Factors related to declining luteal function in women during the menopausal transition.

CONTEXT: Reproductive hormones are incompletely characterized during the menopause transition (MT). HYPOTHESIS: Increased anovulation and decreased progesterone accompany progress through the MT. DESIGN: The Daily Hormone Study (DHS) of the Study of Women's Health Across the Nation (SWAN) included 848 women aged 43-53 yr at baseline who collected daily urine for one cycle or up to 50 d annually for 3 yr. MAIN OUTCOME MEASURES: LH, FSH, estrone conjugates, and pregnanediol glucuronide levels were assessed. Cycles were classified by presumed luteal (ovulatory) status and bleeding. Hormones were related to time in study, age, menopausal status, and selected variables. RESULTS: Ovulatory-appearing cycles declined from 80.9% at baseline to 64.7% by the third assessment (H3). Cycles presumed anovulatory and not ending with bleeding by 50 d (anovulatory/nonbleeding) increased from 8.4 to 24% by H3 and were associated with progress to early perimenopause [odds ratio (OR) = 2.66; confidence interval (CI) = 1.17-6.04] or late perimenopause (OR = 56.21; CI = 18.79-168.12; P < 0.0001), African-American ethnicity (OR = 1.91; CI = 1.06-3.43), and less than high school education (OR = 3.51; CI = 1.62-7.62). Anovulatory cycles ending with bleeding remained at about 10% from baseline to H3; compared with ovulatory cycles, they were associated with obesity (OR = 4.68; CI = 1.33-16.52) and more than high school education (OR = 2.12; CI = 1.22-3.69; P = 0.02). Serum estradiol in both the highest and lowest categories was associated with anovulatory/nonbleeding collections. Pregnanediol glucuronide decreased 6.6% for each year on study. Insulin sensitivity measures did not relate strongly to menstrual cycle hormones. CONCLUSIONS: Anovulation without bleeding represents progression of the MT. A small but detectable decrease in luteal progesterone excretion occurs as women progress through the MT.

Assessing menstrual cycles with urinary hormone assays.

The Study of Women's Health Across the Nation (SWAN) is a multiethnic cohort study of middle-aged women enrolled at seven US sites. A subset of 848 women completed a substudy in which their urinary gonadotropins and sex steroid metabolites were assessed during one complete menstrual cycle or up to 50 consecutive days. Urine was analyzed for LH, FSH, estrone conjugates (E1c), and pregnanediol glucuronide (Pdg). To prepare for serial analysis of this large, longitudinal database in a population of reproductively aging women, we examined the performance of algorithms designed to identify features of the normal menstrual cycle in midreproductive life. Algorithms were based on existing methods and were compared with a "gold standard" of ratings of trained observers on a subset of 396 cycles from the first collection of Daily Hormone Substudy samples. In evaluating luteal status, overall agreement between and within raters was high. Only 17 of the 396 cycles evaluated were considered indeterminate. Of the 328 cycles rated as containing evidence of luteal activity (ELA), 320 were considered ELA by use of a Pdg threshold detection algorithm. Of 51 cycles that were rated as no evidence of luteal activity, only 2 were identified by this algorithm as ELA. Evaluation of the day of the luteal transition with methods that detected a change in the ratio of E1c to Pdg provided 85-92% agreement for day of the luteal transition within 3 days of the raters. Adding further conditions to the algorithm increased agreement only slightly, by 1-8%. We conclude that reliable, robust, and relatively simple objective methods of evaluation of the probability and timing of ovulation can be used with urinary hormonal assays in early perimenopausal women.

Common treatment of polycystic ovarian syndrome and major depressive disorder: case report and review.

We present the case of a young woman with treatment-resistant major depression, who presented to the Mood Disorders Clinic with a Hamilton Psychiatric Rating Scale for Depression (HAM-D-21) score of 28, after a year-long treatment with Effexor-XR. The patient also had untreated Polycystic Ovarian Syndrome (PCOS). The resolution of her depressive symptoms resulted from the treatment for PCOS with metformin and spironolactone. The patient remained euthymic 5 months after discontinuation of the antidepressant while continuing therapy for PCOS. We briefly overview of the pertinent literature of the pathophysiology of PCOS and affective disorders, highlighting an overlap in phenotypical presentations between these two disorders. Dysregulation of the hypothalamo-pituitary axis and various end organ systems are implicated in both PCOS and affective disorders. As such, several clinical and biochemical markers are common to both disorders, namely insulin resistance, obesity, and hyperandrogenism. In addition, these metabolic abnormalities are interrelated, causing women with PCOS or affective disorders to get caught in a "vicious cycle" of hormonal dysregulation. The case report presented here illustrates how treatment of symptoms such as insulin resistance and hyperandrogenism can lead to remission of major depressive disorder and PCOS. We suggest that through treatment of underlying metabolic defects, both the mood of the patient and the metabolic condition of PCOS can be assisted.

The stability of pregnancy intentions and pregnancy-related maternal behaviors.

OBJECTIVES: Our objectives were to characterize the stability of pregnancy intention and to examine whether stability is associated with the timing of prenatal care initiation, smoking during pregnancy, and breastfeeding. METHODS: We use a sample of women from the National Longitudinal Survey of Youth (NLSY) for whom information on pregnancy intention was collected both during pregnancy and after delivery. In bivariate analyses we compare outcomes and characteristics of women whose pregnancy intention changed between the prenatal and postpartum periods. With multivariate methods, we analyze the correlates of switching pregnancy intention as well as the association between switching and maternal behaviors. RESULTS: Women whose pregnancy intention changes between the two assessments are similar in marital status and socioeconomic background to those who report both during pregnancy and after delivery that the pregnancy is unintended. Disagreement during pregnancy between the parents' pregnancy intentions is the most important predictor of instability in the mother's pregnancy intention. Effects of unintended pregnancy on the timing of initiation of prenatal care, smoking during pregnancy, and breastfeeding based on reports after delivery are smaller than those based on reports during pregnancy, although differences are not statistically significant. Adverse effects of unintended pregnancy are greater when pregnancies reported by the mother to be unintended at either assessment are combined into a single category for unintended pregnancy. CONCLUSION: Unstable pregnancy intention may be a marker for adverse maternal behaviors related to infant health.

Effects of simvastatin (40 and 80 mg/day) in patients with mixed hyperlipidemia.

Mixed hyperlipidemia is characterized by both elevated total cholesterol and triglycerides. It is estimated to account for 10% to 20% of patients with dyslipidemia. This study assessed the lipid-altering efficacy and tolerability of simvastatin 40 and 80 mg/day as monotherapy. One hundred thirty patients (62 women [48%], 24 [16%] with type 2 diabetes mellitus, mean age 53 years) with mixed hyperlipidemia (baseline low-density lipoprotein [LDL] cholesterol 156 mg/dl [mean], and triglycerides 391 mg/dl [median) were randomized in a multicenter, double-masked, placebo-controlled, 3-period, 22-week, balanced crossover study, and received placebo, and simvastatin 40 and 80 mg/day each for 6 weeks. Compared with placebo, simvastatin produced significant (p <0.01) and dose-dependent changes in all lipid and lipoprotein parameters (LDL cholesterol 2.1%, -28.9%, and -35.5%; triglycerides -3.5%, -27.8%, and -33.0%; high-density lipoprotein cholesterol 3.3%, 13.1%, and 15. 7%; apolipoprotein B 3.8%, -23.1%, and -30.6%; and apolipoprotein A-I 4.0%, 8.2%, and 10.5% with placebo, and simvastatin 40 and 80 mg/day, respectively). The changes were consistent in patients with diabetes mellitus. One patient taking simvastatin 80 mg/day had an asymptomatic and reversible increase in hepatic transaminases 3 times above the upper limit of normal. Simvastatin 40 and 80 mg/day is effective in patients with mixed hyperlipidemia across the entire lipid and lipoprotein profile. The reductions in LDL cholesterol and triglycerides are large, significant, and dose dependent. The increase in high-density lipoprotein cholesterol was greater than that observed in patients with hypercholesterolemia, and appears dose dependent.

Medication status and polycystic ovary syndrome in women with bipolar disorder: a preliminary report.

BACKGROUND: In patients with epilepsy, polycystic ovary (PCO) syndrome has been reported to be associated with the use of the anticonvulsant divalproex sodium. Whether PCO syndrome is associated with divalproex use in patients with bipolar disorder has not previously been explored. METHOD: Twenty-two female outpatients with a DSM-IV diagnosis of bipolar disorder who were between the ages of 18 and 45 years (inclusive) and who were taking lithium and/or divalproex (10, divalproex monotherapy; 10, lithium monotherapy; 2, divalproex/lithium combination therapy) were evaluated. Patients completed questionnaires about their medical, psychiatric, and reproductive health histories, and body mass indices were calculated. In the early follicular phase of their menstrual cycle, women were examined for hirsutism, given a pelvic ultrasound, and/or assessed for changes in laboratory values such as serum levels of testosterone, free testosterone, estradiol, estrone, dehydroepiandrosterone, dehydroepiandrosterone sulfate, luteinizing hormone, follicle-stimulating hormone, and 17-OH progesterone. RESULTS: All 10 patients on lithium monotherapy, 6 of 10 patients on divalproex monotherapy, and both of the patients on divalproex/lithium combination therapy reported some type of menstrual dysfunction, which, in 4 cases, had preceded the diagnosis of bipolar disorder. Hirsutism was not common in any group, but obesity was prominent in all groups. Ovarian ultrasound revealed an increased number of ovarian follicles in 1 patient taking lithium and in none of the patients taking divalproex. Hormonal screening did not indicate PCO-like changes in any patient. CONCLUSION: In this pilot study of bipolar patients, PCO-like changes were not seen in women receiving divalproex or lithium. However, independent of therapeutic agent used, the bipolar women in this study reported high rates of menstrual disturbances, suggesting that the hypothalamic-pituitary-gonadal axis may be compromised in some women with bipolar disorder.

The effect of pregnancy intention on child development.

In this paper, we use data from the National Longitudinal Survey of Youth to investigate the empirical link between unintended pregnancy and child health and development. An important contribution of our study is the use of information on siblings to control for unmeasured factors that may confound estimates of the effect of pregnancy intentions on infant and child outcomes. Results from our study indicate that unwanted pregnancy is associated with prenatal and postpartum maternal behaviors that adversely affect infant and child health, but that unwanted pregnancy has little association with birth weight and child cognitive outcomes. Estimates of the association between unwanted pregnancy and maternal behaviors were greatly reduced after controls for unmeasured family background were included in the model. Our results also indicate that there are no significant differences in maternal behaviors or child outcomes between mistimed and wanted pregnancies.

Antidepressant medications, mood and male fertility.

By modulating the activity of central neurotransmitters, psychotropic agents may affect reproductive functioning in men and women. Many neurotransmitters influence the hypothalamic-pituitary-gonadal (HPG) axis and can consequently affect menstrual cycling in women and spermatogenesis in men. Emotional state similarly may disrupt reproductive functioning through the effects of stress hormones on the HPG axis. While some data exist on the relationship between stress and menstrual cyclicity in women of reproductive age, little is known regarding the potential effect of emotional state on reproductive function in men. This paper will review: (1) aspects of male reproductive function that may be vulnerable to medication-induced influences; (2) the impact of emotional state on male reproductive function; and (3) the literature on the possible effects of antidepressant medications on male fertility.

Measuring consensus about scientific research norms.

In this paper, we empirically explore some manifestations of norms for the conduct of science. We focus on scientific research ethics and report survey results from 606 scientists who received funding in 1993 and 1994 from the Division of Molecular and Cellular Biology of the Biology Directorate of the National Science Foundation. We also report results for 91 administrators charged with overseeing research integrity at the scientists' research institutions. Both groups of respondents were presented with a set of scenarios, designed by fractional factorial methods, describing different kinds of scientific conduct that in the eyes of some would likely be unethical. Respondents then were asked to evaluate each of these scenarios for how unethical the behavior might be and what kinds of sanctions might be appropriate. We use the responses to consider the nature of consensus around norms related to the practice of science and in particular, similarities and differences between scientists and science administrators. Implications for policy are also discussed.

Black-white differences in social and economic consequences of obesity.

OBJECTIVE: To investigate social and economic effects of obesity for black and white females, and to explore possible explanations for race differences in obesity effects. SUBJECTS: 1354 non-Hispanic black and 3097 non-Hispanic, non-black, women aged 25-33y in 1990 from the National Longitudinal Survey of Youth 1979-1990. MEASUREMENTS: Body mass index (BMI) evaluated at age 17-24y (1982) and 25-33y (1990). METHODS: Logistic and linear regression of six labour market and marriage outcomes on early or attained BMI. Detailed controls for family socioeconomic background. RESULTS: Socioeconomic effects of obesity appear larger for whites than blacks. Obesity is associated with low self-esteem among whites, but not blacks. Differences in self-esteem do not account for race differences in the effects of obesity on socioeconomic status. Lower probability of marriage and lower earnings of husbands among those who marry account for the majority of the income differences between obese white women and those of recommended weight. Occupational differences account for more than one fifth of the effect of obesity on the hourly wages of both white and black women. CONCLUSION: Cultural differences may protect black women from the self-esteem loss associated with obesity for whites. However, differences in self-esteem do not account for the effects of obesity on socioeconomic status. Because the effect of obesity on the economic status of white women works primarily through marriage, it may therefore be less amenable to policy intervention to improve the labor market prospects of obese women.

Reporting unethical research behavior.

Scientists, as professionals, have a responsibility to self-regulate. However, whistleblowing is rare. We investigated scientists' infrequent disclosure of unethical behavior by studying their responses to scenarios describing unethical research acts and compared their responses to those of research administrators. A cross-sectional survey was administered to National Science Foundation-funded principal investigators and their institutions' representatives (IRs) to the Office of Research Integrity. Both scientists and IRs proposed to respond to nearly all research behaviors that they rated as unethical. Scientists more often proposed responses limited to the research team (58% vs. 25% of cases, p < .001) whereas IRs more often proposed to inform an administrator or dean, journal editor, funding agency, professional society, or reporter. The prior behavior and academic rank of the scenario protagonist were associated with responses, but consequences of the unethical behavior were not. Scientists appear to perceive that they uphold their responsibility to respond to unethical behavior by disclosures within the research team, whereas administrators propose to report to externally accountable individuals, raising the question of whether scientists' behavior constitutes professional self-regulation or cover up.

Punishment for unethical behavior in the conduct of research.

PURPOSE: To investigate the perceptions of scientists and institutional representatives (IRs) to the National Institutes of Health's Office of Research Integrity concerning appropriate punishment for unethical research behavior. METHOD: In 1994-95, 606 scientists and 91 IRs rated the ethical behaviors of and suggested appropriate punishments for protagonists in randomly generated scenarios describing scientific research behaviors. The authors evaluated the relationships of the suggested punishments to the protagonists' behaviors and characteristics, and compared recommendations of the scientists and IRs. RESULTS: The respondents suggested punishments for 80% of the scenarios that were rated unethical. Punishments were more often prescribed for behaviors rated more unethical and for repeat offenders. The type of punishment was related to the protagonist's academic status and the nature of the unethical behavior. IRs proposed more and different punishments than did scientists. CONCLUSION: Scientists and IRs proposed that most unethical research behaviors be punished. The decision to punish depended on the unethical level of the behavior. The type of punishment depended on the aims: correcting the wrong, rehabilitation, or sanction. Variation in the respondents' selections of punishments and the IRs' greater propensity to punish suggest that scientists committing similar ethical violations may receive different punishments. Explicit consideration of which punishment is merited under what circumstances should be undertaken by the scientific community.

New insights into erectile dysfunction: a practical approach.

Erectile dysfunction (ED) is the most common sexual problem in men, after premature ejaculation, affecting up to 30 million in the United States. In a society in which sexuality is widely promoted, ED impacts on feelings of self-worth and self-confidence and may impair the quality of life of affected men and their partners. Damage to personal relationships can ensue; and the anger, depression, and anxiety engendered spill over into all aspects of life. Patients are often embarrassed or reluctant to discuss the matter with their primary care practitioners. Unfortunately, many physicians fail to take the opportunity to promote open discussion of sexual dysfunction. They too, may avoid the topic through personal embarrassment. Since the National Institutes of Health (NIH) Consensus Conference on Impotence in 1992, the inadequate level of public and professional understanding of ED has begun to be addressed. As a first step in breaking down the communication barriers between patients and practitioners, it is important that physicians have a thorough understanding of the wide variety of conditions associated with ED and how the different risk factors for ED may be readily identified. This review addresses the diagnosis of ED and identifies diagnostic tests that can be used by primary care physicians to determine the patients most at risk and the treatments most suited to meet the patients' and their partners' goal for therapy.

Differential effect of race on the axial and appendicular skeletons of children.

The prevalence of osteoporosis and the incidence of fractures are substantially lower in black than in white subjects, a finding generally attributed to racial differences in adult bone mass. Whether these racial differences are present in childhood is the subject of considerable interest, as the amount of bone gained during growth is a major determinant of future susceptibility to fractures. We measured the density and size of the vertebrae and femurs of 80 black and 80 white healthy children, 8-18 yr of age, matched for age, gender, height, weight, and stage of sexual development, using computed tomography. Race had a significant and differential effect on the bones in the axial and appendicular skeletons. In the axial skeleton, black children had greater cancellous bone density, but similar cross-sectional area of the vertebral bodies. In contrast, in the appendicular skeleton, black children had greater femoral cross-sectional area, but similar cortical bone area and cortical bone density. Compared to white children, vertebral bone density and femoral cross-sectional area at sexual maturity were, on the average, 10.75% and 5.7% higher, respectively, in black children. Such significant variations may contribute to the racial differences in the prevalence of osteoporosis between black and white adults.

Evaluation of the research norms of scientists and administrators responsible for academic research integrity.

CONTEXT: The professional integrity of scientists is important to society as a whole and particularly to disciplines such as medicine that depend heavily on scientific advances for their progress. OBJECTIVE: To characterize the professional norms of active scientists and compare them with those of individuals with institutional responsibility for the conduct of research. DESIGN: A mailed survey consisting of 12 scenarios in 4 domains of research ethics. Respondents were asked whether an act was unethical and, if so, the degree to which they considered it unethical and to select responses and punishments for the act. PARTICIPANTS: A total of 924 National Science Foundation research grantees in 1993 or 1994 in molecular or cellular biology and 140 representatives from the researchers' institutions to the US Department of Health and Human Services Office of Research Integrity. MAIN OUTCOME MEASURES: Percentage of respondents considering an act unethical and the mean malfeasance rating on a scale of 1 to 10. RESULTS: A total of 606 research grantees and 91 institutional representatives responded to the survey (response rate of 69% of those who could be contacted). Respondents reported a hierarchy of unethical research behaviors. The mean malfeasance rating was unrelated to the characteristics of the investigator performing the hypothetical act or to its consequences. Fabrication, falsification, and plagiarism received malfeasance ratings higher than 8.6, and virtually all thought they were unethical. Deliberately misleading statements about a paper or failure to give proper attribution received ratings between 7 and 8. Sloppiness, oversights, conflicts of interest, and failure to share were less serious still, receiving malfeasance ratings between 5 and 6. Institutional representatives proposed more and different interventions and punishments than the scientists. CONCLUSIONS: Surveyed scientists and institutional representatives had strong and similar norms of professional behavior, but differed in their approaches to an unethical act.

The ethics of scientific research: an analysis of focus groups of scientists and institutional representatives.

BACKGROUND: Little is known about scientists' views on normative research ethics and how these compare with the views of the institutional representatives (IRs) involved in matters of scientific conduct. We qualitatively evaluated scientist and IR perceptions of the norms of science, ethical violations and their harms, factors contributing to violations, and approaches to improve scientific conduct. METHODS: Focus groups were conducted with National Science Foundation investigators and with IRs. Themes were extracted from observation, notes, and transcripts. Consensus and contrasts within and between groups were described. RESULTS: Scientists described a rich set of norms including honesty, integrity, service, sharing, openness, mentoring, and meticulous work habits. Institutional representatives focused on good citizenship and abiding by administrative rules. Both groups listed similar ethical violations, though scientists felt that severe violations were rare, that science was self-correcting, and that the greatest harm from misconduct disclosure was the loss of public trust and funding. Institutional representatives called for increased and less confidential misconduct investigations. Reporting misconduct was strongly supported by IRs but rejected by scientists. Both scientists and IRs believed that formal research ethics education was needed for trainees. CONCLUSIONS: Scientists in these focus groups upheld a complex set of norms that mirror prior codes of science and exceed national misconduct rules. The sharply contrasting views of scientists and IRs concerning responsibility to report misconduct, the utility of misconduct investigation, and penalties for misconduct highlight areas where open discussion and constructive resolution are needed to formulate a functional mechanism to enhance the ethical conduct of science.

Misclassification bias in estimates of bereavement effects.

Prospective studies that examine marital status differences in health and mortality frequently fail to update information on marital status in statistical models. The authors illustrate how the resulting misclassification of marital status can produce substantial bias in estimates of bereavement effects associated with widowhood. They use as their main source of data the Longitudinal Study of Aging (LSOA), 1984-1990, a national survey of persons aged 70 years and older. The estimates are based primarily on 3,192 respondents who were married and cohabiting with their spouses at the time of the baseline survey and who could be matched to their spouses' records. Comparisons of widowhood status derived from matched spouse records with reported marital status recorded in LSOA interviews demonstrate that reliance on interview information leads to substantial misclassification of marital status. Results from survival models indicate that estimates of marital status effects are sensitive to whether and how marital status is updated after baseline interviews. For example, updating marital status in hazard models from interview information alone indicates a protective effect of widowhood, whereas classifying widowhood on the basis of spouses' death records reveals a significant bereavement effect (relative mortality risks between 1.3 and 1.4).