjusted HR for current SSRI/SNRI use remained elevated (HR, 1.68; 95% CI, 1.32-2.14).

Conclusions: Our results lend additional support to an association between SSRI/SNRI use and fragility fractures. Given the high prevalence of antidepressants use, and the impact of fractures on health, our findings may have a significant clinical impact.


The association between endometriosis and chronic endometritis

Abstract:
Objective: To evaluate the association between endometriosis and chronic endometritis.

Methods: Endometrial specimens were obtained from 71 patients, 34 with endometriosis (endometriosis group) and 37 without endometriosis (non-endometriosis group), who underwent hysterectomy, and the specimens were immunostained for the plasmacyte marker CD138. The rate of chronic endometritis was compared between the endometriosis group and the non-endometriosis group. Furthermore, the 71 patients were also divided into two groups, 28 with chronic endometritis (chronic endometritis group) and 43 without chronic endometritis (non-chronic endometritis group). Logistic regression analysis was performed with variables including age, body mass index (BMI), gravidity and parity, and diagnoses of leiomyoma, adenomyosis, and endometriosis on pathology to examine the independent effect of each variable on chronic endometritis. Patients suffering from cervical invasive carcinoma, endometrial carcinoma, and endometrial polyps or treated with gonadotropin-releasing hormone agonists, progestins, or oral contraceptives before surgery were excluded.

Results: Chronic endometritis was identified in 52.94% of the endometriosis group and 27.02% of the non-endometriosis group (p<0.05). Logistic regression analysis revealed that endometriosis was associated with chronic endometritis.

Conclusions: This result suggests a strong association between endometriosis and chronic endometritis.


Impact of ART on pregnancies in California: an analysis of maternity outcomes and insights into the added burden of neonatal intensive care

Abstract:
Objective: We reviewed the occurrence of prematurity, low birth weight, multiple gestations, frequency of stillbirths and maternity care-associated variables including hospital stay and hospital charges of women conceiving using assisted reproductive technology (ART) or artificial insemination (AI) compared with women with a history of infertility who conceived naturally, and all other naturally conceived pregnancies in California at non-federal hospitals between 2009 and 2011. At a single center, infants born after ART/AI were compared with infants provided care in the normal nursery.

Study design: Publically available inpatient data sets from the California Office of Statewide Health Planning and Development for years 2009-2011 using data from all California non-federal hospitals were used to determine the impact of ART on a variety of pregnancy-related outcomes and infant characteristics. Infant data from a single center was used to determine hospital charges for infants delivered over an 18-month period to compare the hospital and physician charges indexed to similar charges for infants admitted to the 'normal' newborn nursery.

Result: Among ART/AI pregnancies, there was a 4-5-fold increase in stillbirths, compared with a 2-3-fold increase among women with infertility compared with other naturally conceiving women. ART/AI pregnancies underwent more cesarean sections (fourfold), and a near fourfold increase in the rate of preterm deliveries. Multiple gestations were increased 24-27-fold compared with naturally conceived pregnancies. Maternal hospital stay and hospital charges were increased among those undergoing ART/AI. Infant charges were increased multi-fold for singletons, twins and triplets delivered after ART/AI compared with naturally conceived infants.

Conclusion: Multiple births, preterm births and a higher overall rate of fetal anomalies were found in California after ART/AI for 2009-2011. Cesarean section rates, longer length of maternal stay and hospital charges among women receiving ART/AI could be lowered if emphasis on elective single embryo transfers was a higher priority among providers. Charges for the care of infants delivered after ART/AI are substantially higher than among naturally conceived infants born late preterm or at term. Families seeking ART/AI need to be informed of the impact of these adverse pregnancy outcomes, including neonatal outcomes and charges for medical care for their infant(s), when considering ART/AI.


Differential glucocorticoid receptor-mediated effects on immunomodulatory gene expression by progestin contraceptives: implications for HIV-1 pathogenesis

Janet P Hapgood

Department of Molecular and Cell Biology University of Cape Town Rondebosch South Africa

Abstract: Whether hormonal contraceptives increase HIV-1 acquisition, transmission and disease progression are critical questions. Clinical research has been hampered by a lack of understanding that different progestins used in contraception exhibit differential off-target effects via steroid receptors other than the progesterone receptor. Of particular, relevance is the relative effects of medroxyprogesterone acetate (MPA) and norethisterone enanthate (NET-EN), widely used as injectable contraceptives in sub-Saharan Africa. While most high-quality clinical studies find no increased risk for HIV-1 acquisition with oral contraception or injectable NET-EN, most do find an increase with MPA, particularly in young women. Furthermore, mounting evidence from animal, ex vivo and biochemical studies are consistent with MPA acting to increase HIV-1 acquisition and pathogenesis, via mechanisms involving glucocorticoid-like effects on gene expression, in particular genes involved in immune function. We report that MPA, unlike NET and progesterone, represses inflammatory genes in human PBMCs in a dose-dependent manner, via the glucocorticoid receptor (GR), at concentrations within the physiologically relevant range. These and published results collectively suggest that the differential GR activity of MPA versus NET may be a mechanism whereby MPA, unlike NET or progesterone, differentially modulates HIV-1 acquisition and pathogenesis in target cells where the GR is the predominant steroid receptor expressed.


Variability in the morphologic assessment of human sperm: use of the strict criteria recommended by the World Health Organization in 2010

Jiali Yang

Huazhong University of Science and Technology

Mingyue Ding

Wuhan National Laboratory for Optoelectronics

Abstract:
OBJECTIVE: To determine the variability in the recognition of normal sperm and various sperm defects using the strict criteria recommended by the World Health Organization (5th edition, 2010).

DESIGN: Sperm morphologic assessment by three experienced evaluators.

SETTING: Image processing laboratory and reproduction research institute.

PATIENT(S): Semen donors from a sperm bank.

INTERVENTION(S): The morphology of 5,296 sperm was evaluated using statistical analyses of variability.

MAIN OUTCOME MEASURE(S): The proportion and coefficients of variation (CVs) of normal sperm, defects of specific parts, and the categories of defects were measured. The degree of agreement between any two of the three evaluators was calculated. The multiple anomalies index, teratozoospermia index, sperm deformity index, and the CVs were also measured.

RESULT(S): The CVs of normal sperm, multiple anomalies index, teratozoospermia index, and sperm deformity index were 4.80%, 4.14%, 5.75%, and 6.81%, respectively. A broader range (4.80%-132.97%) of CVs was observed for the recognition of various defects. The coefficients of the degree of agreement concerning specific morphologic parts of sperm varied (0.387-0.607), with lower relative values for the head and mid-piece than for the tail and cytoplasm.

CONCLUSION(S): The sperm head is more difficult to evaluate than the other parts using the criteria recommended by the World Health Organization in 2010. The degree of agreement concerning specific parts and various defects varied in broad ranges. A stricter definition for each defect is needed.


The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain

Abstract: Low-dose naltrexone (LDN) has been demonstrated to reduce symptom severity in conditions such as fibromyalgia, Crohn's disease, multiple sclerosis, and complex regional pain syndrome. We review the evidence that LDN may operate as a novel anti-inflammatory agent in the central nervous system, via action on microglial cells. These effects may be unique to low dosages of naltrexone and appear to be entirely independent from naltrexone's better-known activity on opioid receptors. As a daily oral therapy, LDN is inexpensive and well-tolerated. Despite initial promise of efficacy, the use of LDN for chronic disorders is still highly experimental. Published trials have low sample sizes, and few replications have been performed. We cover the typical usage of LDN in clinical trials, caveats to using the medication, and recommendations for future research and clinical work. LDN may represent one of the first glial cell modulators to be used for the management of chronic pain disorders.


Anti-N-methyl-aspartate receptor encephalitis in identical twin sisters: role for oophorectomy

Abstract: BACKGROUND: Anti-N-methyl-aspartate receptor encephalitis is a potentially fatal form of encephalitis and frequently associated with ovarian teratomas. Surgical removal of ovarian teratomas improves clinical outcome, but it is unclear whether bilateral salpingo-oophorectomy for normal-appearing ovaries is of clinical benefit. CASE: Our report describes a unique clinical scenario of identical twin sisters with anti-N-methyl-aspartate receptor encephalitis. Neither patient responded to immunosuppressive therapy. Imaging studies showed normal-appearing ovaries. The first twin continued on medical therapy only and died of the disease. The second twin underwent a bilateral salpingo-oophorectomy followed by gradual recovery. CONCLUSION: Based on our experience in two genetically identical individuals, we suggest considering the removal of normal-appearing ovaries in patients with anti-N-methyl-aspartate receptor encephalitis who fail to respond to medical treatment.


Definition and epidemiology of unexplained infertility

Abstract: The diagnosis of unexplained infertility can be made only after excluding common causes of infertility using standard fertility investigations,which include semen analysis, assessment of ovulation, and tubal patency test. These tests have been selected as they have definitive correlation with pregnancy. It is estimated that a standard fertility evaluation will fail to identify an abnormality in approximately 15% to 30% of infertile couples. The reported incidence of such unexplained infertility varies according to the age and selection criteria in the study population. We conducted a review of the literature via MEDLINE. Articles were limited to English-language, human studies published between 1950 and 2013. Since first coined more than 50 years ago, the term unexplained infertility has been a subject of debate. Although additional investigations are reported to explain or define other causes of infertility, these have high false-positive results and therefore cannot be recommended for routine clinical practice. Couples with unexplained infertility might be reassured that even after 12 months of unsuccessful attempts, 50% will conceive in the following 12 months and another 12% in the year after.


The effect of physical activity across the menstrual cycle on reproductive function

K A Ahrens

Eunice Kennedy Shriver National Institute of Child Health and Human Development

Catherine J. Vladutiu

University of North Carolina at Chapel Hill

Jean Wactawski-Wende

Department of Epidemiology and Environmental Health, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY.

Abstract:
Purpose: To evaluate the association between physical activity (PA) across the menstrual cycle and reproductive function.

Methods: The BioCycle Study (2005-2007) followed 259 healthy premenopausal women not using hormonal contraceptives for up to two menstrual cycles (N = 509 cycles). Serum leptin, estradiol, progesterone, luteinizing hormone, follicle-stimulating hormone, and testosterone were measured five to eight times per cycle. Linear mixed models were used to estimate the effect of past-week PA (measured four times during each cycle) on hormone levels. Past-week PA was categorized into tertiles based on metabolic equivalent of task hours per week (cut-points were 15.3 and 35.7). Risk ratios for sporadic anovulation were estimated using generalized linear models. Analyses adjusted for habitual PA (assessed at baseline), body mass index, race, age, and perceived stress. Linear mixed models used inverse probability weights to control for concurrent reproductive hormones and caloric intake.

Results: High past-week PA was inversely associated with leptin (-6.6%; 95% confidence interval, -10.6 to -2.5) and luteal phase progesterone (-22.1%; -36.2 to -4.7) as compared with low past-week PA. High past-week PA was not significantly associated with sporadic anovulation (adjusted risk ratio, 1.5; 0.6 to 3.4).

Conclusions: High levels of PA were modestly associated with changes in select hormones but not sporadic anovulation among moderate to highly active premenopausal women.


[Interconnection between assisted reproductive technologies, pregnancy complications and risk of birth defects]

Abstract: The aim of the article was to investigate the relationship between pregnancy complications, infertility and assisted reproductive technologies (ART). The study was conducted on 1331 couples with complicated reproductive history. It is found that miscarriage and other complications of pregnancy depend rather on the etiopathogenesis of infertility than on the technique of ART. The highest frequency of complications of pregnancy was diagnosed in women with endocrine disorders. In case of congenital malformations in the fetus the frequency of birth defects was 3.6% after in vitro fertilization (IVF) and 1.8% in case of spontaneous pregnancy. It was found an increased risk of birth defects in singleton boys conceived by IVF.


Clitoral vascularization and sexual behavior in young patients treated with drospirenone-ethinyl estradiol or contraceptive vaginal ring: a prospective, randomized, pilot study

Abstract:
INTRODUCTION: Oral contraceptives (OC) are effective for birth control and have good cycle control and tolerability. However, the hormonal components could modify mood and libido.

AIM: The aim of this study is to evaluate the genital vascular effects and sexual behavior of an OC containing 30 μg ethinyl estradiol and 3 mg drospirenone in comparison with a flexible combined contraceptive vaginal ring.

METHODS: Forty women underwent a sonographic assessment of the clitoral anatomy and vascularization and were administered the McCoy Female Sexuality Questionnaire (MFSQ) and the Beck's Depression Inventory questionnaire (BDI). Estradiol, androstenedione, testosterone, and SHBG were assayed. Free Androgen Index (FAI) and Free Estrogen Index (FEI) were calculated. The patients were randomly submitted to OC (group I; n = 21) or vaginal ring (group II; n = 19).

MAIN OUTCOME MEASURES: Ultrasonographic clitoral volume, pulsatility index (PI) of dorsal clitoral arteries, MFSQ, BDI, and hormonal and biochemical assays were analyzed.

RESULTS: After therapy, the testosterone levels were reduced in both groups, whereas estradiol decreased only in group I women. The SHBG increased in all the subjects, and both FAI and FEI decreased. The clitoral volume decreased in all the women. The PI of the dorsal clitoral artery increased only in patients on OC. The hormonal contraception was associated, in both studied groups, with a significant decrease of the two-factor Italian MFSQ score, which was more marked in OC users. In group I subjects, there was a reduction of the number of intercourse/week and a reduction of orgasm frequency during intercourse. The pain during intercourse worsened after OC use. The vaginal ring users reported a vaginal wetness.

CONCLUSIONS: Six-month treatment with hormonal contraception is associated with a diminished MFSQ score. However, the frequency of sexual intercourse and orgasm was reduced only by the use of OC. The OC use was associated with increased pain during intercourse.


Out-of-pocket fertility patient expense: data from a multicenter prospective infertility cohort

Abstract:
PURPOSE: The high costs of fertility care may deter couples from seeking care. Urologists often are asked about the costs of these treatments. To our knowledge previous studies have not addressed the direct out-of-pocket costs to couples. We characterized these expenses in patients seeking fertility care.

MATERIALS AND METHODS: Couples were prospectively recruited from 8 community and academic reproductive endocrinology clinics. Each participating couple completed face-to-face or telephone interviews and cost diaries at study enrollment, and 4, 10 and 18 months of care. We determined overall out-of-pocket costs, in addition to relationships between out-of-pocket costs and treatment type, clinical outcomes and socioeconomic characteristics on multivariate linear regression analysis.

RESULTS: A total of 332 couples completed cost diaries and had data available on treatment and outcomes. Average age was 36.8 and 35.6 years in men and women, respectively. Of this cohort 19% received noncycle based therapy, 4% used ovulation induction medication only, 22% underwent intrauterine insemination and 55% underwent in vitro fertilization. The median overall out-of-pocket expense was $5,338 (IQR 1,197-19,840). Couples using medication only had the lowest median out-of-pocket expenses at $912 while those using in vitro fertilization had the highest at $19,234. After multivariate adjustment the out-of-pocket expense was not significantly associated with successful pregnancy. On multivariate analysis couples treated with in vitro fertilization spent an average of $15,435 more than those treated with intrauterine insemination. Couples spent about $6,955 for each additional in vitro fertilization cycle.

CONCLUSIONS: These data provide real-world estimates of out-of-pocket costs, which can be used to help couples plan for expenses that they may incur with treatment.


Combination contraceptives: effects on weight

Maria F Gallo

Centers for Disease Control and Prevention

Florence Carayon

FHI360; Clinical Sciences; Durham North Carolina USA 27701

Abstract:
Background: Weight gain is often considered a side effect of combination hormonal contraceptives, and many women and clinicians believe that an association exists. Concern about weight gain can limit the use of this highly effective method of contraception by deterring the initiation of its use and causing early discontinuation among users. However, a causal relationship between combination contraceptives and weight gain has not been established.

Objectives: The aim of the review was to evaluate the potential association between combination contraceptive use and changes in weight. SEARCH

Methods: In November 2013, we searched the computerized databases CENTRAL (The Cochrane Library), MEDLINE, POPLINE, EMBASE, and LILACS for studies of combination contraceptives, as well as ClinicalTrials.gov and International Clinical Trials Registry Platform (ICTRP). For the initial review, we also wrote to known investigators and manufacturers to request information about other published or unpublished trials not discovered in our search.
Selection Criteria: All English-language, randomized controlled trials were eligible if they had at least three treatment cycles and compared a combination contraceptive to a placebo or to a combination contraceptive that differed in drug, dosage, regimen, or study length.
Data Collection and Analysis: All titles and abstracts located in the literature searches were assessed. Data were entered and analyzed with RevMan. A second author verified the data entered. For continuous data, we calculated the mean difference and 95% confidence interval (CI) for the mean change in weight between baseline and post-treatment measurements using a fixed-effect model. For categorical data, such as the proportion of women who gained or lost more than a specified amount of weight, the Peto odds ratio with 95% CI was calculated.

MAIN Results: We found 49 trials that met our inclusion criteria. The trials included 85 weight change comparisons for 52 distinct contraceptive pairs (or placebos). The four trials with a placebo or no intervention group did not find evidence supporting a causal association between combination oral contraceptives or a combination skin patch and weight change. Most comparisons of different combination contraceptives showed no substantial difference in weight. In addition, discontinuation of combination contraceptives because of weight change did not differ between groups where this was studied. AUTHORS'

Conclusions: Available evidence was insufficient to determine the effect of combination contraceptives on weight, but no large effect was evident. Trials to evaluate the link between combination contraceptives and weight change require a placebo or non-hormonal group to control for other factors, including changes in weight over time.

The Cochrane Database of Systematic Reviews


Progesterone therapy, endothelial function and cardiovascular risk factors: a  3-month randomized, placebo-controlled trial in healthy early postmenopausal  women

Jerilynn C Prior

Vancouver Hospital and Health Sciences Centre

Christine L Hitchcock

Centre for Menstrual Cycle and Ovulation Research, Division of Endocrinology, University of British Columbia, Vancouver, BC, Canada.

Abstract:
Background: Progesterone is effective treatment for hot flushes/night sweats. The cardiovascular effects of progesterone therapy are unknown but evidence suggests that premenopausal normal estradiol with also normal progesterone levels may provide later cardiovascular protection. We compared the effects of progesterone to placebo on endothelial function, weight, blood pressure, metabolism, lipids, inflammation and coagulation. METHODS AND

Results: We conducted a randomized, double-blind, 3-month placebo-controlled trial of progesterone (300 mg daily) among 133 healthy postmenopausal women in Vancouver, Canada from 2003-2009. Endothelial function by venous occlusion plethysmography was a planned primary outcome. Enrolled women were 1-11 y since last menstruation, not using hormones (for >6 months), non-smoking, without diabetes, hypertension, heart disease or their medications. Randomized (1∶1) women (55 ± 4 years, body mass index 25 ± 3) initially had normal blood pressure, fasting lipid, glucose and electrocardiogram results. Endothelial function (% forearm blood flow above saline) was not changed with progesterone (487 ± 189%, n = 18) compared with placebo (408 ± 278%, n = 16) (95% CI diff [-74 to 232], P = 0.30). Progesterone (n = 65) and placebo (n = 47) groups had similar changes in systolic and diastolic blood pressure, resting heart rate, weight, body mass index, waist circumference, total cholesterol, low-density lipoprotein cholesterol and triglyceride levels. High-density lipoprotein was lower (-0.14 mmol/L, P = 0.001) on progesterone compared with placebo. Fasting glucose, hs-C-reactive protein, albumin and D-dimer changes were all comparable to placebo. Framingham General Cardiovascular Risk Profile scores were initially low and remained low with progesterone therapy and not statistically different from placebo.

Conclusions: Results indicate that progesterone has short-term cardiovascular safety. Endothelial function, weight, blood pressure, waist circumference, inflammation and coagulation were unchanged as were lipids except for HDL-C. The statistically significant decrease in HDL-C levels was not clinically important (based on lack of Cardiovascular Risk Profile change).

Trial Registration: ClinicalTrials.gov NCT00152438.


Are we overusing IVF?

Are we overusing IVF?

Abstract: The indications for IVF have expanded from tubal disorders to many causes of subfertility, including unexplained. But with limited evidence underpinning its extended remit Esme Kamphuis and colleagues explain how the risks could outweigh the benefits.


Oral contraceptives, hormone replacement therapy and breast cancer risk: a cohort  study of 16 928 women 48 years and older

Thuridur Thorbjarnardottir

Centre of Public Health Sciences, University of Iceland , Reykjavik , Iceland.

Abstract:
Background: Findings on potential interactive effects of oral contraceptives (OCs) and hormone replacement therapy (HRT) on breast cancer risk have been inconsistent. We aimed to use population-based cohort data to determine whether former use of OCs affects breast cancer risk among HRT users, taking into account regimens of HRT, duration and currency of use.

Methods: The cohort consisted of 16 928 Icelandic women who visited the Icelandic Cancer Detection Clinic in 1979-2006 and provided information on use of OCs and HRT when they were 48 years or older. By record linkage to the Icelandic Cancer Registry, all breast cancer diagnosed during follow-up was identified. Using Cox regression, hazard ratios (HRs) for breast cancer according to hormone use were estimated, adjusting for menstrual and reproductive risk factors. Also, interaction analyses were carried out.

Results: Breast cancer risk was significantly increased among ever users of combined estrogen and progestin (EP-HRT) preparations (HR=2.61; 95% CI 2.00-3.41) and not among users of estrogen-only regimens (E-only HRT) (HR=1.13; 95% CI 0.85-1.49). Ever users of both OCs and HRT had higher breast cancer risk than users of only one of the two (HR=2.19; 95% CI 1.67-2.87). After restricting the analysis to EP-HRT and focusing on long-term and current use, there was an indication of a negative interaction with ever OC use (p=0.06); HR=2.87; 95% CI 1.79-4.60 for never OC users and HR=2.24; 95% CI 1.51-3.34 for former OC users.

Conclusion: After taking HRT regimen, duration and currency of use into account, the results of our population-based cohort study do not support the notion that former OC use increases breast cancer risk among HRT users, on the contrary there was an indication of a slightly lower risk in former OC users, restricted to current, long-term EP-HRT users.


In vitro effects of coital lubricants and synthetic and natural oils on sperm motility

Abstract:
OBJECTIVE: To evaluate the effects of coital lubricants and oils on sperm motility.

DESIGN: Comparative prospective in vitro study.

SETTING: University Andrology laboratory.

PATIENT(S): Twenty-two normozoospermic donors.

INTERVENTION(S): Semen samples were incubated in modified human tubal fluid (mHTF) control and in 10% Pre-Seed, Astroglide, and KY products (Sensitive, Warming, and Tingling) and baby, canola, sesame, and mustard oils. Total and progressive sperm motility was evaluated before and at 5, 30, and 60 minutes of incubation.

MAIN OUTCOME MEASURE(S): Sperm motility.

RESULT(S): Control samples exhibited no significant decrease in sperm motility. Pre-Seed showed a slight (∼4%) but significant drop in progressive motility after 30 minutes. Total and progressive sperm motility significantly declined under Astroglide, KY products (Sensitive, Warming, and Tingling) and sesame oil incubation. Canola oil significantly decreased total motility after 30 minutes and progressive motility after 5 minutes of incubation. Similarly, baby oil decreased total motility after 60 minutes and progressive motility after 5 minutes. After initial decline, total and progressive sperm motility under Pre-Seed and canola and baby oils remained high. Exposure to mustard oil caused persistent hyperactivation of sperm in each sample with no decrease in motility.

CONCLUSION(S): Sesame oil and synthetic coital lubricants impaired sperm motility and may hamper fertility. Pre-Seed and canola, mustard, and baby oils showed no deleterious effect and may be considered sperm-friendly coital lubricants. Mustard oil exposure resulted in hyperactivation of sperm and needs to be studied further.


Timing of oral contraceptive use and the risk of breast cancer in BRCA1 mutation  carriers

Kotsopoulos J, Lubinski J, Moller P, Lynch HT, Singer CF, Eng C, Neuhausen SL, Karlan B, Kim-Sing C, Huzarski T, Gronwald J, McCuaig J, Senter L, Tung N, Ghadirian P, Eisen A, Gilchrist D, Blum JL, Zakalik D, Pal T, Sun P, Narod SA

Abstract: It is not clear if early oral contraceptive use increases the risk of breast cancer among young women with a breast cancer susceptibility gene 1 (BRCA1) mutation. Given the benefit of oral contraceptives for the prevention of ovarian cancer, estimating age-specific risk ratios for oral contraceptive use and breast cancer is important. We conducted a case-control study of 2,492 matched pairs of women with a deleterious BRCA1 mutation. Breast cancer cases and unaffected controls were matched on year of birth and country of residence. Detailed information about oral contraceptive use was collected from a routinely administered questionnaire. Conditional logistic regression was used to estimate the odds ratios (OR) and 95 % confidence intervals (CI) for the association between oral contraceptive and breast cancer, by age at first use and by age at diagnosis. Among BRCA1 mutation carriers, oral contraceptive use was significantly associated with an increased risk of breast cancer for women who started the pill prior to age 20 (OR 1.45; 95 % CI 1.20-1.75; P = 0.0001) and possibly between ages 20 and 25 as well (OR 1.19; 95 % CI 0.99-1.42; P = 0.06). The effect was limited to breast cancers diagnosed before age 40 (OR 1.40; 95 % CI 1.14-1.70; P = 0.001); the risk of early-onset breast cancer increased by 11 % with each additional year of pill use when initiated prior to age 20 (OR 1.11; 95 % CI 1.03-1.20; P = 0.008). There was no observed increase for women diagnosed at or after the age of 40 (OR 0.97; 95 % CI 0.79-1.20; P = 0.81). Oral contraceptive use before age 25 increases the risk of early-onset breast cancer among women with a BRCA1 mutation and the risk increases with duration of use. Caution should be taken when advising women with a BRCA1 mutation to take an oral contraceptive prior to age 25.


The Genetics of Infertility: Current Status of the Field

Abstract: Infertility is a relatively common health condition, affecting nearly 7% of all couples. Clinically, it is a highly heterogeneous pathology with a complex etiology that includes environmental and genetic factors. It has been estimated that nearly 50% of infertility cases are due to genetic defects. Hundreds of studies with animal knockout models convincingly showed infertility to be caused by gene defects, single or multiple. However, despite enormous efforts, progress in translating basic research findings into clinical studies has been challenging. The genetic causes remain unexplained for the vast majority of male or female infertility patients. A particular difficulty is the huge number of candidate genes to be studied; there are more than 2,300 genes expressed in the testis alone, and hundreds of those genes influence reproductive function in humans and could contribute to male infertility. At present, there are only a handful of genes or genetic defects that have been shown to cause, or to be strongly associated with, primary infertility. Yet, with completion of the human genome and progress in personalized medicine, the situation is rapidly changing. Indeed, there are 10-15 new gene tests, on average, being added to the clinical genetic testing list annually.


15. The menstrual cycle and lipid levels

Sunni L Mumford

Eunice Kennedy Shriver National Institute of Child Health and Human Development

Handbook of diet and nutrition in the menstrual cycle, periconception and fertility


Pilot test and validation of the peak day method of prospective determination of ovulation against a handheld urine hormone monitor

Abstract:
BACKGROUND: Transient exposures may influence fertility and early embryonic development. To assess the time of conception in vivo and conduct concurrent biomonitoring, ovulation must be identified prospectively. We report on the development and validation of a simple, prospective method, the Peak Day method, to determine likely day of ovulation based upon daily observations of cervical fluid.

METHODS: We recruited 98 women to learn the Peak Day method from a brochure, 26 of whom concurrently used the method with blinded daily urine hormone monitoring (estrone glucuronide and luteinizing hormone). All women were instructed to complete an exposure questionnaire immediately upon identifying ovulation. Briefly, the exposure questionnaire captured time-varying and transient exposures such as medication use, water consumption, and amount of sleep. We assessed timely completion of the exposure questionnaire, agreement of women's estimated day of ovulation (EDO) and the EDO by expert review, and agreement between the EDO by expert review and by blinded urine monitoring.

RESULTS: Of 147 cycles evaluated, women selected an EDO in 130 (88%) and subsequently completed the periovulatory exposure questionnaire in 122 (94%) cycles. Of the 26 cycles evaluated with blinded hormonal monitoring, the Peak Day "best quality" algorithm, based upon cervical fluid, identified ovulation ± 3 days of the urine monitor in 24 cycles (92%).

CONCLUSIONS: With simple written instructions, women can identify an estimated day of ovulation and perform periovulatory exposure assessment. The Peak Day method is highly cost-effective and could be applied by researchers to target periconceptional or very early developmental stage exposure assessment.


Stem cell and endometriosis: new knowledge may be producing novel therapies

Jiali Yang

Huazhong University of Science and Technology

Abstract: The human endometrium is a dynamic tissue, which undergoes cycles of growth and regression with each menstrual cycle. Adult progenitor stem cells are likely responsible for this remarkable regenerative capacity; these same progenitor stem cells may also have an enhanced capacity to generate endometriosis if shed in a retrograde fashion. The progenitor stem cells reside in the uterus, and, however, may also travel from other tissues such as bone marrow to repopulate the progenitor population. Mesenchymal stem cells are also involved in the pathogenesis of endometriosis and may be the principle source of endometriosis outside of the peritoneal cavity when they differentiate into endometriosis in ectopic locations. The present short review mainly summarizes the latest observations contributing to the current knowledge regarding the presence and the potential contribution of stem cells in the etiology of endometriosis. All these data can have clinical implications and provide a basis for new potential therapeutic applications.

International journal of clinical and experimental medicine


412: The effect of very short interpregnancy interval on pregnancy outcomes after previous pregnancy loss

Jean Wactawski-Wende

Department of Epidemiology and Environmental Health, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY.

American Journal of Obstetrics and Gynecology


Beyond labor: the role of natural and synthetic oxytocin in the transition to motherhood

Abstract: Emerging research raises questions that synthetic oxytocin during childbirth may alter the endogenous oxytocin system and influence maternal stress, mood, and behavior. Endogenous oxytocin is a key component in the transition to motherhood, affecting molecular pathways that buffer stress reactivity, support positive mood, and regulate healthy mothering behaviors (including lactation). Synthetic oxytocin is widely used throughout labor and postpartum care in modern birth. Yet research on the implications beyond labor of maternal exposure to perinatal synthetic oxytocin is rare. In this article, we review oxytocin-related biologic pathways and behaviors associated with the transition to motherhood and evidence supporting the need for further research on potential effects of intrapartum oxytocin beyond labor. We include a primer on oxytocin at the molecular level.