Search

Objective To define the live birth rates in a large, population-based study of the most common reproductive-age cancers in women. Design Retrospective cohort study. Setting Population-based study. Patients Female cancer patients diagnosed with cancer at age 18 years old or older between 1952–2014 (n = 17,952) were compared to fertility of non-cancer controls (n = 89,436). Interventions Live births in cancer survivors were compared with those in healthy, age-matched controls. Cases and controls were matched in the ratio of 5:1 for birth year, birthplace (Utah, yes/no), and follow-up time in Utah. Main Outcome Measure Rate of at least one live birth, reported as an incidence rate ratio (IRR). Results Of all cancer survivors, 3,127 (17.4%) had at least 1 live birth after treatment in comparison to 19,405 healthy, age-matched controls (21.7%) with the same amount of time exposure for attempting pregnancy. Breast cancer was the most common cancer type (23.1% of patients in cohort). Compared with age-matched, healthy controls, IRR of live birth was 0.69 (95% confidence interval [CI], 0.67–0.70) for all cancer types, 0.25 (95% CI, 0.20–0.33) for leukemia, 0.40 (95% CI, 0.28–0.59) for gastrointestinal cancers, 0.44 (95% CI, 0.41–0.48) for breast cancer, 0.53 (95% CI, 0.47–0.59) for central nervous system cancers, and 0.57 (95% CI, 0.44–0.73) for soft tissue cancers. With all cancer types stratified by age at diagnosis, IRR for live births in cancer survivors aged >41 years at diagnosis was 0.48 (95% CI, 0.44–0.52); IRR was 0.64 (95% CI, 0.61–0.67) in the group aged 31–40 years and 0.71 (95% CI, 0.69–0.74) in the group aged 18–30 years after their cancer treatment. Conclusions Cancer and its treatment were associated with lower live birth rates when comparing women with cancer vs. age-matched, healthy controls.

Endometriosis implants are comprised of glandular and stromal elements, macrophages, nerves, and blood vessels and are commonly accompanied by pelvic pain. We propose that activated macrophages are recruited to and infiltrate nascent lesions, where they secrete proinflammatory cytokines, promoting the production of chemokines, neurotrophins, and angiogenic growth factors that sustain an inflammatory microenvironment. Immunohistochemical evaluation of endometriosis lesions reveals in situ colocalization of concentrated macrophages, brain-derived neurotrophic factor (BDNF), and nerve fibers. These observations were coupled with biochemical analyses of primary eutopic endometriosis stromal cell (EESC) cultures, which allowed defining potential pathways leading to the neuroangiogenic phenotype of these lesions. Our findings indicate that IL-1β potently (EC50 = 7 ± 2 ng/mL) stimulates production of EESC BDNF at the mRNA and protein levels in an IL-1 receptor-dependent fashion. Selective kinase inhibitors demonstrate that this IL-1β effect is mediated by c-Jun N-terminal kinase (JNK), NF-κB, and mechanistic target of rapamycin signal transduction pathways. IL-1β regulation of regulated on activation normal T cell expressed and secreted (RANTES), a prominent EESC chemokine, also relies on JNK and NF-κB. An important clinical implication of the study is that interference with BDNF and RANTES production, by selectively targeting the JNK and NF-κB cascades, may offer a tractable therapeutic strategy to mitigate the pain and inflammation associated with endometriosis.

Bidirectional communication between the immune and neuroendocrine systems is not well understood in the context of traumatic brain injury (TBI). The purpose of this study was to characterize relationships between cerebrospinal fluid (CSF) cortisol and inflammation after TBI, and to determine how these relationships differ by outcome. CSF samples were collected from 91 subjects with severe TBI during days 0–6 post-injury, analyzed for cortisol and inflammatory markers, and compared to healthy controls (n = 13 cortisol, n = 11 inflammatory markers). Group-based trajectory analysis (TRAJ) delineated subpopulations with similar longitudinal CSF cortisol profiles (high vs. low cortisol). Glasgow Outcome Scale (GOS) scores at 6 months served as the primary outcome measure reflecting global outcome. Inflammatory markers that displayed significant bivariate associations with both GOS and cortisol TRAJ (interleukin [IL]-6, IL-10, soluble Fas [sFas], soluble intracellular adhesion molecule [sICAM]-1, and tumor necrosis factor alpha [TNF]-α) were used to generate a cumulative inflammatory load score (ILS). Subsequent analysis revealed that cortisol TRAJ group membership mediated ILS effects on outcome (indirect effect estimate = −0.253, 95% CI (−0.481, −0.025), p = 0.03). Correlational analysis between mean cortisol levels and ILS were examined separately within each cortisol TRAJ group and by outcome. Within the low cortisol TRAJ group, subjects with unfavorable 6-month outcome displayed a negative correlation between ILS and mean cortisol (r = −0.562, p = 0.045). Conversely, subjects with unfavorable outcome in the high cortisol TRAJ group displayed a positive correlation between ILS and mean cortisol (r = 0.391, p = 0.006). Our results suggest that unfavorable outcome after TBI may result from dysfunctional neuroendocrine–immune communication wherein an adequate immune response is not mounted or, alternatively, neuroinflammation is prolonged. Importantly, the nature of neuroendocrine–immune dysfunction differs between cortisol TRAJ groups. These results present a novel biomarker-based index from which to discriminate outcome and emphasize the need for evaluating tailored treatments targeting inflammation early after injury.

Objective To define the live birth rates in a large, population-based study of the most common reproductive-age cancers in women. Design Retrospective cohort study. Setting Population-based study. Patients Female cancer patients diagnosed with cancer at age 18 years old or older between 1952–2014 (n = 17,952) were compared to fertility of non-cancer controls (n = 89,436). Interventions Live births in cancer survivors were compared with those in healthy, age-matched controls. Cases and controls were matched in the ratio of 5:1 for birth year, birthplace (Utah, yes/no), and follow-up time in Utah. Main Outcome Measure Rate of at least one live birth, reported as an incidence rate ratio (IRR). Results Of all cancer survivors, 3,127 (17.4%) had at least 1 live birth after treatment in comparison to 19,405 healthy, age-matched controls (21.7%) with the same amount of time exposure for attempting pregnancy. Breast cancer was the most common cancer type (23.1% of patients in cohort). Compared with age-matched, healthy controls, IRR of live birth was 0.69 (95% confidence interval [CI], 0.67–0.70) for all cancer types, 0.25 (95% CI, 0.20–0.33) for leukemia, 0.40 (95% CI, 0.28–0.59) for gastrointestinal cancers, 0.44 (95% CI, 0.41–0.48) for breast cancer, 0.53 (95% CI, 0.47–0.59) for central nervous system cancers, and 0.57 (95% CI, 0.44–0.73) for soft tissue cancers. With all cancer types stratified by age at diagnosis, IRR for live births in cancer survivors aged >41 years at diagnosis was 0.48 (95% CI, 0.44–0.52); IRR was 0.64 (95% CI, 0.61–0.67) in the group aged 31–40 years and 0.71 (95% CI, 0.69–0.74) in the group aged 18–30 years after their cancer treatment. Conclusions Cancer and its treatment were associated with lower live birth rates when comparing women with cancer vs. age-matched, healthy controls.

Clinical Opinion www. AJOG .org GENERAL GYNECOLOGY A statement on abortion by 100 professors of obstetrics: 40 years later One Hundred Professors of Obstetrics and Gynecology F orty years ago, leaders in obstetrics and gynecology published a com- pelling statement that recognized the legalization of abortion in several states and anticipated the 1973 Supreme Court decision in Roe v Wade. 1 They projected the numbers of legal abortions that likely would be required by women in the United States and described the role of the teaching hospital in meeting that responsibility. 1 They wrote to ex- press their concern for women’s health in a new legal and medical era of re- productive control and to define the responsibilities of academic obstetrician- gynecologists. Since then, we have advanced the fields of reproduction and family planning. Thanks to these developments, women can now prevent pregnancy with safer and more effective forms of contracep- tion (most recently long-acting revers- ible methods), with simple and sensitive hormonal and sonographic methods to determine pregnancy status and dura- tion, and with new methods of infer- tility treatment and prenatal testing that rely on the option of terminating inten- ded pregnancies that are diagnosed as abnormal. To terminate pregnancies, cli- nicians now use misoprostol and mife- pristone for “medical abortion” (which in 2009 accounted for 16.5% of termina- tions in the United States and can be office-based) and use sonographic guid- ance of intrauterine procedures along with new methods for inducing cervical dilation and uterine contraction; patients From the 100 Professors (Appendix). Received Dec. 3, 2012; revised Jan. 23, 2013; accepted March 7, 2013. The author reports no conflict of interest. Reprints not available from the authors. a 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2013.03.007 In this Journal in 1972, 100 leaders in obstetrics and gynecology published a compelling statement that recognized the legalization of abortion in several states and anticipated the 1973 Supreme Court decision in Roe v Wade. They projected the numbers of legal abortions that likely would be required by women in the United States and described the role of the teaching hospital in meeting that responsibility. They wrote to express their concern for women’s health in a new legal and medical era of reproductive control and to define the responsibilities of academic obstetrician-gynecologists. Forty years later, 100 professors examine the statement of their predecessors in light of medical advances and legal changes and suggest a further course of action for obstetrician gynecologists. Key words: abortion, law, teaching hospital benefit from innovations in counseling and new approaches to pain control. 2-6 Studies of abortion practice and out- comes are also much more sophisticated than they were 40 years ago. 7,8 We have had 40 years of medical progress but have witnessed political regression that the 100 professors did not anticipate. In 2011 alone, 24 states passed 92 legislative restrictions on abortion. 9 Waiting periods after consent are now law in 26 states. Alabama, Arizona, Florida, Kansas, Louisiana, North Car- olina, Oklahoma and Texas require pa- tients to view ultrasound images and, in Arizona, Louisiana, Mississippi and Texas, to listen to fetal heart beats. 10 Laws in 27 states force physicians to provide deceptive counseling including false statements about risks of breast cancer, infertility and mental health. They include laws to limit second-trimester abortion under the guise of protecting the fetus from pain (Alabama, Idaho, Indiana, Kansas, Louisiana, Nebraska, and Oklahoma). 11 Laws directed specif- ically at medical education in Arizona, Kansas, and Texas prohibit abortion training in public institutions and another 7 states ban abortion in public hospitals, precluding training in them. 12 What vision of the future of legalized abortion did the 100 professors have? How accurately did they estimate the need for safe, legal abortion and antici- pate their colleagues’ willingness and commitment to meeting it? They wrote, “In view of the impending change in abortion practices generated by new state legislation and federal court de- cisions, we believe it helpful to [respond] to this increasingly liberal course of events.by contributing to the solution of an imminent problem.” 1 Forty years later, the change is not liberal. Its effects will threaten, not improve, women’s health and already obstruct physicians’ evidence-based and patient-centered practices. We review our predecessors’ 1972 statement and judge how it com- ports with what actually occurred and with legislation that has been adopted over the 40 years since their writing and the passage of Roe v Wade. The 100 professors were remarkably prescient in anticipating the need for 1 million legal abortions and today’s abortion rate of 1 in 4 pregnancies. 13,14 They predicted that teaching hospitals with specialized outpatient facilities could meet the demand and believed that abortions were the responsibility of hospitals. But today, 90% of abortions, which include the 10% that are in the second trimester, are done away from hospitals. 15 Many hospitals enforce fetal and maternal health restrictions that are not based in the law but are MONTH 2013 American Journal of Obstetrics & Gynecology FLA 5.1.0 DTD ! YMOB9193_proof ! 15 April 2013 ! 10:46 am ! ce

Clinical Opinion www. AJOG .org GENERAL GYNECOLOGY A statement on abortion by 100 professors of obstetrics: 40 years later One Hundred Professors of Obstetrics and Gynecology F orty years ago, leaders in obstetrics and gynecology published a com- pelling statement that recognized the legalization of abortion in several states and anticipated the 1973 Supreme Court decision in Roe v Wade (Supplementary Data available at www.AJOG.org). 1 They projected the numbers of legal abortions that likely would be required by women in the United States and described the role of the teaching hospital in meeting that responsibility. 1 They wrote to ex- press their concern for women’s health in a new legal and medical era of re- productive control and to define the responsibilities of academic obstetrician- gynecologists. Since then, we have advanced the fields of reproduction and family planning. Thanks to these developments, women can now prevent pregnancy with safer and more effective forms of contracep- tion (most recently long-acting revers- ible methods), with simple and sensitive hormonal and sonographic methods to determine pregnancy status and dura- tion, and with new methods of infer- tility treatment and prenatal testing that rely on the option of terminating inten- ded pregnancies that are diagnosed as abnormal. To terminate pregnancies, cli- nicians now use misoprostol and mife- pristone for “medical abortion” (which in 2009 accounted for 16.5% of termina- tions in the United States and can be office-based) and use sonographic guid- ance of intrauterine procedures along with new methods for inducing cervical From the 100 Professors (Appendix). Received Dec. 3, 2012; revised Jan. 23, 2013; accepted March 7, 2013. The author reports no conflict of interest. Reprints not available from the authors. a 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2013.03.007 In this Journal in 1972, 100 leaders in obstetrics and gynecology published a compelling statement that recognized the legalization of abortion in several states and anticipated the 1973 Supreme Court decision in Roe v Wade. They projected the numbers of legal abortions that likely would be required by women in the United States and described the role of the teaching hospital in meeting that responsibility. They wrote to express their concern for women’s health in a new legal and medical era of reproductive control and to define the responsibilities of academic obstetrician-gynecologists. Forty years later, 100 professors examine the statement of their predecessors in light of medical advances and legal changes and suggest a further course of action for obstetrician gynecologists. Key words: abortion, law, teaching hospital dilation and uterine contraction; patients benefit from innovations in counseling and new approaches to pain control. 2-6 Studies of abortion practice and out- comes are also much more sophisticated than they were 40 years ago. 7,8 We have had 40 years of medical progress but have witnessed political regression that the 100 professors did not anticipate. In 2011 alone, 24 states passed 92 legislative restrictions on abortion. 9 Waiting periods after consent are now law in 26 states. Alabama, Arizona, Florida, Kansas, Louisiana, North Car- olina, Oklahoma, and Texas require pa- tients to view ultrasound images and, in Arizona, Louisiana, Mississippi, and Texas, to listen to fetal heart beats. 10 Laws in 27 states force physicians to provide deceptive counseling including false statements about risks of breast cancer, infertility, and mental health. They include laws to limit second-trimester abortion under the guise of protecting the fetus from pain (Alabama, Idaho, Indiana, Kansas, Louisiana, Nebraska, and Oklahoma). 11 Laws directed specif- ically at medical education in Arizona, Kansas, and Texas prohibit abortion training in public institutions and another 7 states ban abortion in public hospitals, precluding training in them. 12 What vision of the future of legalized abortion did the 100 professors have? How accurately did they estimate the need for safe, legal abortion and antici- pate their colleagues’ willingness and commitment to meeting it? They wrote, “In view of the impending change in abortion practices generated by new state legislation and federal court de- cisions, we believe it helpful to [respond] to this increasingly liberal course of events.by contributing to the solution of an imminent problem.” 1 Forty years later, the change is not liberal. Its effects will threaten, not improve, women’s health and already obstruct physicians’ evidence-based and patient-centered practices. We review our predecessors’ 1972 statement and judge how it com- ports with what actually occurred and with legislation that has been adopted over the 40 years since their writing and the passage of Roe v Wade. The 100 professors were remarkably prescient in anticipating the need for 1 million legal abortions and today’s abortion rate of 1 in 4 pregnancies. 13,14 They predicted that teaching hospitals with specialized outpatient facilities could meet the demand and believed that abortions were the responsibility of hospitals. But today, 90% of abortions, which include the 10% that are in the second trimester, are done away from hospitals. 15 Many hospitals enforce fetal and maternal health restrictions that SEPTEMBER 2013 American Journal of Obstetrics & Gynecology

Objective To better understand the site and mode of action of aromatase inhibitors. Design Prospective study. Setting Academic research environment. Patient(s) Five eumenorrheic (without polycystic ovary syndrome), early follicular phase women with a normal body mass index (mean: 20.47 ± 0.68 kg/m2), and 12 normal weight, midreproductive aged, early follicular phase women with a normal body mass index (mean: 20.8 ± 1.7 kg/m2) as historical controls. Intervention(s) 2.5 mg letrozole daily for 7 days, with daily urine collection (first morning void), thrice weekly blood sampling, and 4 hours of blood sampling every 10 minutes. Main Outcome Measure(s) Serum luteinizing hormone (LH) measured by a well-characterized immunofluorometric assay with LH pulse characteristics compared between treated and control groups using t tests. Result(s) Mean LH and LH pulse amplitude more than doubled in the women who had taken letrozole compared with the controls, but the LH pulse frequency did not differ between the women taking letrozole and the controls. Conclusion(s) These results indicate that the release of negative feedback inhibition of estradiol on the hypothalamic-pituitary axis in normal women by aromatase inhibitors creates an amplitude-related increase in endogenous hypothalamic-pituitary drive. The finding that the mean LH and LH pulse amplitude, but not the frequency, increased after letrozole suggests a possible pituitary site of action.

Polycystic ovary syndrome (PCOS) is a common condition with both a reproductive and metabolic phenotype. Women with PCOS often seek care because of infertility or menstrual cycle irregularities that result from chronic anovulation interspersed with occasional ovulatory cycles. Initially, it is important to delineate a differential diagnosis for oligo- or amenorrhea and to evaluate for disorders that may “masquerade” as PCOS. If fertility is a desired goal, then it is critical to optimize health conditions that impact fertility and gestation. Lifestyle modifications, including nutritional counseling and weight loss, should be a part of all treatment plans. Even minimal (5%) weight loss in obese women with PCOS improves both ovulation and pregnancy rates. The first line of treatment for ovulation induction remains the selective estrogen receptor modulator (SERM) clomiphene citrate. The role of insulin sensitizers, particularly metformin, remains unclear. A recent consensus panel recommended against its routine use in the absence of an elevated glucose or hemoglobin A1c. If a woman fails to achieve pregnancy after a trial of weight loss and six ovulatory cycles induced by clomiphene citrate, then ovulation induction with exogenous gonadotropin, with or without timed intrauterine insemination, or in vitro fertilitization, is a reasonable next step. Women with PCOS are particularly prone to excessive follicle development and are at increased risk for ovarian hyperstimulation syndrome (OHSS). Although limited data exist comparing approaches to ovulation induction or controlled ovarian stimulation in women with PCOS, the American Society for Reproductive Medicine recommends the use of “step-up” or “step-down” protocols in which a low dose of exogenous FSH or combined gonadotropins are employed in an attempt to constrain ovarian responsiveness. In vitro fertilization allows for the transfer of only one embryo or for cryopreservation of all embryos with subsequent transfer of a single embryo in a subsequent cycle without ovarian stimulation. Countless questions regarding pathogenesis and treatment of PCOS create opportunity for basic and clinical research and for refinement of existing therapeutic approaches.

Assisted reproductive technologies are important tools in the clinical armamentarium used to treat both female and male infertility disorders. Pre-implantation genetic diagnosis offers couples at risk of having children with inheritable disorders the ability to analyze the genetic make-up of embryos before transfer. For patients undergoing treatment of cancer with chemotherapy or radiation therapy, these technologies offer the potential for the preservation of future fertility. As technology evolves, it is likely the clinical applications of assisted reproduction will continue to develop and expand in the future to enhance fertility.

Objective To evaluate past oral contraceptive use and angiographic coronary artery disease in women. Setting Academic medical centers. Patient(s) Six hundred seventy-two postmenopausal women enrolled in the Women's Ischemia Syndrome Evaluation (WISE) with coronary risk factors undergoing coronary angiography for suspected myocardial ischemia. Intervention(s) Past oral contraceptive use, assessed by reproductive questionnaire. Main Outcome Measure(s) Quantitative coronary artery disease, assessed by a core angiography laboratory. Result(s) Past oral contraceptive use was associated with a lower mean coronary artery disease severity index score (mean ± SD: 11.8 ± 10.3 vs. 18.7 ± 17.3) compared with non–prior users, despite age adjustment. Past oral contraceptive use remained a significant independent negative predictor of coronary artery disease severity when adjusting for coronary risk factors, including age, diabetes mellitus, triglycerides, low-density lipoprotein cholesterol, smoking, aspirin use, and lipid-lowering medication (model R 2 = 0.19). The modeling indicated that past oral contraceptive use was associated with a 2.44 lower coronary artery disease severity score index. There was no apparent relationship between duration of past oral contraceptive use and the coronary artery disease severity index score. Conclusion(s) Past oral contraceptive use is associated with less coronary artery disease, measured by quantitative coronary angiography, among postmenopausal women with suspected myocardial ischemia. These findings suggest that a prospective study should address the hypothesis that past oral contraceptive use during the premenopausal years might offer women protection from atherosclerotic coronary disease later in life.

Epidemiological and psychophysiological data suggest that groups that differ in reproductive hormones and stress responses also differ in risk for cardiovascular disease. To evaluate the effects of hormone therapy on women's cardiovascular responses to laboratory stressors, 89 healthy postmenopausal women were tested twice, before and after exposure for about 8 weeks to one of the five conditions: placebo, Estratab (primarily estrone), Estratab plus Prometrium (micronized progesterone), Estratab plus Provera (synthetic progestin), and Estratest (same estrogen as in Estratab plus methyltestosterone). Results showed that women assigned to Estratab plus Prometrium and Estratest had diminished systolic blood pressure responses to stress upon retesting, whereas the other groups did not change in the level of their responses. Women assigned to Estratab plus Prometrium had diminished diastolic blood pressure responses during a speech stressor upon retesting, whereas women assigned to Estratab plus Provera increased. Our findings show that hormone therapy does affect women's stress responses, but they do not provide a simple explanation as to why groups at high and low risk for cardiovascular disease differ in reproductive hormones and stress responses.

Objective: To determine whether cognitive behavior therapy (CBT) targeted to problematic attitudes common among women with functional hypothalamic amenorrhea would restore ovarian function. Design: Randomized, prospective, controlled intervention. Setting: Clinical research center in an academic medical institution. Patient(s): Sixteen women participated who had functional hypothalamic amenorrhea; were of normal body weight; and did not report psychiatric conditions, eating disorders, or excessive exercise. Intervention(s): Subjects were randomized to CBT or observation for 20 weeks. Main outcome measure(s): Serum levels of E 2 and P and vaginal bleeding were monitored. Result(s): Of eight women treated with CBT, six resumed ovulating, one had partial recovery of ovarian function without evidence of ovulation, and one did not display return of ovarian function. Of those randomized to observation, one resumed ovulating, one had partial return of ovarian function, and six did not recover. Thus, CBT resulted in a higher rate of ovarian activity (87.5%) than did observation (25.0%), χ 2 = 7.14. Conclusion(s): A cognitive behavioral intervention designed to minimize problematic attitudes linked to hypothalamic allostasis was more likely to result in resumption of ovarian activity than observation. The prompt ovarian response to CBT suggests that a tailored behavioral intervention offers an efficacious treatment option that also avoids the pitfalls of pharmacological modalities.

OBJECTIVES We sought to evaluate hypoestrogenemia of hypothalamic origin and its association with angiographic coronary artery disease (CAD) in premenopausal women. BACKGROUND Coronary artery disease in premenopausal women appears to have a particularly poor prognosis. Primate animal data suggest that premenopausal CAD is strongly determined by psychosocial stress-induced central disruption of ovulatory cycling and resulting hypoestrogenemia. METHODS We assessed reproductive hormone blood levels and angiographic CAD using core laboratories in 95 premenopausal women with coronary risk factors who were enrolled in the National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation and were undergoing coronary angiography for evaluation for suspected ischemia. RESULTS Premenopausal women with angiographic CAD (n = 13) had significantly lower estradiol, bioavailable estradiol, and follicle-stimulating hormone (FSH) (all p < 0.05) than women without angiographic CAD (n = 82), even after controlling for age. Hypoestrogenemia of hypothalamic origin, defined as estradiol

Objective: To determine whether mood, attitudes, or symptoms of disordered eating discriminated women with functional hypothalamic amenorrhea (FHA) from those with organic causes of amenorrhea and eumenorrhea. Design: Cross-sectional comparison of women with FHA, women with organic amenorrhea, and eumenorrheic control women. Setting: Clinical research center in an academic medical institution. Patient(s): Seventy-seven women ≥18 years old with time since menarche ≥5 and ≤25 years were recruited by advertisement. Intervention(s): Ovulation was confirmed in eumenorrheic control women. Causes of anovulation were carefully documented in amenorrheic participants and LH pulse profiles were obtained to document the diagnosis of FHA. All participants were interviewed and completed questionnaires. Main Outcome Measure(s): Self-report measures of dysfunctional attitudes, coping styles, and symptoms of depression and eating disorders. Result(s): Women with FHA reported more depressive symptoms and dysfunctional attitudes than did eumenorrheic women, but not significantly more than women with organic amenorrhea. However, women with FHA reported significantly more symptoms of disordered eating than did either anovulatory or ovulatory women. Conclusion(s): The findings are consistent with the hypothesis that FHA is precipitated by a combination of psychosocial stressors and metabolic challenge.

Objective: To determine whether fasting in women would suppress GnRH/LH drive in a high- versus low-gonadal steroid milieu. Design: Case-control study. Setting: Academic clinical research center. Patient(s): Eleven eumenorrheic women and eleven women taking combined oral contraceptives. Intervention(s): Seven of the eleven women in each group underwent an acute 72-hour fast. Blood samples were obtained at 15-minute intervals for 24 hours before the fast and during the last 24 hours of fasting. Main Outcome Measure(s): Twenty-four–hour profiles of LH, cortisol, and melatonin were assessed. Ovarian activity was tracked with estradiol and progesterone levels, and metabolic responses were gauged by measuring thyroid hormone and β-hydroxy-butyric acid levels. Result(s): Fasting increaseed β-hydroxy-butyric acid and reduced free thyronine. Fasting in the midfollicular phase had no effect on LH pulsatility or on FSH, estradiol, or subsequent luteal-phase progesterone levels. However, fasting elevated cortisol and resulted in a phase advance in melatonin secretion of 81 minutes in both the midfollicular and luteal phases. Conclusion(s): Fasting in women elicited expected metabolic responses and apparently advanced the central circadian clock without compromising reproductive function.

Deterioration in cognitive function-particularly learning, memory, and attention-has been reported by women with breast cancer who receive adjuvant chemotherapy. Deficits in cognitive function reported by women with breast cancer are similar to those experienced by women as a consequence of natural or surgical menopause. The basis of these deteriorations may include reductions in reproductive hormone levels, particularly estrogens and progesterones, that occur as a result of adjuvant chemotherapy. This paper critically examines the literature related to the impact of adjuvant chemotherapy and reproductive hormone changes on cognitive function in women with breast cancer and suggests direction for future research in this area. The paper proposes a framework for investigation of the problem and discusses the challenges associated with the conduct of this research.

Objective To assess the impact of increased consumption of milk, without other dietary advice, on older adults' energy and nutrient intakes, weight, cardiovascular risk factors (blood pressure, plasma lipid levels), and quality of life. Subjects/setting Two hundred four healthy men and women, aged 55 to 85 years, who consumed fewer than 1.5 dairy servings per day were chosen from six US academic health centers. Design Randomized, controlled open trial. Intervention Advice to increase skim or 1% milk intake by 3 cups per day (n=101) or to maintain usual diet (n=103) for 12 weeks after a 4-week baseline period. Main outcome measures Changes in energy and nutrient intake assessed from 3-day food records, body weight, blood pressure, and plasma lipid levels. Statistical analyses performed Group-by-time analysis of variance with repeated-measures, χ 2 test. Results Compliance with the intervention was good. Compared with controls, participants in the milk-supplemented group significantly increased energy, protein, cholesterol, vitamins A, D, and B-12, riboflavin, pantothen ate, calcium, phosphorus, magnesium, zinc, and potassium intakes. Prevalence of nutrient inadequacy, assessed for nutrients with Estimated Average Requirements, decreased among women in the milk group for magnesium (40% .at baseline vs 13% at 12 weeks, P P P P P =.002). Quality of life scores were high at baseline and remained high throughout. Applications/conclusions Older adults can successfully increase milk intake, thereby meaningfully improving their nutrient intakes. Dietitians can play a key role in disseminating this advice. J Am Diet Assoc. 2000; 100:810-817 .

Women with polycystic ovary syndrome come to the gynecologist with a variety of symptoms, including menstrual irregularities, hirsutism, acne, weight gain, obesity, and infertility. An accurate diagnosis requires both confirmation of signs and symptoms of polycystic ovary syndrome and exclusion of other disorders. Once the diagnosis of polycystic ovary syndrome has been established, the presence of concomitant conditions, such as hypertension, dyslipidemia, and diabetes, must be assessed. Because the cause of polycystic ovary syndrome is not clear, treatment options have focused on symptom management. Such treatment options include oral contraceptives, gonadotropin-releasing hormone analogs with “add-back” hormone regimens, antiandrogens, ovulation-inducing agents, electrolysis, nutritional and weight loss counseling, exercise, laparoscopic ovarian drilling, and glucocorticoids. Pathogenic considerations, risk factor assessments, and treatment objectives combine to determine the choice of therapies. It is not clear whether insulin resistance is clinically important or causal in polycystic ovary syndrome symptom complex in all affected women. Polycystic ovary syndrome may be the final common expression of a variety of metabolic or neuroendocrine perturbations. If insulin resistance is a universal feature, it would make sense to treat with an insulin-sensitizing agent in the expectation that symptoms would resolve or improve. If insulin resistance is not the main etiologic factor, however, then insulin-sensitizing agents would be useful as adjunctive agents only for women with clinically important insulin resistance (eg, patients with polycystic ovary syndrome in whom insulin resistance causes hyperglycemia). In such cases an insulin-sensitizing agent could be instituted along with a program of weight loss and exercise. (Am J Obstet Gynecol 1998;179:S109-13.)

Polycystic ovary syndrome (PCOS), a disorder of hyperandrogenism and chronic anovulation affects 5%-10% of all women. Women with PCOS often have elevated cardiovascular risk factors. A total of 244 PCOS cases were identified through the Division of Reproductive Endocrinology at Magee-Womens Hospital and were age-matched to 244 neighborhood controls. The average age of cases and controls was 35.3 +/- 7.4 and 36.7 +/- 7.7. Women with PCOS compared to controls had substantially higher LDL-C and total cholesterol levels at each age group under 45 years after adjustment for body mass index, hormone use, and insulin levels. In the over 40-year age group, little difference was noted between cases and controls. Among cases and controls (40), PCOS predicted LDL-C, total cholesterol and triglycerides, but did not have a significant effect on lipid levels in older cases and controls after controlling for the other variables. The primarily pre- to perimenopausal PCOS casesor =40 years of age have similar LDL-C and total cholesterol levels as their age-matched controls, probably reflecting the LDL-C increase with age among controls.

The present study reduced the levels of ovarian hormones to early postmenopausal levels by a GnRH agonist and evaluated the effects of a temporary suppression of ovarian hormones on premenopausal women’s cardiovascular and neuroendocrine responses to laboratory challenges. The stress responses of 24 healthy young women were evaluated during three tasks during the early follicular phase and then after three monthly injections of Lupron, which suppressed their levels of estradiol, FSH, and LH. Thereafter, half the group resumed menstrual cycles (labeled Cycle), and half continued having Lupron injections in combination with transdermal estradiol (labeled Patch) and all were reevaluated a third time. A third group (labeled Control) of 12 women had four monthly injections of Lupron first and then were evaluated the first time. After their cycles resumed, they were reevaluated twice 3 months apart. Results showed that the magnitude of the blood pressure and catecholamine changes declined over the three evaluations, suggesting that the women’s stress responses habituated. Although the suppression of ovarian hormone levels led to alterations in ovarian hormones for several months, which were accompanied by typical menopausal symptoms, cardiovascular and neuroendocrine responses to stress did not vary. This study did not test the effects of current estrogen exposure or of long term suppression of ovarian hormones upon cardiovascular and neuroendocrine responses. © 1998 Elsevier Science Ltd. All rights reserved.

Objective To determine whether serum levels of vascular permeability factor (VPF) are elevated in patients with ovarian hyperstimulation syndrome (OHSS) and to determine if luteinizing granulosa cells may be a source of VPF. Design Prospective observational study. Setting University IVF and GIFT program. Patients Eight consecutive IVF and GIFT patients at high risk for OHSS. Main Outcome Measures Vascular permeability factor concentration in serum and follicular fluid. Results Serum VPF was significantly higher (15.2 ± 4.0 pM; mean ± SEM) on day +14 in the group who developed severe OHSS compared with those who did not. Follicular fluid VPF (171.5 ± 18.5 pM) was approximately 100-fold greater than serum (1.7 ± 1.3 pM) or peritoneal fluid (2.5 ± 1.3 pM) 36 hours after hCG administration. Conclusion Vascular permeability factor is elevated in patients with severe OHSS and the ovary may be a source of VPF secretion.

Nineteen women in the follicular stage of their menstrual cycles were assessed for immunological responsiveness to a 50-min series of three psychological tasks which reliably elicit cardiovascular and neuroendocrine stress responses. Ten follicular-stage women not subjected to stress served as controls. Stress decreased lymphocyte responsiveness to PHA and PWM, percent of CD4+ cells and the ratio of CD4 + CD8 + cells. Conversely, stress increased natural killer cell number and cytolytic activity, white blood cell, lymphocyte, T and B cell count. Except for natural killer cell number, none of these changes was exhibited by controls. Most of these stress responses are similar to those reported for men and form the basis for a continuing study of the effects of reproductive hormones and stress on cardiovascular and immunological function in women.

Objectives To determine if human sperm recovery during swim-up and sperm survival after 24hours, as obtained from a screening semen specimen, are predictive of subsequent IVF and clinical pregnancy rates (PRs) and to determine if these techniques can identify men with normal semen analysis parameters and poor IVF success. Design Historical prospective study. Setting All semen evaluations and IVF cycles were performed at the University of Pittsburgh, Magee-Womens Hospital, Pittsburgh, Pennsylvania. Patients, Participants Couples undergoing IVF at Magee-Womens Hospital from August 1988 through June 1993. Interventions A screening semen analysis and swim-up procedure were performed on all couples undergoing IVF. The number of spermatozoa recovered after swim-up and the percentage of motile spermatozoa present after a 24-hour incubation were recorded. Main Outcome Measures Fertilization and PRs were compared according to the parameters obtained from routine semen analysis, the number of spermatozoa obtained with swim-up, and the percentage of motile spermatozoa at 24hours. Results Using χ 2 or Fisher's exact test, fertilization rates were significantly different according to the number of spermatozoa recovered after swim-up (≤2.0 and >2.0×10 6 spermatozoa recovered, 48.3% versus 71.4%) as were PRs (16.9% versus 29.8%). Similarly, the percentage of motile spermatozoa present at 24hours (≤20% and >20%) discriminated between fertilization rates (45.9% versus 65.8%) and PRs (16.4% versus 36.5%). Among a subset of men with normal semen analyses and total motile sperm counts≥40×10 6 , the results from swim-up and survival discriminated between men with high and low fertilization and PRs. Receiver operating characteristic analysis revealed that swim-up results better discriminated between pregnant and nonpregnant IVF patients than sperm motility, but that the percentage of motile spermatozoa present at 24hours was no better in this regard than sperm motility. Conclusions The number of spermatozoa recovered after swim-up and the percentage of spermatozoa that maintain their motility after 24hours were both helpful in assessing IVF and PRs and may be helpful in altering physicians to a subset of men having normal semen analysis parameters yet poor IVF success.

Objective To determine whether pelvic endometriosis impairs the efficacy of GIFT. Design Matched follow-up study. Setting University-based assisted reproduction program. Participants Patients undergoing GIFT between 1987 and 1991. Cases had a primary diagnosis of endometriosis. Controls had no endometriosis and were matched with cases according to age, number of mature eggs transferred, and sperm grade. Intervention Gamete intrafallopian transfer was performed in all patients in an identical manner independent of their underlying diagnosis. Main Outcome Measures Pregnancy and delivery rates. Results Of 114 laparoscopic egg retrievals performed in the endometriosis group, there were 37 pregnancies (32.5%) and 27 deliveries (23.7%). Of the 214 retrievals in the control group, there were 101 pregnancies (47.2%) and 76 deliveries (35.5%). Mantel-Haenszel estimates of relative risk indicated that endometriosis significantly impaired pregnancy and delivery rates. There was no statistically significant difference in pregnancy rates according to severity of disease among endometriosis cases. There was no statistically significant difference in pregnancy rates according to severity of disease among endometriosis cases. Conclusions Our finding that GIFT pregnancy rates were lower in women with a primary diagnosis of endometriosis than in matched controls suggests that endometriosis is associated with reduced efficacy of GIFT.

HRT is likely to benefit menopausal women with concurrent conditions. In particular, women with atherosclerosis and its sequelae who use HRT may live longer. Our knowledge concerning the differential pharmacologic, biologic, and clinical effects of various estrogen preparations and routes is rudimentary, particularly in the sick climacteric woman. What data do exist, however, suggest that estrogen use is likely to improve the morbidity or mortality of women with coronary heart disease, myocardial infarction, congestive heart failure, hypertension, peripheral vascular disease, diabetes mellitus, stroke, and thromboembolic disorders. Whether there are any advantages to oral versus nonoral administration in these clinical circumstances has not been concretely determined. In order to minimize hepatic impact, it may be prudent to administer by a nonoral route estrogens that naturally occur in women to those with dyslipidemias, coagulopathies, liver disease, and cholelithiasis. Women who smoke are unlikely to accrue the full benefits of HRT. Although prospective, randomized clinical trials are expensive and tedious to execute, they are needed to determine the impact in sick menopausal women of estrogens and progestins in general and the different preparations, routes, and regimens in particular.

Objective To determine whether weight loss in obese, hyperandrogenic, anovulatory women is associated with resumption of ovulation and/or with changes in insulin, androgen, and gonadotropin concentrations. Design Prospective, randomized, controlled study. Setting University research center. Patients Twelve obese, hyperandrogenic, anovulatory women. Interventions Twelve-week weight loss program in treatment (n = 6); 12-week “waiting list” in control group (n = 6). Main Outcome Measures [1] Ovulation; [2] fasting insulin and glucose measurements; [3] sex hormone-binding globulin (SHBG), total and non-SHBG T concentrations; [4] LH pulse frequency, amplitude, and concentration; and [5] FSH concentration. Results In contrast with the control group who showed no change in weight, ovulation status, or hormone levels, women in the treatment group lost an average of 16.2 kg and showed a significant increase in SHBG, a significant decline in non-SHBG T, and a decline (though nonsignificant) in fasting insulin. Four of six subjects resumed ovulation. However, no changes were evident in LH pulse frequency or amplitude or in mean LH and FSH concentrations. Conclusions Weight loss in obese, hyperandrogenic, anovulatory women appears to reduce insulin and non-SHBG T concentrations despite the absence of a change in gonadotropin secretion and may lead to resumption of ovulation.

Objective To assess the association of cognitive function, emotional, and psychiatric history in women with functional hypothalamic amenorrhea compared with amenorrheic and eumenorrheic controls. Design Each subject was medically evaluated for origin of amenorrhea or to establish eumenorrhea. Subjects completed a structured psychiatric interview and self-report questionnaires. Setting Patients were recruited from a large reproductive endocrinology practice within a tertiary referral center. Patients/Participants Consecutive patients who were eligible for the study were invited to participate. Eumenorrheic controls were recruited to match women with functional hypothalamic amenorrhea by age, sex, weight, and season. Main Outcome Measures Cognitive measures assessed expectation of control, perfectionism, rigidity of ideas and concern about judgments of others (dysfunctional attitudes), coping ability, interpersonal and achievement functioning, and interpersonal dependence. Measures of mood and symptoms included both clinical and self-report scales. Psychiatric diagnoses were determined using Research Diagnostic Criteria and DSM III-R. Results Women with functional hypothalamic amenorrhea endorsed more dysfunctional attitudes, had greater difficulty in coping with daily stresses, and tended to endorse greater interpersonal dependence than eumenorrheic women. Women with organic amenorrhea were statistically not different from either group but tended to report less dysfunctional attitudes and interpersonal dependence, although they displayed comparable difficulty in coping, compared with functional hypothalamic amenorrhea women. Women with functional hypothalamic amenorrhea more often had a history of psychiatric disorders, primarily mood disorders, than eumenorrheic women but were not different from women with organic amenorrhea. Conclusion Women with functional hypothalamic amenorrhea showed increased cognitive dysfunction and psychiatric morbidity.

Objective To examine the hypothalamic-pituitary sites of clomiphene citrate (CC) action in women with polycystic ovarian syndrome (PCOS). Design Prospective controlled trial. Patients, Participants Seventeen women with PCOS and 9 normal-cycling women. Interventions Subjects with PCOS received CC, 150mg/d for 5 days. Main Outcome Measures Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels and LH pulse characteristics and their response to gonadotropin-releasing hormone (GnRH, 10 μ g) were examined before and after 3 days of CC in PCOS subjects during a 12-hour frequent sampling study (n=8). Daily urinary estrone glucuronide and pregnanediol glucuronide levels after CC were compared with concentrations in normal-cycling women through one menstrual cycle. In another nine PCOS subjects, pituitary and ovarian hormonal cyclicity was monitored by daily blood sampling. Results Thirteen of 17 treated cycles were ovulatory with normal luteal phases. In the ovulatory cycles, serum LH, FSH, estradiol (E 2 ), and estrone levels increased after CC. Luteinizing hormone pulse frequency was unchanged, but LH pulse amplitude increased significantly after CC. Both LH and FSH response to exogenous GnRH was significantly attenuated after CC treatment. In anovulatory cycles, serum LH, FSH, and E 2 increased initially and then returned to baseline and remained unchanged for the ensuing 40 days. Conclusions Clomiphene citrate-induced ovulation in women with PCOS is accompanied by increased secretion of LH and FSH with enhanced estrogen secretion. The increased LH pulse amplitude after CC, together with decreased pituitary sensitivity to GnRH, suggests a hypothalamic effect.

Ovarian stimulation after pituitary suppression with gonadotropin-releasing hormone agonists (GnRH-a) has been effective in women who have exhibited a poor response to conventional superovulation strategies. Their effectiveness in unselected women undergoing their first cycle of in vitro fertilization or gamete intrafallopian transfer, however, remains to be established. To address this question, we randomized 114 women to one of two treatment protocols. Protocol 1 consisted of 100 mg of clomiphene citrate on days 5 to 9, followed by 150 IU human menopausal gonadotropin (hMG) beginning on day 9. Protocol 2 consisted of daily GnRH-a beginning in the midluteal phase. Stimulation with 150 IU hMG commenced after pituitary down regulation and ovarian suppression were achieved. Human menopausal gonadotropin was continued in both protocols until adequate follicular development and serum estradiol concentrations were obtained. Protocol 2 patients reached egg retrieval significantly more often (87%) than Protocol 1 patients (61%), but the mean number of mature eggs retrieved and the pregnancy rate per retrieval were not significantly different between the two groups.

Vasomotor symptoms (VMS) have been linked to endothelial dysfunction. Relations may depend on the timing of VMS. We tested relations between early onset VMS and brachial artery flow mediated dilation (FMD) in the Women’s Ischemia Syndrome Evaluation (WISE). 104 women undergoing coronary

Cross-sectional studies suggest that arterial distensibility decreases during menopause; however, relation to hormone therapy (HT) is controversial. We prospectively studied distensibility and HT during menopause. 161 women aged 42 – 61 yr without cardiovascular disease had carotid artery

Women with functional hypothalamic amenorrhea display multiple neuroendocrine aberrations suggestive of altered central neurotransmission. The role of antecedent stress as an explanation for both the neurochemical changes and the dysfunctional behavior of these women is examined by utilizing concepts provided by the animal model of inescapable shock and the human condition of post traumatic stress disorder.

The effects of nocturnal light (500 lux) exposure on plasma melatonin were studied in seven men suffering from unipolar depression and in seven healthy men. Both groups showed significant declines in plasma melatonin concentrations during 1 hour's light exposure. Differential group declines were not detected.