Menstrual Cycle Hormone Changes in Women Traversing Menopause: Study of Women's Health Across the Nation.

Context: Menstrual cycle hormone patterns in women approaching menopause are inadequately studied. Objective: To describe day-to-day menstrual cycle hormones in women as they approach menopause from the Study of Women's Health Across the Nation Daily Hormone Study (DHS). Design: DHS enrollees collected daily urine for one entire menstrual cycle or up to 50 days, whichever came first, annually, up to the final menstrual period (FMP) or for up to 10 years. Setting: Seven sites across the United States. Participants: A total of 511 premenopausal or early perimenopausal women at enrollment, within 10 years before menopause. Intervention: Time-to-FMP measurement. Main Outcome Measures: Evidence of luteal activity (ELA), determined using objective algorithms. Menstrual cycle/segment length; whole cycle, and segment integrated urinary luteinizing hormone, follicle-stimulating hormone, estrone conjugates, and pregnanediol glucuronide (Pdg) for each year, organized around the FMP. Results: Mean menstrual cycle length was remarkably preserved at 26 to 27 days in ELA cycles; non-ELA cycles had greater variability. The percentage of cycles that were ELA remained high until 5 years before the FMP (87.9%); only 22.8% of cycles within 1 year of the FMP were ELA. Whole cycle hormones remained relatively stable up to 3 years before the FMP, when gonadotropins began to increase. Pdg excretion declined slowly with progress to the FMP, but Pdg patterns of ELA cycles remained distinguishable from non-ELA. Conclusions: Menstrual cycle hormone patterns in perimenopausal women resemble those of midreproductive-aged women until 5 years before menopause, and presumably ovulatory cycles retain a potentially fertile pattern up to the end of reproductive life.

Recombinant human relaxin versus placebo for cervical ripening: a double-blind randomised trial in pregnant women scheduled for induction of labour.

BACKGROUND: Nonclinical studies indicate that the hormone relaxin is a good candidate for a safe cervical ripening agent that does not cause uterine contractions. METHODS: This Phase II study (conducted November 2, 2005-October 20, 2006) was a randomised, double blind, placebo controlled trial testing 24-h intravenous infusion of serelaxin (recombinant human relaxin) or placebo for cervical ripening in 72 healthy, primiparous women. Eligible subjects had a singleton pregnancy ≥40 weeks, were planned for elective induction, had vertex presentation of the fetus, intact membranes and a Bishop score at screening ≤4. In Part A of the study, safety evaluation of three escalating doses of serelaxin (7.5, 25 or 75 µg/kg/day) or placebo was performed in 22 subjects admitted to the hospital 24 h prior to scheduled induction (n = 7, 4, 4, and 7 subjects, respectively). The highest safe dose from Part A and placebo were then tested in Part B for safety and cervical ripening (n = 25 subjects/arm). Planned randomisation ratio was of 4:2 (serelaxin:placebo) for each dose group in Part A and 1:1 for Part B. For analysis, subjects in Part B were pooled with those receiving the same dose in Part A and all subjects receiving placebo were pooled. The primary efficacy endpoint was change from baseline in Bishop score at 6, 12 and 24 h or end of study drug administration. Maternal safety evaluations included adverse events and vital signs through 4 weeks. Fetal assessments included serial heart rate monitoring and nonstress testing. Neonatal assessments included Apgar scores, NICU admissions, and adverse events through 4 weeks. RESULTS: Overall, 74 subjects were randomized and 72 were treated. There were no significant differences between the groups receiving the highest safe dose of serelaxin (75 µg/kg/day) and placebo in the primary or secondary efficacy endpoints. Changes from baseline in Bishop score at 24 h were 4.19 ± 1.9 and 3.26 ± 2.26 in the pooled placebo and serelaxin groups, respectively (p = 0.2507). Serelaxin was well tolerated and no anti-serelaxin antibodies were detected in either subjects or neonates. CONCLUSION: Serelaxin infusion at the end of pregnancy was well tolerated but did not advance cervical ripening. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT00259103 (15 November 2005).

Role of Medical Management for Uterine Leiomyomas.

Uterine leiomyomas, or fibroids, are the most common benign tumor in reproductive aged women. Affected women may remain asymptomatic or may report symptoms related to abnormal uterine bleeding, infertility, or pelvic pain and pressure. Depending on a patient's symptomatology and reproductive plans, treatment options include expectant management, medical management (hormonal and non-hormonal), or surgical management (myomectomy or hysterectomy). In those wishing to defer surgical management, non-hormonal therapies such as non-steroidal anti-inflammatory drugs and tranexamic acid have been shown to decrease menstrual blood loss. In patients with more symptomatic leiomyomas, hormonal therapies such as gonadotropin-releasing hormone agonists and selective progesterone receptor modulators are effective at reducing leiomyoma volume, uterine size, and menstrual blood loss. This manuscript will detail the available and emerging hormonal and non-hormonal treatments for symptomatic uterine leiomyomas.

Physical fitness, serum relaxin and duration of gestation.

BACKGROUND: Women are recommended to perform regular exercise during pregnancy but the impact of physical fitness on duration of gestation and miscarriage is inconsistent. In addition, a dose-response relation between the amount of weekly exercise and increased risk of miscarriage in early pregnancy has been observed. Previous studies have mostly used an epidemiologic method. Larger studies using careful measurement of physical fitness are needed. Besides physical fitness, maternal circulating concentrations of the hormone relaxin have been associated with decreased duration of gestation. METHODS: A prospective cohort including 20 women with miscarriage and 460 women with spontaneous onset of labour, recruited from maternal health care centres in central Sweden, were examined in early pregnancy regarding estimated absolute peak oxygen uptake (VO2 peak, est.) by cycle ergometer test, and maternal circulating serum relaxin concentrations. RESULTS: Women with miscarriage displayed the highest level of absolute VO2 peak, est. (2.61 l/min) and the lowest serum relaxin concentrations (640 ng/l). Among women with spontaneous onset of labour, the mean absolute VO2 peak, est. increased successively from the lowest estimated oxygen uptake of 2.31 l/min among those with preterm birth (n = 28), to an oxygen uptake of 2.49 l/min among women with postterm birth (n = 31). An opposite trend was shown regarding serum relaxin concentrations from women with miscarriage to those with postterm birth. Serum relaxin concentrations, but not absolute VO2 peak, est. was significantly and independently associated with duration of gestation in women with miscarriages, and absolute VO2 peak, est., age and multiple pregnancy were independently associated with duration of gestation in women with spontaneous onset of labour. CONCLUSIONS: Physical fitness appears to be a protective factor of established pregnancies and not significantly involved in the risk of early miscarriage. Additional studies are needed to more clearly define the role of relaxin in miscarriage.

Myometrial artery calcifications and aging.

OBJECTIVE: This study aims to determine whether myometrial artery calcifications increase with age and whether uterine sections are an appropriate model for studying vascular aging. METHODS: An observational study of 172 women (aged 45 y or older) who underwent hysterectomy for benign indications at the University Hospital (Newark, NJ) between July 1, 2009 and June 1, 2012 was performed. Women with a history of malignancy, undocumented last menstrual period, or unavailable uterine tissue slides were excluded. H&E-stained uterine sections were evaluated for myometrial artery calcifications (defined as the presence of acellular densely basophilic material within the media of vessels) by a single pathologist in a blinded manner. RESULTS: Between July 1, 2009 and June 1, 2012, hysterectomies were performed on 441 women, 172 of whom met inclusion criteria. Seventeen women (9.9%) had myometrial artery calcifications detectable on H&E-stained tissue sections. None of 84 women aged 45 to 49 years, 2 of 51 women (3.9%) aged 50 to 59 years (aged 56 and 58 y), 10 of 27 women (37%) aged 60 to 69 years, and 5 of 10 women (50%) aged 70 to 81 years had myometrial artery calcifications. The prevalence of myometrial artery calcifications significantly increased with advancing age (P = 0.022). CONCLUSIONS: Myometrial artery calcifications increase with advancing age. Histological sections of uterine tissue from hysterectomy specimens seem to be a useful model for evaluating vascular aging markers.

Does a diagnosis of atrophic vaginitis on Papanicolaou test signify the presence of inflammation?

OBJECTIVE: Vaginal atrophy in menopause shows increased parabasal cells on cytology. This may be accompanied by abundant neutrophils. A shift in maturation index in the absence of significant inflammation is more accurately termed "atrophic pattern." This study aims to determine whether a diagnosis of "atrophic vaginitis" or atrophic pattern on Papanicolaou test is a reliable indicator of what is present on the slide. METHODS: A retrospective review of Papanicolaou test slides from University Hospital Newark was performed. Cases that had been diagnosed as either atrophic vaginitis (n = 100) or atrophic pattern (n = 100) were selected. Exclusion criteria included any additional diagnosis of neoplasia. Slides were re-reviewed and scored based on abundance of neutrophils: 0 to 5, 6 to 10, or more than 10 neutrophils per high-power field (×40), with 10 fields per slide reviewed. Data were analyzed by χ analysis. RESULTS: Among 200 cases with atrophic vaginitis or atrophic pattern, the proportion of those diagnosed with atrophic vaginitis to those diagnosed with atrophic pattern increased across three neutrophil categories (P < 0.0001). CONCLUSIONS: A diagnosis of atrophic vaginitis on Papanicolaou test is reliably associated with increased numbers of neutrophils. A diagnosis of atrophic pattern is indicative of low numbers of neutrophils. As the Papanicolaou test diagnosis of atrophic vaginitis does not correlate with clinical symptoms, a single diagnostic term that does not suggest a disease process would more reliably communicate cytology findings to clinicians.

Effect of single embryo transfer on the risk of preterm birth associated with in vitro fertilization.

PURPOSE: To determine whether elective single embryo transfer (eSET) reduces the risk of preterm delivery associated with in vitro fertilization (IVF). METHODS: This is an observational study of 3125 eSET cycles performed from 2008 to 2009 and reported to the Society for Assisted Reproductive Technology (SART) database. Preterm delivery rates were compared to the overall preterm delivery rate among all patients undergoing IVF over the same time period. RESULTS: The 3125 eSET cycles resulted in 1507 live births (live birth rate 48.2 %) Among these deliveries were 27 twins (1.8 %) and one set of triplets (0.07 %). The overall preterm delivery rate (20-37 weeks gestation) following eSET was 17.6 % (269/1527). This is significantly greater than the preterm birth rate for all patients undergoing IVF over the same time period (12 %, P < 0.001). CONCLUSIONS: Elective single embryo transfer does not reduce the risk of preterm delivery associated with in vitro fertilization (IVF).

Women's health research in the last four decades. Interview by Natasha Leeson.

Gerson Weiss speaks to Natasha Leeson, Assistant Commissioning Editor Gerson Weiss obtained his MD degree from New York University (NY, USA). After an internship in internal medicine at Baltimore City Hospital (MD, USA), he completed residency in obstetrics and gynecology at New York University. Further training in reproductive endocrinology was obtained as a postdoctoral research fellow in physiology at the University of Pittsburgh (PA, USA), in the laboratory of Dr Ernst Knobil. Following this fellowship, Dr Weiss returned to New York University where he ultimately became Professor of Obstetrics and Gynecology, Professor of Pharmacology and Director of the Division of Reproductive Endocrinology and Infertility. In 1986, he became Professor and Chair of the Department of Obstetrics and Gynecology at New Jersey Medical School (NJ, USA). Dr Weiss is the author of more than 274 scientific articles. His research has been continuously funded since 1975 by grants from the NIH, the United Cerebral Palsy Foundation and the Andrew W Mellon Foundation. He has served as a member of the Division of Reproductive Endocrinology of the American Board of Obstetrics and Gynecology, a member of the Reproductive Biology Study Section of the NIH, a member of the Residency Review Committee for Obstetrics and Gynecology of the Accreditation Council for Graduate Medical Education. He has served as the President of the New York Obstetrical Society, the New York Gynecologic Society, the Council of University Chairs of Obstetrics and Gynecology, and the American Board of Obstetrics and Gynecology. He was the Chairman of the Committee on Gynecologic Practices for the American College of Obstetricians and Gynecologists and Chairman of American Board of Obstetrics and Gynecology. He was a member of the Executive Committee of the American Board of Medical Specialties. Dr Weiss is a past President of the Society for Gynecologic Investigation. He currently serves on the NIH's Advisory Committee on Research on Women's Health. Dr Weiss conducts an active clinical practice both in gynecology and reproductive endocrinology and infertility at his institution.

Relaxin and the control of primate parturition.

In primate pregnancy, circulating relaxin, solely a product of the corpus luteum, peaks in the first trimester of pregnancy then declines and levels off for the remainder of pregnancy. Relaxin actions in pregnancy include increasing cervical pro-MMP-1 and pro-MMP-3 and decreasing TIMP-1, changes which soften the cervix. Relaxin, from early pregnancy, increases endometrial natural killer cells, macrophages and neutrophils, blood flow and arterial number. Hyperrelaxinemia correlates with preterm birth.

Negative attitudes and affect do not predict elective hysterectomy: a prospective analysis from the Study of Women's Health Across the Nation.

OBJECTIVE: Cross-sectional studies suggest an association between hysterectomy and negative affect. Using prospective data, we examined the associations of negative affect, attitudes toward aging and menopause, premenstrual symptoms, and vasomotor symptoms with elective hysterectomy in midlife. METHODS: Data were from the Study of Women's Health Across the Nation, a multisite, community-based prospective cohort study of the menopausal transition (n = 2,818). Annually reported hysterectomy at visits 2 to 9 was verified with medical records when available (71%). Anxiety, perceived stress, depressive symptoms, attitudes toward aging and menopause, vasomotor symptoms, and premenstrual symptoms were assessed at baseline using standardized questions. Cox proportional hazards models were used to relate these variables to subsequent elective hysterectomy. Covariates included demographic variables, menstrual bleeding problems, body mass index, hormone levels, and self-rated health, also assessed at baseline. RESULTS: Elective hysterectomy was reported by 6% (n = 168) of participants over an 8-year period. Women with hysterectomy were not higher in negative affect or negative attitudes toward aging and menopause compared with women without hysterectomy. Vasomotor symptoms (hazard ratio [HR], 1.44; 95% CI, 1.03-2.01; P = 0.03) and positive attitudes toward aging and menopause (HR, 1.74; 95% CI, 1.04-2.93) at baseline predicted hysterectomy over the 8-year period, controlling for menstrual bleeding problems, site, race/ethnicity, follicle-stimulating hormone, age, education, body mass index, and self-rated health. Menstrual bleeding problems at baseline were the strongest predictor of hysterectomy (HR, 4.30; 95% CI, 2.05-9.05). CONCLUSIONS: In this prospective examination, negative affect and attitudes were not associated with subsequent hysterectomy. Menstrual bleeding problems were the major determinant of elective hysterectomy.

Endometrial expression of relaxin and relaxin receptor in endometriosis.

Our studies demonstrate significantly lower expression of relaxin and its receptor in ectopic endometriotic tissues than their expression in eutopic endometrium and in endometrium from normal controls. These data suggest that in normal and eutopic endometrium, relaxin may exert a protective effect against endometriosis.

Maternal obesity and associated reproductive consequences.

The prevalence of obesity is continuing to increase among women. Women who are in their reproductive years are disproportionately affected by obesity. The link between obesity and increased morbidity from various conditions, including cardiovascular disease, Type 2 diabetes, osteoarthritis and malignancies, is well established. This article discusses the current state of obesity among reproductive age women in the USA and reviews the impact of maternal obesity on reproduction. The genetic contribution to human obesity is also discussed, as is reproduction following weight reduction surgery.

Cardiovascular risk factor variation within a Hispanic cohort: SWAN, the Study of Women's Health Across the Nation.

OBJECTIVES: Hispanics have less favorable cardiovascular risk profiles relative to other groups, although little is known regarding variability in risk profiles according to country of origin. Our goal was to examine the association of cardiovascular risk factors with country of origin and acculturation in a cohort of middle-aged Hispanic women. SETTING: Baseline data for participants at the New Jersey Site of the Study of Women's Health Across the Nation (SWAN). PARTICIPANTS: 419 women, aged 42-52 years, comprising 142 non-Hispanic Whites and 277 Hispanic: Central American (n = 29), South American (n = 106), Puerto Rican (n = 56), Dominican (n = 42) and Cuban (n = 44). MAIN OUTCOME MEASURES: BMI, smoking, blood pressure, lipid profiles, and presence of hypertension, hyperlipidemia, diabetes and metabolic syndrome were compared using univariate and multivariable models. RESULTS: LDL and HDL varied significantly across Hispanic subgroups (overall P < or = .05). Prevalence of metabolic syndrome was greatest in Puerto Rican women (48.2% vs 40.0%, 35.0%, 13.9% and 29.3% in Central American, South American, Dominican and Cuban women, respectively, P = .016). Central American women were least likely to smoke (P < .05 vs Puerto Rican, Cuban and South American). Prevalence of hypertension and diabetes were similar across groups. Differences in lipids and metabolic syndrome were not explained by acculturation, financial strain, education, physical activity, smoking or dietary fat intake. CONCLUSIONS: There is significant heterogeneity in cardiovascular risk status among middle-aged Puerto Rican, Cuban, Dominican, Central American and South American women, not explained by acculturation or socioeconomic indicators. These differences may be important for targeting screening and preventive interventions.

Qualifications of Physicians Performing Hysterectomy: The Study of Women's Health Across the Nation.

The objective of this study was to evaluate whether physicians performing hysterectomy on participants of the Study of Women's Health Across the Nation (SWAN) are adequately trained to perform this procedure. A multicenter longitudinal study of 3302 women aged 42 to 52 was conducted over 9 years of follow-up. Of the 238 women reporting hysterectomy within the United States, 165 were verified via medical record review. Information regarding training background and board certification status of the physicians performing these hysterectomies was obtained from the American Board of Medical Specialists. Complications of hysterectomy were abstracted from patients' medical records. Of the 165 physicians, 163 (98.8%) obtained board certification and 139 (84.2%) obtained their medical degrees in the United States. Ninety-eight percent of the physicians completed a residency in obstetrics and gynecology. Intra- and postoperative complications were exceedingly low. Physicians performing hysterectomies on participants of SWAN appear adequately trained to carry out this commonly performed procedure.

Circulating relaxin and cervical length in midpregnancy are independently associated with spontaneous preterm birth.

OBJECTIVE: We sought to examine associations among serum relaxin levels, cervical length, and spontaneous preterm birth (sPTB). STUDY DESIGN: We conducted a case-control study within a cohort of 1080 singleton pregnant women. In all, 38 women (3.5%) delivered spontaneously preterm (< 37 completed weeks of gestation). Relaxin was measured in serum in gestational weeks 12 and 19, cervical length only in week 19. Associations to sPTB were evaluated by logistic regression analysis and receiver operating characteristic curves. RESULTS: Cervical length and relaxin in week 19, but not week 12 were associated to sPTB. There were no correlations between cervical length and relaxin level in week 12 (controls: Spearman rho: -0.07, P = .45; cases: Spearman rho: -0.07, P = .72) or week 19 (controls: Spearman rho: -0.03, P = .77; cases: Spearman rho: 0.04, P = .84). CONCLUSION: There were no correlation between relaxin concentrations and the cervical length, indicating that relaxin is probably not the cause of preterm shortening of the cervix.

Circulating dehydroepiandrosterone sulfate concentrations during the menopausal transition.

CONTEXT: A previous report from the Study of Women Across the Nation indicated a rise in dehydroepiandrosterone sulfate (DHEAS) during the menopausal transition using data from three annual visits. OBJECTIVE: Our objective was to examine changes in DHEAS with chronological and ovarian aging, expanding the original analyses to include 10 yr of annual data. DESIGN: A longitudinal observational study and cross-sectional analyses of baseline data were conducted. OUTCOME MEASURES AND SUBJECTS: DHEAS, age, menopause status, ethnicity, smoking, weight, and height were assessed in 2886 women from five ethnic groups aged 42-52 yr at entry. Hysterectomy, bilateral oophorectomy, and hormone use were excluded. RESULTS: Cross-sectional analysis at baseline showed a linear decline in circulating log-transformed DHEAS with increasing age for either the entire cohort (2.81% per year) or for individual ethnicities. A similar negative association with baseline age (2.44% decline per year) was seen in longitudinal linear mixed modeling including observations from premenopause through late postmenopause, an additional 0.33% decline/year. In contradistinction, a late-transition rise in DHEAS was detected when the same women were analyzed by ovarian status. The average increase in mean circulating DHEAS level between early and late menopause transition, beyond changes predicted by aging, was 3.95%, followed by an average decline of 3.96% during the late postmenopause. Approximately 84.5% of the women had an estimated within-woman increase in DHEAS from premenopause/early perimenopause to late perimenopause/early postmenopause. CONCLUSION: These observations underscore differences between cross-sectional and longitudinal studies and the importance of considering ovarian status. Additional investigations regarding adrenal contribution to sex steroids in mid-aged women are warranted.

Relaxin receptor LGR7 (RXFP1) is regulated by estrogen.

Estrogen regulates LGR7 (RXFP1) mRNA expression in an in vitro model of human term pregnancy cervix that utilizes lower uterine segment fibroblasts. LGR7 mRNA levels were increased by estradiol to mean levels of 152%+/- 5.9% above those in untreated control cells. Therefore, estradiol may amplify relaxin's actions in the cervix.

Relaxin in human pregnancy.

Relaxin has beneficial effects upon the endometrium which are responsible for establishment of pregnancy. We have demonstrated that relaxin stimulates endometrial decidualization, the structural and biochemical changes in endometrial parenchymal cells, and the accompanying angiogenesis, modulation of matrix metalloproteinase activity, and increased concentrations in local immune cells which are required for implantation. Our recent data also demonstrate that either too much or too little relaxin can be detrimental. Elevated circulating maternal relaxin concentrations (hyperrelaxinemia) are associated with premature birth. This is likely due to the effects of relaxin at the level of the cervix, via upsetting the balance in the maintenance of cervical connective tissue architecture. In addition, the absence of circulating relaxin during pregnancy in women may have negative consequences upon glucose metabolism.

Relaxin in endometriosis.

Endometriosis is an important contributing factor to chronic pelvic pain and infertility. Matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) have each been implicated in the establishment of endometriotic lesions. Since relaxin regulates the expression of MMPs and VEGF in the endometrium, we tested the hypothesis that relaxin plays a role in endometriosis by comparing the expression of relaxin mRNA and its LGR7 (RXFP1) receptor mRNA in normal human endometrium to those in samples from patients with endometriosis.