Pregnancy in the sixth decade of life: obstetric outcomes in women of advanced reproductive age

Abstract:
CONTEXT: As a result of oocyte donation, women in their sixth decade of life are now able to conceive and carry pregnancies to term. However, little is known about pregnancy outcomes in this population.

OBJECTIVE: To describe pregnancy outcomes in women aged 50 years or older who conceived after in vitro fertilization with donor oocytes.

DESIGN AND SETTING: Retrospective analysis of cycles conducted at a US university assisted reproduction program during calendar years 1991-2001.

PATIENTS: Seventy-seven postmenopausal women with no chronic medical conditions (mean [SD] age, 52.8 [2.9] years; range, 50-63 years) who underwent 121 embryo transfer procedures (89 fresh and 32 frozen). Pregnancy outcomes were ascertained by chart review and telephone follow-up.

MAIN OUTCOME MEASURES: Maternal and neonatal outcomes.

RESULTS: There were 55 clinical pregnancies for a total pregnancy rate of 45.5%. The live birth rate was 37.2%. Of the 45 live births, 31 were singletons, 12 were twins, and 2 were triplets, for which the mean (SD) gestational ages at delivery were 38.4 (2.1) weeks, 35.8 (2.8) weeks, and 32.2 weeks, respectively. Mean (SD) birth weights were 3039 g (703 g), 2254 g (581 g), and 1913 g, respectively. Apgar scores at 1 and 5 minutes were 8.2 (0.9) and 9.1 (0.5), respectively. Of singletons, 68% were delivered by cesarean, and all multiples were delivered by cesarean. Mild preeclampsia was noted in 25% of patients and severe preeclampsia in 10%. Gestational diabetes required diet modification in 17.5%, and 2.5% required insulin.

CONCLUSIONS: Appropriately screened women aged 50 years or older can successfully conceive via oocyte donation and experience similar pregnancy rates, multiple gestation rates, and spontaneous abortion rates as younger recipients. During pregnancy, they appear at increased risk of preeclampsia and gestational diabetes. A majority can expect to deliver via cesarean. However, there does not appear to be any definitive medical reason for excluding these women from attempting pregnancy on the basis of age alone.


2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada

Jacques Brown

Department of MedicineLaval UniversityQuebec CityQCCanada

RG Josse and The Scientific Advisory Council of the Osteoporosis Society of Canada

Abstract:
Objective: To revise and expand the 1996 Osteoporosis Society of Canada clinical practice guidelines for the management of osteoporosis, incorporating recent advances in diagnosis, prevention and management of osteoporosis, and to identify and assess the evidence supporting the recommendations. Options: All aspects of osteoporosis care and its fracture complications - including classification, diagnosis, management and methods for screening, as well as prevention and reducing fracture risk - were reviewed, revised as required and expressed as a set of recommendations.

Outcomes: Strategies for identifying and evaluating those at high risk; the use of bone mineral density and biochemical markers in diagnosis and assessing response to management; recommendations regarding nutrition and physical activity; and the selection of pharmacologic therapy for the prevention and management of osteoporosis in men and women and for osteoporosis resulting from glucocorticoid treatment. Evidence: All recommendations were developed using a justifiable and reproducible process involving an explicit method for the evaluation and citation of supporting evidence. Values: All recommendations were reviewed by members of the Scientific Advisory Council of the Osteoporosis Society of Canada, an expert steering committee and others, including family physicians, dietitians, therapists and representatives of various medical specialties involved in osteoporosis care (geriatric medicine, rheumatology, endocrinology, obstetrics and gynecology, nephrology, radiology) as well as methodologists from across Canada. BENEFITS, Harm and Costs: Earlier diagnosis and prevention of fractures should decrease the medical, social and economic burdens of this disease. Recommendations: This document outlines detailed recommendations pertaining to all aspects of osteoporosis. Strategies for identifying those at increased risk (i.e., those with at least one major or 2 minor risk factors) and screening with central dual-energy x-ray absorptiometry at age 65 years are recommended. Bisphosphonates and raloxifene are first-line therapies in the prevention and treatment of postmenopausal osteoporosis. Estrogen and progestin/progesterone is a first-line therapy in the prevention and a second-line therapy in the treatment of postmenopausal osteoporosis. Nasal calcitonin is a second-line therapy in the treatment of postmenopausal osteoporosis. Although not yet approved for use in Canada, hPTH(1-34) is expected to be a first-line treatment for postmenopausal women with severe osteoporosis. Ipriflavone, vitamin K and fluoride are not recommended. Bisphosphonates are the first-line therapy for the prevention and treatment of osteoporosis in patients requiring prolonged glucocorticoid therapy and for men with osteoporosis. Nasal or parenteral calcitonin is a first-line treatment for pain associated with acute vertebral fractures. Impact-type exercise and age-appropriate calcium and vitamin D intake are recommended for the prevention of osteoporosis. Validation: All recommendations were graded according to the strength of the evidence; where the evidence was insufficient and recommendations were based on consensus opinion alone, this is indicated. These guidelines are viewed as a work in progress and will be updated periodically in response to advances in this field.


Accuracy of the peak day of cervical mucus as a biological marker of fertility

Abstract: The (PD) peak day of cervical mucus is an important biologic marker for the self-determination of the optimal time of fertility in a woman's menstrual cycle. The purpose of this article is to provide evidence (literature and empiric) for the accuracy of the PD of cervical mucus as a biologic marker of peak fertility and the estimated day of ovulation. An analysis of data from four published studies that compared the self-determination of the PD of cervical mucus with the urinary luteinizing hormone (LH) surge was conducted. The four studies yielded 108 menstrual cycle charts from 53 women participants. The 108 cycles ranged in length from 22 to 75 days (mean 29.4 SD 6.0). Ninety-three of the 108 cycles had both an identified PD and LH surge. Data charts showed that 97.8% of the PD fell within +/-4 days of the estimated day of ovulation. Use of a standardized mucus cycle scoring system indicated that the peak in cervical mucus ratings was highest on the day of the LH surge. Self-determination of the PD of cervical mucus is a very accurate means of determining peak fertility and a fairly accurate means of determining the day of ovulation and the beginning of the end of the fertile time.


Community-based exercise program reduces risk factors for falls in 65- to 75-year-old women with osteoporosis: randomized controlled trial

H A McKay

Departments of Human Kinetics, Medicine, Division of Endocrinology and Metabolism, and Human Nutrition, University of British Columbia, Vancouver, British Columbia, Canada.

M A Petit

Vancouver Hospital and Health Sciences Centre

Abstract:
Background: Exercise programs improve balance, strength and agility in elderly people and thus may prevent falls. However, specific exercise programs that might be widely used in the community and that might be "prescribed" by physicians, especially for patients with osteoporosis, have not been evaluated. We conducted a randomized controlled trial of such a program designed specifically for women with osteoporosis.

Methods: We identified women 65 to 75 years of age in whom osteoporosis had been diagnosed by dual-energy X-ray absorptiometry in our hospital between 1996 and 2000 and who were not engaged in regular weekly programs of moderate or hard exercise. Women who agreed to participate were randomly assigned to participate in a twice-weekly exercise class or to not participate in the class. We measured baseline data and, 20 weeks later, changes in static balance (by dynamic posturography), dynamic balance (by a timed figure-eight run) and knee extension strength (by dynamometry).

Results: Of 93 women who began the trial, 80 completed it. Before adjustment for covariates, the intervention group tended to have greater, although nonsignificant, improvements in static balance (mean difference 4.8%, 95% confidence interval [CI] -1.3% to 11.0%), dynamic balance (mean difference 3.3%, 95% CI -1.7% to 8.4%) and knee extension strength (mean difference 7.8%, 95% CI -5.4% to 21.0%). Mean crude changes in the static balance score were -0.85 (95% CI -2.91 to 1.21) for the control group and 1.40 (95% CI -0.66 to 3.46) for the intervention group. Mean crude changes in figure-eight velocity (dynamic balance) were 0.08 (95% CI 0.02 to 0.14) m/s for the control group and 0.14 (95% CI 0.08 to 0.20) m/s for the intervention group. For knee extension strength, mean changes were -0.58 (95% CI -3.02 to 1.81) kg/m for the control group and 1.03 (95% CI -1.31 to 3.34) kg/m for the intervention group. After adjustment for age, physical activity and years of estrogen use, the improvement in dynamic balance was 4.9% greater for the intervention group than for the control group (p = 0.044). After adjustment for physical activity, cognitive status and number of fractures ever, the improvement in knee extension strength was 12.8% greater for the intervention group than for the control group (p = 0.047). The intervention group also had a 6.3% greater improvement in static balance after adjustment for rheumatoid arthritis and osteoarthritis, but this difference was not significant (p = 0.06).

Interpretation: Relative to controls, participants in the exercise program experienced improvements in dynamic balance and strength, both important determinants of risk for falls, particularly in older women with osteoporosis.


C-reactive protein: history and revival

C-reactive protein: history and revival

Abstract: C-reactive protein (CRP) is the prototype acute-phase protein, which can increase up to 1000-fold after the onset of a stimulus. Aside from its disputed role as a marker of infection and/or inflammation in daily clinical practice, the protein has a wide variety of biological properties and functions. Due to its opsonizing abilities and its capability to activate human complement, CRP plays an important role in the innate host defense against different microorganisms, such as bacteria and fungi. The same opsonophagocyting properties can lead to clearance of host cell material, including nuclear constituents. Inflammation is one of the cornerstones in the etiology and pathogenesis of atherosclerosis, which led to worldwide attention being focused on CRP and its role in the process of atherosclerosis. This role may have a dual character. First, CRP levels reflect the 'burden' of inflammation within atherosclerotic lesions, thus reflecting the grade of vulnerability and instability of the plaques. For this reason, an increased level of the protein may be a prelude to rupture of the plaque and, thus, to occlusive arterial disease. Secondly, CRP may play an active role in the atherosclerotic process. CRP plays a role in the expression of different adhesion molecules on endothelial cells and the protein is able to activate human complement within the plaque. Furthermore, the recent discovery of local production of CRP and complement proteins within the plaque suggests an active role for the protein in the inflammatory cascade. Whatever the role for CRP in the atherosclerotic process, it has been proven that an elevated CRP level, with a cut-off point of approximately 3 mg/l, is associated with an increased risk of occlusive arterial disease, especially acute coronary syndromes.


Massive and acute hemoperitoneum due to rupture of the uterine artery by erosion from an endometriotic lesion

Abstract:
OBJECTIVE: To report a case of acute hemoperitoneum due to erosion of the uterine artery by an endometriotic lesion of the left ovary.

DESIGN: Case report and review of literature.

SETTING: University medical center.

PATIENT(S): A 39-year-old nulliparous woman with stage 3 endometriosis.

INTERVENTION(S): Operative laparoscopy followed by laparotomy, oophorectomy, and ligation of the bleeding uterine artery.

RESULT(S): Patient is fully recovered and is attempting to conceive.

CONCLUSION(S): An endometriotic lesion eroded the wall of the uterine artery, causing massive, acute hemoperitoneum. Such an event may be overlooked during laparotomy and attributed to the trauma of surgery.


Peritoneal defects and the development of endometriosis in relation to the timing of endoscopic surgery during the menstrual cycle

Abstract:
OBJECTIVE: In vitro studies demonstrated that implantation on membranes (peritoneum, amniotic membranes) can take place if there are defects on the surface of the membranes. If these mechanisms play a role for the development of endometriosis in vivo, then patients with surgical treatment of peritoneal endometriosis in the luteal phase must have a high recurrence rate.

DESIGN: Retrospective analysis of operation charts and follow-up data.

SETTING: Department of gynecology, in a hospital-based endometriosis treatment center.

PATIENT(S): Two hundred twenty premenopausal women.

INTERVENTION(S): Laparoscopic treatment for peritoneal endometriosis, stage I and II by revised American Society for Reproductive Medicine guidelines.

MAIN OUTCOME MEASURE(S): During the follow-up period of 2 years, symptoms and gynecological and sonographic findings were documented. In case of suspected recurrence a repeat laparoscopy with biopsy was performed to prove the recurrent endometriosis macroscopically and histologically.

RESULT(S): The total recurrence rate after 2 years was 9.6%. The recurrence rate of group III (15%) was twice as high as those of group I (7%) and group II (8%), as indicated by subjective complaints, clinical findings, macroscopy, and histology; no differences were found between groups I and II.

CONCLUSION(S): Endoscopic surgery for the treatment of peritoneal endometriosis should not be performed in the luteal phase.


Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment

Abstract:
OBJECTIVE: To compare the efficacy of low-dose aspirin alone versus low-dose aspirin plus low molecular weight heparin in pregnant women with antiphospholipid syndrome and recurrent miscarriage as prophylaxis against pregnancy loss.

METHODS: From a regional miscarriage clinic, 119 consecutive women with persistently positive tests for lupus anticoagulant and/or anticardiolipin immunoglobulin G and M antibody were invited to participate in a randomized, controlled trial between 1997 and 2000. After ethical approval and adherence to a written protocol, 12 women were unwilling to participate, five failed exclusion/inclusion criteria, and four were nonpregnant. Laboratory analysis was performed by Sheffield University Coagulation Department, electronically generated randomization by Manchester University Centre for Cancer Epidemiology, and data collection and analysis by a research officer at Leeds University. Viability ultrasound every 2 weeks was provided until 12 weeks' gestation before transfer to the pregnancy support antenatal clinic.

RESULTS: Ninety-eight women were randomized before 12 weeks' gestation. Forty-seven received low-dose aspirin 75 mg daily (group A), and 51 received low-dose aspirin plus low molecular weight heparin 5000 U subcutaneously daily (group B) throughout pregnancy. There were 13 pregnancy losses and 34 live births in group A and 11 losses and 40 live births in group B. The live-birth rate was 72% in group A and 78% in group B (odds ratio 1.39, 95% confidence interval 0.55, 3.47). There were no cases of maternal thrombosis in either group.

CONCLUSION: A high success rate is achieved when low-dose aspirin is used for antiphospholipid syndrome in pregnancy. The addition of low molecular weight heparin does not significantly improve pregnancy outcome.


Molecular progress in infertility: polycystic ovary syndrome

Richard S Legro

Penn State Milton S. Hershey Medical Center

Abstract:
OBJECTIVE: To review the evidence that polycystic ovary syndrome is a genetic disease.

DESIGN: Review of published literature.

RESULTS: The existing literature provides a strong basis for arguing that PCOS clusters in families. However, the mode of inheritance of the disorder is still uncertain, although the majority of studies are consistent with an autosomal dominant pattern, modified perhaps by environmental factors. In addition, studies on PCOS cells (theca, muscle, and adipocytes) in culture have documented a persistent biochemical and molecular phenotype that distinguishes them from normal cells. Although several loci have been proposed as PCOS genes including CYP11A, the insulin gene, and a region near the insulin receptor, the evidence supporting linkage is not overwhelming. The strongest case can be made for the region near the insulin receptor gene, as it has been identified in two separate studies. However, the responsible gene at chromosome 19p13.3 remains to be identified. Association studies have provided a number of potential loci with genetic variants that may create or add to a PCOS phenotype, including Calpain 10, IRS-1 and -2, and SHBG.

CONCLUSIONS: Collectively, these findings are consistent with the concept that a gene or several genes are linked to PCOS susceptibility. Because the mutations/genotypes associated with PCOS are rare, and their full impact on the phenotype incompletely understood, routine screening of women with PCOS or stigmata of PCOS for these genetic variants is not indicated at this time. Currently the treatment implications for individually identified genetic variants is uncertain and must be addressed on a case by case basis.


Increased prevalence of insulin resistance in women with a history of recurrent pregnancy loss

LaTasha B Craig

Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Tennessee Health Science Center, Memphis 38163, USA.

William H Kutteh

Abstract:
OBJECTIVE: To determine whether insulin resistance is associated with recurrent pregnancy loss (RPL).

DESIGN: Single center, case-controlled, prospective study.

SETTING: University-associated reproductive endocrinology clinical practice.

PATIENT(S): Seventy-four nonpregnant, nondiabetic women with RPL. Controls were 74 fertile, nonpregnant, nondiabetic women without RPL who had at least one live infant, and were matched by age, race, and body mass index (BMI).

INTERVENTION(S): Both groups consented to obtaining fasting insulin and glucose levels.

MAIN OUTCOME MEASURE(S): Insulin resistance was defined as a fasting insulin level >20 microU/mL or a fasting glucose to insulin ratio of <4.5.

RESULT(S): Among the 74 women with RPL, 20 (27.0%) demonstrated insulin resistance, whereas only 7 of 74 (9.5%) of the matched controls were insulin resistant (odds ratio 3.55; 95% confidence interval 1.40-9.01). The RPL and control groups were similar with respect to age, ethnicity, and BMI. The RPL and control groups had similar fasting glucose levels and glucose-to-insulin ratios. However, fasting insulin levels > or =20 microU/mL were statistically different between the two groups (odds ratio 3.92).

CONCLUSION(S): Women with RPL have a significantly increased prevalence of insulin resistance when compared with matched fertile controls.


Daily fecundability: first results from a new data base

Bernardo Colombo

National Institute of Environmental Health Sciences

Abstract: This multicenter study has produced a database of 7017 menstrual cycles contributed by 881 women. It provides improved knowledge on length and location of the "fertile window" (identified as of up to 12 days duration) and the patterns and level of daily conception probability. The day of ovulation was identified in each cycle from records of basal body temperature and mucus symptoms. By referencing days of intercourse to the surrogate ovulation markers, estimates of daily fecundability were computed either directly or by the Scwartz model, both for single and multiple acts of intercourse in the fertile window. The relationship between coital pattern and fecundability has been explored. Univariate analysis underlines the significant link with fecundability only of the woman's reproductive history.


Should patients with polycystic ovarian syndrome be treated with metformin?: an enthusiastic endorsement

John E Nestler

Virginia Commonwealth University Medical Center

Abstract: Insulin resistance is a prominent feature of polycystic ovarian syndrome (PCOS), and women with the disorder are at increased risk for the development of other diseases that have been linked to insulin resistance-namely, type 2 diabetes and cardiovascular disease. This association between insulin resistance and PCOS must guide the chronic management of the disorder, and accumulating evidence suggests that administration of insulin-sensitizing drugs to individuals at high risk for type 2 diabetes decreases the rate of conversion to overt disease. In contrast, limited evidence exists to suggest that oral contraceptive pills-the currently standard therapy for PCOS-may actually decrease insulin sensitivity and induce impaired glucose tolerance in women with PCOS. Hence, PCOS should be regarded as a general health issue and the use of insulin-sensitizing drugs such as metformin should be considered for the prevention of type 2 diabetes.


Intracytoplasmic sperm injection pregnancy after low-dose human chorionic gonadotropin alone to support ovarian folliculogenesis

Abstract:
OBJECTIVE: To prove that several days of low-dose hCG alone can be used to stimulate folliculogenesis, complete FSH-initiated follicle/oocyte maturation, and achieve pregnancy in assisted reproduction technology.

DESIGN: Case report.

SETTING: Reproductive endocrinology center at an academic institution.

PATIENT(S): A 35-year-old female patient and her partner with male-related infertility.

INTERVENTION(S): After an 8-day priming with hMG (225 IU/d), we administered low-dose hCG (200 IU/d) alone for 5 days in one GnRH-agonist suppressed patient until proper follicle development was obtained and intracytoplasmic sperm injection was performed.

MAIN OUTCOME MEASURE(S): Daily serum levels of LH, FSH, hCG, E(2), P, and T; measurements of follicle number and size; oocytes retrieved and fertilized; pregnancy.

RESULT(S): Although FSH levels rapidly declined after hMG discontinuation, E(2) and large follicles increased during hCG-only administration. Several good quality oocytes were retrieved and fertilized by intracytoplasmic sperm injection; three embryos were transferred and a twin pregnancy ensued.

CONCLUSION(S): Replacement of FSH with low-dose hCG for several days in the late ovulation induction stages of assisted reproduction technology resulted in: [1] continued growth of large ovarian follicles and E(2); [2] an optimal preovulatory follicle pattern consisting of many large and few medium and small follicles; and [3] reproductively competent oocytes and pregnancy.


Risk factors associated with systemic lupus erythematosis in a Mexican  population

Abstract:
Objective: To assess risk factors associated with systemic lupus erythematosus (SLE) in the Mexican population.

MATERIAL AND Methods: A case-control study was conducted on June 1996, at the Reumathology Clinic of Hospital de Especialidades del Centro Médico Nacional Siglo XXI (HE CMN), Instituto Mexicano del Seguro Social, in Mexico City. Cases were one hundred thirty subjects with four or more SLE criteria and disease evolution of +/- 5 years. Controls were hospitalized patients with acute diseases but without autoimmune diseases. Cases and controls were matched 1:1 by age and gender; both groups were evaluated by direct interview through a structured questionnaire. The following risk factors were assessed: genetic family history of SLE and connective tissue disease; socioedemographic (ethnicity, geographic distribution, education, monthly income); hormonal (use of oral contraceptives, replacement therapy and gynecoobstetric background); environmental (use of hair products, living with dogs, bacterial/viral infections, and allergies). Statistical analysis consisted of odd ratios (OR) with 95% confidence intervals (CI) and multivariate analysis using logistic regression.

Results: The multivariate model showed association with family history of SLE (OR 4.2, CI 95% 1.17-15.2), family history of connective tissue disorder (OR 2.6, CI 95% 1.15-4.5), use of oral contraceptives for more than one year (OR 2.1, CI 95% 1.13-4.3), repetitive pharyngitis (OR 2.1, CI 95% 1.18-3.6), and use of medications (OR 5.0 IC 95% 1.62-21.6). No association was found with socieconomic status, hair dye products, asthma, or allergies.

Conclusions: Genetic factors, such as family history of SLE and connective tissue disease in first-degree relatives, persist as important factors in the development of SLE. Other factors, such as use of some drugs, oral contraceptives, and repetitive pharyngitis, may also favor the onset of disease in genetically susceptible hosts. The English version of this paper is available at: http://www.insp.mx/salud/index.html.


Hormonal and reproductive risk factors for development of systemic lupus  erythematosus: results of a population-based, case-control study

Mary Anne Dooley

University of North Carolina at Chapel Hill

Abstract:
Objective: Estrogen and prolactin may accelerate the progression of murine systemic lupus erythematosus (SLE). In humans, 85% of lupus patients are women, which also suggests the importance of hormonal factors in disease pathogenesis. The purpose of this study was to examine hormonal and reproductive risk factors for lupus among women.

Methods: This population-based, case-control study included 240 female SLE patients diagnosed between January 1, 1995 and July 31, 1999 who fulfilled the American College of Rheumatology classification criteria. Female controls (n = 321) were identified through driver's license records. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) as measures of association, adjusting for age, state, race, and education. Analyses were limited to exposures before diagnosis.

Results: Breast-feeding was associated with a decreased risk of developing SLE (OR 0.6, 95% CI 0.4-0.9), with a statistically significant trend for number of babies breast-fed and total weeks of breast-feeding. There were no associations with number of pregnancies or live births. Natural menopause occurred earlier in women with subsequent development of SLE compared with controls (P < 0.001). There was little association between SLE and current use or duration of use of hormone replacement therapy or oral contraceptives, and no association with previous use of fertility drugs.

Conclusion: We found little evidence that estrogenor prolactin-related exposures are associated with an increased risk of lupus. The reduced risk observed among women who had breast-fed one or more babies should be examined in other studies. Early natural menopause, rather than decreasing risk of SLE because of reduced estrogen exposure, may be a marker of susceptibility to development of SLE.


Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women's Health Initiative Randomized Controlled Trial

Writing Group for the Women's Health Initiative Investigators

Abstract:
Context: Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain.

Objective: To assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States.

Design: Estrogen plus progestin component of the Women's Health Initiative, a randomized controlled primary prevention trial (planned duration, 8.5 years) in which 16608 postmenopausal women aged 50-79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993-1998.

Interventions: Participants received conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102).Main outcomes measuresThe primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome. A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes.

Results: On May 31, 2002, after a mean of 5.2 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits. This report includes data on the major clinical outcomes through April 30, 2002. Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 1.29 (1.02-1.63) with 286 cases; breast cancer, 1.26 (1.00-1.59) with 290 cases; stroke, 1.41 (1.07-1.85) with 212 cases; PE, 2.13 (1.39-3.25) with 101 cases; colorectal cancer, 0.63 (0.43-0.92) with 112 cases; endometrial cancer, 0.83 (0.47-1.47) with 47 cases; hip fracture, 0.66 (0.45-0.98) with 106 cases; and death due to other causes, 0.92 (0.74-1.14) with 331 cases. Corresponding HRs (nominal 95% CIs) for composite outcomes were 1.22 (1.09-1.36) for total cardiovascular disease (arterial and venous disease), 1.03 (0.90-1.17) for total cancer, 0.76 (0.69-0.85) for combined fractures, 0.98 (0.82-1.18) for total mortality, and 1.15 (1.03-1.28) for the global index. Absolute excess risks per 10 000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10 000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the global index was 19 per 10 000 person-years.

Conclusions: Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women. All-cause mortality was not affected during the trial. The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD.

JAMA: The Journal of the American Medical Association


Self-selected women with polycystic ovary syndrome are reproductively and metabolically abnormal and undertreated

Abstract:
OBJECTIVE: To determine whether self-selected women with polycystic ovary syndrome (PCOS) are abnormal compared with a control population.

DESIGN: Case-control.

SETTING: Support group meeting organized and initiated by patients.

PATIENT(S): Forty-five self-selected women with PCOS and 80 control women.

INTERVENTION(S): Self-selected women with PCOS at a peer support conference completed a questionnaire, had a brief physical, and gave a fasting blood sample.

MAIN OUTCOME MEASURE(S): Historical, biometric, and assay results.

RESULT(S): Sixty percent of the women attending the conference participated in the study. Most had been diagnosed with PCOS on the basis of ovarian morphology (35%). They were more likely to be nulliparous and have a history of oligomenorrhea (96%). They were hyperandrogenemic (significantly elevated testosterone and DHEAS levels) compared with control women. Self-selected women with PCOS displayed multiple metabolic abnormalities compared with control women, including elevations in blood pressure, waist-hip ratio, fasting insulin, fasting total cholesterol, and fasting low-density lipoprotein cholesterol levels, as well as a significant decrease in fasting glucose-insulin ratio and high-density lipoprotein cholesterol levels.

CONCLUSION(S): Self-selected women with PCOS have reproductive and metabolic abnormalities. The majority of these women received inadequate treatment despite having risk factors for endometrial cancer, diabetes, and/or heart disease. Our study also suggests that women attending or participating in a PCOS support group are willing and likely to participate in clinical studies.


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

Abstract:
OBJECTIVE: To report a rare case of a patient with catamenial hemoptysis, secondary infertility, and endometriosis associated with a unicornuate uterus and noncommunicating rudimentary horn.

DESIGN: Case report.

SETTING: 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.


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

Abstract:
OBJECTIVE: 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.

DESIGN: Retrospective analysis of data from couples undergoing IVF.

SETTING: 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.

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

Patricia A Straneva

Department of Psychology, University of North Carolina at Chapel Hill, 27599-7175, USA. susan_girdler@med.unc.edu

Abstract: 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.

Health Psychology : Official Journal of the Division of Health Psychology,  American Psychological Association


Cognitive therapy of depression: pretreatment patient predictors of outcome

Kate E Hamilton

Department of Psychology, University of Calgary, 2500 University Drive NW, Calgary, Alberta, Canada T2N 1N4.

A John Rush

The University of Texas Southwestern Medical Center

Abstract: 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.


A new approach to the development of assessment guidelines for osteoporosis

JA Kanis, D Black, C Cooper, P Dargent, B Dawson-Hughes, C De Laet, P Delmas, J Eisman, O Johnell, B Jonsson, L Melton, A Oden, S Papapoulos, H Pols, R Rizzoli, A Silman, A Tenenhouse and the CaMos Research Group


Effect of endometriosis on in vitro fertilization

Kurt T. Barnhart

University of Pennsylvania Health System

Abstract:
OBJECTIVE: To investigate the IVF outcome for patients with endometriosis.

DESIGN: Meta-analysis.

SETTING: 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.


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

Abstract: 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.


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

Abstract:
OBJECTIVE: To evaluate the effect of N-acetyl-cysteine (NAC) on insulin secretion and peripheral insulin resistance in subjects with polycystic ovary syndrome (PCOS).

DESIGN: Prospective data analysis.

SETTING: 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.


Severity of premenstrual symptoms in a health maintenance organization population

Abstract:
OBJECTIVE: 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.

METHODS: 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.

RESULTS: 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).

CONCLUSION: 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.


What to do about the polycystic ovary 'epidemic'

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

Current opinion in obstetrics & gynecology


Diagnosing postpartum depression: can we do better?

Denise J Jamieson

National Center for Chronic Disease Prevention and Health Promotion

Sarah Smallwood Fergerson

Department of Gynecology and Obstetrics, Division of Maternal Fetal Medicine, Emory University School of Medicine, Atlanta, Ga 30303, USA.

Abstract:
OBJECTIVE: 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.

STUDY DESIGN: 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.

RESULTS: During the 7-week study period, 72 women participated in the study: 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 being at risk for depression: 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).

CONCLUSION: 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.

American Journal of Obstetrics and Gynecology


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

George Creatsas

National and Kapodistrian University of Athens

Abstract:
OBJECTIVE: 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).

DESIGN: Prospective randomized clinical trial.

SETTING: 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.


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

Abstract:
OBJECTIVE: To more precisely understand the changes in triplet births in recent years.

STUDY DESIGN: Analysis of recent government and medical publications pertaining to triplets.

RESULTS: 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).

CONCLUSION: 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.


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

Abstract:
OBJECTIVE: To assess the reliability and factor structure of the Calendar of Premenstrual Experiences (COPE) in premenstrual syndrome (PMS) patients.

STUDY DESIGN: Healthy women diagnosed with PMS (N = 215) completed daily diaries assessing 22 PMS behavioral and physical symptoms over two consecutive months.

RESULTS: 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, were extracted: 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.

CONCLUSION: 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.


The treatment of postpartum depression: minimizing infant exposures

Abstract: 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.


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

WM Hopman, T Towheed, T Anastassiades, A Tenenhouse, S Poliquin, C Berger, L Joseph, J Brown, T Murray, JD Adachi, D Hanley, EA Papadimitropoulos and the CaMos Research Group.

Abstract:
Background: 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.

Methods: 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.

Results: 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.

Interpretation: 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. Contexte: 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.


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

D D Baird

Epidemiology Branch, National Institute of Environmental Health Sciences, PO Box 12233, Research Triangle Park, NC 27709, USA

Abstract: BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.


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

Abstract:
BACKGROUND: 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.

METHODS: 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.

RESULTS: 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%.

CONCLUSION: 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.


Effect of long-term naltrexone treatment on endocrine profile, clinical features, and insulin sensitivity in obese women with polycystic ovary syndrome


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

Abstract:
STUDY OBJECTIVE: To determine whether routine clinical examination is sufficient for the diagnosis and establishing the location of deeply infiltrating endometriosis (DIE).

DESIGN: Retrospective analysis (Canadian Task Force classification II-2).

SETTING: University-affiliated hospital. Patients. One hundred sixty women with histologically proved deeply infiltrating endometriosis.

MEASUREMENTS AND

MAIN RESULTS: 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).

CONCLUSION: 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.

The Journal of the American Association of Gynecologic Laparoscopists


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

Abstract: 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 in a parabolic curve: 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.


Estrogen production and metabolism in endometriosis

Sijun Yang

Eunice Kennedy Shriver National Institute of Child Health and Human Development

Abstract: 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.

Annals of the New York Academy of Sciences


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

Mohamed F Mitwally

Department of Obstetrics and Gynecology, University of Toronto, and The Samuel Lununfeld Research Institute, Mount Sinai Hospital, Toronto, Canada.

Abstract:
OBJECTIVE: To examine the use of the aromatase inhibitor letrozole with FSH for ovarian stimulation in poor responders undergoing ovarian superovulation and IUI.

DESIGN: Observational cohort study as a prospective clinical trial in patients with unexplained infertility and a low response to ovarian stimulation with FSH.

SETTING: 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.


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

Abstract: 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) from the following variables: 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) over time: <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%.


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

Abstract:
BACKGROUND: 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.

AIMS: To test the hypothesis that stabilising thyroid function post-partum by administering daily thyroxine reduces the rate of occurrence and severity of associated depression.

METHOD: 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.

RESULTS: 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.

CONCLUSIONS: The excess of depression in thyroid-antibody-positive women in the post-partum period is not corrected by daily administration of thyroxine.

The British Journal of Psychiatry : the Journal of Mental Science


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

F Xavier Bosch

Institut d'Investigació Biomédica de Bellvitge

Nubia Muñoz

Centre International de Recherche sur le Cancer

International Agency for Research on Cancer. Multicentric Cervical Cancer Study Group

Abstract:
Background: 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.

Methods: 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.

Findings: 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.

Interpretation: 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.


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

Abstract: 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.


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

Michael S Kramer

Department of Pediatrics, McGill University Faculty of Medicine, Montreal, Quebec, Canada.

Abstract:
OBJECTIVE: 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.

STUDY DESIGN: 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.

RESULTS: 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.

CONCLUSION: 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.

American Journal of Obstetrics and Gynecology


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

Karen A Gelmon

From the British Columbia Cancer Agency, Vancouver Cancer Centre, Vancouver Hospital and Health Sciences Centre, and University of British Columbia, Vancouver, British Columbia, Canada.

Jerilynn C Prior

Abstract:
Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Journal of Clinical Oncology : Official Journal of the American Society of  Clinical Oncology


Postfertilization effect of hormonal emergency contraception

Chris Kahlenborn

The Polycarp Research Institute, Enola, PA, USA

Abstract:
OBJECTIVE: 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 SOURCES AND STUDY SELECTION: 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.

DATA SYNTHESIS: 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.

CONCLUSIONS: 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.


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

Abstract: 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 followed by: 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, LH activity administration can: 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.

The Journal of Clinical Endocrinology and Metabolism


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

Sandra Webb

Government of Western Australia Department of Health

Abstract:
BACKGROUND: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSIONS: 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.


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

Laura A Schieve

Centers for Disease Control and Prevention

Susan Meikle

National Center for Chronic Disease Prevention and Health Promotion

Abstract:
BACKGROUND: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSIONS: 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.


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

Abstract:
OBJECTIVE: To assess whether metformin safely reduced development of gestational diabetes in women with the polycystic ovary syndrome (PCOS).

DESIGN: Prospective and retrospective study.

SETTING: 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.


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

Maryse Bonduelle

Centre for Medical Genetics, Dutch-speaking Brussels Free University (VUB), Laarbeeklaan 101, B-1090 Brussels, Belgium. lgenbem@az.vub.ac.be

Abstract:
BACKGROUND: 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.

METHODS: 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.

RESULTS: 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).

CONCLUSIONS: 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.


Puberty and bone development

Puberty and bone development

Abstract: 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.

Best practice & research. Clinical endocrinology & metabolism


Preeclampsia in multiple gestation: the role of assisted reproductive technologies

Abstract:
OBJECTIVE: To estimate the relationship of assisted reproductive technologies and ovulation-inducing drugs with preeclampsia in multiple gestations.

METHODS: 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.

RESULTS: 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.

CONCLUSION: Women who conceive multiple gestations through assisted reproductive technologies have a 2.1-fold higher risk of preeclampsia than those who conceive spontaneously.


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

B Strömberg

Department of Women and Child Health, University Children's Hospital, 751 85, Uppsala, Sweden. bo.stromberg@kbh.uu.se

Abstract:
BACKGROUND: 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.

METHODS: 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.

FINDINGS: 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.

INTERPRETATION: 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.


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

Susanne K Kjaer

Virus, Lifestyle and Genes, Danish Cancer Institute, Copenhagen, Denmark; Department of Gynaecology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. Electronic address: susanne@...

Abstract: 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.


Ovarian functional disorders

Ovarian functional disorders

Abstract: 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 disorder can be observed: 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 be observed during pregnancy: luteoma, luteal cyst and hyperreactio luteinalis. Finally, ovarian insufficiency may occur too early.