To investigate whether the timing of administration of clomiphene citrate (CC) affects hormone levels, follicular recruitment, reproductive end organs, and pregnancy rates. Prospective, randomized, double-blind trial. Academic center. PATIENT(S): Twenty-three patients with unexplained infertility. INTERVENTION(S): Twenty-three patients with unexplained infertility underwent 45 cycles of CC and IUI. For each cycle, patients were randomized either to receive 100 mg of CC on days 1-5 and placebo on days 5-9 (study group), or placebo on days 1-5 and CC on days 5-9 (control group). MAIN OUTCOME MEASURE(S): The difference in uterine artery PI, number of follicles, endometrial thickness, and pregnancy rates. RESULT(S): Gonadotropins and E2 levels, as well as uterine artery pulsatility index, were significantly higher in the study group on day 5. In addition, in the study group, a longer time interval existed between finishing CC and IUI (8 versus 6 days; MD = 2 days; 95% CI = 1-3) and the pregnancy rate was higher than in the control group (6 versus 0; OR = 15.1; 95% CI = 1.1-72.4). CONCLUSION(S): Clomiphene citrate commenced on day 1 of the menstrual cycle, rather than day 5, results in more rapid follicular growth, a longer CC-free period before IUI, and higher pregnancy rates. Although methodologically sound, our results should be taken with some degree of caution because they are based on a relatively small number of patients.
A variety of embryo-based technologies used in farm animal reproduction, including embryo culture, nuclear transfer, embryo-somatic cell co-culture and asynchronous embryo transfer can lead to the production of large offspring; the so-called large calf/lamb syndrome. In some cases, abnormalities in the fetus and newborn are apparent. The nature of these associations is explored with emphasis on the biological differences between in-vivo- and in-vitro-produced embryos. A unifying framework and research programme aimed at explaining anomalies in early embryo development is then proposed in terms of the response of somatic cells and embryos to cellular stress. The review concludes with a caution against developments in assisted conception technologies, in man and domestic animals, being determined too much by the needs of commerce at the expense of research on the molecular, biochemical and physiological basis of early mammalian development.
Menstrual CycleCycle Length VariabilityMenstrual Cycle BiomarkersProspective Cohort Study
To characterize how the menstrual cycle pattern relates to fertility regardless of potential biases caused by inappropriate coital timing during the menstrual cycle or early embryonal loss. Prospective follow-up study. Healthy couples recruited throughout Denmark. PATIENT(S): Two hundred ninety-five couples who were planning their first pregnancy were followed up from the discontinuation of birth control until a pregnancy was recognized within six menstrual cycles. Early embryonal losses were detected by changes in urinary hCG levels. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The probability of pregnancy occurring within one menstrual cycle (fecundity). RESULT(S): In women who had a cycle length that differed by >10 days from the usual cycle length, fecundity was approximately 25% that of women who had no variation (odds ratio 0.25, 95% confidence interval 0.09-0.68). When the combined effect of cycle variation and cycle length was assessed, cycle variation was a persistent strong predictor of fecundity. CONCLUSION(S): The mechanisms of the present findings probably are female functional disturbances in ovulation, conception, implantation, or sustained pregnancy, linked with variable menstrual cycle length. Thus, identification of medical and environmental causes of abnormal menstrual cycle patterns may provide clues to the causes of infertility. Moreover, the menstrual cycle pattern also should be taken into consideration in the clinical decision-making process.
To determine whether IVF or a standard infertility treatment algorithm results in better outcome and/or lower cost when used as first-line therapy for couples with infertility. Prospective, randomized clinical study. University-affiliated infertility clinic. PATIENT(S): Couples with newly diagnosed infertility and no prior treatment. INTERVENTION(S): Couples were randomized to undergo either IVF (group 1, n = 46) or a standard infertility treatment algorithm (group 2, n = 50) as initial therapy for infertility. MAIN OUTCOME MEASURE(S): Pregnancy rates and costs per couple, per month of treatment, and per pregnancy. RESULT(S): Pregnancy rates were higher in group 2 than in group 1. Costs per couple were not statistically different, although a trend toward higher costs was apparent in group 1, reflected by a higher median cost per clinical pregnancy established and a higher cost per month of treatment. Whereas cost differences between the groups diminished over time, pregnancy rates remained the same. CONCLUSION(S): In vitro fertilization currently does not represent an appropriate first-line treatment option for couples with infertility. The use of a standard infertility treatment algorithm results in a higher pregnancy rate and lower cost and therefore should be the preferred treatment approach.
This article reviews the arguments for the use of multifetal pregnancy reduction (MFPR) for the prevention of preterm deliveries in triplet and higher order multiple pregnancies and evaluates its effectiveness based on data from published studies. The arguments in favour of pregnancy reduction are based on the substantial mortality and morbidity associated with these pregnancies. Triplets and higher order multiples have increased rates of preterm delivery and intrauterine growth retardation, both of which are independent risk factors for death and handicap. Even controlling for gestational age, rates of mortality and handicap are higher for multiples than for singletons. Moreover, the family's risk of losing a child or having a handicapped child is greater because there are more infants at risk. MFPR effectively lowers these risk by reducing the frequency of preterm delivery. However, its effectiveness may be limited. In some studies, the proportion of preterm deliveries in reduced pregnancies remains above levels found in spontaneous twin or singleton pregnancies and MFPR does not appear to reduce the prevalence of low birth weight. Furthermore, the procedure itself it increases the risk of miscarriage, premature rupture of the membranes and causes adverse psychological effects such as grief or depression for many patients. The authors note that a majority of the higher order multiple pregnancies result from a medical intervention in the first place, either through IVF techniques or the use of ovulation stimulation drugs. Although MFPR is an effective measure for reducing the substantial morbidity and mortality associated with higher order multiple pregnancies, preventive methods, such as limiting to 2 the number of embryos transferred for IVF and better control of the use of ovulation induction drugs, remain more effective and less intrusive.
The risk factors for women developing breast and endometrial cancers are all associated with a lifetime of estrogen exposure. Estrogen replacement therapy in particular has been correlated with a slight increased cancer risk. Previously, we showed that equilenin, a minor component of Premarin (Wyeth-Ayerst), was metabolized to highly cytotoxic quinoids which caused oxidative stress and alkylation of DNA in vitro [Bolton, J. L., Pisha, E., Zhang, F., and Qiu, S. (1998) Chem. Res. Toxicol. 11, 1113-1127]. In this study, we have compared the chemistry of the major catechol metabolite of equilin (4-hydroxyequilin), which is found in several estrogen replacement formulations, to the equilenin catechol (4-hydroxyequilenin). Unlike endogenous catechol estrogens, both equilin and equilenin were primarily converted by rat liver microsomes to 4-hydroxylated rather than 2-hydroxylated o-quinone GSH conjugates. With equilin, a small amount of 2-hydroxyequilin GSH quinoids were detected (4-hydroxyequilin:2-hydroxyequilin ratio of 6:1); however, no peaks corresponding to 2-hydroxyequilenin were observed in incubations with equilenin. These data suggest that unsaturation in the B ring alters the regiochemistry of P450-catalyzed hydroxylation from primarily 2-hydroxylation for endogenous estrogens to 4-hydroxylation for equine estrogens. 4-Hydroxyequilenin-o-quinone reacts with GSH to give two mono-GSH conjugates and one di-adduct. The behavior of 4-hydroxyequilin was found to be more complex than 4-hydroxyequilenin as conjugates resulting from 4-hydroxyequilenin were detected in addition to the 4-hydroxyequilin-GSH adducts. The mechanism of decomposition of 4-hydroxyequilin likely involves isomerization to a quinone methide which readily aromatizes to 4-hydroxyequilenin followed by autoxidation to 4-hydroxyequilenin-o-quinone. Similar results were obtained with 2-hydroxyequilin, although, in contrast to 4-hydroxyequilenin, 2-hydroxyequilenin does not autoxidize and the reaction stops at the catechol. Since 4-hydroxyequilin is converted to 4-hydroxyequilenin and 4-hydroxyequilenin-o-quinone, similar effects were observed for this equine catechol, including consumption of NAD(P)H likely by the 4-hydroxyequilenin-o-quinone, depletion of molecular oxygen by 4-hydroxyequilenin or its semiquinone radical, and alkylation of deoxynucleosides and DNA by 4-hydroxyequilenin quinoids. Finally, preliminary studies conducted with the human breast tumor cell line MCF-7 demonstrated that the cytotoxic effects of the catechol estrogens from estrone, equilin, and 2-hydroxyequilenin were similar, whereas 4-hydroxyequilenin was a much more potent cytotoxin ( approximately 30-fold). These results suggest that the catechol metabolites of equine estrogens have the ability to cause alkylation/redox damage in vivo primarily through formation of 4-hydroxyequilenin quinoids.
To study the prevalence of polycystic ovaries (PCO) in women of reproductive age. A total of 189 healthy volunteers aged 20-45 years were examined. The subjects were divided into < or =35 and > or =36 years. Transvaginal ultrasonography was performed and blood samples were collected on cycle day 1-6. The prevalence of PCO in the entire study population was 14.2% (27/189). In the age group of < or =35 years the prevalence was 21.6% (19/88) and in the age group of > or =36 years 7.8% (8/101). Compared to women with normal ovaries, those with PCO had significantly higher serum testosterone (T) concentrations. Women with PCO tended to have lower serum FSH concentrations and higher LH/FSH ratios than controls. Women with PCO had significantly more irregular cycles (44% vs. 19%, p=0.001) and problems in conceiving (25.9% vs. 9.2%, p=0.01) than women with normal ovaries. The findings demonstrate that the prevalence of PCO in healthy women varies with age, being more common among women aged < or =35 years than in those aged > or =36 years. Although the hormonal parameters and clinical findings among women with PCO mimicked those of PCOS, it remains unclear if these women will later develop full-blown syndrome.
Our goal was to study the effect of therapeutic McDonald cerclage on cervical length with the use of transvaginal ultrasonography. Cervical length was measured serially in singleton pregnancies in which there were doubts regarding cervical competence. When shortening of the cervix was substantial before 27 weeks' gestation a McDonald cerclage was applied. Wilcoxon signed rank test was used, and 1-tailed P <.05 was considered significant. In the 34 pregnancies studied, the mean cervical length measured at a mean gestational age of 14 weeks had decreased significantly (P <.0001) from 42 mm (95% confidence interval 38-47) to 21 mm (95% confidence interval 19-23) at a mean gestational age of 20 weeks 5 days, when a cerclage was applied. After the cerclage the mean cervical length increased significantly (P <.0001) to 34 mm (95% confidence interval 30-38) at a mean gestational age of 22 weeks 1 day (95% confidence interval 21 weeks 1 day-23 weeks 2 days). Therapeutic McDonald cerclage results in a longer cervical length as measured by transvaginal ultrasonography.
To determine the prevalence of polycystic ovary syndrome (PCOS) among hyperandrogenic women who report normal menses. Prospective observational study. Academic practice in reproductive endocrinology. PATIENT(S): Fifty-eight consecutively seen new patients with hyperandrogenism who reported normal menses. INTERVENTION(S): Ovulatory status was assessed with timed serum progesterone measurements. The following vaginal ultrasound examination; measurement of the ovarian response of 17-hydroxyprogesterone (17-OHP) after the administration of leuprolide acetate, 1 mg SC; and determination of fasting serum LH, FSH, E2, 17-OHP, insulin, and androgen levels. MAIN OUTCOME MEASURE(S): Determination of ovulatory status, polycystic appearance of ovaries, and increased response of 17-OHP to leuprolide acetate. RESULT(S): Twelve (20.7%) of the hyperandrogenic women were anovulatory and met the usual criteria for the diagnosis of PCOS. The ovulatory patients had lower serum total and unbound testosterone levels. Thirty-one (53.4%) of the ovulatory women had polycystic ovaries on ultrasound examination and/or an increased 17-OHP response to leuprolide acetate, suggesting the diagnosis of PCOS despite the presence of ovulation. Considering both the anovulatory and ovulatory patients, 74% of the hyperandrogenic women studied could have PCOS. CONCLUSION(S): The data suggest that most (74%) hyperandrogenic women who report normal menses have evidence for the diagnosis of PCOS.
To investigate the occurrence of ovarian cancer (OC) arising in ovarian endometriosis (OE) diagnosed in our laboratory, and the relation of the disease to patient age. Histopathological reports were reviewed in cases of endometriosis and ovarian cancer diagnosed between 1982 and 1989 and in 1997. The occurrence of OE and OC was studied in relation to patient age. Of the 796 OE cases, 36 (4.5%) ovarian cancers were found in the eight-year period, and of the 216 OC cases 36 (16.7%) were associated with OE; 12 patients (1.7%) were under 50 years old and 24 (22.9%) were over 50. In 1997 there were 168 cases of OE, and 4 cases were associated with OC. Of the 60 OC cases 4 cases arose in endometriosis. Two patients were over 50 and two under 50. In our report the occurrence of OC arising in OE was most influenced by patient age, the extent of sampling and the consistency of histologic reports about the presence of endometriosis in ovarian adenocarcinoma.
General OB/GYNCesarean Scar DefectSonohysterographyPostmenstrual Spotting
A previously undescribed cause of abnormal uterine bleeding is presented. Nine of 310 women evaluated by sonohysterography for abnormal bleeding demonstrated an 8 to 17 mm gap in the anterior lower uterine segment myometrium at the site of prior cesarean deliveries. All women were premenopausal and had a history of 2 to 12 days of postmenstrual spotting. Presumably a lack of coordinated muscular contractions occurs around the cesarean scar, allowing the defect to collect menstrual debris. Subsequently, the debris leaches out through the cervix for several days after the majority of menstrual flow has ceased.
Ethics/PhilosophyGamete DonationCommodification of ReproductionOocyte Donation
There is a growing threat to the practice of oocyte donation in the United States and all of us should take careful notice. This threat is posed by the escalating fees paid to young women for providing these services. I was shocked by the decision of St. Barnabas Medical Center in Livingston, New Jersey to double the compensation from the community standard of $2,500 to a startling $5,000 per cycle. These new fees were aggressively advertised throughout New Jersey and Manhattan in strategic periodicals, newspapers, and magazines. I was even more dismayed to see physicians and “ethicists” justifying the increase to the media (1) stating “there is nothing inherently wrong with bidding for human eggs.”
For years, I have advocated compensation to oocyte donors based upon time, effort, and risk of involvement. I have addressed this topic at speaking engagements and in position papers, typically defending the belief that physicians are capable of responsible restraint (2, 3). However, I have been increasingly concerned over the encroachment upon the traditional practice by both commercial enterprises and physician-led groups who have inflated the cost of donor compensation 500% in the past decade.
In most countries it is illegal to provide any compensation for oocyte donors. Many believe payment is inappropriate and many more agree that excessive compensation is ethically unacceptable, since it potentially exploits or even coerces young women to participate. Even if one considers the time spent traveling to the local office and waiting for an ultrasound exam to be “work,” donors now will be earning in excess of $300 per hour. I find it hard to believe that anyone thinks this “reasonable compensation” according to the recommendations of the Ethics Committee of the American Society for Reproductive Medicine (4).
If we are truly not guilty of “pimping for patients” (5) and if donors are not “selling eggs,” then we cannot justify another doubling of the compensation. I believe this is a flagrant violation of the Ethical Considerations of Assisted Reproductive Technologies issued in 1994 (4). What is most disappointing is that this violation comes from a highly respected group led by physicians held in esteem within our subspecialty, who stated in The New York Times “I’m not sure $5,000 is enough.” (1) I would ask them, “How much is enough?” Where does this stop and at what price to our patients and our profession? Inevitably, all of us will be forced to raise our compensation rates to meet this challenge. Most importantly, and most unfortunately, these expenses will have to be passed on directly to our patients, who are already spending considerable sums of money to seek this procedure.
I have always opposed government regulation and intervention, and I have often taken a public stand in defending our right to administer our own practices. However, for the first time in my career I am rethinking my position. If physicians are forced to drastically modify their practices to keep pace with commercial ventures or to compete with doctors whose modus operandi is “what the market will bear,” an approach to medicine so flagrantly greedy as to threaten the existence of the field, then I do believe it is time for regulation. These are truly sad events, and if we stand by and allow these changes to become standard operating procedure then we as professionals deserve the public criticism that will inevitably follow.
To investigate the involvement of opioid tone, obesity, and hyperinsulinemia in GH secretion in women with polycystic ovary syndrome (PCOS). Controlled clinical study. Catholic University of Sacred Heart School of Medicine in Rome, Italy. PATIENT(S): Twenty-two patients with PCOS and 14 healthy, normally ovulating volunteers, matched for age and body mass index. INTERVENTION(S): Patients underwent a GH-releasing hormone (GHRH) test and an oral glucose tolerance test before and after 4-5 weeks of treatment with 50 mg/d of naltrexone. MAIN OUTCOME MEASURE(S): Serum concentrations of GH, insulin, glucose, steroids, and gonadotropins, as well as the GH area under the curve (AUC-GH) and the insulin area under the curve (AUC-I), were measured before and after naltrexone treatment. RESULT(S): In patients with PCOS, the administration of naltrexone increased the GH response to the GHRH test without interfering with the insulin response to the oral glucose tolerance test. However, the GH response to the GHRH test was improved significantly only in lean patients with PCOS, whereas obese patients with PCOS did not show any improvement in GH secretion. In obese control subjects, the treatment reduced plasma basal insulin concentrations and increased the AUC-GH, whereas in lean control subjects, the treatment reduced the GHRH-induced response. In normoinsulinemic patients with PCOS, the GH response to the GHRH test increased significantly after treatment, whereas the AUC-I was not affected. In hyperinsulinemic patients with PCOS, treatment with naltrexone significantly reduced the AUC-I, whereas the AUC-GH increased only in lean hyperinsulinemic patients with PCOS. CONCLUSION(S): Naltrexone treatment improves GHRH-induced GH secretion in patients with PCOS. However, this GH response is heterogeneously represented in relation to both obesity and hyperinsulinism.
InfertilityGrief and DepressionCounseling InterventionsCoping Strategies
To identify the levels of grief and depression and the coping mechanisms of women with infertility problems who participated in in vitro fertilization (IVF) or ovulation-induction medication. Pretest and post-test data were obtained from 50 IVF and 50 ovulation-induction medication patients receiving treatment at two urban infertility centers. Both groups of women experienced measurable levels of grief and depression before, during, and after treatment. Higher scores on the Grief Experience Inventory were found for both groups of women when pregnancy did not occur. Age, reproductive problems, years infertile, financial impact, and number of past IVF cycles were not found to influence the reported grief or depression levels. Women in the IVF and ovulation-induction medication groups used isolation coping behaviors such as self-talk and sleep. Because of moderate to high levels of grief and depression, therapeutic counseling may be more effective if initiated before the infertility treatment. Women's present levels of distress and coping strategies should be assessed prior to initiating infertility treatment to provide the patients with opportunities to learn and practice new adaptive behaviors that could enhance their ability to cope with infertility and the associated medical procedures.
Hull MG et al., 1999·Endocrinol Metab Clin North Am
This article has provided outcome-based evidence using easily understood graphic representation of cumulative pregnancy rates whenever possible for the methods used to investigate and treat female infertility. A scheme of basic routine investigations in specialist practice is developed and clear guidance provided on the choice of treatment for each couple.
InfertilityOvarian CancerOvarian Cancer Risk FactorsCancer Risk
The possibility that ovulation induction increases the risk of ovarian cancer remains unproven. However, recent studies suggest that both infertility and endometriosis may be independent risk factors. Despite the various case reports and epidemiological studies performed the association between the use of infertility drugs and ovarian cancer remains weak. The fact that the women who were the first to use ovulation agents are now reaching mid-life means that future studies should show whether any association exists. Hence, there is a need now for large prospective trials to be performed to establish whether an association between ovulation induction agents and ovarian cancer truly exists.
EndometriosisGnRH AgonistsClinical vs Surgical ConfirmationEmpiric Treatment
To evaluate and compare the safety and efficacy of leuprolide versus placebo in managing chronic pelvic pain in women with clinically suspected endometriosis. Women 18-45 years of age with moderate to severe pelvic pain of at least 6 months' duration underwent extensive, noninvasive diagnostic testing and laboratory evaluation, including pelvic ultrasound, complete blood count, determination of erythrocyte sedimentation rate, and endocervical cultures. Those with clinically suspected endometriosis were randomized to double-blind treatment for 3 months with depot leuprolide (3.75 mg/mo) or placebo. The accuracy of the clinical diagnosis of endometriosis was evaluated by posttreatment laparoscopy. Of 100 women randomized, 95 49 in the leuprolide group and 46 in the placebo group. Women in the leuprolide group had clinically and statistically significant (P < or = .001) mean improvements from baseline after 12 weeks of therapy in all pain measures. These mean improvements were significantly greater (P < or = .001) than those in the placebo group. At 12 weeks, mean decreases in physician-rated scores for dysmenorrhea, pelvic pain, and pelvic tenderness were 1.7, 1.0, and 0.8 points greater, respectively, in the leuprolide group than in the placebo group (on a four-point scale). Thirty-eight (78%) of 49 and 40 (87%) of 46 patients in the leuprolide and placebo groups, respectively, had laparoscopically confirmed endometriosis after 12 weeks of treatment. No women withdrew from the study because of adverse events. Depot leuprolide was effective and safe for treating patients with chronic pelvic pain and clinically suspected endometriosis, confirming the potential of its empiric use in these patients.
The magnitude of the relative risk of venous thrombosis caused by low-dose oral contraceptive use is still debated because previous studies might have been affected by diagnostic suspicion and referral bias. We conducted a case-control study in which the effect of diagnostic suspicion and referral bias was excluded. The study was performed in 2 diagnostic centers to which patients with clinically suspected deep vein thrombosis of the leg were referred. History of oral contraceptive use was obtained before objective testing for thrombosis. Young females with an objective diagnosis of deep vein thrombosis were considered case patients, and those who were referred with the same clinical suspicion but who had no thrombosis served as control subjects. Participants were seen between September 1, 1982, and October 18, 1995: 185 consecutive patients and 591 controls aged 15 to 49 years with a first episode of venous thrombosis and without malignant neoplasms, pregnancy, or known inherited clotting defects. The overall odds ratio for oral contraceptive use was 3.2 (95% confidence interval [CI], 2.3-4.5); after adjustment for age, family history of venous thrombosis, calendar time, and center, the odds ratio was 3.9 (95% CI, 2.6-5.7). In the idiopathic group (120 patients and 413 controls, excluding recent surgery, trauma, or immobilization), the odds ratio for oral contraceptive use was 3.8 (95% CI, 2.5-5.9); after adjustment, the odds ratio was 5.0 (95% CI, 3.1-8.2). In this study, in which patients and controls were subj ect to the same referral and diagnostic procedures, we found similar relative risk estimates for oral contraceptive use as in previous studies. We conclude that diagnostic suspicion and referral bias did not play an important role in previous studies and that the risk of venous thrombosis with use of current brands of oral contraceptives still exists.
To examine the risk of multiple sclerosis in users of combined oral contraceptives.
Cohort study conducted between 1968 and 1996 using diagnostic data supplied by General practices throughout the United Kingdom. Royal College of General Practitioners' Oral Contraception Study cohort of initially 46,000 women recruited during the late 1960s. Directly standardised incidence rates of multiple sclerosis were calculated for current, former and never-users of oral contraceptives using first ever cases of multiple sclerosis reported by the general practitioners. The standardisation variables were age, parity, social class and smoking history. Five-year survival rates in the different contraceptive groups were calculated using standard life table techniques. One hundred and fourteen first ever cases of multiple sclerosis had been reported by November 1996 during 564,000 woman-years of observation. The incidence rate in both current and former users was not materially different to that in never-users. Although based on limited evidence there was no suggestion that the five-year survival was affected by a woman's use of combined oral contraceptives. These findings do not suggest a greatly elevated risk of multiple sclerosis during, or after, use of combined oral contraceptives.
Annual report (Jahrbuch) of the Deutsches IVF-Register (DIR) for treatment year 1998. 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).
Relatively little is known about the factors in Canada which lead to osteoporosis and its concomitant fractures. The Canadian Multicentre Osteoporosis Study (CaMos) is a prospective cohort study which will estimate the incidence and prevalence of declining bone mass and fractures. The impact of osteoporosis in Canada will be assessed, including regional variation and the effect of various risk factors. The study will provide information for developing prevention programs. The cohort has been drawn from a random population-based sample of non-institutionalized men and women 25 years old or more and living within 50 km. of nine cities in Canada. Through telephone interviews 9,423 participants have been recruited. All answered an extensive questionnaire, and had physical measurements related to bone quality taken. This paper details the CaMos baseline and five-year follow-up protocol.
The mechanism of action of contraceptive drugs and devices forms an essential part of informed consent for patients considering various methods of family planning. Currently the literature is confusing at best, in part due to non-uniform definitions of basic terms, as well as the misinterpretation of endpoints of current. AAPLOG members take different positions on the issue of contraception per se. The purpose of this document is to investigate and summarize the current evidence-based concerns regarding potential embryocidal mechanisms of action of modern contraceptive drugs and devices.
There are three reasons for concern about embryos conceived during the use of a particular 1. 1) All contraceptive drugs and devices “fail” at a certain rate. As noted in a recent paper, “Unintended pregnancies occur with all contraceptive methods, including IUDs. This provides incontrovertible evidence that fertilization and implantation can occur, albeit rarely, with modern methods of contraception.”1
2. 2) Since pregnancies can and do occur during the use of all contraceptive drugs and devices, then we know by definition that fertilization, which marks the beginning of an embryonic human organism, can and does happen with all contraceptive drugs and devices since by definition, an embryo must be created for pregnancy to occur. That means embryos are created at a certain rate with all contraceptive drugs or devices.
3. 3) The contraceptive drug or device will create a certain environment for the embryos created during their use. This environment may adversely affect embryo survival up to the point of yielding a positive pregnancy test at the end of the cycle (the contraceptive efficacy end point).
The remainder of this article will try to summarize what is known in the published medical literature about the environment facing an embryo who has been created during the use of various kinds of contraceptive drugs or devices.
This review sought to examine the rationale for selecting an oral micronized progesterone formulation rather than a synthetic progestin for some of the main indications for progestogens. Unopposed estrogen use is associated with a high risk (relative risk, 2.1 to 5.7) of endometrial hyperplasia and adenocarcinoma, and it has been understood for some time that a progestogen must be added for at least 10 to 14 days per month to prevent these effects. However, the most commonly used synthetic progestins, norethisterone and medroxyprogesterone acetate, have been associated with metabolic and vascular side effects (eg, suppression of the vasodilating effect of estrogens) in both experimental and human controlled studies. All comparative studies to date conclude that the side effects of synthetic progestins can be minimized or eliminated through the use of natural progesterone, which is identical to the steroid produced by the corpus luteum. The inconvenience associated with the use of injectable, rectal, or vaginal formulations of natural progesterone can be circumvented by using orally administered micronized progesterone. The bioavailability of micronized progesterone is similar to that of other natural steroids, and interindividual and intraindividual variability of area under the curve is similar to that seen with synthetic progestins. A clear dose-ranging effect has been demonstrated, and long-term protection of the endometrium has been established. Micronized progesterone has been used widely in Europe since 1980 at dosages ranging from 300 mg/d (taken at bedtime) 10 days a month for women wishing regular monthly bleeding to 200 mg 14 days a month or 100 mg 25 days a month for women willing to remain amenorrheic. This therapy is well tolerated, with the only specific side effect being mild and transient drowsiness, an effect minimized by taking the drug at bedtime. The prospective, comparative Postmenopausal Estrogens/Progestin Intervention trial has recommended oral micronized progesterone as the first choice for opposing estrogen therapy in nonhysterectomized postmenopausal women.
PregnancyRisk FactorsPreeclampsia and Preterm LaborMultivariate Logistic Regression
Martius JA et al., 1998·Eur J Obstet Gynecol Reprod Biol
The study was conducted to identify medical, obstetrical and social risk factors associated with early preterm births (<32+0 gestational weeks). The Statewide Perinatal Survey of Bavaria is a collection of perinatal data from all Bavarian maternity units using a uniform numbered questionnaire. Data on 106345 singleton births from the 1994 Survey were analysed using univariate and multivariate logistic regression analysis. In the multivariate analysis, early preterm birth was associated with premature rupture of the membranes (odds ratio (OR) 1.6, 95% confidence interval (CI) 1.37-1.86), treatment for infertility (OR 1.7, 95% CI 1.19-2.34), previous induced abortion (OR 1.8, 95% CI 1.57-2.13), maternal age >35 years (OR 1.8, 95% CI 1.47-2.16), premature cervical dilatation (OR 2.3, 95% CI 1.86-2.94), a history of stillbirth (OR 3.2, 95% CI 2.13-4.83), a history of preterm birth (OR 3.3, 95% CI 2.45-4.48), maternal age <18 years (OR 3.4, 95% CI 2.03-5.61), malpresentation (OR 3.9, 95% CI 3.10-4.93), preeclampsia (OR 4.0, 95% CI 3.20-4.94), uterine bleeding (OR 5.0, 95% CI 4.08-6.02), preterm labour (OR 7.0, 95% CI 5.94-8.22), and chorioamnionitis (OR 22.3, 95% CI 17.40-28.66). These data identify a subgroup of women at an increased risk for early preterm birth and may benefit from an intensified prenatal care. Risk factors related to the obstetrical history, genital infections, preeclampsia and maternal age are the most relevant for early preterm birth.
PregnancyPremature Rupture of MembranesC-Reactive Protein in PregnancyChorioamnionitis Detection
The purpose of our study was to analyze the efficacy of serum C-reactive protein (CRP), white blood cell count (WBC) and erythrocyte sedimentation rate (ESR) serial evaluations in the prediction of chorioamnionitis in cases of premature rupture of membranes (PROM). A group of 80 patients with PROM before 35 weeks' gestation were evaluated prospectively and managed expectantly. We applied the expectant management with the permanent use of tocolysis, antibiotics, steroids, amnioinfusions of artificial amniotic fluid and intravaginal chemotherapeutics. Patients were monitored with frequent vital signs, fetal heart rate evaluation and everyday CRP, WBC and ESR. All afterbirths were examined to establish the presence of histologic chorioamnionitis (gold standard of intrauterine infection). S: 59 (73.7%) patients had significant chorioamnionitis on histopathology and only 15 of them had clinical chorioamnionitis. Serum CRP serial determinations (definition 1) > 1.2 mg/dl; 2) > 2.0 mg/dl; 3) > 1.2 mg/dl and increasing in two consecutive days) were found the most reliable with a sensitivity 1) 91.5%; 2) 85%; 3) 88%, specificity 57%; 76%; 86%, positive predictive value 86%; 90%; 94.5%, negative predictive value 70.5%; 64%; 72% and accuracy 82.5%; 82.5%; 87.5% respectively. The efficacy of WBC (abnormal > 12500/mm3; > 15000/mm3; > 12500/mm3 and increasing in two consecutive days) and ESR (abnormal > 60 mm/h; > 60 mm/h and increasing in two consecutive days) serial evaluations was significantly lower. Moreover, in cases of chorioamnionitis CRP increased above the upper limit of normal 3 days earlier than WBC or ESR. S: CRP was found the most reliable indicator of histologic chorioamnionitis and indicated the presence of intrauterine infection earlier than WBC or ESR.
PregnancyTocolytic TherapyBeta-Mimetic AgentsOff-Label Use in Pregnancy
beta-mimetics have been prescribed by physicians to arrest or prevent premature labor for more than 20 years. Although not approved by the Food and Drug Administration (FDA) for tocolytic use, terbutaline sulfate has been the most widely prescribed beta-mimetic in the United States. Recently, the role of terbutaline in the treatment and prevention of preterm labor has been questioned by the FDA. Because the off-label use of drugs is a formally accepted practice in medicine when scientific studies support such use, we reviewed the currently available clinical literature on terbutaline use intravenous, oral, and subcutaneous via infusion pump. This review describes the clinical evidence that supports the safe and effective use of terbutaline as a tocolytic agent in certain patient populations. Practicing physicians should continue to have unrestricted use of terbutaline for tocolysis as one of the few remaining therapeutic options remaining in the fight against preterm birth.
PCOSUltrasound MorphologyOvarian Stromal ChangesTransvaginal Ultrasonography in PCOS
To investigate the relationship between the ovarian stromal area and clinical hormonal characteristics in women with polycystic ovary syndrome (PCOS). Twenty-eight women with PCOS (group 1) and 26 healthy women (group 2) participated in this study. For measuring the ovarian stromal area, transvaginal ultrasonography was performed on all women during the early follicular phase of the menstrual cycle. Venous blood was sampled from the women to determine serum follicle stimulating hormone, luteinizing hormone (LH), estradiol, androstenedione, free testosterone (FT), total testosterone (TT), 17 alpha-hydroxyprogesterone, dehydroepiandrosterone sulfate, and fasting insulin and glucose levels. Two-tailed t and Pearson correlation tests were used for statistical analysis. Women with PCOS were heavier, and their serum FT, TT and LH levels were significantly higher than in the normals (P < .001, P < .012 and P < .001, respectively). The ovarian stromal area measured by transvaginal ultrasonography was also significantly larger than in the normals (P < .001). Only basal serum insulin levels seemed to correlate positively with the ovarian stromal area in women with PCOS (r = .43 P = .09). Although transvaginal ultrasonography has played an important role in the evaluation of women with PCOS, we could not demonstrate a relationship between the ovarian stromal area and hormonal characteristics of PCOS. Therefore, transvaginal ultrasonography and hormonal parameters must be used as complementary diagnostic methods in women with PCOS.
Hormone replacement therapy (HRT, estrogen plus progestagen) in postmenopausal women has beneficial effects on the cardiovascular system. However, effects on blood pressure, determined with office measurements, remain controversial. We studied the effects of HRT in 29 healthy normotensive postmenopausal women (mean age 52.3 [3.8] years, median duration of amenorrhea 34.5 months), using ambulatory blood pressure monitoring at baseline and at 3 and 12 months of follow-up. Women an HRT group (N = 14), treated with 1 mg 17beta-estradiol once daily and 5 or 10 mg dydrogesterone once daily during the third and fourth week of every 4 weeks; and a control group (C-group, N = 15), which did not receive therapy. Blood pressures did not differ between the groups at baseline (HRT group 117.1 (9.2)/74.4 (6.6) mm Hg, C-group 113.8 (11.2)/71.3 (7.4) mm Hg). During the follow-up period, changes from baseline of office blood pressures did not differ significantly between the groups. However, changes (95% CI) of mean 24-h blood pressures differed significantly between the two groups after 1 a decrease of blood pressures was observed in the HRT group (delta systolic/delta diastolic = -5.54 [-8.86 to -2.21]/-4.23 [-6.66 to -1.80] mm Hg), whereas an increase was found in the C-group (+3.33 [-0.69 to +7.35]/+1.67 [-1.75 to +5.09] mm Hg; P [HRT v control group] = .001/.005). We conclude that HRT may have blood pressure lowering properties in healthy, normotensive postmenopausal women.
To investigate the incidence of complications in the use of assisted reproductive technology in the management of infertile couples. Retrospective study. The Egyptian IVF & ET Center, Maadi, Cairo, Egypt. PATIENT(S): Two thousand nine hundred twenty-four patients underwent IVF-ET or intracytoplasmic sperm injection (ICSI) in 3,500 cycles. INTERVENTION(S): IVF-ET, ICSI, ejaculate sperm, epididymal sperm aspiration, and testicular sperm extraction. MAIN OUTCOME MEASURE(S): Complications of the procedure and complications of pregnancy in 702 patients. RESULT(S): Fifteen hundred ovum pickups for IVF-ET and 2,000 ovum pickups for ICSI were performed. Clinical pregnancy occurred in 1,078 patients (30.8%). Four groups of complications were identified. Complications of the procedure occurred in 291 patients (8.3%). Complications of pregnancy included ectopic pregnancy in 1.9%, heterotopic pregnancy in 0.2%. abortion in 20.6%, multiple pregnancy in 28%, pregnancy-induced hypertension in 10%, preterm labor in 21.5%, low birth weight in 30.5%, and intrauterine death in 2%. Coincidental complications occurred in five patients (0.15%). Other complications that were difficult to measure included psychological breakdown and socioeconomic problems. CONCLUSION(S): Assisted reproductive technology is effective for the management of infertility and has an acceptable incidence of complications. Complications rarely endanger the life of the patient. When this line of treatment is offered, the indications should be definitive. Patients should be monitored properly and measures should be taken to minimize the incidence of complications.
PregnancyGroup B Streptococcus ProphylaxisAntibiotic Resistance ConsequencesEarly-Onset Sepsis
Recommendations for the use of antenatal antibiotics in obstetrics have increased in the past few years, especially for prophylaxis against group B streptococci, for prolongation of the latency time in patients with preterm premature rupture of the membranes, and as an adjuvant treatment in preterm labor. Our objective was to determine whether the use of antenatal ampicillin affects the incidence of and resistance of early-onset neonatal sepsis with organisms other than group B streptococci. A prospective cohort study was performed between January 1, 1991, and December 31, 1996. Every case of blood culture-proven neonatal sepsis was prospectively surveyed. The type of bacteria isolated, drug resistance, antenatal antibiotic use and treatment indication, gestational age at delivery, and other antenatal and outcome variables were gathered. Early-onset neonatal sepsis was defined as disease onset within 7 days after birth. A total of 42 cases of early-onset neonatal sepsis among 29,897 neonates delivered were found during the 6-year period. Of these, 15 cases were due to group B streptococci and 27 were the result of non-group B streptococcal organisms (21 gram-negative rods and 6 gram-positive cocci). Among the 27 non-group B streptococcal cases, 15 mothers had received antenatal ampicillin and 13 of the 15 bacterial isolates from these neonates (87%) were resistant to ampicillin, versus only 2 ampicillin-resistant isolates (17%) among the 12 cases in which no antenatal antibiotics were administered (P = .0004). Of the 15 mothers who were treated with ampicillin, 13 received more than 1 dose. In evaluating each year of the study, the overall administration of antibiotics to pregnant women in the antenatal period increased from <10% in 1991 to 16.9% in 1996. The incidence of early-onset neonatal sepsis with group B streptococci decreased during this time, whereas the incidence of early-onset sepsis with non-group B streptococcal organisms, especially Escherichia coli, increased. The increased administration of antenatal ampicillin to pregnant women may be responsible for the increased incidence of early-onset neonatal sepsis with non-group B streptococcal organisms that are resistant to ampicillin. At this time penicillin G, rather than ampicillin, is therefore recommended for prophylaxis against group B streptococci. In addition, future studies are needed to determine whether alternate approaches, such as immunotherapy or vaginal washing, could be of benefit.
Menstrual CycleAnovulation and Systemic DiseaseChronic Fatigue SyndromeImmunomodulatory Effects
A case-control study was conducted to determine whether menstrual and gynecologic abnormalities precede the onset of chronic fatigue syndrome (CFS) in women with this disorder to a greater extent than that observed among healthy controls. We identified 150 women who met the 1988 Centers for Disease Control criteria for CFS from the Brigham and Women's Hospital Cooperative CFS Research Center. A comparison group of 149 women being seen for nongynecologic conditions were selected from the waiting area of the Brigham and Women's Hospital Internal Medicine outpatient department. Women with and without CFS completed self-administered questionnaires on menstrual, reproductive, and medical history. Women with CFS reported increased gynecologic complications and a lower incidence of premenstrual symptomatology. After adjustment for age, a somewhat greater number of cases compared with controls self-reported irregular cycles, periods of amenorrhea, and sporadic bleeding between menstrual periods. Factors suggestive of abnormal ovarian function--such as a history of polycystic ovarian syndrome, hirsutism, and ovarian cysts--were reported more often in CFS cases compared with controls. Frequent anovulatory cycles due to ovarian hyperandrogenism (PCOS) or hyperprolactinemia may increase risk for CFS through loss of the potential immunomodulatory effects of progesterone in the presence of continued estrogen production. We hypothesize that frequent anovulatory cycles due to PCOS and/or hyperprolactinemia may explain the increased reporting of gynecologic complications and the lower reported premenstrual symptomatology observed in women with CFS.
Perimenopause/MenopauseVascular EffectsDoppler Ultrasound AssessmentOral vs Transdermal Comparison
To compare the long-term effects of oral and transdermal hormone replacement therapy (HRT) on carotid and uterine vascular impedance. Sixty-three postmenopausal women were randomized to 1 year's treatment with oral or transdermal sequential combined HRT. Carotid and uterine artery pulsatility indices (PIs) were assessed by color Doppler at baseline, and after 2, 6, and 12 months of treatment. Fifty-eight women completed the trial, 27 in the oral and 31 in the transdermal group. In a subgroup of 30 women, we also performed Doppler measurements in the estrogen-progestin combined phase. The study had 90% power to detect a difference between treatment groups of 0.05 in the carotid artery and of 0.25 in uterine artery PI at the 5% significance level. The carotid PI decreased significantly (P < .001) and similarly during both regimens. This drop was already clearly detectable during the second month, from 0.97 (0.95, 1.01) (mean and 95% confidence intervals [CII) to 0.94 (0.91, 0.97) in the oral and from 0.98 (0.94, 1.00) to 0.92 (0.89, 0.95) in the transdermal group, but it continued up to 12 months (0.85 [0.82, 0.88], 13% of baseline values in the oral group and 0.84 [0.81, 0.871, 14% in the transdermal group). In the uterine arteries, the drop in PI was steeper and greater and reached its maximum at 6 months (39% and 40%, respectively). Drops in carotid and uterine PI correlated positively with baseline PI values, but were not affected by patient age, time from menopause, previous HRT and smoking. Addition of norethisterone acetate did not counteract drops in carotid and uterine PI in either group. Oral and transdermal sequential HRT are similarly effective at 1 year in reducing impedance to flow in carotid and uterine circulation. This long-term vascular effect might explain how HRT protects women from cardiovascular disease.
Ovarian stimulation for in-vitro fertilization (IVF) causes development of several cohorts of follicles. At the time of oocyte collection, oocytes are thus retrieved from a wide range of follicles of different sizes and developmental stages. A relationship between size of follicles and pregnancy rates has earlier been demonstrated. The aim of the present study was to compare fertilization, cleavage and pregnancy rates between oocytes retrieved from large and small follicles in conventional IVF and intracytoplasmic sperm injection (ICSI). A total of 200 conventional IVF patients and 175 ICSI patients underwent oocyte retrieval where oocytes from both large and small follicles were collected. A follicle with a volume of > or = 2 ml, corresponding to a follicular diameter > or = 16 mm as determined by ultrasound, was regarded as a large follicle. Only one cycle from each patient was included. Fertilization and cleavage rates were calculated per patient for oocytes from large and small follicles. The mean fertilization and cleavage rates for conventional IVF and ICSI cycles were calculated. Comparison of pregnancy rates was performed for patients receiving embryos derived from oocytes of only large or only small follicles. For conventional IVF patients, fertilization rates were 71.4 and 58.1% (P < 0.01, Wilcoxon paired test) for oocytes of large and small follicles respectively. The corresponding cleavage rates were 95.4 and 93.9% respectively. The pregnancy rate for the two groups was 47% (60/127) and 15% (2/13) (P < 0.05, chi2 test). For ICSI patients the fertilization rate was 72.0 and 71.1% for oocytes of large and small follicles respectively. The corresponding cleavage rate was 93.0 and 91.1%. The pregnancy rate in the two groups was 41% (46/113) and 42% (5/12). The results show that oocytes from smaller follicles also yield fertilization and pregnancies, although in conventional IVF to a lesser extent than oocytes from larger follicles. For IVF cycles, a higher proportion of immature oocytes (which are normally not included in the ICSI procedure) in the group of oocytes from small follicles is most probably the explanation for the lower fertilization rate. The decrease in pregnancy rate with oocytes from small follicles in the IVF cycles was not observed in the ICSI cycles. The possibility of evaluating the degree of oocyte maturation prior to fertilization may be an advantage of the ICSI technique. This suggests that the disadvantages of oocytes from small follicles might be overcome by means of ICSI.
After menopause, both systolic (SBP) and diastolic (DBP) blood pressure (BP) become higher in women than in men of the same age, suggesting that estrogen deficiency may influence the age-related increase in BP. We studied 30 postmenopausal women (mean age, 55 +/- 5.7 years; time from menopause, 2-5 years) affected by mild hypertension with no target-organ complications by means of 24-h BP monitoring. None of the group were undergoing estrogen replacement therapy or taking antihypertensive drugs. According to a randomized, double-blind protocol, subjects received patches of transdermal estradiol-17beta (E2) or a matched placebo, with crossover after a 7-day washout period. In 12 patients the 24-h peak-to-trough variation in SBP and DBP amounted to less than 10% (nondippers). Administration of E2 significantly decreased 24-h SBP and DBP in the whole cohort (P < .05). Furthermore, E2 restored the expected reduction in BP during nighttime in the nondipper subgroup. It is well known that estrogen replacement therapy protects against the development of both cardiovascular diseases and stroke. Our data suggest that this activity could be attributed, at least in part, to the activity of E2 in preserving physiologic circadian fluctuation of BP.
PCOSInsulin Resistance ScreeningHyperinsulinemiaGlucose-Insulin Ratio
Women with polycystic ovary syndrome (PCOS) are profoundly insulin resistant, and the resultant hyperinsulinemia exacerbates the reproductive abnormalities of the syndrome. Agents that ameliorate insulin resistance and reduce circulating insulin levels could provide a new therapeutic modality for PCOS. Identifying the subset of PCOS women who are most insulin resistant may therefore be useful for selecting women who will respond to this therapy. We examined the correlation of basal and oral glucose-stimulated glucose and insulin levels and fasting and stimulated glucose/insulin (G:I) ratios with parameters of insulin sensitivity obtained by frequently sampled i.v. glucose tolerance test (FSIGT) to assess whether there is a simple screening test for insulin resistance in PCOS. Forty PCOS women (aged 18-40 yr; body mass index, >26 kg/m2) and 15 control women matched for age, weight, and ethnicity underwent both a 75-g oral glucose tolerance test (OGTT) and a FSIGT. The insulin sensitivity index (S(I)) was calculated by application of the minimal model of glucose kinetics to the dynamics of plasma glucose and insulin levels during the FSIGT. The best correlation in PCOS between S(I) and a fasting I ratios (r = 0.73; P < 0.0001). A less substantial, but significant, correlation was found with fasting insulin levels (r = 0.50; P < 0.001), and no significant correlation was found with fasting glucose levels (r = 0.24; P = NS). I was more strongly correlated with S(I) than with integrated glucose and insulin responses during the OGTT. The only stronger correlation was with the OGTT 2 h G:I ratio (r = 0.74; P < 0.001). Stepwise regression analysis with S(I) as the dependent variable and fasting glucose and insulin levels, area under the curve for glucose and insulin, I ratio I ratio was significantly predictive of S(I) in the model (F to remove value = 38.1; P < 0.001). When viewed as a screening test for insulin resistance in PCOS, setting a I ratio of less than 4.5 as abnormal (using an S(I) value below the 10th percentile of our control population as evidence for insulin resistance), I ratio was 95%, the specificity was 84%, the positive predictive value was 87%, and the negative predictive value was 94%. Receiver operator curve analysis I ratio was the single best screening measure for detecting insulin resistance. I ratio may be useful as a screening test for insulin resistance in obese non-Hispanic white PCOS women. This may be a clinically useful parameter for selecting PCOS women most likely to respond to therapeutic interventions that improve insulin sensitivity.
I. Introduction II. Defining the Perimenopause III. Classic Studies of the Perimenopause A. Historical studies B. Early reports of women’s experiences in the perimenopause C. Early prospective menstrual cycle interval and basal temperature documentation IV. Prospective Epidemiological Studies of the Perimenopause A. Manitoba Project on Women and Their Health in the Middle Years B. Massachusetts Women’s Health Study C. Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) Study V. Systematic Studies of the Endocrinology of the Perimenopause A. Cross-sectional (single-cycle) hormonal studies in the perimenopause B. Prospective ovarian hormonal levels in the perimenopause VI. Histological Studies of Ovarian Changes Across the Lifespan VII. Physiological Studies of Changing Ovarian Hormones in Women in Their Forties and Fifties A. Folliculogenesis and ovarian hyperstimulation for in vitro fertilization (IVF) B. Inhibin physiology in women over forty VIII. Hypotheses to Explain Perimenopausal Endocrinology A...
Observational studies have found lower rates of coronary heart disease (CHD) in postmenopausal women who take estrogen than in women who do not, but this potential benefit has not been confirmed in clinical trials. To determine if estrogen plus progestin therapy alters the risk for CHD events in postmenopausal women with established coronary disease. Randomized, blinded, placebo-controlled secondary prevention trial. Outpatient and community settings at 20 US clinical centers. A total of 2763 women with coronary disease, younger than 80 years, and postmenopausal with an intact uterus. Mean age was 66.7 years. Either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily (n = 1380) or a placebo of identical appearance (n = 1383). Follow-up averaged 4.1 years; 82% of those assigned to hormone treatment were taking it at the end of 1 year, and 75% at the end of 3 years. The primary outcome was the occurrence of nonfatal myocardial infarction (MI) or CHD death. Secondary cardiovascular outcomes included coronary revascularization, unstable angina, congestive heart failure, resuscitated cardiac arrest, stroke or transient ischemic attack, and peripheral arterial disease. All-cause mortality was also considered. Overall, there were no significant differences between groups in the primary 172 women in the hormone group and 176 women in the placebo group had MI or CHD death (relative hazard [RH], 0.99; 95% confidence interval [CI], 0.80-1.22). The lack of an overall effect occurred despite a net 11% lower low-density lipoprotein cholesterol level and 10% higher high-density lipoprotein cholesterol level in the hormone group compared with the placebo group (each P<.001). Within the overall null effect, there was a statistically significant time trend, with more CHD events in the hormone group than in the placebo group in year 1 and fewer in years 4 and 5. More women in the hormone group than in the placebo group experienced venous thromboembolic events (34 vs 12; RH, 2.89; 95% CI, 1.50-5.58) and gallbladder disease (84 vs 62; RH, 1.38; 95% CI, 1.00-1.92). There were no significant differences in several other end points for which power was limited, including fracture, cancer, and total mortality (131 vs 123 deaths; RH, 1.08; 95% CI, 0.84-1.38). During an average follow-up of 4.1 years, treatment with oral conjugated equine estrogen plus medroxyprogesterone acetate did not reduce the overall rate of CHD events in postmenopausal women with established coronary disease. The treatment did increase the rate of thromboembolic events and gallbladder disease. Based on the finding of no overall cardiovascular benefit and a pattern of early increase in risk of CHD events, we do not recommend starting this treatment for the purpose of secondary prevention of CHD. However, given the favorable pattern of CHD events after several years of therapy, it could be appropriate for women already receiving this treatment to continue.
Contraception/ComparisonGastrointestinal Side EffectsInflammatory Bowel Disease RiskProtective Health Effects
Using data from a case-control study carried out in Italy 1989-1992, we estimated the odds ratios (OR) and the population attributable risks (AR) for inflammatory bowel diseases (IBD) in relation to smoking, oral contraception and breastfeeding in infancy. The study focused on 819 cases of IBD (594 UC; 225 Crohn's CD) originating from populations resident in 10 Italian areas, and age-sex matched paired controls. Compared with non-smokers, former smokers were at increased risk of UC (OR = 3.0; 95% confidence interval [CI]: 2.1-4.3), whereas current smokers were at increased risk of CD (OR = 1.7; 95% CI: 1.1-2.6). Females who reported use of oral contraceptives for at least one month before onset of symptoms had a higher risk of CD (OR = 3.4; 95% CI: 1.0-11.9), whereas no significant risk was observed for UC. Lack of breastfeeding was associated with an increased risk of UC (OR = 1.5; 95% CI: 1.1-2.1) and CD (OR = 1.9; 95% CI: 1.1-3.3). Being a 'former smoker' was the factor with the highest attributable risk of UC both in males (AR = 28%; 95% CI: 20-35 %) and in females (AR = 12%; 95% CI: 5-18%). Smoking was the factor with the highest attributable risk for CD in males (AR = 31%; 95% CI: 11-50%). Lack of breastfeeding accounted for the highest proportion of CD in females (AR = 11%; 95% CI: 1-22%). Oral contraceptive use accounted for 7% of cases of UC and for 11% of cases of CD. Taken together, the considered factors were responsible for a proportion of IBD ranging from 26% (CD females) to 36% (CD males). It is concluded that other environmental and genetic factors may be involved in the aetiology of IBD.
Ciampelli M et al., 1998·Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology
In recent years the metabolic implications of polycystic ovary syndrome (PCOS) have received a great deal of attention; in fact 50% of women with PCOS are obese and a similar percentage of subjects was found to show exaggerated insulin secretion and reduced insulin-stimulated glucose uptake. The presence of these features in women with PCOS has profound clinical implications in terms of morbidity due to diabetes mellitus, dyslipidemia, hypertension and cardiovascular disease. Moreover, hyperinsulinemia has recently been proposed as a possible independent risk factor for endometrial and breast cancer. In the light of these considerations, the importance of metabolic screening in patients with PCOS in order to improve their quality of life cannot be underestimated. In this review we analyze all the clinical pathologies in which hyperinsulinemia of PCOS could be involved. Furthermore, in order to clarify the possible mechanisms leading to the insulin disorders of the syndrome, we review the available data about the insulin receptor abnormalities, as well as those concerning the insulin resistance and the exaggerated insulin secretion. Finally, we examine the main therapeutic strategies to ameliorate the insulinemic status of PCOS patients in order to potentially be able to prevent the long-term consequences of this syndrome.
Preterm birth, which occurs in 11 percent of all pregnancies, is responsible for the majority of neonatal deaths and nearly one half of all cases of congenital neurologic disability, including cerebral palsy.1Although all births before 37 weeks of gestation are considered premature, births before 32 weeks' gestation (2 percent of all births) account for most neonatal deaths and disorders.2 State and national vital statistics indicate that the incidence of preterm birth has risen over the past 15 years (Figure 1), and it remains twice as high among black women as among white women.35 Preterm birth is commonly categorized . . .