Obstetrics and Gynecology, December 2001

Obstetrics and Gynecology, December 2001 journalScan osteoprosis,osteoporotic,osteoparosis,ossteoporosis,osteoperosis,osteoporesis,osteoporisis,osteporosi,osteoporis,ostoeporosis,osteoposoris,osteoporosis,osteop,osteoaporosis,osteoportic,ostioporosis,osteoporosos,osteperosis,osteoporiosis,osteoporosisj,ostoparosis,osteoporosi,osteoporoosis,osteoporosois,ostoperosis,osteoporsis,osteporosis,osteoporsosis,osteopotrosis,osteopoross,osteoporsos,osteoproisis,ostoporosis,osteoproosis,osteopprosis,orosis Peter Kovacs, MD, Albert Einstein College of Medicine, New York, NY. Medscape Medscape Ob/Gyn & Women's Health 12/19/2001 6 2 <H3>Obstetrics and Gynecology</H3>From Obstetrics and GynecologyNovember 2001 (Volume 95, Number 5)<h4>Venlafaxine in the Treatment of Premenstrual Dysphoric Disorder</h4> Freeman EW, Rickels K, Yonkers KA, Kunz NR, McPherson M, Upton GV Obstetrics and Gynecology. 2001;95(5):737-744<h3>Summary</h3> Venlafaxine, a selective serotonin and norepinephrine reuptake inhibitor, is effective in the treatment of premenstrual dysphoric disorder. Although a large group of women experience premenstrual symptoms, only about 3% to 5% of women are diagnosed with premenstrual dysphoric disorder (PMDD). Recently, changes in central nervous system neurotransmitter levels have been thought to play a role in the etiology of PMDD. Selective serotonin reuptake inhibitors (SSRIs) have been shown to be effective in the management of PMDD. This study evaluated the effects of venlafaxine, a selective serotonin and norepinephrine reuptake inhibitor, on PMDD. Women of reproductive age with premenstrual symptoms were evaluated for inclusion. Symptoms were evaluated by a daily symptom report. Initial evaluation was performed in the postmenstrual phase. A second screening was performed in the luteal phase of the menstrual cycle. Major psychiatric disease was ruled out by a thorough psychiatric evaluation. After the 2 initial screenings, potential candidates were placed on placebo for 1 month. Patients who remained eligible after this month of placebo use were randomly assigned to venlafaxine or placebo. The starting dose was 50 mg venlafaxine, which was increased if response was suboptimal. Participants were followed for 4 treatment cycles. Data were collected for daily symptom scores and depression scores. Women on other medications for PMDD were not eligible. Out of 164 women screened, data were available on 143 (venlafaxine n = 68, placebo n = 75). Baseline characteristics were similar, except for higher daily symptom scores in the venlafaxine group. Discontinuation rates were similar in the 2 groups (35% vs 36%). Improvement in daily symptom scores was significantly greater in the venlafaxine group. This improvement was already evident in the first treatment cycle. Overall improvement was 57% in the venlafaxine group and 31% in the placebo group. The depression score also significantly improved with venlafaxine. The study medications were overall well tolerated, but insomnia, dizziness, decreased libido, and nausea were more frequent in the venlafaxine group. In conclusion, this study showed that venlafaxine, a selective serotonin and norepinephrine reuptake inhibitor, is effective in the treatment of PMDD. <H3>Clinical Commentary</H3> About 30% to 40% of women experience various premenstrual symptoms during the menstrual cycle. These symptoms typically occur in the luteal phase and disappear with onset of menses. There are many symptoms identified as premenstrual symptoms; some affect mood and some are somatic. In about 3% to 5% of women, these symptoms interfere with their everyday activity; these women are diagnosed with PMDD. Several hypotheses exist linking premenstrual symptoms to various metabolic changes, to breakdown products of progesterone, and most recently to changes in neurotransmitter levels. Currently available effective treatments are calcium and SSRIs. Certain somatic symptoms can be individually treated; for example, severe bloating or breast tenderness can be treated with diuretics. This study tested a new drug, venlafaxine, a selective serotonin and norepinephrine reuptake inhibitor, in the management of PMDD. The study has a prospective, randomized, double-blind, placebo-controlled design. Patients were self-referred; they were requesting treatment for PMDD. Their symptoms were thoroughly evaluated, both in the premenstrual and postmenstrual phase. Women with major psychiatric disease were excluded. After screening, patients were randomly assigned to treatment. Despite the randomization, symptom scores were still higher in the venlafaxine group. This difference was accounted for during analysis. There was a considerable positive effect with placebo alone, but venlafaxine proved to be superior in all treatment cycles, with ultimately close to 60% of participants improving. Medications were taken every day. It has been shown that SSRI given in luteal phase only is as effective as with continuous use. It is unknown, however, what effect this intermittent inhibition of serotonin uptake has on central nervous system function. It would be interesting to see whether intermittent venlafaxine use has similar beneficial effects. With intermittent use, tolerance to the drug can be reduced. Venlafaxine was generally well tolerated, but certain bothersome side effects were more common with its use. This could compromise the benefits that it offers. It would be interesting to know whether venlafaxine is superior to SSRIs in the management of PMDD. Future studies will have to address these questions. Overall venlafaxine improved daily premenstrual symptom scores and depression scores in women with PMDD.<A HREF="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11704162&dopt=Abstract">Abstract</A><CENTER><HR WIDTH=50%></CENTER><h4>Efficacy and Safety of a Transdermal Contraceptive System</h4> Smallwood GH, Meador ML, Lenihan JP, Shangold GA, Fisher AC, Creasy GW; Ortho Evra/Evra 002 Study Group Obstetrics and Gynecology. 2001;95(5):799-805<h3>Summary</h3> The contraceptive patch was well tolerated, had good cycle control, and provided effective contraception. Hormonal contraception is highly effective in preventing pregnancies in clinical trials, but a higher failure rate is usually associated with typical use, mostly as a result of incorrect use. If compliance with hormonal contraception increased, the contraceptive efficacy would improve as well. This study evaluated the contraceptive efficacy, cycle control, and safety profile of a transdermal contraceptive system. The Ortho Evra transdermal patch delivers 150 mcg norelgestromin and 20 mcg ethinyl estradiol daily. This study was a prospective, multicenter, open-label, noncomparative study; 1754 healthy, reproductive age women were enrolled at 73 clinical sites. Data were available from 1672 subjects. Women who were sexually active, at risk for pregnancy, and had regular menstrual cycles were included. Those who were taking any other hormonal preparations or had a contraindication to steroid use were not eligible. The patch was applied to the upper torso (except for breast), to the buttocks, or to the upper arm. If a patch accidentally detached, it was replaced with another. Patients were instructed to follow their everyday routine, including their regular physical activities (eg, exercise, swimming). Three weeks of patch use was followed by a patch-free week. Patients were asked to record any bleeding or any adverse effect daily on report cards. Data were collected for pregnancy rates, the number of bleeding, spotting days, and adverse effects. Seventy-two percent of the participants completed the study. They used the contraceptive patch for 6 or 13 months. There were 6 pregnancies in over 10,000 cycles. The overall probability of pregnancy over 13 cycles was 0.7%. Pregnancy rates resulting from method failure (n = 5) were 0.4%. The overall Pearl index was 0.71. Breakthrough bleeding was rare (1.5% to 3.7% in various cycles). Breakthrough bleeding or spotting occurred in 17.5% of cycles in the first month and in < 10% of cycles from cycle 6 onward. Adverse events were rare and generally mild. The most common adverse events were nausea, headache, emotional lability, breast tenderness, and application-site reaction. The contraceptive patch was well tolerated, had good cycle control, and provided effective contraception. <H3>Clinical Commentary</H3> Several contraceptive methods are currently available. Some are reversible, some are irreversible, and their efficacy varies. Efficacy is also lower with typical use when compared with perfect use. Despite the various available methods, still 50% of pregnancies are unintended, and 50% of those are terminated. Hormonal methods are very effective when used properly. Unfortunately many women discontinue their use because of side effects or fear of serious adverse effects. A disadvantage of oral contraceptive pills (OCPs) is that they need to be taken every day, and if pills are missed their efficacy is compromised. This study evaluated a transdermal delivery system of steroid hormones that only needs to be changed once a week. Contraindications to patch use were similar to contraindications to OCP use. Women were allowed to follow their everyday routine. There was only a 1.9% complete detachment rate. This is reassuring because women were allowed to exercise and swim while wearing the patch. A separate study evaluated detachment rates in different climate and exercise conditions and reported similar low rates. The incidence of local skin reaction was low. There were 6 pregnancies in over 10,000 cycles, and the overall pregnancy rate was very low. However, this could reflect better compliance by motivated participants in a study setting. Pregnancy rates are expected to be higher with typical use. Participants had to be within 35% of their ideal body weight. Four of the 6 pregnancies occurred among women with a body weight > 90 kg. It would be interesting to know why mainly normal weight participants were enrolled and what the efficacy is among obese users. Side effects were generally rare. Unexpected bleeding was the most common; it occurred in 17.5% of first cycles. It is important to counsel women about side effects before they initiate hormone use. Most of these side effects disappear by the third month. This was seen in this trial as well, with unexpected bleeding in 11% of cycles at the third month and in fewer than 10% thereafter. Studies should also evaluate the noncontraceptive benefits of the transdermal contraceptive patch. In conclusion, the contraceptive patch is safe and highly effective. With this more patient-friendly method (once-weekly use), compliance and success should improve.<A HREF="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11704172&dopt=Abstract">Abstract</A><CENTER><HR WIDTH=50%></CENTER><h4>Menstrual Reduction With Extended Use of Combination Oral Contraceptive Pills: Randomized Controlled Trial</h4> Miller L, Notter KM Obstetrics and Gynecology. 2001;95(5):771-778<h3>Summary</h3> Extended OCP use was well tolerated and resulted in less bleeding/ spotting episodes and fewer bleeding days. Currently OCPs are used in 28-day cycles; however, continuing the active pills during the standard pill-free week could reduce the frequency of withdrawal bleeding. This study evaluated bleeding patterns, patient satisfaction, and compliance with extended OCP use. Reproductive age women with no contraindication to hormone use were eligible. They were recruited at 4 study sites and randomly assigned to the usual 28-day cycle or to an extended, 49-day cycle. Patients and providers were not blinded to assignment. They all used the same OCP (30 mcg ethinyl estradiol + 300 mcg norgestrel). Patients kept a diary and recorded pill taking, adverse events, and bleeding/spotting days. The study period was 12 months; data were analyzed on the basis of trimesters (84 days). Ninety women were randomized, 53 completed the study (28-day group n = 24; 49-day group n = 29). Dropout was mainly attributed to loss to follow-up. Baseline demographic characteristics (age, body mass index [BMI], parity, smoking habits, and education) were similar. The number of bleeding and bleeding/spotting episodes was lower in the extended OCP group in all 4 trimesters. The number of spotting days was not different. The number of bleeding days was lower in the 49-day group in all 4 trimesters. Reduced bleeding was reflected in reduced use of sanitary products in the 49-day group. Amenorrhea, frequent menses, or prolonged menses rates were similar. Compliance with pill taking did not differ between the 2 groups. Weight gain was greater in the 28-day group, but the difference was not statistically significant (5 lbs vs 1 lb). Side effects were overall infrequent; headaches and tiredness were more common in the 28-day group. Those who completed the study were equally satisfied with their method. In conclusion, extended OCP use was well tolerated and resulted in fewer bleeding/spotting episodes and fewer bleeding days. <H3>Clinical Commentary</H3> Most of the women at some point during their reproductive years will use OCPs. Used appropriately, hormonal methods are highly effective and also provide noncontraceptive benefits. There are some side effects (nausea, headache, mood changes, and breast tenderness) associated with OCP use. Side effects typically occur during the first 3 months of use and thereafter become less frequent and less bothersome. Breakthrough bleeding and spotting also typically occur in the first 3 months of use. The benefit of extended use would be a reduction of premenstrual symptoms and reduction in menstrual blood loss. Earlier studies reported increased frequency of intermittent spotting with extended OCP use, but this could be an acceptable trade-off for women who have significant premenstrual symptoms. This study evaluated the frequency and severity of bleeding episodes with extended use and compared with bleeding episodes with the 28-day use. Patients were similar at baseline and were randomly assigned to the 2 alternative regimens. They were not blinded to treatment assignment, however, possibly introducing reporting bias. Compliance was similar with both methods, and even in this research setting, there was more than a 50% dropout. Data analysis was based on trimesters of 84 days. This could bias the results, because with the 49-day regimen there would be only 1 scheduled withdrawal in the first and fourth trimesters. The trimesters were not compared with each other within the 49-day group to assess for such an effect, although the crude numbers suggest increased number of bleeding or spotting episodes in the 2nd and 3rd trimesters. Similar differences are not seen with the 28-day schedule. The total number of bleeding days was reduced in all 4 trimesters with the extended use. The difference was barely significant in the 2nd (P = .05) and 3rd (P = .03) trimesters, although the reduction in sanitary product use suggests fewer bleeding episodes. Extending the active pill use has several benefits. It allows a convenient withdrawal-bleeding schedule and could reduce blood loss in cases of bleeding disorders. Women who have severe dysmenorrhea or severe premenstrual symptoms may also benefit from such use. This was not analyzed in this report.<A HREF="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11704167&dopt=Abstract">Abstract</A><CENTER><HR WIDTH=50%></CENTER><H3>Human Reproduction</H3>From Human ReproductionDecember 2001 (Volume 16, Number 12)<h4>Polycystic Ovary Syndrome and the Risk of Spontaneous Abortion Following Assisted Reproductive Technology Treatment</h4> Wang JX, Davies MJ, Norman RJ Human Reproduction. 2001;16(12):2606-2609<h3>Summary</h3> Patients with polycystic ovary syndrome (PCOS) were more likely to miscarry; however, this increased risk was not independent from other confounding variables. This study evaluated an association between spontaneous abortion and PCOS. Patients undergoing infertility treatment from 1987-1999 were included. Data were collected for age, BMI (kg/m2), indication for infertility treatment, method of treatment (IVF vs intracytoplasmic sperm injection [ICSI] vs gamete intrafallopian transfer [GIFT]), maximum estradiol during ovarian stimulation, history of previous miscarriage, and the presence or absence of PCOS. PCOS was diagnosed on the basis of elevated serum androgen levels and an ultrasound finding of multiple small follicles (polycystic appearance). All patients underwent similar ovarian hyperstimulation. About 5% of women in each group had GIFT; the rest underwent ICSI or IVF. Data were available from 1018 pregnancies. There were 373 pregnancies among PCOS patients and 645 among non-PCOS patients. Non-PCOS patients had the diagnosis of male factor infertility, tubal infertility, unexplained infertility, or endometriosis. At baseline, women with PCOS were younger, had higher BMI and higher maximum estradiol levels, and were more likely to have a history of spontaneous miscarriage. Twenty-one percent of the pregnancies were miscarried. The risk of spontaneous abortion was 25% in the PCOS group and 18% in the non-PCOS group. A univariate analysis, not controlling for other confounding factors, showed an increased incidence of spontaneous abortion with increasing age, with higher estradiol levels, with increasing BMI, with past history of miscarriage, and with the diagnosis of PCOS. The risk of miscarriage was reduced for cycles in which ICSI was performed. Because PCOS patients were younger, had higher BMI, and were more likely to have a history of miscarriage, a multivariate analysis controlling for these factors was performed. This multivariate analysis showed that PCOS alone (after controlling for other confounding variables) was no longer associated with higher spontaneous abortion rates. In conclusion, women with PCOS were more likely to miscarry; however, this increased risk was not independent from other confounding variables. <H3>Clinical Commentary</H3> Several studies have assessed the risk of spontaneous abortion among women with PCOS. Most studies showed an increased risk. PCOS typically is diagnosedon the basis of clinical or laboratory evidence of hyperandrogenism and ovulatory dysfunction. This study diagnosed patients on the basis of hyperandrogenism and ovarian morphology. European studies tend to diagnose patients on the basis of polycystic ovarian morphology; however, not all PCOS patients will have such an ovarian structure, and many women with polycystic ovaries do not fit the diagnosis of PCOS. The current study does not report menstrual irregularities among PCOS patients. More than 50% of PCOS subjects will have various degrees of insulin resistance; this also was not evaluated . There was an overall 21% miscarriage rate in this study. There were important differences between the PCOS and non-PCOS patients at baseline. Some of these factors (eg, age, history of miscarriage) are known to affect the risk of spontaneous abortion. Several of these important confounding variables (age, weight, history of miscarriage) were taken into account in the final analysis. However, other important factors were not evaluated. With uterine cavity abnormalities, there is an increased incidence of miscarriage. There are known endocrine factors that affect spontaneous abortion rates (eg, luteal phase defect, thyroid abnormalities). Most miscarriages occur as the result of chromosomal abnormalities. Such an evaluation was not performed. Differences in factors that were not assessed could be responsible for the differences observed. After controlling for the confounding variables, PCOS was no longer independently associated with spontaneous abortions. Recently, several small studies evaluated the benefits of insulin-sensitizing medications in association with infertility treatment and PCOS. They showed improved ovulation rates, treatment outcome, and decreased miscarriage rates. However, such treatment has not been approved by the FDA. There are several factors that affect infertility treatment success rates among PCOS patients. It is important that these factors be identified before infertility treatment and that patients are counseled about their options, so as not to raise expectations too high.<A HREF="http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11726582&dopt=Abstract">Abstract</A><CENTER><HR WIDTH=50%></CENTER>From Human ReproductionNovember 2001 (Volume 16, Number 11)<h4>A Prospective Controlled Study of the Effect of Intramural Uterine Fibroids on the Outcome of Assisted Conception</h4> Hart R, Khalaf Y, Yeong CT, Seed P, Taylor A, Braude P Human Reproduction. 2001;16(11):2411-2417<h3>Summary</h3> After controlling for age and number of embryos transferred, the ongoing pregnancy rate was reduced among women with small intramural fibroids undergoing IVF-ET. Uterine myomas are common benign tumors. They are frequently found during infertility evaluation. They can be located submucosally, intramurally, or subserosally. The removal of submucosal myomas improves implantation and pregnancy rates in an in vitro fertilization (IVF) setting, but the effect of intramural fibroids on IVF outcome is not clear. This prospective study evaluated the effect of small intramural myomas on IVF outcome. All women undergoing infertility treatment were included in the analysis. A total of 322 women without fibroids and 106 women with intramural fibroids (< 5 cm) were evaluated. Cause of infertility, length of infertility, number of previous treatment cycles, and baseline follicle stimulating hormone (FSH) levels were similar. However, women with fibroids were older. The proportion of women older than 40 was also higher in the fibroid group (20.9% vs 8.8%). Saline hysterosonography was performed in women with fibroids to rule out a submucous component. Ovarian stimulation, oocyte retrieval, laboratory procedures, and embryo transfer (ET) technique were similar between the 2 groups. Cycle parameters and the number of embryos available for transfer were also similar. Implantation rates, clinical pregnancy rates, and ongoing pregnancy rates were significantly lower among women with fibroids. Logistic regression analysis revealed that after controlling for the number of embryos transferred and age, the clinical pregnancy rate was no longer different. There was a trend for reduced implantation rates after controlling for age and number of embryos transferred, but the difference did not reach statistical significance. The ongoing pregnancy rate was, however, reduced among women with intramural fibroids once age and number of embryos were controlled for (OR: 0.46 95% CI: 0.24-0.88). This prospective study showed that age and number of embryos transferred had a significant impact on pregnancy rates. Once age and number of embryos transferred were controlled for, the ongoing pregnancy rate was still reduced among women with small intramural fibroids undergoing IVF-ET. <H3>Clinical Commentary</H3> Uterine fibroids are benign tumors found in as many as 50% of women. Fibroids are frequently found in women undergoing infertility evaluation, although a cause-effect relationship with infertility has not been established. It has been shown, however, that removal of submucous myomas that distort the uterine cavity can improve pregnancy rates in an IVF setting. Several studies have tried to assess the effects of intramural fibroids on pregnancy rates and to evaluate whether removal of these tumors improves outcome. Different studies used different tumor size cutoffs to decide which myomas to remove and which ones not. There is very little information available on the effect of smaller fibroids on fertility. This study evaluated the association of < 5-cm myomas on pregnancy rates in an IVF setting. There was no group-specific intervention in the study; all patients received similar infertility treatment. Women with any etiology of infertility were included. Baseline characteristics were similar except for age. It is known that with increasing age of the woman, the success of infertility treatment is reduced. This was corroborated by this report. Women older than 40 had a significantly reduced chance of pregnancy. There were 2.5 times more women older than 40 in the fibroid group. To correct for age differences, the authors performed a logistic regression analysis. The number of embryos available for transfer was similar, but thereno data were presented on the quality of embryos. Embryo quality is also an important factor that determines success. Once age and number of embryos were controlled for, there was no difference in the implantation and clinical pregnancy rates, but the ongoing pregnancy rates were lower in the fibroid group. This suggests higher miscarriage rates; however, the number of miscarriages in the groups is not reported. Spontaneous miscarriage rates are also higher with increasing age of the woman. Most of these losses occur as the result of chromosomal abnormalities. Chromosomal studies were not performed. Without such evaluation, one cannot attribute the increased number of losses to the presence of uterine fibroids. To take it a step further, if we remove small intramural myomas with the hope of improving ongoing pregnancy rates, there will be a number of patients whose ovarian function will be affected as a result of the surgery. Currently there is no cause-effect relationship between intramural fibroids and infertility or subfertility. This study found that women with intramural fibroids have lower ongoing pregnancy rates; however, important confounding variables (genetic etiology of miscarriage) were not controlled for. Further studies accounting for all known confounding variables need to assess the association between intramural fibroids and fertility. If such an association is established, we still need to evaluate whether removal of those myomas has any beneficial effects.<A HREF="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11679530&dopt=Abstract">Abstract</A><CENTER><HR WIDTH=50%></CENTER><H3>JAMA</H3>From JAMANovember 14, 2001 (Volume 286, Number 18)<h4>Tamoxifen and Breast Cancer Incidence Among Women With Inherited Mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial</h4> King MC, Wieand S, Hale K, et al. JAMA. 2001;286(18):2251-2256<h3>Summary</h3> Tamoxifen use for breast cancer prevention by women older than 35 years of age seemed to have a beneficial effect among BRCA2 mutation carriers but did not have the same protective effect among BRCA1 mutation carriers. The Breast Cancer Prevention trial was conducted by the National Surgical Adjuvant Breast and Bowel Project. The trial was a randomized, prospective, placebo-controlled trial evaluating the effect of tamoxifen on breast cancer prevention among high-risk women. High-risk status was established by the Gail model. Women older than 35 years with a risk of 1.66% or greater based on the Gail model, those with lobular carcinoma in situ, and those older than 60 years were eligible for participation. The study showed a protective effect with tamoxifen use. There was about a 50% reduction in the risk of developing invasive breast cancer. This benefit was independent of family history. This study also evaluated the possible beneficial effects among carriers of BRCA1 or BRCA2 mutations. The risk of breast cancer is significantly higher among women with these mutations, and they tend to develop cancer at a younger age. Over 13,000 women were followed in the trial; mean follow-up was 5.7 years. Participants gave blood at enrollment, and it was stored for later analysis. During the follow-up period, 320 subjects developed invasive cancer. Blood tests were available for 288 (90%). Blood samples were tested for the presence of BRCA1 or BRCA2 mutations. Because of the randomization, carriers were equally likely to be in the tamoxifen or the placebo group. Of the 288 women tested, 19 were identified as carriers of 1 of the 2 mutations (BRCA1 n = 8; BRCA2 n = 11). Carriers of 1 of these mutations were more likely to have a positive family history of breast cancer. Carriers were also younger. Tamoxifen did not reduce the risk of breast cancer among BRCA1 carriers when compared with placebo (RR: 1.67; 95% CI: 0.32-10.7). BRCA2 carriers on tamoxifen, however, were less likely to develop cancer, but this finding was statistically not significant (RR: 0.48; 95% CI: 0.37-1.56). Patients without these mutations had a 50% reduced risk of developing cancer if they were on tamoxifen (RR: 0.48; 95% CI: 0.37-0.61). Most of the cancers were estrogen-receptor negative among BRCA1 carriers, whereas most were estrogen-receptor positive in BRCA2 carriers. Tamoxifen use for breast cancer prevention by women older than 35 years of age seemed to have a beneficial effect among BRCA2 mutation carriers but did not have the same protective effect among BRCA1 mutation carriers. <H3>Clinical Commentary</H3> There are 180,000 to 190,000 new cases of breast cancer annually. It is the second leading cause of cancer death. A woman has a lifetime risk of 1:8 for developing invasive breast cancer. This risk is increased in carriers of certain mutations, such as BRCA1 and BRCA2. These women typically have a strong family history of breast cancer and develop cancer at a younger age. These cancers are typically estrogen-receptor negative and have a poor prognosis. The NSABP-BCPT evaluated the effect of tamoxifen on breast cancer incidence among high-risk women. Two smaller European studies did not show a protective effect. It should be noted that participants in those studies were allowed to use estrogen preparations, and in 1 study the participants were not considered high risk. By contrast, BCPT showed a 50% reduction in the risk of developing invasive cancer. Both those with a positive family history and those without had similar benefits. Tamoxifen use also reduces the risk of estrogen-receptor positive cancer among BRCA1 and BRCA2 mutation carriers. Since the beginning of the trial, tests were developed to detect BRCA mutations. This report discusses findings of mutation analysis among women who were diagnosed with cancer during the follow-up. Blood was collected at enrollment and was tested later. BRCA mutation carriers were equally likely to be on tamoxifen or placebo as a result of randomization. Mutations were identified in 19 women.The low number of patients with mutations is most likely responsible for the nonsignificant findings. Still, BRCA2 mutation carriers seemed to benefit from tamoxifen while BRCA1 carriers did not. Tamoxifen acts by binding to the estrogen receptor. It has an antiestrogenic, antiproliferative effect in the breast. Therefore, cancers that have very low levels of estrogen receptor will not respond to tamoxifen. The trial showed that the risk of developing estrogen-receptor-negative cancer was not reduced. Because cancers that develop in BRCA1 carriers are frequently estrogen-receptor negative, it is not surprising that there was no invasive cancer incidence reduction in this group. It takes several years for breast cancer to reach a stage when it can be diagnosed. It is not known whether tamoxifen prevents development of cancer or treats very early cases. If a patient has a subclinical, estrogen-receptor-negative cancer, it is not going to regress in response to tamoxifen. This could be the case in BRCA1 carriers, as they tend to develop cancer at a younger age, and the cancers tend to be estrogen-receptor negative. These carriers do, however, benefit from a reduction in circulating estrogen levels. Oophorectomy at a young age (< 35 years) reduces their risk of breast cancer. Prophylactic mastectomy also greatly reduces the risk. It is possible that if tamoxifen is initiated before the age of 35, it could lead to reduced risk of breast cancer in BRCA1 mutation carriers as well. Future studies will have to evaluate the effects of tamoxifen initiated at a younger age.<A HREF="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11710890&dopt=Abstract">Abstract</A><CENTER><HR WIDTH=50%></CENTER><h4>Long and Highly Irregular Menstrual Cycles as a Marker of Type 2 Diabetes Mellitus</h4> Solomon CG, Hu FB, Dunaif A, et al. JAMA. 2001;286(18):2421-2426<h3>Summary</h3> The risk of developing diabetes is increased among women with long or highly irregular cycles; the increased risk cannot be explained by differences in weight, smoking habits, family history, OCP use, or clinical evidence of hyperandrogenism. This study (Nurses Health Study II) is a prospective, observational study evaluating the association between menstrual cycle characteristics and the risk of developing type 2 diabetes mellitus. Data were collected from 116,671 nurses. Information (baseline demographic [18-22 years] and menstrual cycle characteristics) was reported by the participants. The menstrual cycle was considered normal if the length was 26-31 days, short if it was < 21 days, and long if it was > 40 days. Patients were asked to report history of severe acne, any infertility treatment, and history of hirsutism diagnosed by a physician. Those who reported diabetes were asked separately about the method of diagnosis. Women who did not respond, who had diabetes at baseline, who used OCPs throughout the follow-up period, or for whom the diagnosis of diabetes could not be confirmed were excluded. At baseline, women with short cycles were more likely to be smokers, to have a positive family history of diabetes, to have a history of OCP use, and to be nonwhite. Women with long cycles had higher BMI at baseline than women with normal cycle length. Women with long or short cycles were more likely to report acne, hirsutism, infertility treatment, and gestational diabetes. During follow-up, 507 cases of diabetes were diagnosed. The risk for diabetes was not significantly increased among women with short cycles, even after adjusting for BMI, daily activity, family history, OCP use, and smoking status. Women with cycle lengths between 21 and 39 days had similar risk for developing diabetes. However, women with long or highly irregular cycles had an increased risk for developing diabetes (RR: 2.08; 95% CI: 1.62-2.66) when compared with women with normal cycles. Adjusting for weight change did not modify this risk. The risk was also increased among patients who did not report severe acne or hirsutism. An increased risk was found among lean and obese patients with long cycles; however, the association was stronger among obese women. This increased risk was independent of family history. Similarly, increased risk was observed among women who never used OCPs and had long cycles. The authors conclude that risk of developing diabetes is increased among women with long or highly irregular cycles and that the increased risk cannot be explained by differences in weight, smoking habits, family history, OCP use, or clinical evidence of hyperandrogenism. <H3>Clinical Commentary</H3> Diabetes affects about 5% to 6% of the adult population. About 90% of the cases are type 2, which is characterized by peripheral resistance to insulin. Poorly controlled diabetes leads to significant morbidity. Many patients with diabetes are not diagnosed early on and already have some morbidity related to diabetes when the diagnosis is made. It is important to identify risk factors, so people at risk can be screened and treated early. There are several known risk factors, such as a strong family history, obesity, history of gestational diabetes, OCP use, and PCOS. This is a prospective observational study. Demographic and cycle characteristics were self reported, and this is one of the limitations of the study. The confirmation of the diagnosis of diabetes was also based on patient reports; however, when the medical records of a small group of patients were reviewed, there was a 98% correlation between patient self-reports and laboratory diagnosis. The risk of diabetes is increased among patients with PCOS. PCOS is characterized by irregular menstrual cycles and clinical or laboratory evidence of hyperandrogenism. Patients were asked about clinical evidence of hyperandrogenism. If the increased risk was only present among those who had evidence of hyperandrogenism, one could conclude that the PCOS patients were selected out by the long menstrual cycles. This does not seem to be the case, however, because the risk of diabetes was elevated even after adjusting for hyperandrogenism. OCPs are known to affect glucose tolerance, but OCP use in this report did not explain the findings either. Insulin resistance is more common among obese patients, and they are at increased risk for developing diabetes. While the association between diabetes and long cycles was stronger among obese women, lean women with irregular cycles were still at increased risk. Because other factors that affect cycle length (eg, eating disorder, thyroid disease, hyperprolactinemia) were not evaluated, we do not know what effect they have on the risk of developing diabetes. It is also possible that women with irregular cycles are seen by physicians more often and are more likely to be screened for diabetes. The chance of a screening bias is reduced by the fact that all participants worked in the healthcare system and should have been aware of their risks. This report suggests that women with long or highly irregular cycles are at an increased risk for diabetes and that this risk seems to be independent of other known risk factors. Women with a long history of irregular bleeding, especially if other risk factors are present, should be screened for diabetes on a regular basis.<CENTER><HR WIDTH=50%></CENTER><H3>Fertility and Sterility</H3>From Fertility and SterilityNovember 2001 (Volume 76, Number 5)<h4>A 5-Year Follow-up Study on the Use of a Levonorgestrel Intrauterine System in Women Receiving Hormone Replacement Therapy</h4> Varila E, Wahlstrom T, Rauramo I Fertility and Sterility. 2001;76(5):969-973<h3>Summary</h3> The levonorgestrel intrauterine system (IUS) provided adequate protection against estrogen stimulation during estrogen replacement therapy. Hormone replacement therapy (HRT) consists of estrogen and progesterone replacement during menopause. While estrogen can be given in various ways, progesterone is usually given orally. This study evaluated the endometrial effects of a progesterone-releasing IUS, Mirena (Mirena/Levonova, Leiras Oy, Turku, Finland). It can be left in place for 5 years before it needs to be replaced. The initial trial evaluating this method was designed to last 12 months. After 12 months, the participants were allowed to continue using the IUS. Forty women were enrolled; 29 decided to continue using the IUS. This study reports findings based on these 29 cases. All patients were menopausal, on average 5.7 years past menopause. They all received estrogen replacement in the form of a transdermal patch or oral preparations. The endometrial thickness and endometrial histology were assessed at baseline and at the completion of follow-up. Estrogen and progesterone effects on the endometrium were evaluated and graded separately. Data were collected for bleeding and spotting episodes. All levonorgestrel IUS insertions were successful. Insertion was generally well tolerated: 32/40 participants reported no or minimal pain at the initial insertion. The removal of the IUS was also easy. Endometrial thickness decreased with the levonorgestrel IUS from a mean of 5 mm at baseline to 2.4 mm after 5 years. Tissue exam at 12 months revealed suppressed endometrium in all women. After 5 years, there was a moderate or strong progestin effect in 28/29 participants. Estrogenic stimulus was minimal. Seven patients had a 3-month washout period after 5 years of IUS use. During those 3 months, the endometrium reverted to an atrophic state with minimal evidence of progestin effect. During the first year of follow-up, 90% of women had no bleeding days, and 64% were completely amenorrheic. In the last 3 months of the 5-year follow-up, only 3/29 women had spotting; the rest were amenorrheic. In conclusion, this study showed that the levonorgestrel IUS provided adequate protection against estrogen stimulation during estrogen replacement therapy. <H3>Clinical Commentary</H3> HRT successfully reduces vasomotor symptoms, improves vaginal atrophy, and protects the bones against bone loss. It induces a favorable lipid profile and may reduce the risk of cardiovascular disease. Despite its beneficial effects, many postmenopausal women elect not to take HRT, the main reason being fear of developing cancer in response to HRT. Those who do initiate HRT frequently discontinue it within a few months secondary to side effects and bleeding episodes. However, most women become amenorrheic with continuous combined HRT. Unopposed estrogen stimulates the endometrium and can lead to hyperplasia or cancer. Therefore, it is important to add progesterone to the estrogen replacement formulation for women with an intact uterus. While estrogen can be given in various ways, progesterone is usually given orally, and fluctuating serum levels can lead to bothersome side effects, such as irritability and breast tenderness. Moreover, once oral progesterone preparations are absorbed, they pass through the liver and can reduce the beneficial lipoprotein changes induced by estrogen. However, progesterone can be administered locally. There are vaginal preparations, and there is the levonorgestrel-releasing IUS. Local administration of progesterone can result in the desired endometrial effects and can limit the undesired systemic effects. This study evaluated the endometrial effects and found that the IUS leads to profound endometrial suppression. Tissue analysis revealed a dominant progestin effect. No patients developed hyperplasia or cancer while using the IUS. There was a favorable bleeding profile with high amenorrhea rates and few bleeding episodes. Insertion and removal of the IUS was managed without any significant difficulty. This study had only 1 arm; the IUS was not compared with any other progesterone delivery methods. One of the benefits of local progesterone use is reducing systemic side effects, but such data were not collected. In addition, women were allowed to use different doses and formulations of estrogen. It is not clear whether the IUS provides adequate protection for all formulations and doses of estrogen. Women were generally of normal weight, although BMIs are not reported. It would be interesting to know whether the IUS provides adequate protection for obese HRT users. Also, effects on lipoproteins should be evaluated. The reported data are promising -- the levonorgestrel IUS seems to provide adequate endometrial protection. Further evaluation is warranted.<A HREF="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11704119&dopt=Abstract">Abstract</A><CENTER><HR WIDTH=50%></CENTER><H3>Journal of Clinical Endocrinology and Metabolism</H3>From Journal of Clinical Endocrinology and MetabolismNovember 2001 (Volume 86, Number 11)<h4>Osteoporosis in Eating Disorders: A Follow-up Study of Patients With Anorexia and Bulimia Nervosa</h4> Zipfel S, Seibel MJ, Lowe B, Beumont PJ, Kasperk C, Herzog W Journal of Clinical Endocrinology and Metabolism. 2001;86(11):5227-5233<h3>Summary</h3> The findings of this study show that patients with chronic anorexia nervosa (especially those with binge eating/purging) are at the highest risk for osteopenia and osteoporosis. Patients with bulimia nervosa had normal bone mineral density (BMD) and bone turnover markers. Eating disorders, anorexia nervosa and bulimia nervosa, are associated with significant morbidity. Osteoporosis and related fractures are examples of this increased morbidity. This study is a longitudinal follow-up of BMD and bone turnover markers in a group of women with eating disorders. Fifty-one patients with eating disorders were identified; complete data were available for 38 (anorexia nervosa n = 24, bulimia nervosa n = 14). They were followed for an average of 3.6 years. Eating disorder was diagnosed on the basis of DSM-IV criteria. Patients were evaluated at baseline and at the end of follow-up. Risk factors for osteoporosis and estrogen exposure were evaluated. A similar evaluation was performed in age-matched healthy control patients. BMD and serum and urinary bone turnover markers were measured at baseline and at the completion of the study. Patients were also assessed for recovery of menstrual function. Recovery was defined by an increase of BMI over 18.5 kg/m2 and resumption of menses for at least 6 months. Age at the onset of disease and duration of disease were not different between the anorexia and bulimia nervosa patients. Baseline BMIs were 13.7 kg/m2 in the anorexia nervosa group and 20.0 kg/m2 in the bulimia nervosa group. Length of secondary amenorrhea was 2.6 years in the anorexia nervosa and 0.6 years in the bulimia nervosa group. Lumbar BMD was reduced in the anorexia nervosa group (t score -1.08 SD) and was normal in the bulimia nervosa group (t score 0.05 SD). At baseline, 34.8% and 13.0% of patients with anorexia nervosa had osteopenia and osteoporosis, whereas there was only 1 patient with bulimia nervosa who had osteopenia. Nine patients with anorexia nervosa and 5 patients with bulimia nervosa recovered. Those patients who reached normal weight (> 18.5 kg/m2) during follow-up had no significant annual BMD change. Those patients who had anorexia nervosa and did not recover had an annual loss of BMD of 3.7%. Their BMD was significantly reduced when compared with baseline values. There was no significant change in the BMD values among patients who recovered (+0.7%). Those patients with anorexia nervosa who recovered were more likely to receive estrogen replacement therapy. Patients with bulimia nervosa maintained BMD in the normal range and bone turnover markers were normal as well. Patients with anorexia nervosa had elevated calcium, phosphorus, albumin, and parathyroid hormone levels. Those who recovered had lower levels of these markers. Logistic regression analysis revealed that the most important factors affecting BMD were the subtype of anorexia nervosa (binge eating/purging) and BMI at follow-up. The findings of this study show that patients with chronic anorexia nervosa (especially those with binge eating/purging) are at the highest risk for osteopenia and osteoporosis. Patients with bulimia nervosa had normal BMD and bone turnover markers. <H3>Clinical Commentary</H3> One's eating habits influence his or her risk of developing cardiovascular disease, diabetes, cancer, or other morbidity, such as osteoporosis. Eating disorders, anorexia nervosa and bulimia nervosa, occur in 0.5% to 2% of the population. Certain groups of women (adolescents) are at particular risk for eating disorders. These eating disorders have major impact on normal bone development. Women reach their peak bone mass during the early reproductive years. The most effective way of preventing osteoporosis and related fractures is reaching a higher peak bone mass during these years. This study prospectively evaluated BMD and bone turnover markers in a group of young women with eating disorders. Patients were identified on the basis of DSM-IV criteria. Patients with anorexia nervosa had much lower BMI, longer periods of secondary amenorrhea, and significantly lower BMD compared with healthy controls; their relative estrogen exposure was also lower. It is known that in addition to genetic factors, nutritional and hormonal factors determine peak bone mass. Adequate nutrition, adequate calcium intake, and estrogen exposure are all important determinants. During the follow-up period, comparisons were made between those who recovered and those who did not. Patients who did not recover had extremely low BMI and lost bone rapidly. This was reflected by increased levels of markers for bone resorption. Those who recovered and reached normal weight had no significant change in BMD. These patients were more likely to receive estrogen replacement therapy and had higher relative estrogen exposure, consistent with resumption of menses. The subtype of anorexia nervosa had a major impact on BMD. The binge eating/purging type had worse prognosis. Bulimic patients did not appear to be at risk for osteoporosis; however, these patients had normal BMI and had higher relative estrogen exposure. This study reports BMD and serum marker data; we do not know whether there were any fractures during follow-up, and if there were, which patients were at particular risk. This study shows that patients with anorexia nervosa who recover maintain BMD, but we do not know whether they fully recover and reach similar peak bone mass when compared with women without eating disorders. It is also not known whether they need any extra treatment to achieve higher BMD. Further longer-term studies will have to answer these questions. This study highlights how important it is to identify those patients at risk and provide them with appropriate care early on. As most patients with significant eating disorders are young, they are not necessarily forthcoming with their problem. We have to rely on subtle clinical signs and physical findings when evaluating these patients.<A HREF="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11701682&dopt=Abstract">Abstract</A><CENTER><HR WIDTH=50%></CENTER><H3>American Journal of Obstetrics and Gynecology</H3>From American Journal of Obstetrics and GynecologyNovember 2001 (Volume 185, Number 5)<h4>Effects of Low-Dose Continuous Combined Conjugated Estrogens and Medroxyprogesterone Acetate on Menopausal Symptoms, Body Weight, and Metabolism in Postmenopausal Women</h4> Gambacciani M, Ciaponi M, Cappagali B, Genazzani AR American Journal of Obstetrics and Gynecology. 2001;185(5):1180-1185<h3>Summary</h3> Low-dose HRT was effective in maintaining BMD and reducing postmenopausal symptoms and was generally well tolerated. This is a prospective, randomized, open-label trial of low-dose, continuous, combined HRTwith 0.3 mg conjugated equine estrogens (CEE) and 2.5 mg medroxyprogesterone acetate (MPA). Healthy, normal-weight women who recently became postmenopausal were invited to participate. They were randomly assigned to treatment or no treatment. There were 30 patients in both arms of the study. Women who recently received hormonal preparations, glucocorticoids, or were diagnosed with a disease that affects bone metabolism were ineligible. Data were collected for changes in BMI, BMD, serum and urinary markers of bone turnover, vasomotor symptoms, and bleeding episodes. At baseline, there were no differences between the 2 groups with regard to age, menopausal status, smoking habits, comorbidities, and hormone (FSH, estradiol) levels. Fifty percent of the women in the control group and 73% of the women in the HRT group completed the study. Twelve of the 15 women who dropped out from the control group requested HRT for menopausal symptoms. In the HRT group, 20 of the 23 women who completed the study were amenorrheic by the end of the 2-year follow-up period. None of the patients on HRT had abnormal endometrial findings on endometrial biopsy at the completion of the study. There was no improvement with the menopausal symptoms in the control group, whereas there was a significant reduction in the severity of menopausal symptoms in the HRT group. This difference was significant from baseline and control values. There was a significant 3% weight gain in the control group, whereas there was a nonsignificant 1.3% weight gain in the HRT group. Bone turnover markers (serum osteocalcin, urinary hydroxyprolin) were reduced in the HRT group and increased in the control group. This bone turnover difference was reflected in differences in BMD. In the control group, lumbar BMD decreased by 7.9% after 2 years; in the HRT group, BMD increased by 2.7%. In conclusion, low-dose HRT was effective in maintaining BMD and reducing postmenopausal symptoms and was generally well tolerated. <H3>Clinical Commentary</H3> There are several well-documented beneficial effects of postmenopausal HRT. HRT is effective in treating postmenopausal symptoms (vasomotor, atrophic changes) and maintains BMD. It also has beneficial effects on the lipid profile; observational studies showed a 50% reduction of cardiovascular morbidity with HRT, but this has not been supported by results of recent prospective trials. Unopposed estrogen increases the risk of endometrial cancer, and there is slight increase in breast cancer risk with HRT. These risks and some of the bothersome side effects lead to high discontinuation rates with HRT. This prospective, open-label trial compared low-dose HRT with no treatment. Unfortunately, no placebo was used in the control group and the patients and treating physicians were aware of treatment assignment. Although this is less important when objective outcomes are compared (serum and urinary markers), it could lead to reporting bias when subjective markers are compared (menopausal symptoms, bleeding). There was a higher dropout rate in the control group. It is possible that women who knew that they were not receiving treatment were more likely to withdraw from the study. It is also not known whether those who completed the study in the control group differed from those who did not. While 20 out of the 23 women who were on HRT and completed the study were amenorrheic at the completion of the study, similar information is not available for the women in the control group. Because abnormal bleeding/spotting is a main reason why women discontinue HRT, it would be important to report such data. Recently, a multicenter, prospective, double-blind, placebo-controlled trial (the Women's HOPE trial) evaluated various doses of combined HRT among postmenopausal women with similar characteristics. They also reported beneficial bone and vasomotor effects. They reported a more favorable bleeding pattern with lower dose HRT and improvements in the lipid profile. Neither of these reports reported fracture and cardiovascular disease data. On the basis of these reports, it seems that lower-dose HRT can be beneficial for newly menopausal women. Further studies will have to assess fracture and cardiovascular disease risks with these new regimens. It is hoped that the introduction of low-dose HRT will improve patient compliance and that more women will benefit from such treatment.<A HREF="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11717654&dopt=Abstract">Abstract</A><CENTER><HR WIDTH=50%></CENTER>