Endometrial progesterone receptors and markers of uterine receptivity in the window of implantation

M A Fritz

Uniformed Services University of the Health Sciences

Abstract:
OBJECTIVE: To compare the expression of endometrial P receptors (PR) levels with markers of endometrial receptivity during the window of implantation.

DESIGN: Prospective, controlled study to examine endometrial PR and three cycle-specific integrins in endometrial biopsies obtained during the window of implantation.

SETTING: An academic teaching hospital.

PATIENTS: One hundred seventy-five endometrial biopsies from regularly cycling women with luteal phase defect (LPD; group 1; n = 80), medically treated LPD (group 2; n = 16), minimal and mild endometriosis with aberrant alpha v beta 3 expression (group 3; n = 21), fertile controls (group 4; n = 26), and infertile controls (group 5; n = 32).

MAIN OUTCOME MEASURE: Immunohistochemical staining intensity of each antigen using the semi-quantitative grading system (HSCORE), compared using analysis of variance with Scheffe's correction.

RESULTS: Among the five groups studied, nuclear PR expression was significantly elevated in glandular epithelial cells from tissue samples with histologic delay > or = 3 days consistent with luteal phase deficiency (LPD; group 1). Failure of PR down-regulation was associated with aberrant alpha v beta 3 integrin expression. Medical correction of LPD was associated with return of normal endometrial histology, normal integrin expression, and the loss of epithelial PR, similar to controls. The other two cycle-dependent integrin markers, alpha 1 beta 1 and alpha 4 beta 1, were not different between groups. In women with aberrant alpha v beta 3 and "in phase" endometrium, epithelial PR expression was not different from controls.

CONCLUSIONS: The establishment of normal endometrial receptivity appears to be tightly associated with the down-regulation of epithelial PR. Histologic delay, consistent with LPD, is associated with a failure of PR down-regulation and the lack of normal markers of endometrial receptivity. Occult uterine receptivity defects (aberrant beta 3 expression in otherwise normal histology) are regulated differently, suggesting alternate mechanisms also exist which influence endometrial receptivity.


The length of the cervix and the risk of spontaneous premature delivery. National Institute of Child Health and Human Development Maternal Fetal Medicine Unit Network

D McNellis

Eunice Kennedy Shriver National Institute of Child Health and Human Development

Abstract:
BACKGROUND: The role of the cervix in the pathogenesis of premature delivery is controversial. In a prospective, multicenter study of pregnant women, we used vaginal ultrasonography to measure the length of the cervix; we also documented the incidence of spontaneous delivery before 35 weeks' gestation.

METHODS: At 10 university-affiliated prenatal clinics, we performed vaginal ultrasonography at approximately 24 and 28 weeks of gestation in women with singleton pregnancies. We then assessed the relation between the length of the cervix and the risk of spontaneous preterm delivery.

RESULTS: We examined 2915 women at approximately 24 weeks of gestation and 2531 of these women again at approximately 28 weeks. Spontaneous preterm delivery (at less than 35 weeks) occurred in 126 of the women (4.3 percent) examined at 24 weeks. The length of the cervix was normally distributed at 24 and 28 weeks (mean [+/- SD], 35.2 +/- 8.3 mm and 33.7 +/- 8.5 mm, respectively). The relative risk of preterm delivery increased as the length of the cervix decreased. When women with shorter cervixes at 24 weeks were compared with women with values above the 75th percentile, the relative risks of preterm delivery among the women with shorter cervixes were as follows: 1.98 for cervical lengths at or below the 75th percentile (40 mm), 2.35 for lengths at or below the 50th percentile (35 mm), 3.79 for lengths at or below the 25th percentile (30 mm), 6.19 for lengths at or below the 10th percentile (26 mm), 9.49 for lengths at or below the 5th percentile (22 mm), and 13.99 for lengths at or below the 1st percentile (13 mm) (P < 0.001 for values at or below the 50th percentile; P = 0.008 for values at or below the 75th percentile). For the lengths measured at 28 weeks, the corresponding relative risks were 2.80, 3.52, 5.39, 9.57, 13.88, and 24.94 (P < 0.001 for values at or below the 50th percentile; P = 0.003 for values at the 75th percentile).

CONCLUSIONS: The risk of spontaneous preterm delivery is increased in women who are found to have a short cervix by vaginal ultrasonography during pregnancy.


The corpus luteum insufficiency: a multifactorial disease

Abstract: The pulsatile release pattern of LH during the entire menstrual cycle is well defined; however, the response of corpora lutea to these LH pulses in patients suffering from corpus luteum insufficiencies (CLI) is largely unknown. Patients suffering from CLI were selected from infertile patients on the basis of low progesterone (P < 25 nmol/L) in a blood sample withdrawn during a monitoring cycle. During the next cycle, nine blood samples were collected during the follicular and luteal phase and follicular development was assessed by vaginal sonography. Of 109 patients who had a CLI in the monitoring cycle, 55 had a CLI again, and 38 women agreed to undergo assessment of pulsatile hormone secretion. These women again had P < 25 nmol/L at days 6 and 7 of the luteal phase and blood samples were withdrawn through antecubital vein catheters from 0900-1700 h at 10-min intervals on days 7, 8, or 9 following ovulation. From 38 patients with such defined CLI, 16 (42%) had no LH episode and significantly lower basal LH levels in comparison with 14 control subjects. Thirteen (34%) of the patients had normal appearing LH episodes despite too low P and E2 concentrations, but their CL did not react to the LH episodes. The remaining 9 patients (24%) had normal LH episodes; their CL reacted to these episodes, but their basal P levels were too low. In all blood samples LH was not only determined using an immunoassay but also by the mouse Leydig cell testosterone production bioassay. It could be established that no CLI exists, which is due to the release of bioinactive LH. It is anticipated that the differentiation of three different types of CLI, one of hypothalamic and two of ovarian origin, may allow the development of differential diagnostic and therapeutic tools in the future.

The Journal of Clinical Endocrinology and Metabolism


Characterization of idiopathic premature ovarian failure

Abstract:
OBJECTIVE: To characterize women with idiopathic premature ovarian failure (POF) by their ovarian ultrasonographic appearances to establish the prevalence of follicular activity and relationship to autoimmunity, estrogen status, and historical background.

DESIGN: Retrospective analysis of clinical, endocrine, autoimmune, ultrasonographic, and bone densitometry parameters.

SETTING: Reproductive Endrocrinology Clinics of The Middlesex Hospital, London, United Kingdom.

PATIENTS: Data from 135 women with idiopathic POF were analyzed. A reference group of 18 women with normal ovarian function, studied in their follicular phase, was used for comparison of endocrine and ultrasound data. A reference group of 57 women with normal ovarian function was used for comparison of bone densitometry measurements.

MAIN OUTCOME MEASURES: Serum E2 concentrations, autoantibody screen, ultrasonographic measures of ovarian volume, uterine cross-sectional area and endometrial thickness and dual roentgenogram bone mineral densitometry of the lumbar spine.

RESULTS: The detection of ovaries by ultrasound (in 76%) and follicular activity (in 60% of patients) was associated with higher bone mineral density compared with women in whom ovaries could not be identified. Of 13 patients presenting with primary amenorrhea, ultrasonography identified ovaries in 62% and follicles in 38% whereas 38% had positive autoimmunity. Evidence of autoimmunity was found in 31% of patients overall and these were indistinguishable from the nonautoimmune remainder in every respect.

CONCLUSIONS: Ovarian follicular activity, previously considered to be rare, as in the "resistant ovary syndrome," is found in the majority of women with POF using pelvic ultrasonography. Patients presenting with primary amenorrhea have a similar degree of ovarian function, determined by ultrasound, and autoimmunity as those presenting with secondary amenorrhea. The role of autoimmunity in the pathogenesis of POF is not distinguished from nonautoimmune ovarian damage by the measurements made in this study.


Maternal blood C-reactive protein, white blood cell count, and temperature in preterm labor: a comparison with amniotic fluid white blood cell count

Abstract:
OBJECTIVE: To compare the diagnostic and prognostic performance of maternal blood C-reactive protein, white blood cell count (WBC), and temperature with that of amniotic fluid (AF) WBC in preterm labor.

METHODS: One hundred two women with preterm labor and intact membranes were studied. Maternal blood was collected to measure C-reactive protein concentration and WBC, and maternal temperature was also measured. Amniotic fluid obtained by amniocentesis was cultured and WBC determined. Receiver operating characteristic curve, logistic regression, and survival techniques were used for analysis.

RESULTS: Patients with acute histologic chorioamnionitis had significantly higher median C-reactive protein concentration, WBC, temperature, and AF WBC than patients without this lesion (P < .05). Receiver operating characteristic curve and survival analysis demonstrated that an elevated C-reactive protein, WBC, or AF WBC was strongly associated with the likelihood of histologic chorioamnionitis, shorter interval to delivery, clinical chorioamnionitis, and neonatal morbidity (P < .05 for each). Of all the tests, AF WBC was the best independent predictor of a positive AF culture (odds ratio [OR] 16.8), interval to delivery (hazard ratio 5.7), clinical chorioamnionitis (OR 15.2), neonatal sepsis (OR 16.8), and significant neonatal complications (OR 7.4), after other confounding variables were adjusted (P < .05 for each).

CONCLUSION: An elevated C-reactive protein, WBC, or AF WBC identified patients with intrauterine infection and adverse perinatal outcomes. Amniotic fluid WBC was a better independent predictor of these outcomes than C-reactive protein, WBC, or temperature.


Field trial of billings ovulation method of natural family planning

H Bhargava

Division of Reproductive Health and Nutrition, Indian Council of Medical Research (ICMR), Ansari Nagar, New Delhi.

Abstract: There are couples with unmet family planning needs and couples who do not use any modern method, yet they desire to space or avoid pregnancies. Many of them look for safe and effective options like the natural family planning methods. The Billings Ovulation Method based on single index cervical mucus parameter is one such option. The present multicentre trial conducted in India has shown an encouraging use-effectiveness of the method, indicating method failure as low as 1.5 +/- 0.3 and use-failure 15.9 +/- 0.8 per 100 users at 21 months. The method continuation rates have also been as high as 88.3/100 users at 6 months and 52.0/100 users at 21 months.


Follistatins neutralize activin bioactivity by inhibition of activin binding to its type II receptors

C J de Vries

Hubrecht Institute for Developmental Biology and Stem Cell Research

Abstract: Follistatin is an activin-binding protein, which inhibits activin bioactivity in several biological systems. In the present study it is demonstrated that preincubation of iodinated activin A with follistatin, purified from porcine follicular fluid, completely abolished the binding of activin to activin type IIA, IIB2 and IIB4 receptors, and consequently to activin type IB receptor, transiently transfected in COS cells. Binding of activin A to membrane proteins on the activin-responsive P19 embryonal carcinoma cells was also prevented by this follistatin preparation. The same results were obtained with a carboxy-terminally truncated form of follistatin (FS-288), which is only present in minor amounts in the purified follistatin preparation. Since FS-288 has a high affinity for heparan sulfate proteoglycans on the cell surface, we tested whether membrane-bound FS-288 presents activin A to the different activin receptors, thereby facilitating activin binding. FS-288 did bind to the cell surface of transfected COS cells, but inhibited the binding of activin A to its receptors IIA, IIB2 and IIB4. Furthermore, after addition of FS-288 to K562 erythroleukemia cells, the total binding of activin via cell surface-bound FS-288 was increased, whereas the binding of activin A to activin type II and type I receptors present on these cells was inhibited. These findings reveal that different forms of follistatin can neutralize activin bioactivity by interference with binding of activin to all known activin type II receptors, rather than that they inhibit the binding of the type I receptor to the activin/activin type II receptor complex. In addition, our studies indicate that cell surface-associated follistatin cannot present ligand to signalling receptors.


Third generation oral contraceptives and risk of venous thromboembolic disorders:  an international case-control study. Transnational Research Group on Oral  Contraceptives and the Health of Young Women

M Thorogood

London School of Hygiene & Tropical Medicine

Abstract:
Objective: To test whether use of combined oral contraceptives containing third generation progestogens is associated with altered risk of venous thromboembolism.
Design: Matched case-control study.
Setting: 10 centres in Germany and United Kingdom.

Subjects: Cases were 471 women aged 16-44 who had a venous thromboembolism. Controls were 1772 women (at least 3 controls per case) unaffected by venous thromboembolism who were matched with corresponding case for age and for hospital or community setting.

Main Outcome Measures: Odds ratios derived with stratified analyses and unconditional logistic regression to adjust for potential confounding variables.

Results: Odds ratios (95% confidence intervals) for venous thromboembolism were: for any oral contraceptives versus no use, 4.0 (3.1 to 5.3); for second generation products (low dose ethinyl-oestradiol, no gestodene or desogestrel) versus no use, 3.2 (2.3 to 4.3); for third generation products (low dose ethinyloestradiol, gestodene or desogestrel) versus no use, 4.8 (3.4 to 6.7); for third generation products versus second generation products, 1.5 (1.1 to 2.1); for products containing gestodene versus second generation products, 1.5 (1.0 to 2.2); and for products containing desogestrel versus second generation products, 1.5 (1.1 to 2.2). Probability of death due to venous thromboembolism for women using third generation products is about 20 per million users per year, for women using second generation products it is about 14 per million users per year, and for non-users it is five per million per year.

Conclusions: Risk of venous thromboembolism was slightly increased in users of third generation oral contraceptives compared with users of second generation products.


Endometriosis and Spontaneous Abortion in Infertility and Reproductive Medicine Clinics of North America


Infertility in Novak's Gynecology, 12th Edition


Indications for and Technique of Myomectomy in Infertile Reproductive Medicine Clinical North America


Endometriosis: The Immunoendocrine Factor


Polycystic ovary syndrome: pathophysiology and outcome with in vitro fertilization

Abstract:
OBJECTIVE: To assess the efficacy of IVP-ET in infertile women with the polycystic ovary syndrome (PCOS) and to provide a comprehensive review of contemporary therapeutic options and their complications as reflected in the current literature.

DESIGN: Pertinent studies in medical literature identified through computerized bibliographic search and via manual review of relevant scientific publications.

RESULTS: In vitro fertilization and ET is an effective therapy for PCOS patients who are refractory to ovulation induction in vivo or who have coexisting infertility factors. The use of GnRH agonist (GnRH-a) is associated with significant reductions in the incidence of pregnancy loss and may improve fertilization and cleavage rates. In the PCOS patient, the use of purified FSH preparations does not appear to improve pregnancy rates nor other clinical parameters when compared with hMG. Severe ovarian hyperstimulation syndrome (OHSS) is an important consideration when PCOS patients undergo superovulation protocols. Strategies for OHSS prevention include the use of intravenous albumin immediately after oocyte retrieval, triggering of ovulation with a GnRH-a, or withholding menotropin therapy for several days before hCG administration. Cryopreservation of all embryos for future transfer in an artificial cycle has also proven to be an effective alternative in PCOS patients at high risk for severe OHSS.

CONCLUSIONS: Pregnancy rates for PCOS patients undergoing IVF-ET are comparable with those for women with tubal factor infertility. Therefore, IVF-ET should be offered to patients with PCOS who are refractory to conventional infertility modalities.


Correlation between cytokine levels of amniotic fluid and histological chorioamnionitis in preterm delivery

Abstract: The aim of this study was to investigate the correlation between the cytokine levels in the amniotic fluid (AF) and the histological stage of chorioamnionitis (CAM) in premature labor. AF of 6 cases (7 samples of AF were obtained as one was a twin pregnancy) in whom CAM was diagnosed histologically, and 12 cases without CAM were included in this study. Amniotic fluid was obtained within 24 hours prior to delivery. Cytokine levels (IL-2, -4, -6, TNF-alpha, IFN-gamma) in AF were measured by an ELISA method. Levels of IL-2 and -6 in the CAM-positive group (mean +/-S.E., 52.9 +/- 83.9 pg/ml, and 20,537.9 +/- 8853.7 pg/ml, respectively) were higher than those in the CAM-negative group (i.e. undetectable, and 65.6 +/- 27.5, respectively) with a statistical significance of p < 0.05, p < 0.001, respectively. There was a positive linear relationship between IL-6 levels of AF and the placental histological inflammatory stages of Blanc in the CAM-positive group. From these results it would appear that the IL-6 level in AF is the most sensitive test in the detection of extraamniotic infection or intraamniotic infection in preterm labor with intact membranes and also indicates the severity infection.


Low and conventional dose transdermal oestradiol are equally effective at preventing bone loss in spine and femur at all post-menopausal ages

Sharon Evans

Robert Jones and Agnes Hunt Orthopaedic Hospital

Abstract:
OBJECTIVES: We wished to appraise the effectiveness of hormone replacement therapy (HRT) in early (< 67 years) and late (> 67 years) post-menopausal women referred to a metabolic outpatient clinic for assessment of their bone status. Because older women often experience side-effects with conventional HRT, a low dose preparation (Estraderm 25) was also compared with conventional HRT (Estraderm 50).

DESIGN AND SETTING: Since all patients were symptomatic, the investigation was open and not placebo controlled. Patients were offered HRT and told about the two dosages. If they wished to use HRT, allocation of dosage was made randomly unless there were reasons to use a specific dose.

PATIENTS: One hundred and ninety-six women were studied over 1 or 2 years with 80 reaching 3 years of treatment. Patients were divided into those under 67 years and those over 67 years at the start of treatment. Each group was further divided into those taking Estraderm 25 and those taking Estraderm 50 with norethisterone if appropriate.

MEASUREMENTS: Bone mineral density (BMD) was measured (DXA, Hologic) at the lumbar spine and femoral neck at 0 year (196 patients), at 1 year (169 patients), at 2 years (139 patients) and at 3 years (80 patients). Patients losing bone were expressed as those whose 3 year BMD was lower than initial or as those whose BMD at 3 years had fallen by more than twice the coefficient of variation for that site (non-responders).

RESULTS: In lumbar spine, BMD increased maximally in the first year in all groups and the gain was maintained after 3 years. The change was similar whether patients were divided by age or dosage. For those on Estraderm 25, mean change after 3 years was 8.1 +/- 6.8% and on Estraderm 50, 9.0 +/- 8.3% (combined 8.7 +/- 7.8%). Only 3.9% of patients were non-responders at the lumbar spine after 3 years. At femoral neck, changes were significant at 3 years only in the Estraderm 25 > 67 years and Estraderm 50 < 67 years groups and averaged 2.3 +/- 5.4% for all patients. At the femoral neck, 10.4% of patients were non-responders after 3 years. Percentage change of BMD over 3 years at lumbar spine correlated with that at the femoral neck (r = 0.56). Percentage change of BMD at lumbar spine over 3 years correlated with menopausal age (r = 0.295). No relation was found between dosage of Estraderm/kg body weight and response of BMD at either site.

CONCLUSIONS: Transdermal oestrogen is effective at preventing bone loss in the spine at all post-menopausal ages and is capable of doing this in low dosage. Prevention of bone loss at the femoral neck is less certain and the average change in BMD over 3 years was significantly lower (P < 0.001) than in the lumbar spine. Use of Estraderm 50 is not associated with a greater response of bone mass and there was no evidence of an increasing BMD response as oestradiol dosage/kg body weight increased.


DIR Jahrbuch 1995 (Deutsches IVF-Register Annual Report 1995)

Abstract: Annual report (Jahrbuch) of the Deutsches IVF-Register (DIR) for treatment year 1995. DIR is the German national IVF/ICSI registry, founded 1982 — the oldest continuously operating ART registry. Voluntary professional-society database with high de-facto coverage of German fertility centres. Reports cycles, transfers, pregnancies and clinical outcomes by treatment type (IVF, ICSI, frozen embryo transfer, donor). German-language registry document. Used as a Phase B historical-archive source for the ART Registry Comparison study (cross-registry classification by reporting completeness on 7 framework dimensions).


Exercise-associated menstrual disturbances

Jerilynn C Prior

Vancouver Hospital and Health Sciences Centre

Reproductive Endocrinology, Surgery and Technology


Epithelial Ovarian Cancer: Epidemiology, Screening, and Prevention in Menopausal Medicine (1996)


Effect of different progestagens in low oestrogen oral contraceptives on venous  thromboembolic disease. World Health Organization Collaborative Study of  Cardiovascular Disease and Steroid Hormone Contraception

Abstract: A multinational hospital-based case-control study of the risk of venous thromboembolic disease associated with combined oral contraceptives (OCs) done in 1989-93 prompted a separate inquiry comparing the risk of venous thromboembolism (VTE) associated with low oestrogen (< 35 micrograms ethinyloestradiol) OCs containing levonorgestrel with risks in low oestrogen preparations containing the third-generation progestagens desogestrel or gestodene. This analysis of data from 9 countries, involved 769 cases and 1979 age matched hospital controls and, in one centre, 246 community controls matched on age and general practice. 137 cases and 203 controls were current users of levonorgestrel (odds ratio [OR with 95% confidence interval] 3.5 [2.6-4.7]), with non-users as the reference; 35 cases and 28 controls were current users of desogestrel (9.1 [4.9-17.0]), and 36 cases and 28 controls were current users of gestodene (9.1 [4.9-16.7]). The ratios of these risks, compared with levonorgestrel, were 2.6 (1.4-4.8) for both products separately. Risk estimates adjusted for body mass index (BMI) were 3.4, 7.3, and 10.2 for levonorgestrel, desogestrel, and gestodene, respectively, compared with non-users, and 2.2 and 3.0 for desogestrel and gestodene, respectively, compared with levonorgestrel. 48 (68%) cases and 48 (86%) controls exposed to desogestrel or gestodene were from the UK (Oxford region). In this centre risk estimates compared with non-users, adjusted for BMI, were 2.6, 5.3, and 5.7 for levonorgestrel, desogestrel, and gestodene, respectively. Current users of low oestrogen dose combined OCs containing desogestrel or gestodene appear to be at higher risk of VTE than users of combined OCs containing levonorgestrel. The possibility that these unexpected results on a secondary study objective are due to chance, bias, or residual confounding cannot be excluded entirely and the results need to be confirmed by independent studies. They are at variance with the apparently more favourable metabolic effects of the newer progestagens. Whether the new progestagens are associated with lower risk of arterial disease (stroke and myocardial infarction) must be evaluated further.


Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis  associated with oral contraceptives containing a third-generation progestagen

Kitty W M Bloemenkamp

Department of Obstetrics, Gynecology, Thrombosis and Hemostasis Research Centre, University Hospital Leiden, The Netherlands.

Abstract: Recent concern about the safety of combined oral contraceptives (OCs) with third-generation progestagens prompted an examination of data from a population-based case-control study (Leiden Thrombophilia Study). We compared the risk of deep-vein thrombosis (DVT) during use of the newest OCs, containing a third-generation progestagen, with the risk of "older" products. We also investigated the influence of family history of thrombosis, previous pregnancy, age, and the thrombogenic factor V Leiden mutation. We selected 126 women with DVT and 159 controls aged 15-49 (mean age 34.9) and premenopausal and found, as compared with non-users, the highest age-adjusted relative risks to be that for an OC containing desogestrel and 30 micrograms ethinyloestradiol (relative risk [RR] 8.7, 95% CI 3.9-19.3). We found lower relative risks for all other types of OC, ranging from 2.2 to 3.8. In a direct comparison, users of the desogestrel-containing oral contraceptive had a 2.5-fold higher risk (95% CI 1.2-5.2) than users of all other OC types combined. The relative risk for the desogestrel-containing OC was similar among women with and without a family history--ie, preferential prescription because of family history cannot explain our findings. Nor could the excess risk be explained by previous pregnancy, and it was highest in the youngest age categories, where we would expect most new users. The age-adjusted RR for the desogestrel-containing contraceptive was 9.2 (3.9-21.4) among non-carriers of the factor V Leiden mutation and 6.0 (1.9-19.0) among carriers of the mutation. This latter risk is superimposed on the 8-fold increased risk of venous thrombosis for carriers of the factor V Leiden mutation. The risk of carriers using the desogestrel-containing OC as compared with noncarrier non-users will therefore be increased almost 50-fold. Use of low-dose OCs with a third-generation progestagen carries a higher risk of DVT than the previous generation of OCs. The absolute risk of DVT associated with these OCs seems to be especially high among carriers of the factor V Leiden mutation and among women with a family history of thrombosis. However, the higher risk associated with OC with a third-generation progestagen compared with previous generations was also present in women without factor V Leiden and with no family history.


Venous thromboembolic disease and combined oral contraceptives: results of  international multicentre case-control study. World Health Organization  Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception

Abstract: The composition and use of oral contraceptives (OCs) have changed since their cardiovascular side-effects were established 20 years ago. This report describes the risk of idiopathic venous thromboembolic (VTE) events (deep vein thrombosis [DVT] and/or pulmonary embolism [PE]) in association with current use of combined OCs among 1143 cases aged 20-44 and 2998 age-matched controls, as evaluated in a hospital-based, case-control study in 21 centres in Africa, Asia, Europe, and Latin America. OC use was associated with an increased risk of VTE in Europe (odds ratio 4.15 [95% CI 3.09-5.57]) and in non-European ("developing") countries (3.25 [2.59-4.08]). Risk estimates were generally higher for DVT than for PE but no consistent trend by certainty of diagnosis (definite, probable, possible) was found. Increased risk was apparent within 4 months of starting OCs, was unaffected by duration of current episode of OC use, and had disappeared within 3 months of stopping OCs. Relative risk estimates of VTE associated with OC use were unaffected by age of user, by history of hypertension (excluding hypertension in pregnancy), or in any consistent way by smoking. However, in both groups of countries increased body mass index (BMI) was an independent risk factor for VTE, and OC-associated odds ratios were higher among those with a BMI above 25 kg/m2 than among those with smaller BMIs. OC-associated risk estimates were high among women in Europe with a history of hypertension in pregnancy. Odds ratios associated with the use of OCs containing a third-generation progestagen were higher than those observed with progestagens of the first (norethindrone type) and second (norgestrel group) generation. Odds ratios associated with first and second generation progestagens tended to be lower, though not significantly, when used in combination with low (< 50 micrograms oestrogen) rather than higher oestrogen doses. This study confirms an association between OC use and VTE in Europe and the developing countries, although overall risk estimates associated with use were lower than demonstrated in most previous studies of non-fatal idiopathic VTE.


Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in  women using oral contraceptives with differing progestagen components

Hershel Jick

Boston Collaborative Drug Surveillance Program

Abstract: Concern about the risks of cardiovascular illness in women using combined oral contraceptives (OC) containing the progestagens desogestrel and gestodene prompted two studies of data from the UK General Practice Research Database. We compared the risks of certain cardiovascular illnesses in otherwise healthy women exposed to one of three OCs containing < 35 micrograms oestrogen plus levonorgestrel, desogestrel, or gestodene. In the first study, based on some 470 general practices, there were 15 cases of unexpected idiopathic cardiovascular death among 303,470 women who were current users of one of the study OCs. The estimated incidence rates were 8/184,536 (4.3 per 100,000) woman-years at risk for users of combined OCs containing levonorgestrel, 2/135,567 (1.5 per 100,000) for desogestrel users, and 5/105,201 (4.8 per 100,000) for gestodene users. The relative risk (RR) estimates were 0.4 (95% CI 0.1-2.1) and 1.4 (CI 0.5-4.5) for desogestrel and gestodene, respectively, compared with levonorgestrel. In the second study, derived from some 370 general practices, there were 80 cases of nonfatal venous thromboembolism (VTE) in a cohort of 238,130 otherwise healthy women. The incidence rates of VTE per 100,000 woman-years at risk were 16.1 for levonorgestrel users, 29.3 for desogestrel, and 28.1 for gestodene. The adjusted RR estimates from the cohort analysis were 1.9 (1.1-3.2) and 1.8 (1.0-3.2) for desogestrel and gestodene users, respectively, compared with users of levonorgestrel. In a nested case-control analysis the adjusted matched RR estimates were 2.2 (1.1-4.4) and 2.1 (1.0-4.4) for desogestrel and gestodene users, respectively, compared with users of levonorgestrel. The excess risk for nonfatal VTE associated with the new generation of combined OCs containing low-dose oestrogen and the progestagens desogestrel or gestodene compared with levonorgestrel is estimated to be 16 per 100,000 woman-years.


Prophylactic estrogen in recurrent postpartum affective disorder

Abstract: Seven women with histories of puerperal psychosis and four with histories of puerperal major depression were consecutively treated with high-dose oral estrogen immediately following delivery. None of the women had histories of nonpuerperal affective disorder, and all women were affectively well throughout the current pregnancy and at delivery. Despite the high risk for recurrent illness in this population, only one woman developed relapse of postpartum affective disorder. All others remained entirely well and required no treatment with psychotropic medications during the 1 year follow-up period. This low rate of relapse, 9% compared to an expected 35-60% without prophylaxis, suggests that oral estrogen may stem the rapid rate of change in estrogen following delivery, thereby preventing the potential impact on dopaminergic and serotonergic neuroreceptors. It is hypothesized that the rapid rate of change of estrogen after delivery creates an "estrogen withdrawal state." This may be a critical factor in driving acute puerperal affective psychosis and early-onset puerperal major depression.


Timing of sexual intercourse in relation to ovulation. Effects on the probability of conception, survival of the pregnancy, and sex of the baby

A J Wilcox

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

C R Weinberg

Abstract:
BACKGROUND: The timing of sexual intercourse in relation to ovulation strongly influences the chance of conception, although the actual number of fertile days in a woman's menstrual cycle is uncertain. The timing of intercourse may also be associated with the sex of the baby.

METHODS: We recruited 221 healthy women who were planning to become pregnant. At the same time the women stopped using birth-control methods, they began collecting daily urine specimens and keeping daily records of whether they had sexual intercourse. We measured estrogen and progesterone metabolites in urine to estimate the day of ovulation.

RESULTS: In a total of 625 menstrual cycles for which the dates of ovulation could be estimated, 192 pregnancies were initiated, as indicated by increases in the urinary concentration of human chorionic gonadotropin around the expected time of implantation. Two thirds (n = 129) ended in live births. Conception occurred only when intercourse took place during a six-day period that ended on the estimated day of ovulation. The probability of conception ranged from 0.10 when intercourse occurred five days before ovulation to 0.33 when it occurred on the day of ovulation itself. There was no evident relation between the age of sperm and the viability of the conceptus, although only 6 percent of the pregnancies could be firmly attributed to sperm that were three or more days old. Cycles producing male and female babies had similar patterns of intercourse in relation to ovulation.

CONCLUSIONS: Among healthy women trying to conceive, nearly all pregnancies can be attributed to intercourse during a six-day period ending on the day of ovulation. For practical purposes, the timing of sexual intercourse in relation to ovulation has no influence on the sex of the baby.


Preterm labor: emerging role of genital tract infections

Abstract: Preterm birth complicates 8-10% of all pregnancies in the United States and is the leading cause of infant morbidity and mortality. Neonatal morbidity and mortality is concentrated among very low-birthweight and extremely premature infants, particularly those delivered prior to 30 weeks' gestational age. In addition to the contribution of preterm birth to neonatal morbidity and mortality, the economic costs associated with this pregnancy complication are staggering. Efforts to reduce the preterm birth rate have been largely focused on prevention and early intervention with treatment for preterm labor. Mixed results regarding the success of prematurity prevention programs have been reported, and controversy continues to surround the efficacy of tocolytic therapy in the treatment of preterm labor. Although neonatal survival for infants born at early gestational ages has steadily improved in recent years, survival of infants delivered prior to 24 weeks' gestation remains very poor. Additionally, despite this decline in neonatal mortality, the United States still lags behind most industrialized nations in infant mortality, and no change in the rate of low birthweight has occurred in recent decades. Multiple lines of evidence support a role for infection as an etiologic factor in preterm labor. Although this association has been well known for many years, a wealth of new data is emerging, linking subclinical genital tract infection with spontaneous preterm birth, particularly among pregnancies that result in birth prior to 30 weeks' gestational age as a result of spontaneous preterm labor or preterm, premature rupture of membranes. Conversely, preterm birth that occurs closer to term is less likely to be associated with genital tract infection. Improved understanding of the link between genital tract infection and preterm birth now provides an exciting potential for the development of sensitive new markers to identify women at risk and effective interventions to prevent preterm birth. A review and comment on this growing literature is provided.


Evidence of a distinct derangement of opioid tone in hyperinsulinemic patients with polycystic ovarian syndrome: relationship with insulin and luteinizing hormone secretion

Abstract: Recent data indicate that an altered opioid tone could be involved in the LH hypersecretion and metabolic alterations seen in polycystic ovary syndrome (PCOS). The aim of the present study was to investigate the presence of a common mechanism of action of opioids on altered insulin and gonadotropin release in patients suffering from PCOS. Twenty-eight women affected by PCOS and 8 normal ovulatory women were studied; an oral glucose tolerance test (OGTT) and GnRH tests were performed during the follicular phase before and after 6 weeks of naltrexone treatment (50 mg/day, orally). Plasma levels of sex hormone-binding globulin and steroids were assayed in the basal samples, whereas FSH and LH were analyzed during the GnRH stimulus. Insulin and glucose were assayed by the OGTT. Based on the insulinemic response to OGTT, 17 women were classified as hyperinsulinemic and 11 as normoinsulinemic. No difference in glucose and hormone plasma concentrations was observed before and after naltrexone treatment in both groups. Only basal sex hormone-binding globulin values were higher in normoinsulinemic compared to hyperinsulinemic subjects. Administration of the opioid antagonist significantly reduced the insulin response to OGTT only in the hyperinsulinemic group. No difference were found in the LH increment after the GnRH stimulus in both group of patients before treatment; on the contrary, naltrexone administration reduced the LH response to GnRH in hyperinsulinemic women but failed to be effective in normoinsulinemic subjects. Only 5 patients showed no concordance of drug-induced changes in insulin and LH secretion. In control subjects, naltrexone failed to have any effect on insulin or LH secretion. These data support the involvement of endogenous opioids in the regulation of insulin and LH secretion in a specific group of PCOS patients exhibiting an exaggerated insulin response to OGTT.

The Journal of Clinical Endocrinology and Metabolism


Natural family planning. An alternative

Natural family planning. An alternative

Abstract: The scientific foundations and most notable features of modern natural family planning (NFP) methods are described. NFP techniques require observation of the signs and symptoms occurring during the fertile and infertile phases of the menstrual cycle. Abstinence during the fertile period is implied when NFP is used to avoid pregnancy. Modern NFP methods are associated with success rates similar to those of oral contraceptives, the IUD, and condoms. NFP methods are based on such phenomena as the limited survival time of the ovum and sperm, the occurrence of ovulation only once per cycle, the ability to diagnose ovulation using simple means, and the ability of human beings to delay sexual satisfaction. Among the advantages of NFP methods are low cost, brevity of the required training time, increased knowledge of the body and capacity for self control, shared responsibility by both partners, and moral and religious acceptability. The Billings and symptothermal methods have shown average use-effectiveness rates ranging from 71.5 to 89.5% and from 83.4 to 97.8%, respectively. All studies of symptothermal methods conducted since 1985 have shown Pearl indexes under 5. The symptothermal method is based on observation of the duration of previous cycles, cervical mucus, basal body temperature, and optionally on palpation of the cervix and other symptoms such as breast swelling, acne, intermenstrual bleeding, and mood changes. Use of the symptothermal method requires special graph paper for recording the temperature and other symptoms. The beginning of the fertile phase is recognized by subtracting 19 from the shortest cycle in the past year, or by the appearance of cervical changes or changes in the mucus.

Revista De Enfermeria (Barcelona, Spain)


Outcome of pregnancies in women with treated or untreated hyperprolactinemia

Abstract: The outcome of 103 pregnancies in 64 women with constant hyperprolactinemia was evaluated. Seventy-eight pregnancies had been induced with bromocriptine and 25 occurred without any treatment. In all, 66% of the pregnancies ended in delivery, 17% in miscarriage, 10% in tubal pregnancy and 7% in induced abortion. The pregnancy of women with untreated hyperprolactinemia was more frequently ectopic when compared to those in women treated by bromocriptine. Obstetric complications as well as signs of tumoral enlargement during pregnancy were rare in hyperprolactinemic women treated or untreated with bromocriptine. Untreated hyperprolactinemia as a risk factor in tubal pregnancy is proposed.

European Journal of Obstetrics, Gynecology, and Reproductive Biology


Prevention of de-novo adhesion formation after laparoscopic myomectomy: a randomized trial to evaluate the effectiveness of an oxidized regenerated cellulose absorbable barrier

Abstract: To evaluate the effectiveness of the oxidized regenerated cellulose absorbable barrier (Interceed, TC7) in the prevention of de-novo adhesion formation after laparoscopic myomectomy, a prospective and randomized study was performed at the Department of Obstetrics and Gynaecology of the University of Cagliari, Cagliari, Italy. A total of 50 pre-menopausal non-pregnant women, aged 23-42 years, who submitted to laparoscopic myomectomy from January 1993 to June 1994, were randomized to surgery alone (control group, n = 25) or surgery and oxidized regenerated cellulose barrier (Interceed group, n = 25). Neither group received any other treatment for adhesion prevention. A second-look laparoscopy was performed 12-14 weeks after laparoscopic myomectomy. The incidence of adhesion-free patients was assessed at second-look laparoscopy by an investigator not informed of the treatment. The numbers of adhesion-free patients were three out of 25 (12%) in the control group and 15 out of 25 (60%) in the treatment group (P < 0.05). In conclusion, the oxidized regenerated cellulose absorbable barrier significantly reduced de-novo adhesion formation after laparoscopic myomectomy.


Naltrexone treatment restores menstrual cycles in patients with weight  loss-related amenorrhea

Abstract:
Objective: To evaluate whether the efficacy of naltrexone administration in patients with hypothalamic amenorrhea correlates to the response to an acute naloxone test.
Design: Thirty patients with hypothalamic amenorrhea associated with weight loss were studied. After naloxone test (4 mg in bolus IV) patients were divided into two groups: group A, nonresponsive (n = 15) and group B, responsive (n = 15). Group A underwent two cycles of hormonal replacement therapy with E2 patches and medroxyprogesterone acetate. Then all patients were administered naltrexone at the dosage 50 mg/d orally for 6 months. A third group of 10 amenorrheic patients were treated with oral placebo with the same schedule.

Results: Plasma gonadal steroid levels increased in all patients and in 24 of 30 patients the menstrual bleeding occurred within 90 days from the beginning of treatment. After 6 months from naltrexone discontinuation, 18 of 24 patients still showed the occurrence of menstrual cycles. Luteinizing hormone plasma levels and LH pulse amplitude increased after 3 months of treatment and remained unchanged 6 months after naltrexone suspension. Plasma FSH levels did not show any change in any patient. The body mass index increased after 3 months in all patients who menstruated. Patients treated with placebo did not show any significant change in gonadotropins and gonadal steroid plasma levels.

Conclusions: The present study supports the efficacy of naltrexone therapy for patients with hypothalamic amenorrhea either responsive or nonresponsive to naloxone test.


Endometrial biopsy findings in infertility: analysis of 12,949 cases

Abstract:
OBJECTIVE: Endometrial biopsy has been an important way of assessing infertile couples for several years. In this review of a wide-ranging series of endometrial biopsies of infertile couples in the Turkish population it was our aim to find the distribution of results according to the years 1956-1966, 1967-1980, 1981-1992.

SETTING: University hospital.

SUBJECTS: 12,949 endometrial biopsies, referred to our gynecological pathology laboratory for infertility investigation between 1956 and 1992.

METHOD: Patient report files from pathology laboratory data, analyzed retrospectively. The assessment of the biopsies is made by the same pathologist.

RESULTS: 78.8% of cases had primary infertility, 21.2% secondary. Most of them were in the age group 26-35 years (48.8%). 37.58% of cases were found to show normal secretory endometrium, 20.95% proliferative endometrial changes, and 28.22% signs of luteal phase defect (LPD). Other local endometrial factors were also encountered, but in 1.79% the sample was considered insufficient for diagnosis. Moreover, in nine cases, malignancy was diagnosed with the help of endometrial biopsy. During the study period, cases of normal secretory endometrium and tuberculous endometritis were observed to decrease and LPD to increase significantly. It is worthy to note that in only 28 (0.21%) cases had endometrial biopsies been performed during a pregnancy cycle.

CONCLUSION: We conclude that endometrial biopsy not only shows the hormonal response of endometrium but gives additional information about the local factors of endometrium concerning atrophy, specific and non-specific infections, and malignancy.

International Journal of Fertility and Menopausal Studies


Implications of idiopathic preterm delivery for previous and subsequent pregnancies

J Kristensen

Department of Obstetrics and Gynecology, Rigshospitalet, University of Copenhagen, Denmark.

Abstract:
OBJECTIVE: To describe the relationship between pregnancy complications and fetal outcome in first and second pregnancies, focusing on idiopathic and indicated preterm birth of singleton infants in either pregnancy.

METHODS: Included in the study were 13,967 women in Denmark who gave birth to their first singleton infant in 1982 and a second infant in 1982-1987. Information on pregnancy and birth was obtained by linking the National Medical Birth Register and the National Register of Hospital Discharges, based on personal identification numbers.

RESULTS: The risk of a preterm second birth in women with idiopathic and indicated preterm first birth did not differ significantly (15.2 and 12.8%, respectively). However, women with idiopathic preterm birth in the first pregnancy tended to repeat idiopathic preterm birth twice as often as women with indicated preterm birth repeated indicated preterm birth (11.3 versus 6.4%). Adjustment by logistic regression analysis for other risk factors for preterm birth did not influence the relative risk (6.0 before 32 weeks and 4.8 for 32-36 weeks) of a second preterm birth after a first preterm birth. Women with idiopathic preterm delivery in their first and second pregnancies gave birth to infants with lower birth weight than in previous or subsequent pregnancies. Emergency cesarean delivery in a first term pregnancy was a risk factor for subsequent idiopathic preterm birth.

CONCLUSION: Idiopathic preterm birth is associated with emergency cesarean delivery at term in previous pregnancies and infants with lower birth weight in previous and subsequent pregnancies.


Physician and Nurses’ Knowledge and Use of Natural Family Planning

Abstract: Perinatal health professionals are in key positions to either promote or dissuade the use of Natural Family Planning (NFP). The purpose of this article is to describe a survey conducted with perinatal physicians and nurses on their knowledge and professional use of NFP. Four hundred and fifty physicians and nurses (150 MDs and 300 RNs) were sent a questionnaire on the use of and knowledge of NFP. One hundred sixty-six (or 37%) returned the completed questionnaires. Fifty-two percent of the nurses who returned the questionnaires and 48% of the physicians indicated they were taught about NFP in basic (generic) medical or nursing school. The average lecture time spent on the subject in either nursing or medical school was less than one hour. The majority learned about NFP through self-education or on-the-job training. Only four (1 RN and 3 MDs) are certified to teach NFP. Fifty-three percent of the nurses and 44% of physicians would not advise the use of NFP to avoid pregnancy. The most frequent reasons given for not promoting the use of NFP to either avoid or achieve pregnancy were that it is not effective, not natural, too difficult to learn, better methods are available, and it only works for highly motivated educated women.


Correlation between the American Fertility Society classifications of adnexal adhesions and distal tubal occlusion, salpingoscopy, and reproductive outcome in tubal surgery

Abstract:
OBJECTIVE: To compare the prognostic value of salpingoscopy with a current classification system of adnexal adhesions and distal tubal occlusion in patients with tubal infertility undergoing reconstructive tubal surgery.

DESIGN: Prospective clinical study.

SETTING: Department of Obstetrics and Gynecology of the Catholic University, a tertiary care University Center in Rome, Italy.

PATIENTS: Fifty-five infertile patients with either adnexal adhesions (29 patients) or hydrosalpinx (26 patients) undergoing reconstructive tubal surgery.

INTERVENTIONS: Salpingoscopy performed concomitantly to salpingo-ovariolysis or salpingoneostomy at the time of either operative laparoscopy or laparotomy using microsurgical techniques.

MAIN OUTCOME MEASURES: Salpingoscopic findings were compared with a current classification system of adnexal adhesions and distal tubal occlusion. The patients were followed for a mean follow-up of 49 months; the pregnancy rates achieved were correlated with the salpingoscopic findings and the classification system used.

RESULTS: There was a significant correlation between the salpingoscopic grade and the occurrence of a term pregnancy for both the salpingo-ovariolysis and salpingoneostomy groups of patients. There was no significant correlation between the classification system used and the occurrence of a term pregnancy for both groups of patients.

CONCLUSION: Salpingoscopy plays an important role in selecting the patients who may benefit the most from reconstructive tubal surgery.


Meta-analysis of the role of oral contraceptive agents in inflammatory bowel  disease

Abstract: Numerous epidemiological studies have been performed to determine factors that might contribute to the development of inflammatory bowel disease. Although the role of oral contraceptive agents in Crohn's disease (CD) and ulcerative colitis (UC) have been assessed, most studies were of small sample size and characterised by low statistical precision. A meta-analysis was performed to increase the statistical power and to investigate the association between the use of oral contraceptives and the development of CD and UC. The study was based on a search of a Medline database from 1975 to October 1993 and a review of reference lists from published articles, reviews, symposia proceedings, and abstracts from major gastrointestinal meetings. All studies specifically designed to evaluate this association were selected. The combined results of nine studies--two cohort studies (30,379 unexposed and 30,673 exposed patients) and seven case-control studies (482 CD, 237 UC, and 3198 controls)--which satisfied our selection criteria were evaluated. The pooled relative risk (adjusted for smoking) associated with oral contraceptive use was 1.44 (1.12, 1.86) for CD and 1.29 (0.94, 1.77) for UC. These results suggest modest associations between the use of oral contraceptives and the development of CD and UC. As these associations are weak, non-causal explanations for the findings cannot be eliminated.


Natural family planning

Natural family planning

Abstract: A better understanding of reproductive anatomy and physiology has led to newer methods of natural family planning, including the ovulation method and the symptothermal method. Studies have shown that 1 percent of couples who consistently and correctly use either of these methods conceives during one year of use. However, in the absence of standardized interpretation of study results, use-effectiveness data of these methods vary widely. The lactational amenorrhea method may be used in selected patients during the first six months postpartum, and its effectiveness in avoiding pregnancy is reported to be as high as 98 percent. Advocates of natural family planning promote these methods as inexpensive and safe ways to determine periods of peak fertility and point to the potential benefit of increased communication in a relationship.


Breast and ovarian cancer incidence after infertility and in vitro fertilisation

Abstract: Concern has been expressed that exposure to fertility drugs might be associated with a risk of ovarian cancer. We have examined the incidence of breast and ovarian cancer in a cohort of 10,358 women referred for in-vitro fertilisation (IVF) treatment in Victoria, Australia, between 1978 and 1992. The "exposed" group (n = 5564) had had ovarian stimulation to induce multiple folliculogenesis and the "unexposed" group (n = 4794) had been referred for IVF but were untreated or had had "natural cycle" treatment without ovarian stimulation. Duration of follow-up ranged from 1 to 15 years. Cases of cancer were determined by record linkage with data from population-based cancer registries. 34 cases of invasive breast cancer and 6 of invasive ovarian cancer were observed. A comparison with the expected numbers, derived by applying age-standardised general population rates to the cohort gave standardised incidence ratios (SIR) for breast cancer of 0.89 (95% CI 0.55-1.46) in the exposed group and 0.98 (0.62-1.56) in the unexposed group, and for ovarian cancer SIRs were 1.70 (0.55-5.27) and 1.62 (0.52-5.02), respectively. Rates of all cancers were not significantly different from general population rates. The relative risk (RR) of cancer, adjusted for age and infertility type, was, in the treated group compared with the untreated group, 1.11 (95% CI 0.56-2.20) for breast cancer and 1.45 (0.28-7.55) for ovarian cancer. The risk of body of uterus cancer was increased in the exposed and unexposed groups combined (SIR 2.84 [1.18-6.81]). Women with unexplained infertility, independent of IVF exposure, had significantly increased risks of ovarian cancer (RR = 19.19 [2.23-165.0]) and body of uterus cancer (RR = 6.34 [1.06-38.0]) compared with women with known causes of infertility. This relatively short-term follow-up suggests that ovarian stimulation with IVF is not associated with an increased risk of breast cancer. Although there was no significantly increased risk of ovarian cancer after ovarian stimulation with IVF the small number of cases limits the conclusions that can be drawn. Longer-term follow-up of large cohorts of women who have been in IVF programmes will be necessary.


The effectiveness of preterm-birth prevention educational programs for high-risk women: a meta-analysis

Abstract:
OBJECTIVE: To evaluate whether preterm-birth prevention educational programs are effective at reducing neonatal mortality, low birth weight (LBW), and preterm delivery.

DATA SOURCES: A MEDLINE literature search of English-language studies was performed, supplemented by a bibliography search of original research and review articles to locate studies assessing preterm-birth prevention programs.

METHOD OF STUDY SELECTION: We identified 31 studies that reported results from trials evaluating preterm-birth prevention programs. From this group, only the six randomized controlled trials evaluating preterm-birth prevention education programs satisfied criteria of homogeneity to be included in a meta-analysis. One of these six studies was a subset of another study and was excluded except when reporting outcomes that were not included in the larger report.

DATA EXTRACTION AND SYNTHESIS: Two independent reviewers assessed study methodology and identified the following

outcomes: LBW frequency, preterm birth frequency, neonatal survival, birth weight, gestational age at delivery, and preterm labor diagnosis rates. When data were combined using meta-analytic techniques, no significant benefits were found for preterm-birth education programs in preventing neonatal death (cumulative relative risk [RR] 1.00, 95% confidence interval [CI] 0.99-1.01), LBW rates (RR 0.99, 95% CI 0.88-1.11), or preterm delivery rates (RR 1.08, 95% CI 0.92-1.27). The only statistically significant effect of preterm birth education programs appears to be an increase in the frequency at which preterm labor is diagnosed (RR 1.71, 95% CI 1.41-2.08).

CONCLUSION: Preterm-birth prevention educational programs appear to have little benefit in reducing preterm birth and may result in an increased rate of diagnosis of preterm labor.


Pregnancies and births resulting from in vitro fertilization: French national registry, analysis of data 1986 to 1990. FIVNAT (French In Vitro National)

Abstract:
OBJECTIVE: To describe the characteristics of pregnancies and children at birth resulting from IVF-ET and to assess whether they differ from those after natural conception.

DESIGN: Prospective multicenter survey.

SETTING: A national registry, representing 80% of all French IVF-ET activity for the period 1986 to 1990.

PATIENTS: Data on 7,024 pregnancies, 5,371 deliveries, and 6,879 newborn infants.

INTERVENTIONS: A form is completed for every clinical pregnancy.

MAIN OUTCOME MEASURES: Spontaneous abortion, ectopic pregnancy, multiple pregnancy, prematurity, hypotrophy, perinatal and neonatal mortality, and congenital malformations rates.

RESULTS: The spontaneous abortion and ectopic pregnancy rates were, respectively, 17.6% and 5.8%. More than a quarter (26.8%) of the deliveries were multiple births. The preterm birth rate (29.3%), the low birth weight rate (36.2%), and the perinatal and neonatal mortality rates were higher than the national average. The rate of malformations (2.8%) was comparable with the general population (2.1%).

CONCLUSION: Assisted conception frequently results in multiple pregnancy, and this is the main determinant of pregnancy outcome. Nevertheless, it is not the only risk factor for prematurity, which is also more frequent among IVF singleton newborn. The prevalence of congenital malformations is not higher than after natural conception.


Progesterone therapy in women with complex partial and secondary generalized seizures

Abstract: This open trial assessed the effects of adjunctive progesterone therapy on seizure frequency in 25 women with catamenial exacerbation of complex partial (CPS) and secondary generalized motor (SGMS) seizures. Progesterone was well tolerated by 23 of the 25 women and had readily reversible dose-related side effects of asthenia and emotional depression in two. Eighteen women (72%) experienced a decline in seizure frequency during a 3-month treatment period compared with the 3 months prior to therapy (p < 0.01). Average daily CPS frequency declined by 54% (p < 0.01), SGMS by 58% (p < 0.02).


Effect of opioid blockade on insulin metabolism in polycystic ovarian disease

Abstract: A total of 17 women affected by polycystic ovarian disease (PCOD) were studied to evaluate the involvement of endogenous opioids in the pathophysiology of the hyperinsulinism in PCOD by administering naltrexone, an oral opioid antagonist. An oral glucose tolerance test (OGTT) was performed at baseline (on day 5 of the cycle) and repeated after 6 weeks of naltrexone administration. Plasma glucose, insulin and connecting peptide (c-peptide) concentrations were evaluated in all samples. Based on their insulinaemic response to OGTT, patients were classified as hyperinsulinaemic or normoinsulinaemic. Naltrexone treatment significantly (P < 0.007) reduced the insulin response to OGTT in the hyperinsulinaemic group without affecting the c-peptide incremental area; in the normoinsulinaemic group there was a slight, but not significant, increase in both c-peptide and insulin incremental areas. The two groups showed similar c-peptide incremental areas after naltrexone treatment. There was no significant difference in the c-peptide:insulin incremental areas molar ratio between the two groups; after treatment, a significant increase in this ratio was observed in both groups. When we considered the data as an expression of the fractional hepatic extraction of insulin, we found a lower value for hyperinsulinaemic in comparison with normoinsulinaemic patients (not significant), and a significant (P < 0.01) improvement of this parameter in the hyperinsulinaemic group after naltrexone administration. In conclusion, we suggest that the contribution to hyperinsulinaemia in PCOD patients may be at least in part due to both increased pancreatic secretion and reduced hepatic removal of insulin. Chronic pharmacological inhibition of opioid tone could improve the insulin plasma concentration by acting chiefly on the liver metabolism of insulin in hyperinsulinaemic patients.


Color flow pulsed Doppler ultrasound in diagnosing luteal phase defect

Abstract:
OBJECTIVE: To determine whether color flow pulsed Doppler analysis of corpus luteum blood flow in normal cycles differs from cycles with a luteal phase defect.

DESIGN: A prospective study of natural ovarian cycles.

SETTING: The University of Vermont Reproductive Endocrinology and Infertility Service.

PATIENTS: Ten women with regular menstrual cycles and at risk for luteal phase defect (LPD) four with unexplained infertility, two with recurrent abortion, and four with age > 35 years.

INTERVENTIONS: All women were examined by transvaginal color flow pulsed Doppler during the early follicular, late follicular, early luteal, midluteal, and late luteal phase of the menstrual cycle. Venous blood for P concentration was drawn on each day of Doppler exam. Urine testing for LH surge and endometrial biopsy during the late luteal phase were performed on each patient.

MAIN OUTCOME MEASURES: Lowest resistance index associated with the highest amplitude signal from intraovarian vessels of each ovary, dated endometrial biopsies, serum P.

RESULTS: Mean resistance indexes in LPD patients (n = 3) were significantly higher compared with normal women (n = 6) throughout the follicular and luteal phases. One patient remained anovulatory and was excluded from statistical analysis. Although systolic and diastolic velocities generally were observed to be lower in LPD patients compared with normal women, these differences were not statistically significant. High correlations were observed between P and resistance index within each luteal time point, achieving its highest value during the midluteal phase.

CONCLUSIONS: This initial study provides evidence that color flow pulsed Doppler analysis of blood flow impedance to the corpus luteum may aid in assessing luteal phase adequacy.


Tubal cannulation

Tubal cannulation

Abstract: While uterotubal chromopertubations were performed early in the 1970s with the introduction of hysteroscopy, cornual cannulation was extended and adapted to fluoroscopy. The disadvantages of fluoroscopy include the difficulty in ruling out tubal spasm, inability to evaluate distal tubal disease, and other pelvic abnormalities. Tubal cannulation has emerged as an excellent alternative to treat patients with cornual obstruction. Only those patients in whom cannulation fails should be subjected to microsurgical reconstruction. While cannulation with coaxial catheters began under fluoroscopy, the use of the hysteroscope simplifies the technique. With laparoscopy the hysteroscopic approach enables tubal cannulation and evaluation of the entire pelvis. Treatment of additional problems affecting the fallopian tubes, particularly adhesions and endometriosis, is possible. Laparoscopy helps in monitoring the procedure and visual assessment of tubal patency. The ability to observe the uterotubal junctions directly by hysteroscopy provides an excellent approach for tubal cannulation. There are two techniques to cannulate the fallopian tubes, either with coaxial catheters or catheters with distal balloons, but the result obtained with these two techniques is similar. The simplicity of coaxial catheters makes this approach more appealing, and with the hysteroscope one can avoid exposure to radiation. The results obtained with tubal cannulation are encouraging and this procedure should be offered as the initial method to attempt treatment of tubal cornual obstruction. Often it can represent an excellent alternative to microsurgical tubal anastomosis, avoiding a laparotomy and extended disability.

Obstetrics and Gynecology Clinics of North America


The effect of consecutive cycles of clomiphene citrate therapy on endometrial thickness and echo pattern

Abstract:
OBJECTIVE: To determine whether successive cycles of clomiphene citrate affect endometrial thickness.

METHODS: Thirty-four women presenting for treatment of anovulation, oligoovulation, or follicle maturation defects were given the smallest dose of clomiphene citrate necessary to attain a mature follicle. If no pregnancy ensued, the same dose was continued if a follicle 18-24 mm in diameter and a serum estradiol (E2) level greater than 200 pg/mL were achieved. Ethinyl E2 was supplemented for poor cervical mucus only. Endometrial thickness and echo patterns were measured each cycle at peak follicular maturation.

RESULTS: There was no difference in mean endometrial thickness during the first six cycles of therapy, nor was there a trend for thickness to increase or decrease with successive cycles with or without the addition of ethinyl E2. There was no change in the distribution of echo patterns with successive cycles of clomiphene citrate. Post-treatment measures of thickness and echo pattern did not differ from baseline pre-treatment values. The homogeneous hyperechogenic pattern was the rarest. Mean serum E2 and progesterone levels at mid-cycle did not change with successive cycles.

CONCLUSION: One proposed mechanism for the dichotomy between ovulation and pregnancy rates after clomiphene citrate therapy is that the drug adversely affects the endometrium. If clomiphene citrate does affect implantation adversely, the mechanism does not seem to be related to thinning the endometrium or causing an echo pattern that indicates a poor prognosis. The data also suggest that estrogen supplementation does not influence endometrial thickness and would best be used exclusively for hostile cervical mucus.


Flutamide in the treatment of hirsutism: long-term clinical effects, endocrine changes, and androgen receptor behavior

Abstract:
OBJECTIVE: To investigate the long-term effects of treatment with low doses of flutamide on clinical and hormonal parameters, as well as on the androgen receptor status, in hirsute women.

DESIGN: Eighteen hirsute patients with regular menses were studied basally and during treatment with 125 mg flutamide, three times per day for 12 months. Barrier or intrauterine contraception was used during the study in sexually active women. Safety parameters were assessed throughout the study. Hirsutism, graded by the modified Ferriman-Gallwey score, and hormonal parameters were evaluated basally and at 4-month intervals during treatment. Gonadotropin-releasing hormone and ACTH stimulation tests were performed before and after 3 to 4 months of therapy. In addition, the concentration of androgen receptors in mononuclear leukocytes was measured, in both the follicular and luteal phases of the menstrual cycle, basally and after 4 months of flutamide treatment.

RESULTS: Flutamide was well tolerated in all women, with the noticeable exception of one patient who presented increased serum transaminase after 8 months of therapy. Hirsutism markedly improved in all women during the treatment (Ferriman-Gallwey score after 1 year: 4.1 +/- 0.5 versus 14.1 +/- 0.9). A reduction of serum androgens was found, whereas no change was observed in either basal or GnRH-stimulated gonadotropins or in the cortisol and 17 alpha-hydroxyprogesterone response to ACTH. Cycles remained ovulatory. Before treatment, the number of androgen receptors was higher in the luteal than in the follicular phase. This rhythmic differentiation disappeared after the patients had been given the antiandrogen drug.

CONCLUSIONS: Flutamide is effective in the treatment of hirsutism but requires constant surveillance of liver function. Androgen receptor blockade might be potentiated by a reduction of serum androgens. Flutamide affects androgen receptor behavior during the menstrual cycle. The meaning of this finding remains to be elucidated.


Reduction of ovarian adhesions by the use of Interceed. Ovarian Adhesion Study Group

Abstract:
OBJECTIVE: To evaluate the efficacy of Interceed (TC7) Absorbable Adhesion Barrier, an oxidized regenerated cellulose fabric, as a barrier to the development of postsurgical ovarian adhesions after surgery involving the ovaries.

METHODS: In a multicenter randomized study, 55 patients with bilateral ovarian disease were treated at initial laparotomy. At the end of the procedure, one ovary was assigned randomly to be wrapped with Interceed and the other was left uncovered. A second-look laparoscopy was performed 10-98 days later to evaluate the occurrence and severity of adhesions and the raw ovarian surface area exposed after lysis of adhesions.

RESULTS: At second-look laparoscopy, 26 of 55 Interceed-treated ovaries were free of adhesions, compared with 14 of 55 untreated control ovaries, a statistically significant difference (P = .028, Fisher exact test). At second-look laparoscopy, ovaries treated with Interceed formed adhesions less extensively (1.66 +/- 0.34 cm2) than did untreated ovaries (2.75 +/- 0.60 cm2) and with a greater reduction of raw ovarian surface area (difference in area differential -1.89 +/- 0.96 cm2; P = .055, paired t test). Adhesion scores at second-look laparoscopy were reduced significantly for ovaries treated with Interceed compared with untreated ovaries (P = .02, Wilcoxon signed-rank test). No adverse events were recorded during the course of the study.

CONCLUSION: Treatment of ovaries with Interceed significantly reduced the occurrence and severity of postsurgical ovarian adhesions.


Obesity and cancer

Obesity and cancer

Abstract: Large-scale studies have demonstrated that obesity increases the risk of developing some forms of cancer. The association between obesity and cancer may result from factors such as fat distribution or sex hormone levels. Studies have also shown a relationship between a high-fat, low-fiber diet and cancer risk. High estrogen levels and low progesterone levels are associated with an increased risk of endometrial cancer. Obesity is known to raise estrogen levels and may lower progesterone levels. Obesity may increase the risk of breast cancer, but the evidence is less clear, since factors, such as age, country of origin, body-fat distribution, and family history, also play a major role in determining breast cancer risk. Sex hormones, insulin, and nutritional factors are also involved in the etiology of breast cancer. The incidence of lung cancer is inversely related to body weight.


Latency period after preterm premature rupture of membranes: a comparison of ampicillin with and without sulbactam

M. Fontenot

Louisiana State University Health Sciences Center Shreveport

Abstract:
OBJECTIVE: To compare ampicillin with and without sulbactam with respect to the effect on the latency period after preterm premature rupture of membranes (PROM).

METHODS: Patients with PROM at 25-35 weeks' gestation were offered participation in a randomized blinded trial comparing ampicillin-sulbactam with ampicillin. Evaluations for cervical pathogens were performed on admission and patients were followed-up with daily maternal and fetal evaluation. Maternal and neonatal outcomes were analyzed using indicated techniques.

RESULTS: Fifty-three women were studied, with 25 receiving ampicillin-sulbactam and 28 receiving ampicillin. The ampicillin-sulbactam group had a significantly longer latency period (433 +/- 625 versus 143 +/- 165 hours, P = .03) and significantly fewer neonatal complications (five versus 20, P < .001). Although no neonatal infectious complications were observed in sulbactam-treated cases, there were four cases of neonatal sepsis and two of neonatal pneumonia in the ampicillin group. Also, significantly more neonates in the ampicillin group required prolonged oxygen and ventilatory support. There was no significant difference in maternal morbidity.

CONCLUSIONS: In our population with preterm PROM, a broad-spectrum antibiotic that provides anaerobic coverage appears to extend latency and decrease neonatal morbidity without increasing adverse maternal outcome.


Insulin resistance, insulin-like growth factor I and breast cancer: a hypothesis

Abstract: Consideration of existing data regarding clinical and biochemical risk factors for the development of breast cancer leads to the hypothesis that enhanced insulin-like growth factor I (IGF-I) activity plays a significant role in the development of this disease. Abnormal IGF-I activity may be related to events occurring prenatally, during puberty, or during adult life. Insulin resistance, a common feature in populations characterized by high caloric intake, may result in the amplification of IGF-I action at the tissue level by altering serum concentrations of IGF-I binding proteins. Several approaches toward testing the hypothesis are proposed, and potential opportunities for clinical application are described.


Women at risk for postpartum-onset major depression

Abstract: There is considerable evidence that the childbearing years represent a time when women are highly vulnerable to developing mood disorders. Prospective, cross-sectional, and retrospective studies have demonstrated that more than 10% of new adult mothers will experience a major depressive episode during the first postpartum year. Changes in the health care delivery system will result in increased pressure on the obstetrician/gynecologist to identify and treat women with postpartum-onset depression. Despite shortcomings in the available literature, prospective studies have identified risk factors for developing postpartum depression. Furthermore, the clear overlap between the normal sequelae of childbirth and the symptoms of major depression, including alterations in sleep, energy, libido, appetite, and body weight, underscores the need to develop guidelines for early identification. We furnish a brief overview of postpartum mood disorders with a primary focus on the antenatal and postnatal risk factors for developing postpartum depression. Based on the extent literature and our clinical experience, a set of recommendations for early identification and treatment is provided.

American Journal of Obstetrics and Gynecology


Preliminary Meta-Analysis Comparing In Vitro Fertilization with Surgical Treatment for Moderate and Severe Endometriosis


Pulsatile release patterns of luteinizing hormone and progesterone in relation to symptom onset in women with premenstrual syndrome

Abstract:
OBJECTIVE: To explore the pulsatile-release characteristics of LH and P in women with premenstrual syndrome (PMS) compared with age-matched phase-matched controls.

DESIGN: Prospective, repeated measures, two-group study.

SETTING: Human volunteers in an academic research environment.

PARTICIPANTS: Six women with rigorously defined prospectively determined PMS; six age-matched phase-matched controls.

MAIN OUTCOME MEASURES: Frequency, amplitude, concentration, and coincident pulsatile release characteristics of LH and P at three symptom-related points of the luteal phase.

RESULTS: No significant between-group differences in frequency, amplitude, or concentration were found. In pooled data, significant coincident pulsing between LH and P was demonstrated. The length of time between LH and P pulses systematically increased across the luteal phase, a finding not previously reported. In the PMS group only, significant coincident pulsing occurred at an unexpected zero time lag on the symptom-onset sampling day.

CONCLUSION: A progressively increasing coupling interval may reflect the gradual decline of the corpus luteum. Presence of a zero time lag between LH and P at symptom onset in women with PMS may indicate an aberrance in corpus luteum response to LH stimulation.


Clinical and endocrine effects of finasteride, a 5 alpha-reductase inhibitor, in women with idiopathic hirsutism

Abstract:
OBJECTIVE: To evaluate the effects of long-term administration of finasteride on hirsutism score, basal gonadotropin, and androgen secretion in women with idiopathic hirsutism.

DESIGN: Randomized single-blinded study.

PATIENTS: Eighteen patients with moderate-severe hirsutism were recruited for the study.

INTERVENTIONS: Nine hirsute patients received 7.5 mg/d oral finasteride for a period of 9 months whereas the other nine were treated with placebo. Hirsutism score, serum basal gonadotropin, androgens, estrogen, and sex hormone-binding globulin (SHBG) levels were evaluated in all patients before treatment and every 3 months during treatment.

RESULTS: After 6 and 9 months of treatment, the hirsutism score improved significantly in the patients receiving finasteride, whereas no significant modifications were observed in patients treated with placebo. The side effects observed were headache and depression of modest entity during the 1st month of treatments, whereas libido did not change. Serum levels of LH, FSH, androstenedione, unbound T, DHEAS, E2, 17 alpha-hydroxyprogesterone, and SHBG did not change during therapy. Hirsute patients treated with finasteride exhibited a marked decrease of dihydrotestosterone and a significant increase of T serum levels from the 3rd and 6th months of treatment, respectively.

CONCLUSION: Finasteride decreased the hirsutism score of patients affected by idiopathic hirsutism with few side effects during treatment. No modification of libido was observed.


Laparoscopic implant of Gore-Tex surgical membrane

J Crain

Women's Specialty Center, Charlotte, North Carolina, USA.

Abstract:
One of the major postoperative complications of reproductive surgery is the formation of adhesions. 1, 2 Over the past several decades a number of methods have been explored to solve this problem, g, 4 Recently there has been renewed interest in covering the damaged peritoneal surface with an absorbable or nonabsorbable barrier as a means of preventing adhesions after fertility-enhancing surgery. Currently, two barriers are commercially available for clinical use: Interceed Absorbable Adhesion Barrier (Ethicon, Somerville, NJ), which is composed of oxidized regenerated cellulose, and the Gore-Tex Surgical Membrane (W. L. Gore & Associates, Inc., Flagstaff, AZ), constructed of expanded polytetrafluoroethylene (e-PTFE). Interceed has been investigated both experimentally and clinically and has proved effective in some circumstances. 5,6 Studies also report on the laparoscopic application of Interceed in fertility-enhancement procedures.7, 8 Recent reports, however, have questioned the product's degree of effectiveness and raised concern about possible residual effects it may have on peritoneal tissue? 11 Gore-Tex Surgical Membrane has been indicated for use in peritoneal reconstruction since 1983, and experimental and clinical reports describe its effectiveness in preventing adhesion formation. 12-14
Interceed is an absorbable material that is phagocytized by macrophages within 1 month. Gore-Tex Surgical Membrane is nonabsorbable and is intended to be a permanent implant. Since all published reports on the clinical application of the Gore-Tex membrane discuss implantation by laparotomy, ~g, 14 the ease of use of this product in laparoscopic surgery is of particular interest. Moreover, because of its permanence, its long-term safety and effectiveness merit examination. A prospective, multicenter clinical study was undertaken to evaluate the ease of using Gore-Tex Surgical Membrane laparoscopically.

The Journal of the American Association of Gynecologic Laparoscopists


Ultrasonographic characteristics of first-trimester gestations in recurrent spontaneous aborters

Abstract:
OBJECTIVE: To compile, for the first time, serial ultrasonographic findings during the first trimester of pregnancy in women with a history of primary recurrent spontaneous abortion so as to define the dynamics of early normal and abnormal gestations in this category of gravidas.

STUDY DESIGN: Transvaginal ultrasonograms were obtained weekly from 5 to 12 weeks' gestational age in 40 women, 10 each of four groups: recurrent spontaneous aborters and primiparas (controls), with both successful and failed gestations.

RESULTS: Embryonic heart motion was detected in 40-50% of successful pregnancies during the fifth week of gestation and in the balance by the sixth week, while heart motion was detected in no more than 50% of pregnancies that later failed. Of the failed pregnancies, all were evident by the eighth week of gestation, including those with previously documented viability. The gestational sac size and crown-rump length were smaller than expected in both failed groups, with the sac size difference evident as early as week 5 and the crown-rump length difference apparent by week 7.

CONCLUSION: Appropriate timing of the initial ultrasonogram in recurrent aborters (i.e., 8 weeks' gestational age) can identify, by means of heart motion and gestational sac features, all pregnancies that will ultimately fail.


Estrogen acutely increases peripheral blood flow in postmenopausal women

P Collins

Royal Brompton & Harefield NHS Foundation Trust

Abstract:
PURPOSE: To test the acute effect of estrogen on peripheral blood flow and vascular resistance in postmenopausal women.

PATIENTS AND

METHODS: Eleven normotensive, post-menopausal female volunteers (mean age 53 +/- 6 years) were studied. Six women were in natural menopause and 5 had had a hysterectomy (mean age of the menopause 49 +/- 3 years). We used a double-blind, randomized protocol to assess the acute response to sublingual estradiol-17 beta (1 mg) on the forearm resistance vessels, compared with sublingual placebo. Blood flow was measured by strain-gauge plethysmography, and mean peripheral vascular resistance was then calculated. Mean blood pressure was also measured.

RESULTS: The mean blood flow induced by estradiol-17 beta after 40 minutes was significantly greater than that induced by placebo (3.9 +/- 0.5 mL/100 mL per minute versus 2.4 +/- 0.4 mL/100 mL per minute, respectively, P < 0.05). The forearm resistance was significantly reduced at 40 minutes after estradiol-17 beta compared with placebo (25.7 +/- 4.4 resistance units (RU) to 44.4 +/- 6.4 RU, respectively, P < 0.05). Mean blood pressure 40 minutes after the administration of estradiol-17 beta was no different when compared with placebo (91 +/- 1.5 mm Hg versus 90 +/- 2.5 mm Hg, respectively, P = NS).

CONCLUSIONS: These results indicate that the acute administration of estradiol-17 beta affects blood flow in the peripheral vasculature in human subjects. The mechanism of this effect has not been determined, but it may explain some of the beneficial effects of estrogen on the vascular system and have future therapeutic potential in postmenopausal women.


Elusive fertility: fecundability and assisted conception in perspective

Abstract:
The last decade has transformed the physician's approach to infertility. The development of IVF for its treatment has so improved our capacity to overcome this most distressing of disabilities that we now need to revise many of our working ideas on how it can come about. This is not because new causes have been discovered. Rather, an appreciation has been gained of how apparently minor disturbances can combine to cause a major disruption in the expectation of pregnancy.
At the best of times-and sometimes, no doubt, at the worst of times getting pregnant is a matter of chance. The parameter that describes this chance is the monthly probability of conception, known among epidemiologists as fecundability (f) (probability of achieving pregnancy in one menstrual cycle), and is similar to "monthly fecundity" (monthly probability of a live birth in one cycle exposed to the risk of pregnancy) (1). Like every statistic in biology, fecundability has a wide distribution of values in the population (modeled in Fig. 1). Figure 1 also illustrates a group of couples with a fecundability value of zero-meaning complete infertility, or sterility, which affects perhaps 5% of couples attempting to achieve a pregnancy.


A double-blind trial of oral progesterone, alprazolam, and placebo in treatment of severe premenstrual syndrome

Abstract:
OBJECTIVE: To determine the effectiveness of oral micronized progesterone, alprazolam, and placebo in premenstrual syndrome (PMS) treatment and the effect of clinical contact on treatment responses.

DESIGN: Randomized, double-blind, placebo-controlled 3-month parallel treatment arms with flexible dosage and with the length of clinical contact randomized within each treatment group.

SETTING: University hospital PMS medical treatment outpatient program in obstetrics/gynecology department.

SUBJECTS: Among volunteers for PMS treatment, 444 were evaluated and 185 meeting defined PMS criteria were randomized to treatment; treatment data are available for 170. There were no medical withdrawals for adverse events.

INTERVENTION: A double-blinded protocol in which 300 mg of oral micronized progesterone, 0.25 mg of alprazolam, or placebo was administered four times a day from day 18 of the menstrual cycle through day 2 of the next cycle, including taper. The mean daily dose at the third treatment was 1760 mg of progesterone or 1.5 mg of alprazolam. Subjects were randomized to brief (< 20 minutes) or extended (50 minutes) visits.

MAIN OUTCOME MEASURES: Daily symptom report (DSR) scored for total DSR symptoms, four DSR factors.

RESULTS: Alprazolam was significantly better than placebo or progesterone for total premenstrual symptoms and DSR factors of mental function, pain, and mood. Thirty-seven percent of the alprazolam group experienced a 50% reduction in total DSR scores. There were no clinically significant withdrawal symptoms when alprazolam administration was restricted to the luteal phase. Oral micronized progesterone therapy was no better than placebo. Brief vs extended visits had no effect on treatment outcome. Treatment response was associated with severity of premenstrual symptoms at baseline but with no other diagnostic variables.

CONCLUSIONS: Alprazolam has a role in PMS treatment and offers a therapy limited to the luteal phase. Oral micronized progesterone is ineffective for PMS.


Efficacy of oral micronized progesterone in the treatment of luteal phase defects

Abstract:
OBJECTIVE: Vaginal progesterone suppositories are an accepted treatment for infertility attributed to luteal phase defects. Although oral micronized progesterone may be preferable to suppositories for many patients, there are no studies on its use for patients with luteal phase defects. This study evaluated the efficacy of oral micronized progesterone for the treatment of luteal phase defects.

STUDY DESIGN: Seven women with luteal phase defects previously corrected by vaginal suppositories were administered oral micronized progesterone (200 mg by mouth three times a day). Endometrial biopsies were performed to evaluate treatment efficacy. Questionnaires were used to assess side effects, including sedation.

RESULTS: On oral micronized progesterone, all patients had in-phase endometrial biopsies. Despite complaints of drowsiness, the majority of patients preferred the oral formulation over the vaginal route of administration.

CONCLUSION: We conclude that oral micronized progesterone is efficacious in the treatment of luteal phase defects.


The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey

Abstract:
BACKGROUND AND OBJECTIVE: The original Whickham Survey documented the prevalence of thyroid disorders in a randomly selected sample of 2779 adults which matched the population of Great Britain in age, sex and social class. The aim of the twenty-year follow-up survey was to determine the incidence and natural history of thyroid disease in this cohort.

DESIGN, PATIENTS AND

MEASUREMENTS: Subjects were traced at follow-up via the Electoral Register, General Practice registers, Gateshead Family Health Services Authority register and Office of Population Censuses and Surveys. Eight hundred and twenty-five subjects (30% of the sample) had died and, in addition to death certificates, two-thirds had information from either hospital/General Practitioner notes or post-mortem reports to document morbidity prior to death. Of the 1877 known survivors, 96% participated in the follow-up study and 91% were tested for clinical, biochemical and immunological evidence of thyroid dysfunction.

RESULTS: Outcomes in terms of morbidity and mortality were determined for over 97% of the original sample. The mean incidence (with 95% confidence intervals) of spontaneous hypothyroidism in women was 3.5/1000 survivors/year (2.8-4.5) rising to 4.1/1000 survivors/year (3.3-5.0) for all causes of hypothyroidism and in men was 0.6/1000 survivors/year (0.3-1.2). The mean incidence of hyperthyroidism in women was 0.8/1000 survivors/year (0.5-1.4) and was negligible in men. Similar incidence rates were calculated for the deceased subjects. An estimate of the probability of the development of hypothyroidism and hyperthyroidism at a particular time, i.e. the hazard rate, showed an increase with age in hypothyroidism but no age relation in hyperthyroidism. The frequency of goitre decreased with age with 10% of women and 2% of men having a goitre at follow-up, as compared to 23% and 5% in the same subjects respectively at the first survey. The presence of a goitre at either survey was not associated with any clinical or biochemical evidence of thyroid dysfunction. In women, an association was found between the development of a goitre and thyroid-antibody status at follow-up, but not initially. The risk of having developed hypothyroidism at follow-up was examined with respect to risk factors identified at first survey. The odds ratios (with 95% confidence intervals) of developing hypothyroidism with (a) raised serum TSH alone were 8 (3-20) for women and 44 (19-104) for men; (b) positive anti-thyroid antibodies alone were 8 (5-15) for women and 25 (10-63) for men; (c) both raised serum TSH and positive anti-thyroid antibodies were 38 (22-65) for women and 173 (81-370) for men. A logit model indicated that increasing values of serum TSH above 2mU/l at first survey increased the probability of developing hypothyroidism which was further increased in the presence of anti-thyroid antibodies. Neither a positive family history of any form of thyroid disease nor parity of women at first survey was associated with increased risk of developing hypothyroidism. Fasting cholesterol and triglyceride levels at first survey when corrected for age showed no association with the development of hypothyroidism in women.

CONCLUSIONS: This historical cohort study has provided incidence data for thyroid disease over a twenty-year period for a representative cross-sectional sample of the population, and has allowed the determination of the importance of prognostic risk factors for thyroid disease identified twenty years earlier.


Fluoxetine in the treatment of premenstrual dysphoria. Canadian Fluoxetine/Premenstrual Dysphoria Collaborative Study Group

Abstract:
BACKGROUND: Premenstrual dysphoria shares certain features with depression and anxiety states, which have been linked to serotonergic dysregulation. We evaluated the efficacy and safety of fluoxetine (which selectively inhibits the reuptake of serotonin) in the treatment of premenstrual dysphoria.

METHODS: The trial consisted of a single-blind, placebo washout period lasting two menstrual cycles, followed by a randomized, double-blind, placebo-controlled trial of fluoxetine at a dose of either 20 mg or 60 mg per day or placebo for six menstrual cycles. Healthy women meeting criteria for what was then called late-luteal-phase dysphoric disorder were recruited at seven university-affiliated women's health clinics in Canada. The primary outcome measure consisted of visual-analogue scales for tension, irritability, and dysphoria during the late luteal phase of each cycle.

RESULTS: Of 405 women enrolled in the placebo washout period, 313 subsequently entered the randomized phase of the study, which lasted six menstrual cycles, and 180 completed it. Fluoxetine at a dose of 20 or 60 mg per day was significantly superior to placebo in reducing symptoms of tension, irritability, and dysphoria, as measured by the visual-analogue scales (P < 0.001). The women who received 60 mg of fluoxetine per day reported significantly more side effects than those who received 20 mg per day or placebo (P < 0.001).

CONCLUSIONS: Fluoxetine is useful in the treatment of premenstrual dysphoria. Treatment with fluoxetine at a dose of 20 mg per day reduces the potential for side effects while maximizing therapeutic efficacy.


The limited value of hysterosalpingography in assessing tubal status and  fertility potential

Douglas S. Rabin

Eunice Kennedy Shriver National Institute of Child Health and Human Development

Abstract:
Design: To determine whether the diagnostic accuracy and prognostic value of hysterosalpingography (HSG) could be improved if routine spot films were replaced by an on-line recorded gynecoradiologic study.
Setting: Medical school-affiliated private infertility center.
Patients: In 1992, a review of 152 infertile women with infertility who demonstrated a normal HSG, by standard criteria of spot film evaluation, in 117 (77%). They were further investigated by gynecoradiologic study if the HSG revealed asymmetrical tubal filling, an increased perfusion pressure, and/or evidence for abnormal tubal spill. In 1993, 47 women with normal HSG by spot film criteria underwent bilateral selective salpingography and were subdivided into those with normal (group I, n = 23) and abnormal (group II, n = 24) tubal perfusion pressures.

Intervention: Patients in both study groups then were treated for their infertility independently of pressure perfusion measurements.
Main Outcome Measure: Clinical pregnancy rates (PRs) over the ensuing 6 to 10 months.

Results: Among 117 women with apparently normal spot film HSG, 64 (55%) demonstrated asymmetrical tubal filling, 32 (27%) demonstrated abnormal spillage into the peritoneal cavity, and 55 (47%) demonstrated abnormally elevated injection pressures. Among 98 women who underwent bilateral selective salpingography, 43 (44%) demonstrated bilaterally normal tubal perfusion pressures and 55 (56%) showed an abnormally elevated pressure in at least one oviduct. Of 47 women that were followed prospectively in 1993, patients with normal perfusion pressure (group I) demonstrated a significantly higher PR than women with elevated tubal pressure (group II) from 2 months and on after the procedure.

Conclusions: Routine spot film HSG is of limited value in assessing tubal status beyond the determination of tubal patency. Especially with regard to fertility potential, HSG should be replaced by gynecoradiologic study.


Luteal phase estradiol and pregnancy outcome in gonadotropin releasing hormone agonist/human menopausal gonadotropin-treated gamete intrafallopian transfer cycles

Abstract: To correlate luteal estradiol (E2) levels with pregnancy outcome, 36 consecutive conceptions resulting from gamete intrafallopian transfer in gonadotropin releasing hormone agonist/human menopausal gonadotropin (GnRH-a/hMG) cycles were analyzed. GnRH-a was initiated during the preceding luteal phase. HMG was adjusted individually. Human chorionic gonadotropin (hCG), 5,000 IU, was administered when E2 was > 500 pg/mL and the leading follicle > 17 mm (day 0). The luteal phase was supported by (1) hCG, 1,500 IU in three doses from day 5 and (2) progesterone (P) from day 7. E2 and P levels were analyzed in three groups of patients: normally progressing pregnancy (NPP), abortion (AB) and preclinical abortion (PAB). No significant differences in mean E2 levels were seen between the groups from day 0 through day 5 after hCG. Midluteal E2 levels were significantly different between the groups (P < .05). Late luteal E2 values were significantly higher for NPP than for either AB or PAB (P < .05). There were no significant differences in luteal P values between the NPP, AB and PAB groups. Decreased luteal E2 appears to be associated with early pregnancy wastage; this may be due to inadequate endometrial support.