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EndometriosisPulmonary EndometriosisUnicornuate UterusGnRH Agonist Therapy

Pulmonary endometriosis in a patient with unicornuate uterus and noncommunicating rudimentary horn

Matalliotakis IM et al., 2002Fertil Steril

To report a rare case of a patient with catamenial hemoptysis, secondary infertility, and endometriosis associated with a unicornuate uterus and noncommunicating rudimentary horn. Case report. University hospital. PATIENT(S): A 29-year-old woman who developed progressive catamenial hemoptysis and secondary infertility was evaluated at the University Hospital of Crete. INTERVENTION(S): The complete history, laboratory data, laparoscopic findings, and chest magnetic resonance image of this patient were analyzed. A GnRH agonist, leuprolide acetate, was successfully administered. MAIN OUTCOME MEASURE(S): Diagnosis and appropriate treatment of pulmonary endometriosis in a patient with rudimentary uterine horn. RESULT(S): Treatment with a GnRH agonist achieved suppression of both menstruation and hemoptysis. After 6 months of normal menstrual activity, the symptoms reappeared. The patient was again treated with leuprolide acetate (3.75 mg/mo IM) for 6 months and remained asymptomatic. In fact, the patient became pregnant after cessation of therapy. Finally, the patient was treated successfully with removal of the rudimentary uterine horn during cesarean section. Three-year follow-up showed disappearance of the chest symptoms. CONCLUSION(S): Pulmonary endometriosis and unicornuate uteri are rare. To our knowledge, this is the first case of catamenial hemoptysis with a congenital müllerian anomaly. We describe successful management using a combination of GnRH agonist and surgical resection of the rudimentary uterine horn.

InfertilityIVF OutcomesPrognostic FactorsCumulative Rates

Factors influencing the cumulative conception rate and discontinuation of in vitro fertilization treatment for infertility

Sharma V et al., 2002Fertil Steril

To examine the cumulative conception rate and live birth rate in women undergoing IVF and to assess the influence of prognostic factors on cumulative conception rate and discontinuation of treatment. Retrospective analysis of data from couples undergoing IVF. Assisted conception unit of a university hospital. PATIENT(S): Two thousand fifty-six patients undergoing 2708 cycles of IVF from April 1992 to March 1999. MAIN OUTCOME MEASURE(S): Cumulative conception rate by age, number of oocytes retrieved, and embryos transferred, and the influence of these factors on dropout rates. RESULT(S): The cumulative conception rate and cumulative live birth rate after four attempts were 75% and 66%, respectively. The cumulative conception rate differed significantly between women 35 years of age or younger and those older than 35 years who had five or more oocytes retrieved (83% vs. 63%). When fewer than five oocytes were retrieved in women 35 years of age or younger, the cumulative conception rate decreased to 33%. Overall, 36% of patients continued treatment after the first attempt; these patients were more likely to have more than five oocytes retrieved and more than two embryos available for transfer. The cumulative conception rate was greater when the female partner was 35 years of age or younger and had more than five oocytes retrieved and more than two embryos were available for transfer. These factors influenced dropout rates.

Menstrual CyclePMDD PathophysiologyEndogenous OpioidsPain Sensitivity

Menstrual cycle, beta-endorphins, and pain sensitivity in premenstrual dysphoric disorder

Straneva PA et al., 2002Health Psychol

This study examined pain sensitivity and pain modularity mechanisms (e.g., beta-endorphin levels, blood pressure) in women with premenstrual dysphoric disorder (PMDD; n = 27) and healthy controls (n = 27) during the follicular and luteal phases of the menstrual cycle. Physiological measures were taken during rest and ischemic pain testing. In both cycle phases, PMDD women (a) displayed lower resting cortisol and beta-endorphin levels and (b) exhibited shorter pain threshold and tolerance times and greater pain unpleasantness ratings during pain. PMDD women also reported greater pain unpleasantness and intensity and had lower beta-endorphin levels in their luteal phase and tended to display higher blood pressure levels at rest and during pain testing. Results suggest that endogenous opioids may be pathophysiologically relevant to PMDD and that the hypothalamic-pituitary-gonadal axis may modulate pain sensitivity in PMDD.

Ethics/PhilosophyDepression TreatmentPredictor Analysis

Cognitive therapy of depression: pretreatment patient predictors of outcome

Beck AT et al., 2002Clin Psychol Rev

This review examines the role of patient predictors of outcome in cognitive therapy of depression. Studies that meet eligibility criteria are reviewed for demonstrated linkage between various predictors (i.e., pretreatment severity, historical features, demographic predictors, dysfunctional attitudes and other cognitive features, and treatment acceptability) and outcome, and several effects are found. Notably, high pretreatment severity scores are associated with poorer response to cognitive therapy, as are high chronicity, younger age at onset, an increased number of previous episodes, and marital status. High pretreatment levels of dysfunctional attitudes and certain beliefs about the nature of depression were also found to predict differential response to cognitive therapy of depression. Limitations of the research and directions for further investigations of patient predictors of outcome in cognitive therapy of depression are provided.

EndometriosisIVF OutcomesEndometriosis and IVFReproductive Outcomes

Effect of endometriosis on in vitro fertilization

Barnhart K et al., 2002Fertil Steril

To investigate the IVF outcome for patients with endometriosis. Meta-analysis. Academic research center. PATIENT(S): A MEDLINE search and review of the literature were performed. Patients were classified by level of endometriosis, and controls were classified according to the indication for IVF. INTERVENTION(S): Bivariate analysis and multivariate logistic regression was used to estimate overall effect and control for confounding. MAIN OUTCOME MEASURE(S): Pregnancy rates, fertilization rate, implantation rates, and numbers of oocytes retrieved. RESULT(S): Twenty-two published studies were included in the overall analysis. The chance of achieving pregnancy was significantly lower for endometriosis patients (odds ratio, 0.56; 95% confidence interval, 0.44-0.70) when compared with tubal factor controls. Multivariate analysis also demonstrated a decrease in fertilization and implantation rates, and a significant decrease in the number of oocytes retrieved for endometriosis patients. Pregnancy rates for women with severe endometriosis were significantly lower than for women with mild disease (odds ratio, 0.60; 95% confidence interval, 0.42-0.87). CONCLUSION(S): Patients with endometriosis-associated infertility undergoing IVF respond with significantly decreased levels of all markers of reproductive process, resulting in a pregnancy rate that is almost one half that of women with other indications for IVF. These data suggest that the effect of endometriosis is not exclusively on the receptivity of the endometrium but also on the development of the oocyte and embryo.

Fertility AwarenessStandard Days MethodProspective TrialsPregnancy Rates

Efficacy of a new method of family planning: the Standard Days Method

Arévalo M et al., 2002Contraception

The Standard Days Method is a fertility awareness-based method of family planning in which users avoid unprotected intercourse during cycle Days 8 through 19. A prospective multi-center efficacy trial was conducted to test, in a heterogeneous population, the contraceptive efficacy of the Standard Days Method. A total of 478 women, age 18-39 years, in Bolivia, Peru, and the Philippines, with self-reported cycles of 26-32 days, desiring to delay pregnancy at least one year were admitted to the study. A single decrement multi-censoring life table analysis of the data indicate a cumulative probability of pregnancy of 4.75% over 13 cycles of correct use of the method, and a 11.96% probability of pregnancy under typical use. This article describes the study and the results. Results suggest that despite its requirement that couples modify their sexual behavior when the woman is fertile, the Standard Days Method provides significant protection from unplanned pregnancy and is acceptable to couples in a wide range of settings.

PCOSInsulin SensitizersInsulin ResistanceNovel Therapies

N-acetyl-cysteine treatment improves insulin sensitivity in women with polycystic ovary syndrome

Fulghesu AM et al., 2002Fertil Steril

To evaluate the effect of N-acetyl-cysteine (NAC) on insulin secretion and peripheral insulin resistance in subjects with polycystic ovary syndrome (PCOS). Prospective data analysis. Volunteer women in an academic research environment. PATIENT(S): Six lean and 31 obese subjects, aged 19-33 years. INTERVENTION(S): Patients were treated for 5-6 weeks with NAC at a dose of 1.8 g/day orally. A dose of 3 g/day was arbitrarily chosen for massively obese subjects. Six of 31 obese patients with PCOS were treated with placebo and served as controls. MAIN OUTCOME MEASURE(S): Before and after the treatment period, the hormonal and lipid blood profile and insulin sensitivity, assessed by an hyperinsulinemic euglycemic clamp, were evaluated and an oral glucose tolerance test (OGTT) was performed. RESULT(S): Fasting glucose, fasting insulin, and glucose area under curve (AUC) were unchanged after treatment. Insulin AUC after OGTT was significantly reduced, and the peripheral insulin sensitivity increased after NAC administration, whereas the hepatic insulin extraction was unaffected. The NAC treatment induced a significant fall in T levels and in free androgen index values (P<.05). In analyzing patients according to their insulinemic response to OGTT, normoinsulinemic subjects and placebo-treated patients did not show any modification of the above parameters, whereas a significant improvement was observed in hyperinsulinemic subjects. CONCLUSION(S): NAC may be a new treatment for the improvement of insulin circulating levels and insulin sensitivity in hyperinsulinemic patients with polycystic ovary syndrome.

Menstrual CycleSymptom SeverityEpidemiologyPopulation-Based Studies

Severity of premenstrual symptoms in a health maintenance organization population

Sternfeld B et al., 2002Obstet Gynecol

To describe severity of emotional and physical symptoms in a large diverse sample; to examine demographic, health status, and behavioral correlates of symptom severity; and to describe use of medications and alternative remedies for premenstrual symptoms. A total of 1194 women, ages 21-45, selected from members of a large northern California health maintenance organization, completed daily ratings of symptom severity for two menstrual cycles. An empirically derived algorithm defined symptom severity groups as minimal (n = 186), moderate (n = 801), severe (n = 151), or premenstrual dysphoric disorder (n = 56). Symptom severity as a continuous variable was defined by the two-cycle mean symptom ratings in the luteal phase. Demographic, health status, and behavioral factors and use of treatments for premenstrual symptoms were assessed by self-report. Luteal phase symptom-specific ratings were generally significantly greater in the premenstrual dysphoric disorder group than in the other groups (P <.001). Symptom severity score increased with each comorbidity and decreased with each year of age. Symptom severity was also inversely associated with oral contraceptive use (emotional symptoms) and better perceived health (physical symptoms). Hispanics reported greater severity of symptoms, and Asians less, relative to whites. Use of herbal and nutritional supplements for premenstrual symptoms steadily increased from 10.8% in the minimal group to 30.4% in the premenstrual dysphoric disorder group (P <.01). The degree of premenstrual symptom severity varies in the population, is relatively constant within each woman over two consecutive cycles, particularly for emotional symptoms, and is influenced by age, race/ethnicity, and health status.

PCOSDiagnostic CriteriaPrevalence Trends

What to do about the polycystic ovary 'epidemic'

Thacher SS, 2002Curr Opin Obstet Gynecol

University department of Obstetrics and Gynaecology, Jessop Wing, Sheffield Correspondence to Professor William Ledger, Head of Reproductive Medicine,

PostpartumPostpartum Depression ScreeningDepression DiagnosisEdinburgh Postnatal Depression Scale

Diagnosing postpartum depression: can we do better?

Fergerson SS et al., 2002Am J Obstet Gynecol

The purpose of this study was to evaluate the efficacy of the Edinburgh Postnatal Depression Scale versus routine clinical evaluation to detect postpartum depression among a low-income inner-city population and to evaluate risk factors associated with a positive score on the Edinburgh Postnatal Depression Scale. On the basis of the day of the month, all English-speaking patients who were seen for their postpartum visit were assigned either to routine clinical evaluation for postpartum depression or routine clinical evaluation plus the use of the 10-question Edinburgh Postnatal Depression Scale. During the 7-week study period, 72 women 35 women in the routine evaluation group and 37 women in the Edinburgh Postnatal Depression Scale group. Women who completed the Edinburgh Postnatal Depression Scale were significantly more likely than those in the routine evaluation group to be identified as 11 of 37 women (30%) versus 0 of 35 women (P <.001). A failed attempt at breast-feeding was associated with an increased risk of a score of > or =10 on the Edinburgh Postnatal Depression Scale (relative risk, 3.78; 95% CI, 1.03-13.89). The Edinburgh Postnatal Depression Scale appears to be a valuable and efficient tool for the identification of patients who are at risk for postpartum depression.

PCOSOral ContraceptivesHormonal TreatmentMetabolic Effects

Androgen and lipid profiles in adolescents with polycystic ovary syndrome who were treated with two forms of combined oral contraceptives

Mastorakos G et al., 2002Fertil Steril

To compare the effects of cyproterone acetate and desogestrel, as part of combined oral contraceptives, on lipid metabolism and hirsutism of adolescents with polycystic ovary syndrome (PCOS). Prospective randomized clinical trial. Outpatient gynecology clinic (referral center) of a university. PATIENT(S): Twenty-eight adolescent girls with clinical and biological hyperandrogenism and six or less menses during the past 12 months. INTERVENTION(S): Group A (n = 14) received 0.15 mg of desogestrel plus 0.030 mg of ethinyl estradiol daily. Group B (n = 14) received 2 mg of cyproterone acetate plus 0.035 mg of ethinyl estradiol daily. Treatment was given for 21 days followed by a 7-day rest for a period of 12 months. MAIN OUTCOME MEASURE(S): Hirsutism and lipid profile were evaluated before initiation and at 3, 6, 9, and 12 months of treatment. Androgen profile was evaluated before and at 12 months of treatment. RESULT(S): A significant decline of the Ferriman-Gallway hirsutism score was observed from the sixth month of therapy in both groups. During therapy, the levels of testosterone, free testosterone, Delta(4)-androstenedione, and 17OH-progesterone decreased significantly, whereas sex hormone-binding globulin (SHBG) increased significantly in both groups. The level of total cholesterol and low density lipoprotein (LDL) cholesterol increased significantly, whereas high density lipoprotein (HDL) cholesterol and apolipoprotein A-I increased significantly from the third month of therapy in both groups. Total cholesterol/HDL cholesterol and LDL cholesterol/HDL cholesterol ratios remained unchanged. The levels of triglycerides increased significantly in the cyproterone acetate-treated group after the third month. CONCLUSION(S): Treatment of adolescent girls with PCOS with the two studied formulations is comparably effective in decreasing hirsutism and androgen levels. Both combined oral contraceptives are associated with an increase of total cholesterol, LDL cholesterol, and HDL cholesterol levels and no change of the total cholesterol/HDL cholesterol and LDL cholesterol/HDL cholesterol ratios. Treatment with the cyproterone acetate combined oral contraceptive is associated with a tendency toward increasing the levels of triglycerides.

PregnancyTriplet PregnanciesPreterm Birth and Infant MortalityMultiple Birth Complications

Triplet births in the United States. An epidemic of high-risk pregnancies

Keith LG et al., 2002J Reprod Med

To more precisely understand the changes in triplet births in recent years. Analysis of recent government and medical publications pertaining to triplets. Triplet births are at much greater risk than singletons of poor birth outcomes. More than 9 of 10 triplet births are born preterm (< 37 completed weeks of gestation) as compared with < 1 of 10 singleton infants. The average weight of a triplet newborn (1,698 g) is one-half that of a singleton newborn (3,358 g). The infant death rate for triplet and other higher-order multiple births is 12 times higher than that for singletons (93.7 as compared with 7.8 infant deaths per 1,000 live births). Based on their frequency of preterm birth, low birth weight and infant death rate, it is appropriate to characterize all triplet pregnancies as high risk.

Menstrual CycleSymptom MeasurementPremenstrual DiariesInstrument Validation

Measurement properties of the calendar of premenstrual experience in patients with premenstrual syndrome

Feuerstein M et al., 2002J Reprod Med

To assess the reliability and factor structure of the Calendar of Premenstrual Experiences (COPE) in premenstrual syndrome (PMS) patients. Healthy women diagnosed with PMS (N = 215) completed daily diaries assessing 22 PMS behavioral and physical symptoms over two consecutive months. Internal consistency (alpha) was high (.93-.94) for the COPE total score and behavioral subscale score and moderately high (.79) for the physical subscale score. Test-retest correlations produced lower estimates of reliability (.55-.59). Four factors, accounting for 64% of the total variance, mood symptoms, somatic/cognitive symptoms, appetitive symptoms and fluid retention symptoms. Symptom reports increased in consecutive luteal phases for three of the four factors; however, the factor structure remained consistent in consecutive months. The COPE diary is a reliable instrument for identifying fluctuations in behavioral and physical symptoms during the luteal phase, and PMS symptoms can be reliably conceptualized within four factors. Symptom expression may increase in response to daily self-monitoring.

PostpartumPostpartum Depression TreatmentPharmacotherapy During Lactation

The treatment of postpartum depression: minimizing infant exposures

Newport DJ et al., 2002J Clin Psychiatry

The first 3 postpartum months represent a high-risk period for psychiatric illnesses. This article reviews the prevalence and diagnostic criteria for postpartum illnesses, including the "maternal blues," postpartum depression, and postpartum psychosis. Pharmacologic treatment of these disorders is often complicated by a patient's desire to breast-feed, yet there are no controlled trials of antidepressant treatment during lactation. Infant exposure and limitations to monitoring infant sera are reviewed. Lastly, a model and guide for reducing fetal and infant exposures is presented.

General OB/GYNResearch Methodology

Is there regional variation in the SF-36 scores of Canadian adults?

WM Hopman et al., 2002Can J Public Health

Canadian normative data for the Medical Outcomes Study 36-item short form (SF-36) have recently been published. However, there is evidence from other countries to suggest that regional variation in health-related quality of life (HRQOL) may exist. We therefore examined the SF-36 data from nine Canadian centres for evidence of systematic differences. Bayesian hierarchical modelling was used to compare the differences in the eight SF-36 domains and the two summary component scores within each of the age and gender strata across the nine sites. Five domains and the two summary component scores showed little clinically important variation. Other than a small number of exceptions, there was little overall evidence of HRQOL differences across most domains and across most sites. Our finding of only a few small differences suggests that there is no need to develop region-specific Canadian normative data for the SF-36 health survey. Les données normatives canadiennes s’appliquant à la version abrégée du questionnaire sur l’évolution médicale comportant 36 questions (SF-36) ont été publiées récemment. Toutefois, les données recueillies dans d’autres pays suggèrent qu’il peut exister des variations régionales au niveau de la qualité de vie reliée à l’état de santé (HRQOL). Nous avons donc étudié les données du SF-36 provenant de neuf centres canadiens pour démontrer les différences systématiques. Méthodes: Un modèle hiérarchique bayésien a été utilisé pour comparer les différences entre les résultats des huit domaines du SF-36 et des deux composantes sommaires pour chaque strate d’âge et de sexe, et ce, pour les neuf centres. Résultats: Les résultats de cinq domaines et des deux composantes sommaires démontraient des différences peu significatives cliniquement. Outre de rares exceptions, il y avait peu d’évidence de variations du HRQOL entre la plupart des domaines et des centres. Interprétation: Les résultats obtenus, ne démontrant que de légères différences, suggèrent qu’il n’est pas nécessaire d’établir des données normatives spécifiques aux régions du Canada pour le questionnaire de santé SF-36.

Research

Changes with age in the level and duration of fertility in the menstrual cycle

Dunson DB et al., 2002Human Reproduction

Most analyses of age-related changes in fertility cannot separate effects due to reduced frequency of sexual intercourse from effects directly related to ageing. Information on intercourse collected daily through each menstrual cycle provides the data for estimating day-specific probabilities of pregnancy for specific days relative to ovulation, and these estimates allow unconfounded analysis of ageing effects. A total of 782 healthy couples using natural family planning methods contributed prospective data on 5860 menstrual cycles. Day of ovulation was based on basal body temperature measurements. Estimates of day-specific probabilities of pregnancy and the length of the fertile window were compared across age groups. Nearly all pregnancies occurred within a 6 day fertile window. There was no evidence for a shorter fertile window in older men or women. On average, the day-specific probabilities of pregnancy declined with age for women from the late 20s onward, with probabilities of pregnancy twice as high for women aged 19-26 years compared with women aged 35-39 years. Controlling for age of the woman, fertility was significantly reduced for men aged >35 years. Women's fertility begins to decline in the late 20s with substantial decreases by the late 30s. Fertility for men is less affected by age, but shows significant decline by the late 30s.

InfertilityThin Endometrium TreatmentOocyte DonationAntifibrotic Therapy

Combined treatment by pentoxifylline and tocopherol for recipient women with a thin endometrium enrolled in an oocyte donation programme

Lédée-Bataille N et al., 2002Hum Reprod

To evaluate the effect of an antifibrotic treatment by a combination of pentoxifylline (PTX) and tocopherol (vitamin E) in patients with a thin endometrium who were enrolled in an oocyte donation programme. Eighteen oocyte recipients who failed to develop a pre-ovulatory endometrial thickness of at least 6 mm after receiving vaginal micronized estradiol were enrolled in the study. The patients received a combination of PTX (800 mg/day) and vitamin E (1000 IU/day) for 6 months. The main outcome measurements were the change in endometrial thickness and the pregnancy and delivery rates after treatment. Endometrial thickness increased significantly (P <0.001), with a mean of (+/-SD) 4.9 +/-0.6 mm before and 6.2 +/- 1.4 mm after treatment, with 72% (13/18) of patients being good responders. Five patients either did not respond to the treatment or responded only slightly. Three patients, of which two had received previous radiotherapy, became spontaneously pregnant, and two became pregnant after embryo transfer. Three patients did not have embryo transfer. A total of four babies were delivered. The pregnancy rate was thus 33% and the delivery rate 27%. Treatment by combination of PTX and vitamin E appears to improve the pregnancy rate in patients with a thin endometrium by increasing the endometrial thickness and improving ovarian function. This was especially noticeable in patients who had previously received total body irradiation.

EndometriosisClinical Examination LimitationsAnatomic ClassificationPelvic Exam Accuracy

Routine clinical examination is not sufficient for diagnosing and locating deeply infiltrating endometriosis

Chapron C et al., 2002J Am Assoc Gynecol Laparosc

To determine whether routine clinical examination is sufficient for the diagnosis and establishing the location of deeply infiltrating endometriosis (DIE). Retrospective analysis (Canadian Task Force classification II-2). University-affiliated hospital. Patients. One hundred sixty women with histologically proved deeply infiltrating endometriosis. MAIN Speculum examination allowed endometriotic lesions to be viewed in only 14.4% (23) of patients, and a classic, painful, spheric nodule was palpated in only 43.1% (69). Results of routine clinical examination varied significantly with location of DIE. Whereas a nodule was found in 80.0% (24) of patients with vaginal endometriosis, this rate dropped to only 35.3% (6) and 33.3% (34) in those with DIE of the digestive tract and uterosacral ligaments, respectively (p <0.0001). High locations of DIE lesions at the level of uterosacral ligaments, bottom of the pouch of Douglas, and upper one-third of the posterior vaginal wall explain why results of routine clinical examination are so poor. The term "deep endometriosis infiltrating the rectovaginal septum" is generally incorrect in the true anatomic sense.

Research

The impact of testosterone imbalance on depression and women's health

Rohr UD, 2002Maturitas

Women suffer more often from depression than males, indicating that hormones might be involved in the etiology of this disease. Low as well as high testosterone (T) levels are related to depression and well-being in women, T plasma levels correlate to depression at about 0.4-0.6 ng/ml plasma free T a minimum of depression is detected. Lower levels are related to depression, osteoporosis, declining libido, dyspareunia and an increase in total body fat mass. Androgen levels in women decrease continuously to about 50% before menopause compared to a 20-year-old women. Androgen levels even decline 70% within 24 h when women undergo surgical removal of the ovaries. Conventional oral contraception or HRT cause a decline in androgens because of higher levels of SHBG. Hyperandrogenic states exist, like hirsutism, acne and polycystic ovary syndrome. Social research suggests high androgen levels cause aggressive behavior in men and women and as a consequence may cause depression. Higher androgen values are more pronounced at young ages and before and after delivery of a baby and might be responsible for the "baby blues". It was found that depression in pubertal girls correlated best with an increase in T levels in contrast to the common belief that "environmental factors" during the time of growing up might be responsible for emotional "up and downs". T replacement therapy might be useful in perimenopausal women suffering from hip obesity, also named gynoid obesity. Abdominal obesity in men and women is linked to type 2 diabetes and coronary heart diseases. Testosterone replacement therapy in hypoandrogenic postmenopausal women might not only protect against obesity but also reduce the risk of developing these diseases. Antiandrogenic progestins might be useful for women suffering from hyperandrogenic state in peri- and postmenopause. Individual dosing schemes balancing side effects and beneficial effects are absolutely necessary. Substantial interindividual variability in T plasma values exists, making it difficult to utilize them for diagnostic purposes. Therefore a "four-level-hormone classification scheme" was developed identifying when estradiol (E) and T levels are out of balance. (1) Low E-low T levels are correlated with osteoporosis, depression, and obesity; (2) high E-low T with obesity, decreased libido; (3) high T-low E levels with aggression, depression, increased libido, and substance abuse; (4) high E-high T with type II diabetes risk, breast cancer and cardiovascular risk. Testosterone delivery systems are needed where beneficial and negative effects can be balanced. Any woman diagnosed for osteoporosis should be questioned for symptoms of depression.

EndometriosisEstrogen Production and MetabolismAromatase ActivityAromatase Inhibitors

Estrogen production and metabolism in endometriosis

Bulun SE et al., 2002Annals of the New York Academy of Sciences

Aromatase activity is absent in normal endometrium. In contrast, aromatase is expressed aberrantly in endometriosis, which gives rise to strikingly high levels of aromatase activity in this tissue. Both aromatase expression and activity are stimulated by PGE2. This results in local production of estrogen, which induces PGE2 formation and establishes a positive feedback cycle. Another abnormality in endometriosis, that is, deficient 17beta-HSD type 2 expression, impairs the inactivation of estradiol to estrone. These molecular aberrations collectively favor accumulation of increasing quantities of estradiol and PGE2 in endometriosis. The clinical relevance of these findings was exemplified by the successful treatment of an unusually aggressive case of postmenopausal endometriosis using an aromatase inhibitor.

InfertilityAromatase InhibitorsAdjunct TherapiesLetrozole

Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders

Mitwally MF et al., 2002Fertil Steril

To examine the use of the aromatase inhibitor letrozole with FSH for ovarian stimulation in poor responders undergoing ovarian superovulation and IUI. Observational cohort study as a prospective clinical trial in patients with unexplained infertility and a low response to ovarian stimulation with FSH. Two tertiary referral infertility clinics associated with the Reproductive Sciences Division, University of Toronto. PATIENT(S): Twelve patients with unexplained infertility undergoing IUI who received FSH alone in 25 prior cycles with poor response (less than three dominant follicles). INTERVENTION(S): Patients were offered letrozole, 2.5 mg/day from day 3-7 of the menstrual cycle with FSH (50-225 IU/day) starting on day 5-7. hCG (10,000 IU) was given when two leading follicles were >/=2 cm followed by IUI. MAIN OUTCOME MEASURE(S): Number of mature follicles (>1.8 cm), FSH dose, endometrial thickness, and pregnancy rate. RESULT(S): Improved response to FSH stimulation with letrozole co-treatment was evidenced by the significantly lower FSH dose associated with significantly higher number of mature follicles. During letrozole plus FSH stimulation cycles, clinical pregnancy was achieved in three cycles (21%). CONCLUSION(S): In this preliminary report, we demonstrate a potential benefit of aromatase inhibition for improving ovarian response to FSH in poor responders.

Contraception/ComparisonVenous ThromboembolismProgestin Generation ComparisonCase-Control Study

Oral contraceptives and venous thromboembolism: a five-year national case-control study

Lidegaard Ø et al., 2002Contraception

The objective of this study was to assess the influence of oral contraceptives (OCs) on the risk of venous thromboembolism (VTE) in young women. A 5-year case-control study including all Danish hospitals was conducted. All women 15-44 years old, suffering a first ever deep venous thrombosis or a first pulmonary embolism (PE) during the period January 1, 1994, to December 30, 1998, were included. Controls were selected annually, 600 per year in 1994-1995 and 1200 per year 1996-1998. Response rates for cases and controls were 87.2% and 89.7%, respectively. After exclusion of nonvalid diagnoses, pregnant women, and women with previous thrombotic disease, 987 cases and 4054 controls were available for analysis. A multivariate, matched analysis was performed. Controls were matched to cases within 1-year age bands. Adjustment was made for confounding influence (if any) age, year, body mass index, length of OC use, family history of VTE, cerebral thrombosis or myocardial infarction, coagulopathies, diabetes, years of schooling, and previous birth. The risk of VTE among current users of OCs was primarily influenced by duration of use, with significantly decreasing odds ratios (OR) <1 year, 7.0 (5.1-9.6); 1-5 years, 3.6 (2.7-4.8); and >5 years, 3.1 (2.5-3.8), all compared with nonusers of OCs. After adjustment for confounders, current use of OCs with second- (levonorgestrel or norgestimate) and third- (desogestrel or gestodene) generation progestins when compared with nonuse resulted in ORs for VTE of 2.9 (2.2-3.8) and 4.0 (3.2-4.9), respectively. After adjusting for progestin types and length of use, the risk decreased significantly with decreasing estrogen dose. With 30-40 microg as reference, 20 and 50 microg products implied ORs of 0.6 (0.4-0.9) and 1.6 (0.9-2.8), respectively (p(trend) = 0.02). After correction for duration of use and differences in estrogen dose, the third/second-generation risk ratio was 1.3 (1.0-1.8; p <0.05). In conclusion, use of OCs was associated significantly to the risk of VTE. The risk among current users was reduced by more than 50% during the first years of use. The risk increased more than 100% with increasing estrogen dose, and the difference in risk between users of thirdand second-generation OCs, after correction for length of use and estrogen dose, was 33%.

PostpartumPostpartum DepressionThyroid Antibody PositivityRandomized Controlled Trial

Randomised trial of thyroxine to prevent postnatal depression in thyroid-antibody-positive women

Harris B et al., 2002Br J Psychiatry

Women who are positive for thyroid antibodies in early gestation are prone to post-partum depression, apparently independent of thyroid dysfunction, as measured by serum levels of free thyroxine, free triodothyroxine and thyroid-stimulating hormone. This finding may be due to infrequent monitoring of thyroid function, because hyperthyroidism, hypothyroidism and combinations of both may occur post-partum. To test the hypothesis that stabilising thyroid function post-partum by administering daily thyroxine reduces the rate of occurrence and severity of associated depression. In a randomised double-blind placebo-controlled trial, 100 microg of thyroxine or placebo was given daily to 446 thyroid-antibody-positive women (342 of whom were compliant) from 6 weeks to 6 months post-partum, assessing their psychiatric and thyroid status at 4-weekly intervals. There was no evidence that thyroxine had any effect on the occurrence of depression. The 6-month period prevalence of depression was similar to that reported previously. The excess of depression in thyroid-antibody-positive women in the post-partum period is not corrected by daily administration of thyroxine.

Contraception/ComparisonCervical Cancer RiskHPV and Cervical CancerCase-Control Study

Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: the IARC multicentric case-control study

Moreno V et al., 2002Lancet

Use of oral contraceptives could increase risk of cervical cancer; however the effect of human papillomavirus (HPV), the main cause of cervical cancer, is not usually taken into account. We aimed to assess how use of oral contraceptives affected risk of cervical cancer in women who tested positive for HPV DNA. We pooled data from eight case-control studies of patients with histologically confirmed invasive cervical carcinoma (ICC) and from two studies of patients with carcinoma in situ (ISC). Information about use of oral contraceptives was obtained from personal interviews. Effects were estimated as odds ratios, with logistic-regression models adjusted for possible confounders. 1465 of 1561 (94%) patients with ICC, 211 of 292 (72%) with ISC, and 255 of 1916 (13%) controls were positive for HPV DNA. Compared with never-users, patients who had used oral contraceptives for fewer than 5 years did not have increased risk of cervical cancer (odds ratio 0.73; 95% CI 0.52-1.03). The odds ratio for use of oral contraceptives was 2.82 (95% CI 1.46-5.42) for 5-9 years, and 4.03 (2.09-8.02) for use for 10 years or longer, and these risks did not vary by time since first or last use. Long-term use of oral contraceptives could be a cofactor that increases risk of cervical carcinoma by up to four-fold in women who are positive for cervical HPV DNA. In the absence of worldwide information about HPV status, extra effort should be made to include long-term users of oral contraceptives in cervical screening programmes.

Fertility AwarenessHormone MonitoringUser Experience and ComplianceLongitudinal Survey

Acceptability of personal hormone monitoring for contraception: longitudinal and contextual variables

Severy LJ et al., 2002J Soc Psychol

A new contraceptive technology may advance the science of family planning but may do little to affect health if potential users do not deem it an acceptable method. The authors conducted an acceptability study of a newly developed contraceptive method--personal hormone monitoring. A sample of 480 English volunteers present at the 6th month of a 13-month longitudinal study completed surveys regarding their attitudes toward a personal hormone monitor for the purpose of contraception. The authors used the participants' responses to determine (a) the extent to which the participants accepted the monitor, (b) how their ratings of acceptability changed over time, (c) the extent to which contextual variables predicted changes in acceptability over time, and (d) whether those contextual variables predicted final acceptability of the monitor. Results suggested that no single method of family planning is best for everyone and specified the people for whom personal hormone monitoring may be most suitable.

PregnancyUltrasound vs LMP DatingClassification and PrevalenceVariability in Ovulation Timing

How does early ultrasound scan estimation of gestational age lead to higher rates of preterm birth?

Yang H et al., 2002Am J Obstet Gynecol

Early ultrasound scanning estimation of gestational age is known to increase the reported preterm delivery rate (<37 completed weeks) compared with estimation by date of the last normal menstrual period, but it is unclear how this systematic difference arises. This study was a hospital-based study of 44,623 women who delivered a live-born or stillborn infant between January 1, 1978, and March 31, 1996, and who had both last normal menstrual period-based and early (usually at 16-18 weeks) ultrasound scan-based gestational age estimates. Cross-classification of the 2 estimates by completed weeks was used to examine the direction and magnitude of the differences between them and to compare the resulting classifications of preterm birth. The early ultrasound scan-based gestational age distribution was shifted uniformly to the left (ie, lower gestational age) relative to the last normal menstrual period gestational age distribution; the early ultrasound scan-based preterm delivery rate was 9.1%, which was 19.5% (n = 659 births) higher than the 7.6% rate by last normal menstrual period (P <.0001). The last normal menstrual period estimate exceeded the early ultrasound scan estimate far more often than the reverse, up to and including early ultrasound scan estimates of 40 weeks. No concentration of 4-week discrepancies was observed in either direction, as would be expected with random or systematic errors in recall of the last normal menstrual period. The absolute number of births at 37 to 39 weeks of gestation (by last normal menstrual period) that were reclassified as preterm (n = 1206 births) was much higher than the number of preterm births at 34 to 36 weeks of gestation that were reclassified as term (n = 581 births). The net increase of 625 preterm births (from 581 to 1206 births) that resulted from reclassification of births at 37 to 39 last normal menstrual period weeks accounted for 95% of the total 659-birth increase in early ultrasound scan-based preterm births at all last normal menstrual period gestational ages. Early ultrasound scanning reduces the gestational age estimate across the entire gestational age range; early ultrasound scan-based reclassification of gestational age results in a substantial increase in the prevalence of preterm births. Small downward reclassifications exceed upward reclassifications of similar magnitude, which is consistent with previous reports that delayed (>14 days) ovulation is more frequent than early (<14 days) ovulation.

Perimenopause/MenopauseNon-Hormonal TreatmentsPhytoestrogen TherapyRandomized Controlled Trial

Effect of soy phytoestrogens on hot flashes in postmenopausal women with breast cancer: a randomized, controlled clinical trial

Van Patten CL et al., 2002J Clin Oncol

Vasomotor symptoms, such as hot flashes and night sweats, in breast cancer survivors are often worsened by chemotherapy and tamoxifen, and/or the discontinuation of hormone replacement therapy at diagnosis. This study evaluated the acceptability and effectiveness of a soy beverage containing phytoestrogens as a treatment for hot flashes in postmenopausal women with breast cancer. A randomized, placebo-controlled, double-blind clinical trial was conducted in postmenopausal women with moderate hot flashes who were previously treated for early-stage breast cancer. Women were stratified for tamoxifen use and randomized to a soy beverage (n = 59) containing 90 mg of isoflavones or to a placebo rice beverage (n = 64). Women recorded the number and severity of hot flashes daily with a daily menopause diary for 4 weeks at baseline and for 12 weeks while consuming 500 mL of a soy or placebo beverage. There were no significant differences between the soy and placebo groups in the number of hot flashes or hot flash scores. However, presumably because of a strong placebo effect, both groups had significant reductions in hot flashes. Mild gastrointestinal side effects were experienced by both groups but occurred with greater frequency and severity with soy. The mean serum genistein concentration at 6 weeks was significantly higher in women who consumed soy (0.61 +/- 0.43 micromol/L) compared with placebo (0.43 +/- 0.37 micromol/L) (P =.02). Overall acceptability and compliance were high and similar in both groups. The soy beverage did not alleviate hot flashes in women with breast cancer any more than did a placebo. Future research into other compounds is recommended to identify safe and effective therapies for hot flashes in breast cancer survivors.

Contraception/ComparisonMechanism of ActionEmergency ContraceptionPostfertilization Effects

Postfertilization effect of hormonal emergency contraception

Kahlenborn C et al., 2002Ann Pharmacother

To assess the possibility of a postfertilization effect in regard to the most common types of hormonal emergency contraception (EC) used in the US and to explore the ethical impact of this possibility. DATA A MEDLINE search (1966-November 2001) was done to identify all pertinent English-language journal articles. A review of reference sections of the major review articles was performed to identify additional articles. Search terms included emergency contraception, postcoital contraception, postfertilization effect, Yuzpe regimen, levonorgestrel, mechanism of action, Plan B. The 2 most common types of hormonal EC used in the US are the Yuzpe regimen (high-dose ethinyl estradiol with high-dose levonorgestrel) and Plan B (high-dose levonorgestrel alone). Although both methods sometimes stop ovulation, they may also act by reducing the probability of implantation, due to their adverse effect on the endometrium (a postfertilization effect). The available evidence for a postfertilization effect is moderately strong, whether hormonal EC is used in the preovulatory, ovulatory, or postovulatory phase of the menstrual cycle. Based on the present theoretical and empirical evidence, both the Yuzpe regimen and Plan B likely act at times by causing a postfertilization effect, regardless of when in the menstrual cycle they are used. These findings have potential implications in such areas as informed consent, emergency department protocols, and conscience clauses.

InfertilityLH Activity ProtocolsFSH and LH InteractionsOvarian Stimulation Safety

Stimulation and growth of antral ovarian follicles by selective LH activity administration in women

Filicori M et al., 2002J Clin Endocrinol Metab

Intensive FSH stimulation is a key tool of assisted reproduction technology but can cause severe complications through the development of an excessive number of small ovarian follicles. We tested the hypothesis that, in the late stages of ovulation induction, LH activity in the form of low-dose human CG (hCG) can stimulate and selectively modulate ovarian follicle function and growth, independently of FSH administration. Four groups of GnRH agonist-suppressed normoovulatory women (10 each group) received recombinant human FSH (r-hFSH) (150 IU/d) for 7 d group A, r-hFSH 150 IU/d alone; group B, r-hFSH 50 IU/d and hCG 50 IU/d; group C, r-hFSH 25 IU/d and hCG 100 IU/d; group D, hCG 200 IU/d alone. Despite several days of lowered or absent r-hFSH administration, 70% of hCG-treated patients successfully completed treatment. In these subjects, preovulatory E2 levels and large (>14 mm diameter) ovarian follicle development were not reduced; conversely, the number of small (<10 mm diameter) ovarian follicles was significantly decreased in groups B-D vs. group A. Low-dose hCG administration did not cause follicle luteinization. We conclude that, following FSH priming, 1) stimulate folliculogenesis for several days, in spite of rapidly declining FSH levels; and 2) hasten small follicle demise. Therefore, LH activity administration could be used to design radically novel ovulation induction regimens that, by partly or completely replacing mid-/late follicular phase FSH administration, may reduce costs and improve safety of assisted reproduction technology.

InfertilityBirth Defect RiskCongenital MalformationsSafety Concerns

The risk of major birth defects after intracytoplasmic sperm injection and in vitro fertilization

Hansen M et al., 2002N Engl J Med

It is not known whether infants conceived with use of intracytoplasmic sperm injection or in vitro fertilization have a higher risk of birth defects than infants conceived naturally. We obtained data from three registries in Western Australia on births, births after assisted conception, and major birth defects in infants born between 1993 and 1997. We assessed the prevalence of major birth defects diagnosed by one year of age in infants conceived naturally or with use of intracytoplasmic sperm injection or in vitro fertilization. Twenty-six of the 301 infants conceived with intracytoplasmic sperm injection (8.6 percent) and 75 of the 837 infants conceived with in vitro fertilization (9.0 percent) had a major birth defect diagnosed by one year of age, as compared with 168 of the 4000 naturally conceived infants (4.2 percent; P<0.001 for the comparison between either type of technology and natural conception). As compared with natural conception, the odds ratio for a major birth defect by one year of age, after adjustment for maternal age and parity, the sex of the infant, and correlation between siblings, was 2.0 (95 percent confidence interval, 1.3 to 3.2) with intracytoplasmic sperm injection, and 2.0 (95 percent confidence interval, 1.5 to 2.9) with in vitro fertilization. Infants conceived with use of assisted reproductive technology were more likely than naturally conceived infants to have multiple major defects and to have chromosomal and musculoskeletal defects. Infants conceived with use of intracytoplasmic sperm injection or in vitro fertilization have twice as high a risk of a major birth defect as naturally conceived infants.

Contraception/ComparisonLow Birth WeightBirth WeightSingleton Outcomes

Low and very low birth weight in infants conceived with use of assisted reproductive technology

Schieve LA et al., 2002N Engl J Med

The increased risk of low birth weight associated with the use of assisted reproductive technology has been attributed largely to the higher rate of multiple gestations associated with such technology. It is uncertain, however, whether singleton infants conceived with the use of assisted reproductive technology may also have a higher risk of low birth weight than those who are conceived spontaneously. We used population-based data to compare the rates of low birth weight (less-than-or-equal 2500 g) and very low birth weight (<1500 g) among infants conceived with assisted reproductive technology with the rates in the general population. We studied 42,463 infants who were born in 1996 and 1997 and conceived with assisted reproductive technology and used as a comparison group 3,389,098 infants born in the United States in 1997. Among singleton infants born at 37 weeks of gestation or later, those conceived with assisted reproductive technology had a risk of low birth weight that was 2.6 times that in the general population (95 percent confidence interval, 2.4 to 2.7). The use of assisted reproductive technology was associated with an increased rate of multiple gestations; however, its use was not associated with a further increase in the risk of low birth weight in multiple births. Among twins, the ratio of the rate of low birth weight after the use of assisted reproductive technology to the rate in the general population was 1.0 (95 percent confidence interval, 1.0 to 1.1). Infants conceived with assisted reproductive technology accounted for 0.6 percent of all infants born to mothers who were 20 years of age or older in 1997, but for 3.5 percent of low-birth-weight and 4.3 percent of very-low-birth-weight infants. The use of assisted reproductive technology accounts for a disproportionate number of low-birth-weight and very-low-birth-weight infants in the United States, in part because of absolute increases in multiple gestations and in part because of higher rates of low birth weight among singleton infants conceived with this technology.

PCOSMetformin in PregnancyGestational Diabetes PreventionPCOS Management

Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome

Glueck CJ et al., 2002Fertil Steril

To assess whether metformin safely reduced development of gestational diabetes in women with the polycystic ovary syndrome (PCOS). Prospective and retrospective study. Outpatient clinical research center. PATIENT(S): The prospective study included 33 nondiabetic women with PCOS who conceived while taking metformin and had live births; of these, 28 were taking metformin through delivery. The retrospective study included 39 nondiabetic women with PCOS who had live birth pregnancies without metformin therapy. INTERVENTION(S): Metformin, 2.55 g/d, throughout pregnancy in women with PCOS. MAIN OUTCOME MEASURE(S): Development of gestational diabetes in women with PCOS. RESULT(S): Before metformin therapy, after covariance adjustment for age, the two cohorts did not differ in height, weight, basal metabolic index, insulin, insulin resistance, or insulin secretion. Both cohorts had high fasting insulin, were insulin resistant, and had high insulin secretion. Among the 33 women who received metformin, gestational diabetes developed in 1 of 33 (3%) pregnancies versus 8 of 12 (67%) of their previous pregnancies without metformin. Among the 39 women who did not take metformin, gestational diabetes developed in 14 of 60 (23%) pregnancies. When all live births were combined, gestational diabetes occurred in 22 of 72 pregnancies (31%) in women who did not take metformin versus 1 of 33 pregnancies (3%) in those who took metformin. With gestational diabetes as the response variable and age at delivery and treatment group (metformin or no metformin) as explanatory variables, the odds ratio for gestational diabetes in women with metformin versus without metformin was 0.093 (95% CI: 0.011 to 0.795). With gestational diabetes in 93 pregnancies as the response variable and age at delivery and treatment group (metformin no metformin) as explanatory variables, the odds ratio of gestational diabetes in pregnancies in women taking metformin versus without metformin was 0.115 (95% CI: 0.014 to 0.938). CONCLUSION(S): In PCOS, use of metformin is associated with a 10-fold reduction in gestational diabetes (31% to 3%). It also reduces insulin resistance and insulin secretion, thus decreasing the secretory demands imposed on pancreatic beta-cells by insulin resistance and pregnancy.

PregnancyICSI vs IVF ComparisonICSI SafetyCongenital Malformations

Neonatal data on a cohort of 2889 infants born after ICSI (1991-1999) and of 2995 infants born after IVF (1983-1999)

Bonduelle M et al., 2002Hum Reprod

To evaluate the safety of ICSI, this study compared data of IVF and ICSI children by collecting data on neonatal outcome and congenital malformations during pregnancy and at birth. The follow-up study included agreement to genetic counselling and eventual prenatal diagnosis, followed by a physical examination of the children after 2 months, after 1 year and after 2 years. 2840 ICSI children (1991-1999) and 2955 IVF children (1983-1999) were liveborn after replacement of fresh embryos. ICSI was carried out using ejaculated, epididymal or testicular sperm. In the two cohorts, similar rates of multiple pregnancies were observed. ICSI and IVF maternal characteristics were comparable for medication taken during pregnancy, pregnancy duration and maternal educational level, whereas maternal age was higher in ICSI and a higher percentage of first pregnancies and first children born was observed in the ICSI mothers. Birthweight, number of neonatal complications, low birthweight, stillbirth rate and perinatal death rate were compared between the ICSI and the IVF groups and were similar for ICSI and IVF. Prematurity was slightly higher in the ICSI children (31.8%) than in the IVF children (29.3%). Very low birthweight was higher in the IVF pregnancies (5.7%) compared with ICSI pregnancies (4.4%). Major malformations (defined as those causing functional impairment or requiring surgical correction), were observed at birth in 3.4% of the ICSI liveborn children and in 3.8% of the IVF children (P = 0.538). Malformation rate in ICSI was not related to sperm origin or sperm quality. The number of stillbirths (born > or =20 weeks of pregnancy) was 1.69% in the ICSI group and 1.31% in the IVF group. Total malformation rate taking into account major malformations in stillborns, in terminations and in liveborns was 4.2% in ICSI and 4.6% in IVF (P = 0.482). The comparison of ICSI and IVF children taking part in an identical follow-up study did not show any increased risk of major malformations and neonatal complications in the ICSI group.

Research

Puberty and bone development

Saggese G et al., 2002Best practice & research. Clinical endocrinology & metabolism

Puberty has a key role for bone development. Skeletal mass approximately doubles at the end of adolescence. The main determinants of pubertal gain of bone mass are the sex steroids, growth hormone and insulin-like growth factors (by their effects on bone and muscle mass), 1,25-dihydroxyvitamin D (by stimulating calcium absorption and retention) and muscle mass (by regulating modelling/remodelling thresholds). Calcium intake is an additional factor influencing bone formation. The interactions among these factors are undefined. The accrual of bone mass during puberty is a major determinant of peak bone mass and, thereby, of the risk of osteoporotic fractures during advanced age.

PregnancyPreeclampsiaMultiple Gestation RisksMaternal Complications

Preeclampsia in multiple gestation: the role of assisted reproductive technologies

Lynch A et al., 2002Obstet Gynecol

To estimate the relationship of assisted reproductive technologies and ovulation-inducing drugs with preeclampsia in multiple gestations. This historical cohort study was conducted on 528 multiple gestations from a Colorado health maintenance organization. Using univariate and logistic regression analysis, we determined if women who conceived a multiple gestation as a result of assisted conception were at a greater risk of preeclampsia than those who conceived spontaneously. Between January 1994 and November 2000, there were 330 unassisted and 198 assisted multiple gestations. Sixty-nine multiple gestations followed assisted reproductive technologies (in vitro fertilization and gamete intrafallopian transfer). Human menopausal gonadotropins and clomiphene citrate were associated with 38 and 91 of the multiple gestations, respectively. Compared with unassisted multiple gestations, the relative risk of mild or severe preeclampsia among mothers who received assisted reproductive technologies was 2.7 (95% confidence interval [CI] 1.7, 4.7) and 4.8 (CI 1.9, 11.6), respectively. Adjusted for maternal age and parity, women who received assisted reproductive technologies were two times more likely to develop preeclampsia (odds ratio 2.1, CI 1.1, 4.1) compared with those who conceived spontaneously. The adjusted odds ratios of nulliparity and maternal age for preeclampsia were 2.1 (CI 1.3, 3.4) and 1.1 (CI 1, 1.1), respectively. Although the incidence of preeclampsia was greater in mothers who received clomiphene citrate and human menopausal gonadotropins, this association did not reach statistical significance at the P <.05 level. Women who conceive multiple gestations through assisted reproductive technologies have a 2.1-fold higher risk of preeclampsia than those who conceive spontaneously.

InfertilityLong-term Child OutcomesNeurological SequelaeChild Development

Neurological sequelae in children born after in-vitro fertilisation: a population-based study

Strömberg B et al., 2002Lancet

There is an absence of population-based long-term studies on the risk of neurological sequelae in children born after in-vitro fertilisation (IVF). Our aim was to compare the frequency of such problems between IVF-born children and controls. We did a population-based retrospective cohort study in which we compared development of neurological problems in 5680 children born after IVF, with 11360 matched controls. For 2060 twins born after IVF, a second set of controls (n=4120), all twins, were selected. We obtained data on neurological problems from the records of the Swedish habilitation centres. Children born after IVF are more likely to need habilitation services than controls (odds ratio 1.7, 95% CI 1.3-2.2). For singletons, the risk was 1.4 (1.0-2.1). The most common neurological diagnosis was cerebral palsy, for which children born after IVF had an increased risk of 3.7(2.0-6.6), and IVF singletons of 2.8 (1.3-5.8). Suspected developmental delay was increased four-fold (1.9-8.3) in children born after IVF. Twins born after IVF did not differ from control twins with respect to risk of neurological sequelae. Low-birthweight and premature infants were more likely to need habilitation than fullterm babies. Maternal age did not affect risk. Our study suggests that children born after IVF have an increased risk of developing neurological problems, especially cerebral palsy. These risks are largely due to the high frequency of twin pregnancies, low birthweight, and prematurity among babies born after IVF. To limit these risks, we recommend that only one embryo should be transferred during IVF.

InfertilityOvarian Cancer RiskOvarian Cancer EpidemiologyLong-term Safety

Infertility, fertility drugs, and ovarian cancer: a pooled analysis of case-control studies

Ness RB et al., 2002Am J Epidemiol

Controversy surrounds the relations among infertility, fertility drug use, and the risk of ovarian cancer. The authors pooled interview data on infertility and fertility drug use from eight case-control studies conducted between 1989 and 1999 in the United States, Denmark, Canada, and Australia. Odds ratios and 95% confidence intervals were calculated, adjusting for age, race, family history of ovarian cancer, duration of oral contraception use, tubal ligation, gravidity, education, and site. Included in the analysis were 5,207 cases and 7,705 controls. Among nulligravid women, attempts for more than 5 years to become pregnant compared with attempts for less than 1 year increased the risk of ovarian cancer 2.67-fold (95% confidence interval (CI): 1.91, 3.74). Among nulliparous, subfertile women, neither any fertility drug use (odds ratio (OR) = 1.60, 95% CI: 0.90, 2.87) nor more than 12 months of use (OR = 1.54, 95% CI: 0.45, 5.27) was associated with ovarian cancer. Fertility drug use in nulligravid women was associated with borderline serous tumors (OR = 2.43, 95% CI: 1.01, 5.88) but not with any invasive histologic subtypes. Endometriosis (OR = 1.73, 95% CI: 1.10, 2.71) and unknown cause of infertility (OR = 1.19, 95% CI: 1.00, 1.40) increased cancer risk. These data suggest a role for specific biologic causes of infertility, but not for fertility drugs in overall risk for ovarian cancer.

PCOSUltrasound CriteriaOvarian Functional DisordersAnovulation Classification

Ovarian functional disorders

Robert Y et al., 2000J Radiol

Ovarian hormonal function is under hypothalamo-hypophysis control during the genital life of women. Local hormonal production induces follicular stimulation and maturation. Two main types of functional unilocular cyst, related to an ovulation mechanism, and polycystic ovaries. The former is a follicular cyst related to the absence of LH stimulation, or a luteal cyst, which may be anechoic or display a heterogeneous content (pseudo-septa, pseudo-solid but avascular mass). The latter includes the polycystic ovarian syndrome, which is characterized by an increased ovarian area ( 6cm(2)), stroma and follicles number, the multifollicular ovaries, which are related to functional hypothalamic anovulation and characterized by a normal ovarian size with increased follicles number, and macropolycystic ovaries which are observed in case of previous pelvic infection disease or surgery. Functional disorders may luteoma, luteal cyst and hyperreactio luteinalis. Finally, ovarian insufficiency may occur too early.

EndometriosisDiaphragmatic ExcisionLaparoscopic VisualizationLong-term Symptom Relief

Diaphragmatic endometriosis: diagnosis, surgical management, and long-term results of treatment

Redwine DB, 2002Fertil Steril

To describe symptoms, surgical diagnosis and treatment, and long-term outcome of patients with symptomatic diaphragmatic endometriosis. Observational follow-up study. American tertiary referral center for the surgical treatment of endometriosis. PATIENT(S): Eight patients with diaphragmatic endometriosis causing severe or disabling symptoms. INTERVENTION(S): Laparoscopic diagnosis of diaphragmatic endometriosis followed by upper abdominal laparotomy for full-thickness resection of the diaphragm. MAIN OUTCOME MEASURE(S): Reduction of several symptoms as measured on a 5-point ranked ordinal scale administered by a phone survey up to 7 years after surgery. RESULT(S): Laparoscopy from an umbilical port may identify small "sentinel lesions" of endometriosis on the anterior or mid diaphragm. Eight symptomatic patients all had significant invasive disease with dimensions up to 5 cm across of the posterior right diaphragm, which could not always be seen from the umbilical port site. All such lesions can be seen by a laparoscope placed beneath the right costal margin. Laparoscopic treatment of symptomatic disease is not rational given the posterior placement of the disease out of sight behind the liver and the full-thickness nature of the disease in all eight patients. Laparotomy with full thickness resection of the diaphragm resulted in complete eradication of symptoms in seven of eight patients, and good symptomatic reduction in one. CONCLUSION(S): Treatment of diaphragmatic endometriosis by laparotomy results in a high rate of symptom relief. Laparoscopic treatment of diaphragmatic endometriosis will result in a high rate of incomplete diagnosis and incomplete treatment with a high rate of continuing symptoms.

Research

Acute respiratory failure and short-term outcome after premature rupture of the membranes and oligohydramnios before 20 weeks of gestation

Lindner W et al., 2002The Journal of pediatrics

To study the effect of premature rupture of membranes and oligohydramnios before 20 weeks of gestation (PROM20) on acute respiratory morbidity and on short-term outcome in infants with a gestational age >or=24 weeks. A historic cohort study was performed of all infants born after PROM20 with a gestational age greater-than-or-equal24 weeks between 1990 and 1999. Control infants were matched for year of birth, gestational age, and birth weight. PROM20 infants had an increased acute respiratory morbidity (higher ventilator settings and increased incidence of hypoxemia, hypercapnia, and pulmonary hypertension) and a trend to more air leaks. Although not statistically different, PROM20 infants had more complications (neonatal survival, 68% vs 95%; severe intracranial hemorrhage, 31% vs 6%; chronic lung disease in surviving infants, 46% vs 17%). The relative risk for combined morbidity (death, intracranial hemorrhage, chronic lung disease) was increased (3.0, P =.019) when compared with matched control infants. However, 31% of the surviving PROM20 infants were discharged without apparent morbidity. Expectant treatment in women with PROM20 and present neonatal intensive care has improved the survival of PROM20 infants despite severe initial respiratory failure. However, chronic morbidity still occurred.

PostpartumPostpartum Depression Risk FactorsPredictors of Adverse OutcomesCase-Control Studies

Obstetric, somatic, and demographic risk factors for postpartum depressive symptoms

Josefsson A et al., 2002Obstet Gynecol

To identify and test the predictive power of potential independent risk factors of postpartum depressive symptoms during pregnancy and the perinatal period. We conducted a case-control study where 132 women with postpartum depressive symptoms were selected as an index group and 264 women without depressive symptoms as a control group. Data related to sociodemographic status, medical, gynecologic, and obstetric history, pregnancy, and perinatal events were collected from standardized medical records. The strongest risk factors for postpartum depressive symptoms were sick leave during pregnancy and a high number of visits to the antenatal care clinic. Complications during pregnancy, such as hyperemesis, premature contractions, and psychiatric disorder were more common in the postpartum depressed group of women. No association was found between parity, sociodemographic data, or mode of delivery and postpartum depressive symptoms. Women at risk for postpartum depression can be identified during pregnancy. The strongest risk factors, sick leave during pregnancy and many visits to the antenatal care clinic, are not etiologic and might be of either behavioral or biologic origin. The possibilities of genetic vulnerability and hormonal changes warrant further investigation to reach a more thorough understanding.

PregnancyImplantation MechanismsMolecular PathwaysEarly Pregnancy Loss

Implantation and the survival of early pregnancy

Norwitz ER et al., 2002N Engl J Med

The implantation of fertilized ova and the formation of the placenta are crucial steps in reproduction. This review summarizes current information about these steps, including some of the molecular mechanisms that mediate them and how they may go awry, with consequent loss of the pregnancy.

Contraception/ComparisonFactors Influencing ComplianceNatural Family Planning SatisfactionMethod-Specific Concerns

Factors influencing women's satisfaction with birth control methods

den Tonkelaar D et al., 2002Eur J Contracept Reprod Health Care

To study the extent to which variation in satisfaction with a birth control method is explained by variation in perceived physical and psychological effects. A population survey among 1466 German women was carried out. Within the overall sample, 1303 women had ever used oral contraceptives, 996 had relied on condoms, 342 had ever used intrauterine devices (IUD), 428 had used natural family planning and 139 women were sterilized. For each method a woman had ever used, she answered questions about satisfaction with the method, concerns about getting pregnant or suffering health risks during use, ease of use, changes in sexual relationship, relationship with the partner and mood. Past and current users of oral contraceptives and IUDs and sterilized women additionally reported changes in menstrual bleeding. Variation in satisfaction was, for a large part, explained by variation in health concerns among oral contraceptive users, by variation in perceived changes in the quality of the sexual relationship among condom users, by perceived ease of use among IUD users and sterilized women, and by variation in pregnancy concern among natural family planning users. Counselling about these perceived experiences is most likely to result in greater satisfaction and therefore improved compliance.

PregnancyAmniotic Fluid InfectionNeonatal Adverse OutcomesAmniotic Fluid Cytokines

Amniotic fluid infection, cytokines, and adverse outcome among infants at 34 weeks' gestation or less

Hitti J et al., 2002Obstet Gynecol

We examined the hypothesis that amniotic fluid (AF) infection and elevated cytokine concentrations may cause neonatal injury beyond that expected solely from prematurity. The effects of exposure to AF infection and elevated cytokine concentrations were measured in 151 infants born to afebrile women in preterm labor with intact membranes at less than or equal to 34 weeks' gestation. Amniotic fluid was collected by amniocentesis for culture and determination of tumor necrosis factor-alpha and interleukin-6. Cytokine concentrations, stratified by AF infection, were compared for three gestational age groups. We then examined the associations between a positive AF culture or elevated AF tumor necrosis factor-alpha concentration and adverse neonatal outcomes, adjusted for birth weight. Amniotic fluid from 45 (30%) of 151 pregnancies had microorganisms, an elevated tumor necrosis factor-alpha concentration, or both. Amniotic fluid cytokine concentrations were significantly higher among women in preterm labor at less than or equal to 30 weeks, compared with 31-34 weeks. Nine of 11 infants who died at less than or equal to 24 hours of age had AF infection or elevated AF tumor necrosis factor-alpha. For the 140 surviving infants, AF infection and/or an elevated AF tumor necrosis factor-alpha was associated with respiratory distress syndrome (adjusted odds ratio [OR] 1.7), grade 3-4 intraventricular hemorrhage (adjusted OR 2.2), necrotizing enterocolitis (adjusted OR 1.8), and multiple organ dysfunction (adjusted OR 3.0). Among infants born at less than or equal to 34 weeks to women who have intact membranes and are initially afebrile, those exposed to AF bacteria or cytokines have more adverse neonatal outcomes than unexposed infants of similar birth weight.

Perimenopause/MenopauseLuteal Phase DefectsEstradiol and Progesterone in PerimenopauseDisturbances in Perimenopause

The ageing female reproductive axis II: ovulatory changes with perimenopause

Prior JC, 2002Novartis Found Symp

Perimenopause, a complex physiological transition for midlife women, begins with changes in experiences many years before cycles become irregular, oestradiol levels decrease or follicle-stimulating hormone levels increase. Erratic and average higher oestradiol levels as well as shorter luteal phase lengths and lower progesterone levels occur during perimenopause. These ovarian changes may be causally related to lower inhibin production but the dynamic prospective inter-relationships within women are not well documented. This review will first define perimenopause and then explore the limited published data on ovulatory characteristics in perimenopause. In addition, it will report preliminary prospective observational data on menstrual cycles and ovulation in initially ovulatory women followed through the perimenopause. Prospective data suggest that ovulation disturbances begin early in perimenopause and increase with irregular cycles. Combined with higher oestradiol levels they may cause menorrhagia. It is not yet known whether disturbances of ovulation relate to bone loss in perimenopausal, as in premenopausal, women. It is also not known whether progesterone therapy can effectively counteract the end organ (breast, endometrial, brain) effects of higher/erratic oestradiol levels and effectively treat perimenopausal vasomotor and other symptoms.