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Background: Approximately 20% of women with endometrial cancer have advanced-stage disease or suffer from a recurrence. For these women, prognosis is poor, and palliative treatment options include hormonal therapy and chemotherapy. Lack of predictive biomarkers and suboptimal use of existing markers for response to hormonal therapy have resulted in overall limited efficacy., Objective: This study aimed to improve the efficacy of hormonal therapy by relating immunohistochemical expression of estrogen and progesterone receptors and estrogen receptor pathway activity scores to response to hormonal therapy., Study Design: Patients with advanced or recurrent endometrial cancer and available biopsies taken before the start of hormonal therapy were identified in 16 centers within the European Network for Individualized Treatment in Endometrial Cancer and the Dutch Gynecologic Oncology Group. Tumor tissue was analyzed for estrogen and progesterone receptor expressions and estrogen receptor pathway activity using a quantitative polymerase chain reaction-based messenger RNA model to measure the activity of estrogen receptor-related target genes in tumor RNA. The primary endpoint was response rate defined as complete and partial response using the Response Evaluation Criteria in Solid Tumors. The secondary endpoints were clinical benefit rate and progression-free survival., Results: Pretreatment biopsies with sufficient endometrial cancer tissue and complete response evaluation were available in 81 of 105 eligible cases. Here, 22 of 81 patients (27.2%) with a response had estrogen and progesterone receptor expressions of >50%, resulting in a response rate of 32.3% (95% confidence interval, 20.9-43.7) for an estrogen receptor expression of >50% and 50.0% (95% confidence interval, 35.2-64.8) for a progesterone receptor expression of >50%. Clinical benefit rate was 56.9% for an estrogen receptor expression of >50% (95% confidence interval, 44.9-68.9) and 75.0% (95% confidence interval, 62.2-87.8) for a progesterone receptor expression of >50%. The application of the estrogen receptor pathway test to cases with a progesterone receptor expression of >50% resulted in a response rate of 57.6% (95% confidence interval, 42.1-73.1). After 2 years of follow-up, 34.3% of cases (95% confidence interval, 20-48) with a progesterone receptor expression of >50% and 35.8% of cases (95% confidence interval, 20-52) with an estrogen receptor pathway activity score of >15 had not progressed., Conclusion: The prediction of response to hormonal treatment in endometrial cancer improves substantially with a 50% cutoff level for progesterone receptor immunohistochemical expression and by applying a sequential test algorithm using progesterone receptor immunohistochemical expression and estrogen receptor pathway activity scores. However, results need to be validated in the prospective Prediction of Response to Hormonal Therapy in Advanced and Recurrent Endometrial Cancer (PROMOTE) study., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Endometriosis, a systemic disease that is often painful and chronic, affects ∼10% of reproductive-age women. The disease can have a negative impact on a patient's physical and emotional well-being, quality of life, and productivity. Endometriosis also places significant economic and social burden on patients, their families, and society as a whole. Despite its high prevalence and cost, endometriosis remains underfunded and underresearched, greatly limiting our understanding of the disease and slowing much-needed innovation in diagnostic and treatment options. Due in part to the societal normalization of women's pain and stigma around menstrual issues, there is also a lack of disease awareness among patients, health care providers, and the public. The Society for Women's Health Research convened an interdisciplinary group of expert researchers, clinicians, and patients for a roundtable meeting to review the current state of the science on endometriosis and identify areas of need to improve a woman's diagnosis, treatment, and access to quality care. Comprehensive and interdisciplinary approaches to disease management and increased education and disease awareness for patients, health care providers, and the public are needed to remove stigma, increase timely and accurate diagnosis and treatment, and allow for new advancements., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The most common location of extragenital endometriosis is the bowel. Medical treatment may not provide long-term improvement in patients who are symptomatic, and consequently most of these patients may require surgical intervention. Over the past century, surgeons have continued to debate the optimal surgical approach to treating bowel endometriosis, weighing the risks against the benefits. In this expert review we will describe how the recommended surgical approach depends largely on the location of disease, in addition to size and depth of the lesion. For lesions approximately 5-8 cm from the anal verge, we encourage conservative surgical management over resection to decrease the risk of short- and long-term complications., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Raloxifene and tamoxifen are Food and Drug Administration-approved for breast cancer risk reduction; in 2013, the US Preventive Services Task Force recommended these drugs for breast cancer risk reduction in high-risk women. Information on the use of raloxifene and tamoxifen for breast cancer risk reduction in the general population indicates that the risk is believed to be low; however, there is little literature., Objective: The purpose of this study was to assess the use of breast cancer risk reduction medications by breast cancer risk level in an older cohort of women., Study Design: Women who were enrolled in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial were assessed for the use of raloxifene, tamoxifen, and other medications. The data sources for use of the drugs were a mailed medication use questionnaire in 2013 and linked Medicare Part D claims files from 2010-2014. Estimated breast cancer risk within 5 years was assessed with the use of the modified Gail model and self-reported breast cancer risk factors; comorbidities were assessed through a questionnaire., Results: A total of 22,235 women completed the medication use questionnaire; of these, 13,640 women (61%) had linked Part D data. In 2013, 45% of the women were 65-74 years old, and 55% of the women were 75-84 years old. From the medication use questionnaire, raloxifene use (past month) was 1.8%, 2.5%, and 4.0% for women with breast cancer risk within 5 years of <1.66%, 1.66-3.0%, and ≥3%, respectively (probability value trend, <.0001). From Part D, for any use during the period among women with coverage, raloxifene rates were 3.3%, 4.0%, and 6.6% for the 3 categories for breast cancer risk within 5 years (probability value trend, <.0001); use was 7.4% and 3.3% in women with and without osteoporosis, respectively. Raloxifene use significantly decreased from 2010-2014, and specifically from 2012-2014, both for all women and for women with breast cancer risk within 5 years of ≥3%. Tamoxifen use from Part D was 0.36%, 0.45%, and 0.85% for the 3 categories for breast cancer risk within 5 years (probability value trend, .009)., Conclusion: Raloxifene use was low overall but increased modestly with breast cancer risk, and usage decreased from 2010-2014. Tamoxifen use was very low., (Published by Elsevier Inc.)

Issues of sexuality, intimacy, and early menopause significantly impact the quality of life of patients following the diagnosis and treatment of ovarian cancer. These are undertreated problems. Successful treatment requires the provider's awareness of the problem, ability to identify it, and willingness to treat it. Unfortunately many providers do not address these issues in the pretreatment or perioperative period. Furthermore, patients do not often alert their providers to their symptoms. While systemic hormone therapy may improve many of the issues, they are not appropriate for all patients given their action on estrogen receptors. However, other nonhormonal treatments exist including selective serotonin reuptake inhibitors, antiepileptics, natural remedies, and pelvic floor physical therapy. In addition psychological care and the involvement of the partner can be helpful in managing the sexual health concerns of these patients. At the time of diagnosis or at initial consultation, women should be informed of the potential physiologic, hormonal, and psychosocial effects of ovarian cancer on sexuality and that there is a multimodal approach to dealing with symptoms., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Spontaneous preterm birth remains a leading cause of neonatal morbidity and mortality among nonanomalous neonates in the United States. Spontaneous preterm birth tends to recur at similar gestational ages. Intramuscular 17-alpha hydroxyprogesterone caproate reduces the risk of recurrent spontaneous preterm birth. Unfortunately, one-third of high-risk women will have a recurrent spontaneous preterm birth despite 17-alpha hydroxyprogesterone caproate therapy; the reasons for this variability in response are unknown., Objective: We hypothesized that clinical factors among women treated with 17-alpha hydroxyprogesterone caproate who suffer recurrent spontaneous preterm birth at a similar gestational age differ from women who deliver later, and that these associations could be used to generate a clinical scoring system to predict 17-alpha hydroxyprogesterone caproate response., Study Design: Secondary analysis of a prospective, multicenter, randomized controlled trial enrolling women with ≥1 previous singleton spontaneous preterm birth <37 weeks' gestation. Participants received daily omega-3 supplementation or placebo for the prevention of recurrent preterm birth; all were provided 17-alpha hydroxyprogesterone caproate. Women were classified as a 17-alpha hydroxyprogesterone caproate responder or nonresponder by calculating the difference in delivery gestational age between the 17-alpha hydroxyprogesterone caproate-treated pregnancy and her earliest previous spontaneous preterm birth. Responders were women with pregnancy extending ≥3 weeks later compared with the delivery gestational age of their earliest previous preterm birth; nonresponders delivered earlier or within 3 weeks of the gestational age of their earliest previous preterm birth. A risk score for nonresponse to 17-alpha hydroxyprogesterone caproate was generated from regression models via the use of clinical predictors and was validated in an independent population. Data were analyzed with multivariable logistic regression., Results: A total of 754 women met inclusion criteria; 159 (21%) were nonresponders. Responders delivered later on average (37.7±2.5 weeks) than nonresponders (31.5±5.3 weeks), P<.001. Among responders, 27% had a recurrent spontaneous preterm birth (vs 100% of nonresponders). Demographic characteristics were similar between responders and nonresponders. In a multivariable logistic regression model, independent risk factors for nonresponse to 17-alpha hydroxyprogesterone caproate were each additional week of gestation of the earliest previous preterm birth (odds ratio, 1.23; 95% confidence interval, 1.17-1.30, P<.001), placental abruption or significant vaginal bleeding (odds ratio, 5.60; 95% confidence interval, 2.46-12.71, P<.001), gonorrhea and/or chlamydia in the current pregnancy (odds ratio, 3.59; 95% confidence interval, 1.36-9.48, P=.010), carriage of a male fetus (odds ratio, 1.51; 95% confidence interval, 1.02-2.24, P=.040), and a penultimate preterm birth (odds ratio, 2.10; 95% confidence interval, 1.03-4.25, P=.041). These clinical factors were used to generate a risk score for nonresponse to 17-alpha hydroxyprogesterone caproate as follows: black +1, male fetus +1, penultimate preterm birth +2, gonorrhea/chlamydia +4, placental abruption +5, earliest previous preterm birth was 32-36 weeks +5. A total risk score >6 was 78% sensitive and 60% specific for predicting nonresponse to 17-alpha hydroxyprogesterone caproate (area under the curve=0.69). This scoring system was validated in an independent population of 287 women; in the validation set, a total risk score >6 performed similarly with a 65% sensitivity, 67% specificity and area under the curve of 0.66., Conclusions: Several clinical characteristics define women at risk for recurrent preterm birth at a similar gestational age despite 17-alpha hydroxyprogesterone caproate therapy and can be used to generate a clinical risk predictor score. These data should be refined and confirmed in other cohorts, and women at high risk for nonresponse should be targets for novel therapeutic intervention studies., Competing Interests: Conflict of Interest/Disclosure Statement: Dr. Sean Esplin serves on the scientific advisory board and holds stock in Sera Prognostics, a private company that was established to create a commercial test to predict preterm birth and other obstetric complications. Dr. Tracy Manuck is also on the scientific advisory board for Sera Prognostics. The remaining authors report no conflict of interest., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Racial/ethnic disparities in preterm birth remain a major public health challenge in the United States. While 17-alpha hydroxyprogesterone caproate (17OHP-C) is recommended for preterm birth prevention in women with a prior preterm birth, non-Hispanic black women continue to experience higher rates of recurrent preterm birth than white women receiving the same treatment. Further investigation of disparities in 17OHP-C use and adherence is warranted., Objective: We sought to evaluate whether racial and ethnic disparities exist in the use of and adherence to 17OHP-C within a population of eligible women., Study Design: This was a retrospective cohort study of women with a prior spontaneous, singleton preterm birth who were eligible for 17OHP-C for preterm birth prevention and received care at a single institution from 2010 through 2014. Associations between self-identified race/ethnicity (non-Hispanic black vs women in all other racial/ethnic groups) and documented counseling about 17OHP-C, receipt of any 17OHP-C, and adherence to 17OHP-C administration were each estimated by bivariable analysis and multivariable logistic regression. Adherence to 17OHP-C was defined as not >1 missed dose, initiation <20 weeks' gestational age, and continuation until 37 weeks or delivery., Results: Of 472 women who were clinically eligible for 17OHP-C, 72% (N = 296) had documented 17OHP-C counseling and 48.9% (N = 229) received 17OHP-C. There were no differences in likelihood of 17OHP-C counseling or receipt of 17OHP-C based on race/ethnicity. While overall 83% (N = 176) of women were adherent to 17OHP-C, only 70% (N = 58) of non-Hispanic black women were adherent, compared to 91% (N = 118) of all other women (P < .001). Non-Hispanic black women had more missed doses (2.4 vs 0.4 doses, P < .001) and later initiation of care (12.0 vs 10.2 weeks, P < .001) than women in other racial/ethnic groups. After adjustment for potential confounders, non-Hispanic black women were significantly less likely to be adherent to 17OHP-C (adjusted odds ratio, 0.16; 95% confidence interval, 0.04-0.65). A significant interaction between non-Hispanic black race/ethnicity and public insurance was identified (adjusted odds ratio, 0.16; 95% confidence interval, 0.05-0.52)., Conclusion: In a diverse cohort of women eligible for preterm birth prevention, non-Hispanic black women are at an increased risk of nonadherence to 17OHP-C. Non-Hispanic black women with public insurance are at a particularly increased risk of nonadherence., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Prematurity is the leading cause of neonatal morbidity and death among nonanomalous neonates in the United States. Intramuscular 17-alpha hydroxyprogesterone caproate injections reduce the risk of recurrent prematurity by approximately one third. Unfortunately, prophylactic 17-alpha hydroxyprogesterone caproate is not always effective, and one-third of high-risk women will have a recurrent preterm birth, despite 17-alpha hydroxyprogesterone caproate therapy. The reasons for this variability in response are unknown. Previous investigators have examined the influence of a variety of factors on 17-alpha hydroxyprogesterone caproate response but have analyzed data that used a fixed outcome of term delivery to define progesterone response., Objective: We hypothesized that the demographics, history, and pregnancy course among women who deliver at a similar gestational age with 17-alpha hydroxyprogesterone caproate for recurrent spontaneous preterm birth prevention differs when compared with those women who deliver later with 17-alpha hydroxyprogesterone caproate and that these associations could be refined by the use of a contemporary definition of 17-alpha hydroxyprogesterone caproate "responder.", Study Design: This was a planned secondary analysis of a prospective, multicenter, longitudinal study of women with ≥1 previous documented singleton spontaneous preterm birth at <37 weeks gestation. Data were collected at 3 prespecified gestational age epochs during pregnancy. All women who were included in this analysis received 17-alpha hydroxyprogesterone caproate during the studied pregnancy. We classified women as a 17-alpha hydroxyprogesterone caproate responder or nonresponder by calculating the difference in delivery gestational age between the 17-alpha hydroxyprogesterone caproate-treated pregnancy and her earliest spontaneous preterm birth. Responders were defined as those with pregnancy that extended ≥3 weeks later with 17-alpha hydroxyprogesterone caproate, compared with the delivery gestational age of their earliest previous spontaneous preterm birth. Data were analyzed with the use of chi-square test, t-test, and logistic regression., Results: One hundred fifty-five women met the inclusion criteria. The 118 responders delivered later on average (37.7 weeks gestation) than the 37 nonresponders (33.5 weeks gestation; P < .001). Among responders, 32% (38/118 women) had a recurrent spontaneous preterm birth. Demographics (age, race/ethnicity, education, and parity) were similar between groups. In the regression model, the gestational age of the previous spontaneous preterm birth (odds ratio, 0.68; 95% confidence interval, 0.56-0.82; P < .001), vaginal bleeding/abruption in the current pregnancy (odds ratio, 0.24; 95% confidence interval, 0.06-0.88; P = .031), and first-degree family history of spontaneous preterm birth (odds ratio, 0.37; 95% confidence interval, 0.15-0.88; P = .024) were associated with response to 17-alpha hydroxyprogesterone caproate. Because women with a penultimate preterm pregnancy were more likely to be 17-alpha hydroxyprogesterone caproate nonresponders, we performed an additional limited analysis examining only the 130 women whose penultimate pregnancy was preterm. In regression models, the results were similar to those in the main cohort., Conclusion: Several historic and current pregnancy characteristics define women who are at risk for recurrent preterm birth at a similar gestational age, despite 17-alpha hydroxyprogesterone caproate therapy. These data should be studied prospectively in larger cohorts and combined with genetic and environmental data to identify women who are most likely to benefit from this intervention., (Copyright © 2016 Elsevier Inc. All rights reserved.)

In the treatment of women with abnormal uterine bleeding, once a thorough history, physical examination, and indicated imaging studies are performed and all significant structural causes are excluded, medical management is the first-line approach. Determining the acuity of the bleeding, the patient's medical history, assessing risk factors, and establishing a diagnosis will individualize their medical regimen. In acute abnormal uterine bleeding with a normal uterus, parenteral estrogen, a multidose combined oral contraceptive regimen, a multidose progestin-only regimen, and tranexamic acid are all viable options, given the appropriate clinical scenario. Heavy menstrual bleeding can be treated with a levonorgestrel-releasing intrauterine system, combined oral contraceptives, continuous oral progestins, and tranexamic acid with high efficacy. Nonsteroidal antiinflammatory drugs may be utilized with hormonal methods and tranexamic acid to decrease menstrual bleeding. Gonadotropin-releasing hormone agonists are indicated in patients with leiomyoma and abnormal uterine bleeding in preparation for surgical interventions. In women with inherited bleeding disorders all hormonal methods as well as tranexamic acid can be used to treat abnormal uterine bleeding. Women on anticoagulation therapy should consider using progestin-only methods as well as a gonadotropin-releasing hormone agonist to treat their heavy menstrual bleeding. Given these myriad options for medical treatment of abnormal uterine bleeding, many patients may avoid surgical intervention., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: This study reports the gynecologic conditions in postmenopausal women (intact uterus on enrollment) in the National Surgical Adjuvant Breast and Bowel Project (NSABP) study of tamoxifen and raloxifene (STAR)/P-2 trial., Study Design: This study, with a median follow-up period of 81 months, evaluated the incidence rates/risks of gynecologic conditions among women who were treated with tamoxifen and raloxifene., Results: Compared with women who received tamoxifen therapy, women who received raloxifene therapy had a lower incidence of uterine cancer (relative risk, 0.55)/endometrial hyperplasia (relative risk, 0.19), leiomyomas (relative risk, 0.55), ovarian cysts (relative risk, 0.60), and endometrial polyps (relative risk, 0.30) and had fewer procedures performed. Women receiving tamoxifen therapy had more hot flashes (P < .0001), vaginal discharge (P < .0001), and vaginal bleeding (P < .0001)., Conclusion: Our results suggest that tamoxifen has more of an estrogenic effect on the gynecologic reproductive organs. These effects should be considered in counseling women on options for breast cancer prevention., Competing Interests: The authors report no conflict of interest, (Copyright © 2011. Published by Mosby, Inc.)

Objective: Our purpose was to investigate the long-term effects of raloxifene, compared with opposed and unopposed estrogen replacement therapy, on echocardiographic parameters of left ventricular systolic function in healthy postmenopausal women. A total of 157 women were studied in 2 randomized, double-blind, placebo-controlled, 2-year studies., Study Design: In study I, 60 postmenopausal women who had undergone hysterectomy received daily raloxifene, 60 mg (n = 15); raloxifene, 150 mg (n = 15); conjugated equine estrogens (CEE), 0.625 mg (n = 15); or placebo (n = 15). In study II, 97 postmenopausal women who had not undergone hysterectomy received daily raloxifene, 60 mg (n = 24); raloxifene, 150 mg (n = 24); CEE, 0.625 mg, plus medroxyprogesterone acetate (MPA), 2.5 mg (n = 24); or placebo (n = 25). M-mode, quantitative 2-dimensional and Doppler echocardiographic measurements were performed at baseline and after 1 and 2 years., Results: Neither after 1 year nor after 2 years of treatment were echocardiographic parameters found to differ from baseline in both raloxifene groups, as well as in the unopposed CEE and the CEE/MPA groups, compared with the placebo group., Conclusion: Within 2 years of raloxifene treatment, no effect on echocardiographic parameters of left ventricular systolic function was found. Unopposed CEE or CEE/MPA also showed no effect.

Objective: This study was undertaken to evaluate serum leptin concentrations in women with endometriosis during treatment with danazol and with leuprolide depot., Study Design: Twenty patients aged 18 to 42 years with regular menses and documented pelvic endometriosis were recruited from a university hospital setting. Treatment was 200 mg danazol 3 times daily for 6 months or 3.75 mg leuprolide depot every 28 days for 6 months. Serum leptin concentrations were measured before, during, and after treatment. A single blood sample was taken from each of 10 control women without endometriosis for comparison. Serum leptin level was measured with a radioimmunoassay kit with human leptin, and analysis of variance and paired t tests were used for statistical analysis., Results: Serum leptin levels were almost the same among women with endometriosis as in the control group. Leptin levels were higher among women with endometriosis during treatment with danazol and leuprolide(P <.001). Three months after treatment, leptin values remained moderately higher than before treatment., Conclusion: Danazol and leuprolide increased serum leptin levels. The mechanism of leptin increase is unclear. Further studies are needed to determine whether an adipogonadal axis exists.

Tamoxifen was approved for breast cancer prevention in October 1998. Thus, for the first time, we as gynecologists are being asked to prescribe this drug to healthy women. In the past each one of us has cared for women with breast cancer who have been treated with tamoxifen by oncologists or breast surgeons for the malignancy. Effects of tamoxifen on the uterus resulting in carcinomas, hyperplasia, and polyps are well known. Furthermore, tamoxifen has estrogenic properties in the venous system, increasing the incidence of deep vein thrombosis and pulmonary emboli. A new SERM (selective estrogen receptor modulator), raloxifene, has been approved for prevention and treatment of osteoporosis in postmenopausal women. It does not have stimulatory effects on the endometrium; however, it is estrogenic in the venous system. Preclinical data, as well as the breast cancer incidence reported in studies of the skeleton, seem to indicate that its effects in the breast are similar to those of tamoxifen. This article reviews tamoxifen and the new SERM, raloxifene, in an attempt to help gynecologists better understand each compound and what data are currently known, what we hope to learn from future studies, and what currently makes sense for clinical practice.

Objective: The aim of this study was to determine which factors in the perioperative period influence the success of endometrial ablation in alleviating menorrhagia., Study Design: We performed a retrospective chart review of 120 women aged 27 to 49 years who underwent endometrial ablation after 2 months of preoperative treatment with danazol (Danocrine, 800 mg/d orally) or leuprolide (Lupron, 3.75 mg in one intramuscular injection each month). Patients who required medical management or additional operations to control the vaginal bleeding during follow-up (median follow-up, 37 weeks) were considered to have ablation failures., Results: Sixty-three percent of patients (76/120) had a successful procedure. The chance of success was greater if a cavity of normal appearance was found (odds ratio, 2.3; P =.04). The finding of an intramural fibroid before the procedure resulted in a reduced trend toward success (odds ratio, 0.4; P =.06). The use of danazol pretreatment improved the rate of success overall (odds ratio, 2.2; P =.05) and especially among women <40 years old (P =.01), Conclusion: Perioperative findings may provide useful information in counseling patients regarding endometrial ablation. Success is greater among patients with a normal intrauterine cavity and after preoperative treatment with danazol.

Objective: We sought to compare the uterine effects of raloxifene with those of continuous-combined hormone replacement therapy., Study Design: This randomized, double-blind 24-month study involved 136 postmenopausal women who received raloxifene 150 mg/d or conjugated equine estrogens 0.625 mg/d with medroxyprogesterone acetate 2.5 mg/d. After baseline evaluations, endometrial biopsy specimens were obtained, and endometrial thickness was measured annually by means of transvaginal ultrasonography. Statistical analyses were performed with an intention-to-treat approach., Results: In the raloxifene group at the end point of the study 94.4% of biopsy specimens showed normal benign postmenopausal endometrium and 5.6% were classified as benign stimulatory endometrium. In the continuous-combined hormone replacement therapy group at the end point of the study 78.7% of biopsy specimens showed normal benign postmenopausal endometrium, 19. 1% were classified as benign stimulatory endometrium, and 2.1% showed benign abnormal postmenopausal endometrium. Mean endometrial thickness was unchanged from baseline with raloxifene and was increased significantly by 0.5 mm at 12 months with continuous-combined hormone replacement therapy., Conclusion: Raloxifene 150 mg/d did not increase endometrial thickness or cause endometrial proliferation in healthy postmenopausal women.

The purpose of this review is to assimilate relevant experimental and clinical information available on selective estrogen receptor modulators with respect to their potential use as agents to improve women's health in the postmenopausal years. In addition, the mechanisms of action of these drugs are outlined. Selective estrogen receptor modulators represent an exciting group of antiestrogens that possess agonist action on bone, lipids, and lipoproteins and antagonistic action in the endometrium and breast. Thus in theory these drugs may preserve bone density and reduce the risk of osteoporotic fracture and coronary heart disease at the same time that they lower the incidences of breast and endometrial neoplasms. Short-term data with the use of raloxifene suggest that bone is preserved and lipid profiles are less atherogenic. Long-term studies are needed to determine whether raloxifene or other selective estrogen receptor modulators are associated with any decrease in the risk of breast or endometrial cancer.

Objective: Our goal was to evaluate the efficacy and side effects of danazol 200 mg daily given only in the luteal phase of the menstrual cycle to treat premenstrual syndrome and premenstrual mastalgia., Study Design: We conducted a randomized, double-blind, placebo-controlled study of 3 menstrual cycles in a postgraduate medical school and National Health Service hospital. The subjects of the study were 100 women who had been referred to the premenstrual syndrome clinic at the North Staffordshire Hospital for the management of premenstrual syndrome and premenstrual breast pain. Outcome measures for the study included assessment of improvement in symptoms measured by specific daily visual analogue scales for 4 principal symptoms of premenstrual syndrome and for premenstrual mastalgia and assessment of side effects and adverse events., Results: Significant improvement in symptoms was seen in visual analog scores for mastalgia in months 1 (P =.03), 2 (P =.004), and 3 (P =.01) of the study during active therapy compared with placebo. No improvement was seen for any other symptom or for the global premenstrual syndrome score. Side effects on danazol and on placebo were equal and minimal., Conclusions: Luteal phase-only danazol is not effective for the treatment of the general symptoms of premenstrual syndrome but appears highly effective for the relief of premenstrual mastalgia. This approach to therapy is associated with few side effects. Studies of cyclic mastalgia using strict diagnostic criteria are required to see whether the freedom from symptomatic side effects is found in longer-term studies and to determine whether such a regimen avoids potentially detrimental effects on the lipid status.

Objective: Chronic exposure of oophorectomized guinea pigs to 17beta-estradiol causes leiomyoma formation. Our aims were to determine whether these leiomyomas can become estradiol independent after exposure to estradiol and if raloxifene inhibits leiomyoma growth when given concomitantly with estradiol., Study Design: To induce leiomyoma development, 6 oophorectomized animals received two estradiol implants for 140 days. Next, the estradiol implants were replaced with empty implants in 3 animals, whereas the other 3 received 2 new estradiol implants and raloxifene given per os 10 mg/kg per day for 60 days. Tumor size was monitored biweekly by ultrasonography., Results: On estradiol removal, abdominal wall leiomyomas regressed within 15 to 30 days; when estradiol implants were reintroduced, leiomyomas redeveloped. Within 30 days on raloxifene, all abdominal leiomyomas (n = 9) regressed as determined by ultrasonography and verified at laparotomy. Serum raloxifene and estradiol levels were 432 +/- 46 pg/mL and 78 +/- 13 pg/mL (mean +/- SEM, n = 3), respectively, after 60 days of treatment., Conclusions: Leiomyomas did not become estradiol independent, even after long exposure to estradiol; ultrasonography allowed frequent, noninvasive assessment of leiomyoma size, and raloxifene rapidly regressed leiomyomas in this animal model.

Objectives: Our objective was to study the effects of tamoxifen on cerebral arterial reactivity., Study Design: We studied the reactivity of both the internal carotid artery and the middle cerebral artery during a 12-month period of administration of either oral tamoxifen or transdermal estradiol or no treatment. A total of 45 healthy postmenopausal women who had undergone hysterectomy were followed up. Patients were randomly allocated to treatment with either oral tamoxifen 20 mg/day or transdermal estradiol 50 microg/day or nothing (15 patients in each group). They all underwent Doppler examinations of the internal carotid artery and middle cerebral artery at the beginning of the study and after 2, 6, and 12 months of treatment. The pulsatility index was measured., Results: In the women given transdermal estradiol the pulsatility index of both the internal carotid artery and the middle cerebral artery was significantly reduced compared with that in the controls. Tamoxifen did not induce variations of pulsatility index in either artery during all the study period. The difference between the effect of the two drugs on the pulsatility index of both arteries was highly significant., Conclusions: Our findings demonstrate that tamoxifen does not cause any variation in the pulsatility index of cerebral arteries. The action of transdermal estradiol on the pulsatility index of cerebral arteries in postmenopausal women is the expression of a generalized action of estrogens on arterial vessels, and if this expression plays a role in the protective effect of hormone replacement therapy on risk of cardiovascular disease, tamoxifen treatment in healthy postmenopausal women should be considered with renewed caution.

Objective: We evaluated subtle endometrial morphologic changes in postmenopausal women assigned to placebo, raloxifene hydrochloride 200 or 600 mg/day, or conjugated estrogens (Premarin 0.625 mg/day) according to a new estrogenicity scoring system. Raloxifene, a new selective estrogen receptor modulator, was not expected to stimulate the endometrium., Study Design: Baseline and end point endometrial biopsies were performed during this double-blind, placebo-controlled 8-week study. A scoring system that was based on standard glandular and stromal morphologic criteria was used to quantitate estrogen-induced effects. Baseline, end point, and baseline-to-end point changes were analyzed for treatment differences., Results: Treatment groups were similar at baseline with most women showing no estrogenic effects. At end point, statistically significant moderate and marked estrogenic effects were noted in 77% of estrogen-treated women versus 15% of placebo-treated women versus 0% of raloxifene-treated women., Conclusions: As expected, estrogen treatment stimulated postmenopausal endometrium. In contrast, raloxifene did not induce histopathologic evidence of endometrial stimulation in healthy postmenopausal women.

A prior report suggested that active-duty pregnant women are at increased risk for low-birth weight infants and a higher perinatal mortality rate. The present double-blind investigation was designed to prospectively evaluate that risk and to test the efficacy of 17 alpha-hydroxyprogesterone caproate to prevent reported complications. Three groups of active-duty women were studied, beginning between 16 and 20 weeks' gestation. They were similar for parity, previous abortion, race, cigarette smoking, and marital status. Of these, 80 were given 17 alpha-hydroxyprogesterone caproate, 88 received placebo, and 78 declined to participate in the protocol. There was no significant differences in the three groups when comparisons were made for low-birth weight infants and for perinatal mortality. However, when comparison was made to a military dependent population, they had a significantly worse outcome with regard to both perinatal mortality (p = 0.001) and infants with a birth weight less than 2,500 gm (p = 0.01). We concluded that pregnant military personnel were at increased risk for adverse pregnancy outcome, but that this risk was not altered by therapy with 17 alpha-hydroxyprogesterone caproate.

Although anovulation associated with hyperprolactinemia is not an uncommon cause of infertility, the precise mechanism of the pathogenic process that induces hyperactivity (hypertrophy with hyperplasia) of pituitary lactotropes is unknown. We have recently experienced a case of anovulation and hyperprolactinemia in a woman with ergot alkaloid intolerance in whom ovulation was restored by tamoxifen citrate administration. Since tamoxifen citrate administration also suppressed prolactin levels, it was suggested that a low but sustained serum level of estradiol and consequently continuous estrogenic stimulation may be an important causative factor in the development of hyperprolactinemic anovulation.

Twenty patients with endometriosis diagnosed by laparoscopy were treated with the antiestrogen, antiprogesterone gestrinone (R-2323) for 6 to 8 months. The drug was administered in a dose of 5 mg twice weekly. According to the American Fertility Society's classification of endometriosis, five patients were classified as having mild (Stage I), eight as having moderate (Stage II), and seven as having severe endometriosis (Stage III). All patients became amenorrheic at the end of the second month of treatment, and symptomless at the end of the third month. Of nine women who had the potential and the desire to conceive, three conceived within 3 months after termination of treatment. Two more became pregnant within 1 year, and another, 14 months after termination of treatment. Five pregnancies progressed to term. One patient aborted. Two of the three women who did not conceive had subfertile husbands. Major side effects recorded were seborrhea and acne, which subsided after discontinuation of therapy. Treatment of endometriosis with gestrinone offers the advantage of effective clearing of lesions with relatively low dosage and frees the patient from the daily administration of drugs required by similar conservative hormonal therapies.

A shift in progesterone-to-estradiol balance to estradiol dominance is assumed to be a prerequisite for regular uterine contractions. To antagonize this effect in premature labor 24 consecutive women were treated with intravenous cortisol for 3 days and with weekly intramuscular injections of 17 alpha-hydroxyprogesterone caproate (17 OHP-C). Twenty-four similar patients treated with ritodrine served as a reference group. The delivery was postponed by at least 1 week in 21 patients (87.5%) in the steroid treatment group and in 18 patients (75%) in the ritodrine group. The premature labor lasted for 5.1 +/- 0.4 hours (mean +/- SEM) with steroid therapy and for 2.2 +/- 0.3 hours with ritodrine. In singleton pregnancies the gestational length and birth weight of the newborn infants were greater in the steroid treatment group (N = 23, 39.1 +/- 0.3 weeks, 3,460 +/- 119 gm) than in the ritodrine group (N = 24, 37.7 +/- 0.4 weeks, 3,106 +/- 118 gm). Steroid treatment suppressed serum estradiol concentrations (maximally by 60%) and, to a lesser extent, testosterone, estriol, and progresterone levels (maximally by 30%).