Ospemifene 12-month safety and efficacy in postmenopausal women with vulvar and vaginal atrophy.

OBJECTIVE: Assessment of 12-month safety of ospemifene 60 mg/day for treatment of postmenopausal women with vulvar and vaginal atrophy (VVA). METHODS: In this 52-week, randomized, double-blind, placebo-controlled, parallel-group study, women 40-80 years with VVA and an intact uterus were randomized 6 : 1 to ospemifene 60 mg/day or placebo. The primary objective was 12-month safety, particularly endometrial; 12-week efficacy was assessed. Safety assessments included endometrial histology and thickness, and breast and gynecological examinations. Efficacy evaluations included changes from baseline to week 12 in percentage of superficial and parabasal cells and vaginal pH. RESULTS: Of 426 randomized subjects, 81.9% (n = 349) completed the study with adverse events the most common reason for discontinuation (ospemifene 9.5%; placebo 3.9%). Most (88%) treatment-emergent adverse events with ospemifene were considered mild or moderate. Three cases (1.0%) of active proliferation were observed in the ospemifene group. For one, active proliferation was seen at end of study week 52, and diagnosed as simple hyperplasia without atypia on follow-up biopsy 3 months after the last dose. This subsequently resolved with progestogen treatment and dilatation and curettage. In six subjects (five ospemifene (1.4%), one placebo (1.6%)) endometrial polyps were found (histopathology); however, only one (ospemifene) was confirmed as a true polyp during additional expert review. Endometrial histology showed no evidence of carcinoma. Statistically significant improvements were seen for all primary and secondary efficacy measures and were sustained through week 52 with ospemifene vs. placebo. CONCLUSIONS: The findings of this 52-week study confirm the tolerance and efficacy of oral ospemifene previously reported in short- and long-term studies.

Women's decision-making determinants in choosing uterine artery embolization for symptomatic fibroids.

OBJECTIVE: To determine what symptoms of leiomyomata uteri prompted women to seek uterine artery embolization (UAE) and what factors were most frequently cited in the decision making leading to choosing UAE over other treatments. STUDY DESIGN: Eighty-four consecutive women with symptomatic leiomyoma presenting for UAE completed a questionnaire that inquired about their pelvic symptoms and the issues that were important in their decision to request UAE. All subjects previously had been told that they were surgical candidates. RESULTS: Pelvic symptoms that the 84 women most frequently noted were bleeding (n = 61), anemia (41), pelvic pain (29), frequent urination (24) and pelvic pressure (21). The majority of women (78) reported significant worry about their health from the fibroids, and (72) reported that the symptoms caused daily discomfort. Although the majority of women wanted a treatment that would give permanent relief of symptoms and thought UAE would do this, other factors frequently cited in the decision making included quality-of-life reasons, such as the desire to avoid adverse effects of other treatments (76), anticipated prolonged postoperative recovery from surgery (70) and avoiding surgery (66). Many women considered the uterus an important female organ, believed that the uterus was a source of femininity (33), stated that the uterus was necessary to maintain self-image (49) and reported that the uterus was necessary to maintain sexual image (49). CONCLUSION: In this cohort of women with symptomatic leiomyomas, treatment preferences did not interfere with the current lifestyle. In addition, the uterus was considered a source of femininity and sexuality. It is not clear whether women requesting UAE differ from women requesting surgical intervention in terms of how they assess the importance of the uterus, but these data suggest that many women still consider the uterus an important aspect of their femininity and that those seeking nonsurgical options should be thoroughly counseled about uterine function and how it relates to sexuality.

Epoetin alfa use in gynecology. Past, present and future.

Perioperative anemia is a common complication of major surgery that may lead to prolonged and debilitating fatigue and reduction in health-related quality of life (QOL). Treatment with recombinant human erythropoietin (r-HuEPO, epoetin alfa) has been shown to increase perioperative hemoglobin (Hb) and hematocrit (HCT) levels, thereby facilitating postoperative recovery in orthopedic surgery patients. Treatment with epoetin alfa has also been shown to increase Hb and HCT levels and improve QOL in anemic cancer patients undergoing chemotherapy. The clinical and QOL benefit of using epoetin alfa in these patient populations provides the rationale for its use in patients undergoing gynecologic surgery. Because persistent fatigue is the most common complaint of patients following hysterectomy, the use of epoetin alfa should be considered to preoperatively correct anemia in this patient population. Research has been initiated to increase our understanding of the role of epoetin alfa in treating anemic patients (Hb levels < or = 13 g/dL) undergoing surgery for benign gynecologic disease, especially as it relates to postoperative QOL. Future studies should investigate the use of epoetin alfa in patients with gynecologic cancers. These studies should confirm the role of epoetin alfa in combination with iron supplementation to improve perioperative Hb/HCT levels and overall QOL in patients undergoing gynecologic surgery.

Aggressive versus moderate lipid-lowering therapy in postmenopausal women with hypercholesterolemia: Rationale and design of the Beyond Endorsed Lipid Lowering with EBT Scanning (BELLES) trial.

BACKGROUND: Electron beam tomography (EBT) is a noninvasive technique that allows the study of the entire coronary artery tree during a brief imaging session without the injection of any contrast media. Atherosclerosis is identified vicariously through the visualization of coronary calcific deposits. Quantitative assessments of calcium burden, such as calcium volume scores, have been shown to be a useful means to assess treatment-related changes in the extent of atherosclerotic plaques. Historically, the elderly female population has received less medical recognition regarding the risk and severity of coronary heart disease (CHD). METHODS: In the BELLES (Beyond Endorsed Lipid Lowering with EBT Scanning) trial, the presence of asymptomatic CHD in 600 postmenopausal women will be assessed by EBT. In this 1-year, multicenter, randomized, double-blind, parallel-group study, aggressive lipid-lowering treatment will be compared with moderate lipid-lowering treatment in postmenopausal women with hypercholesterolemia. The hypothesis we will test is that aggressive lipid-lowering therapy with 80 mg/d atorvastatin can produce greater reductions in atherosclerotic plaque burden as assessed by volumetric calcium scores than a moderate treatment with 40 mg/d pravastatin. The primary outcome measure will be the percent change from baseline in total CVS determined by EBT at 12 months. CONCLUSIONS: The results of the BELLES trial will help assess the actual incidence of CHD in postmenopausal women and the relative ability of two different lipid-lowering therapies to halt its progression.

Androgen replacement in menopause.

Menopause and the years leading to the menopausal transition are associated with significant decline in sex steroid levels. In contrast to the abrupt decline in estrogens at the time of menopause, a fall in the circulating testosterone and the adrenal preandrogens most closely parallel increasing age. Their accelerated decrease occurs in the years preceding menopause. It is now recognized that the decline in androgens plays a significant role in affecting perimenopausal and menopausal symptomatology and quality of life. Loss of circulating levels of androgens affects libido, vasomotor symptoms, mood and well-being, bone structure, muscle mass. Also, it influences cardiovascular profile. In the menopausal female (in whom these symptoms are clearly linked to low levels of bioavailable testosterone levels), hormone replacement therapy may be of benefit. Recently, interest is increasing in the use of androgen replacement not only for women who have undergone premature or surgical menopause but also for those who experience natural menopause and premenopausal loss of libido from diminished free testosterone.

Diagnosis and treatment of atrophic vaginitis.

Up to 40 percent of postmenopausal women have symptoms of atrophic vaginitis. Because the condition is attributable to estrogen deficiency, it may occur in premenopausal women who take antiestrogenic medications or who have medical or surgical conditions that result in decreased levels of estrogen. The thinned endometrium and increased vaginal pH level induced by estrogen deficiency predispose the vagina and urinary tract to infection and mechanical weakness. The earliest symptoms are decreased vaginal lubrication, followed by other vaginal and urinary symptoms that may be exacerbated by superimposed infection. Once other causes of symptoms have been eliminated, treatment usually depends on estrogen replacement. Estrogen replacement therapy may be provided systemically or locally, but the dosage and delivery method must be individualized. Vaginal moisturizers and lubricants, and participation in coitus may also be beneficial in the treatment of women with atrophic vaginitis.

Androgen cotherapy in menopause: evolving benefits and challenges.

The hormonal effects of estrogen and androgen were first investigated at the beginning of the twentieth century. Estrogen, which was first synthesized in the 1920s, has been shown to improve menopausal symptoms, decrease the incidence of osteoporosis, have a beneficial impact on plasma lipid profiles, probably reduce ischemic cardiovascular disease, and possibly improve cognition. In addition, retrospective studies have found a decreased incidence of Alzheimer's disease among women receiving estrogen replacement therapy compared with those not receiving this form of postmenopausal therapy. Androgen has been written about in the medical literature since 1936, when Mocquot and Moricard described its use to relieve vasomotor symptoms in postmenopausal women. During the 1940s and 1950s numerous reports appeared in the literature describing the effectiveness of estrogen-androgen combination therapy for improving the overall feeling of well-being, energy level, libido, and quality of life for postmenopausal women. Recent studies have also shown estrogen-androgen therapy to contribute to the prevention of osteoporosis and reduce serum levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. Both historical data and evolving data support further evaluation of the use of estrogen-androgen replacement therapy in postmenopausal women.

Vasomotor flushes in menopausal women.

Vasomotor symptoms after menopause are multifactorial in origin but result primarily from the loss of estrogen as ovarian function ceases. Although hot flushes typically last for 0.5 to 5.0 years after natural menopause, they may persist for as long as 15 years in a small percentage of postmenopausal women. In contrast, hot flushes tend to last longer and be more severe in surgically menopausal women. One of the major complaints associated with vasomotor symptoms is insomnia, which can have a domino effect on the patient's overall quality of life. Conventional hormone replacement therapy is effective in controlling vasomotor symptoms, including insomnia, for most postmenopausal women. However, data suggest that estrogen-androgen replacement therapy provides additional relief for women with persistent or severe vasomotor symptoms, especially women scheduled to undergo surgical menopause.

Operational improvement of gynecologic laparoscopic operating room services: an internal review.

BACKGROUND: To reorganize reusable laparoscopic instrumentation to promote instrument accessibility, minimize instrument breakage, eliminate infrequently used instruments on permanent trays, and help control maintenance costs. TECHNIQUE: The Robert Wood Johnson University Hospital Gynecologic Steering Committee evaluated during a 5-month period the storage, use, and maintenance of gynecologic laparoscopic instrument sets used in the surgical suite. Acting on this data, the committee oversaw the following changes. Infrequently used instruments were removed from permanent trays and separately packaged. Two types of gynecologic laparoscopy trays were prepared: one for laparoscopic bilateral tubal ligations and one for both diagnostic and operative laparoscopy. A double-decker compartmentalized tray in which instruments were sterilized and stored replaced the extant single-layer ones in which instruments were stacked on each other. To facilitate instrument identification and function, a surgical manual was compiled with photographs of each instrument and a description of its use. EXPERIENCE: After implementation of these changes, maintenance and sterilization costs for a 10-month period were compared with those for the previous 10 months. There was a savings of $13,889. The ratio of total costs divided by number of cases performed during the two study periods was also compared. There was a savings of $31 per case. CONCLUSION: Savings were achieved by reorganizing this operating room's handling of reusable gynecologic laparoscopy equipment. By eliminating infrequently used instruments from the permanent trays and by using a double decker compartmentalized tray that was used during surgery, sterilization, and storage, both sterilization costs and maintenance costs were reduced.

The clinical platform for the 17beta-estradiol vaginal releasing ring.

All women, regardless of race, culture, or socioeconomic background, experience urogenital atrophy as a result of hypoestrogenism from the menopause. As women go through the aging cycle, their vaginal and urethral epithelium become progressively deprived of estrogen and the tissue loses epithelial thickness, rugation, moisture, vasculature, and elasticity. The pH increases to above 5, infections in the urinary tract and vagina become more prevalent and cytologic study reflects loss of estrogen by a decrease in superficial cells and an increase in basal and parabasal cells. Replacement of estrogen to reverse these changes is the standard of care, with recent attention focused on the local delivery of estrogen by the vaginal route. The first vaginal ring delivery system of estrogen to the urogenital tract recently has been introduced, with the data confirming efficacy and safety of this delivery method for the treatment of urogenital atrophy. In addition, data on the 17beta-estradiol-releasing ring also support excellent patient acceptance of this local vaginal delivery system of estrogen therapy.

Peripheral progesterone (P) levels and endometrial response to various dosages of vaginally administered P in estrogen-primed women.

OBJECTIVE: To compare the pharmacokinetics and pharmacodynamics of 100 mg/d, 200 mg/d, and 400 mg/d (200 mg two times per day) of P administered vaginally for 14 days to estrogen-primed postmenopausal women. DESIGN: Randomized, open-label, three-way crossover study. SETTING: Two university-based investigative sites. PATIENT(S): Twenty healthy postmenopausal women with histologically normal endometria. INTERVENTION(S): Oral 17 beta-E2 was given each day of a 28-day cycle; a P vaginal suppository was inserted daily according to the randomization schedule during days 15-28 of each cycle; blood samples were collected; an endometrial biopsy was obtained on day 25; and patients were crossed over to the next treatment cycle after a washout period of at least 30 days. MAIN OUTCOME MEASURE(S): Mean P blood levels, endometrial dating/conversion. RESULT(S): There was good vaginal absorption of P for all dosages. Endometrial conversion occurred in all 200- and 400-mg/d P-dosed cycles, whereas the 100-mg/d dosage failed to convert primed endometria consistently. There also was a significantly increased tendency for earlier bleeding and spotting with the 100-mg/d dosage. CONCLUSION(S): Both the 200- and 400-mg/d dosage regimens consistently convert an estrogen-primed endometrium, and yield appropriate endometrial dating and bleeding patterns. However, the 400-mg/d dosage attains the highest sustained blood levels and may be the best dosage regimen for further study.

Evaluation of a vaginal moisturizer in baboons with decreasing ovarian function.

Decrease of estrogen concentrations in postmenopausal women leads to many urogenital problems including vaginal dryness, atrophy, stenosis, itching, and irritation, along with sexual dysfunction. Systemic estrogen replacement is effective in many women but may not be effective in others because estrogen therapy may be contraindicated for medical reasons. The reproductive tract in nonhuman female primates has been used successfully as a model for a variety of research including, but not limited to, anatomy and physiology, reproduction, cancer, infectious disease, and menopause. The baboon is especially valuable because of the similarity of its menstrual cycle to women's, prior research with this animal, and its adaptability to captivity. A nonhormonal, nonsystemic, bio-adhesive vaginal moisturizer was evaluated in baboons as a possible alternative to hormonal therapy for vaginal symptoms due to a decrease in estrogen concentrations. Eight baboons with decreasing ovarian function were used in a two-part study to evaluate vaginal health with pliability, elasticity, mucosal secretion, pH, and histologic features as criteria. The first study involved a single intravaginally administered dose of test product, with evaluation at 20 min and 24 h later. The second study consisted of five doses given at 24-h intervals, with daily evaluations for 9 consecutive days. There was marked improvement in vaginal pliability, elasticity, and secretions, with decreased pH and thickness of the vaginal epithelium. These effects appeared 1 or 2 days after drug administration, reached the maximum on day 4, and mostly decreased by day 8. However, increased secretions, vaginal elasticity, and vacuolization of the epithelium in biopsy specimens persisted to the last day of observation. The study results indicate the efficacy of the test product and the value of the baboon as a model to study decreasing ovarian function and vaginal health.

Psychosexual gynecology.

The psychosexual health of the female patient not only is affected by her overall gynecologic well-being but also may be greatly influenced by cultural myths and attitudes, psychological health, and social support. For primary care physicians to incorporate the psychosexual issues of a woman into her overall medical care, there must exist a sensitivity to the patient's needs, an atmosphere for open discussion regarding sexual and psychological concerns, an office staff to provide appropriate medical support, and the availability of experienced specialists in cases in which referral is necessary. The quality of the physician-patient interaction as well as the degree of empathy shown to women with gynecologic problems may exacerbate or improve psychosexual outcomes.

Influence of menopause on sexuality.

Menopause is associated with anatomical, physiological and psychological changes that often influence sexuality in the aging female. The decreased estrogen levels have a multitude of effects on sexual function, including decreased support of female pelvis, loss of ability to adequately lubricate the urogenital tissue, and changes in body configuration. This situation is aggravated by the alterations in the skin, breasts, muscles and skeleton caused by estrogen loss. For many women, these changes translate into a poorer self-image, diminution of self-esteem and, eventually, a loss of sexual desire. Societal expectations also have a negative impact on sexuality, as most cultures still believe that older women become sexually retired. Although this attitude is changing, cross-sectional studies still show that there are negative sexuality changes associated with menopause and that postmenopausal women note a loss of sexual desire. Age and relationship status are also important correlates of sexual activity and sexual satisfaction. With increasing age, the frequency of most types of sexual activity decreases and sexual dysfunctions increase. Urogenital atrophy due to loss of estrogen is one of the most important contributors to the decline in sexual activity with the menopause. Partner availability and partner function are important contributors as well to the decline of sexual activity, since older men, like older women, often have sexual dysfunctions. Overall, decreased sexual desire and loss of vaginal lubrication in the female and erectile difficulties in the male, or absence of a partner, are commonly reported causes of increasing sexual difficulties for the older female. Hormone replacement therapy not only ameliorates the local anatomic and physiologic changes, but also may have positive psychological benefits.(ABSTRACT TRUNCATED AT 250 WORDS)

Irregular bleeding, body mass index and coital frequency in Norplant contraceptive users.

Seventy-five women with a mean age of 27.5 years who requested Norplant implants for contraception were studied over a five-year period. The patients kept daily diaries of their vaginal bleeding and coital frequency, and were seen at least every six months at which time their weight was measured. This study examines the impact of Norplant implants use on menstrual regularity, body mass index and coital frequency. Irregular bleeding was most prevalent during the first two years of Norplant implants use and accounted for the primary reason for discontinuation of this method. No increase in Body Mass Index (BMI) was noted in Norplant implants users over the five-year study period. Women with irregular bleeding did not have a higher or lower BMI compared to women with regular bleeding and irregular bleeding patterns did not impact on coital frequency. Over five years, four pregnancies occurred during Norplant implant use. Norplant implants are a highly effective contraceptive method and women using this method should not expect an increase in body weight. Irregular bleeding is most frequent during the first two years of use and menstrual cyclicity resumes in the majority of women by the third year of use and continues to the fifth year of use.

PIP: Medical researchers recruited 75 women to participate in a 5-year prospective study of Norplant use that examined their bleeding patterns, changes in Body Mass Index (BMI), the effect BMI had on the bleeding pattern, and the effect irregular bleeding had on coital frequency. Clinicians took a complete medical and sexual history and performed a physical and pelvic examination. Follow up visits occurred at 1, 3, 6, and 12 months after insertion of the Norplant contraceptive implant and every 6 months thereafter until removal at 5 years. The clients maintained a daily record of coital activity and bleeding/spotting patterns. Thirty women completed 5 years of Norplant use. Irregular bleeding occurred most frequently during the 1st 2 years of Norplant use. Its frequency decreased as duration of Norplant use increased. For example, 22.35% of the women experienced spotting and bleeding between menstrual periods in the 1st year, 12.25% in the 2nd year, and 3.1% at 5 years. BMI was similar for women with and without irregular bleeding patterns. BMI did not change significantly over the 5 years. Irregular bleeding did not affect coital frequency. The mean coital frequency for the women was 18-20 acts of sexual intercourse per month. Irregular bleeding (32%) and planned pregnancy (12%) were the leading reasons for discontinuation of Norplant. Most of the women who quit using Norplant for irregular bleeding reasons did so during the 1st 2 years. Just 5 pregnancies occurred during Norplant use. These results suggest that clinicians should adequately counsel potential Norplant users about irregular bleeding to reduce discontinuation for irregular bleeding.

The changes before 'the change'. Strategies for the transition to the menopause.

As women enter their fifth decade, the gradual depletion of their ovarian follicles as they make the transition to the menopause can have medically important adverse consequences. Their physicians need to review with them the changes that can occur during this period (including irregular bleeding, sexual dysfunction, and other perimenopausal symptoms) and inform them about available treatments. Patients considering pregnancy should be offered fertility testing, and those who wish to avoid pregnancy should be made aware of the benefits and risks of oral contraceptive therapy. Preventive health measures should be discussed.

Nonhormonal alternatives for the management of early menopause in younger women with breast cancer.

Current medical practice recommends the use of alternatives to estrogen-replacement therapy for the treatment of menopausal sequelae in younger women with breast cancer, although this clinical recommendation is undergoing reappraisal. Until prospective randomized studies addressing hormone use in this population are available, estrogen use in breast cancer patients will remain controversial. Because estrogen-replacement therapy is not the standard of practice and there is limited information available on nonestrogen therapies, women with breast cancer who are menopausal may not be prescribed or counseled about nonestrogen options. The efficacy, safety, and extent of use of most nonestrogen treatment modalities (other hormonal preparations, nonhormonal drugs, homeopathic preparations, and non-drug treatments) are not well documented and, unlike estrogen, many are selective in their benefit and do not share estrogen's universal impact. The use of several nonestrogen approaches for the prevention and treatment of osteoporosis has been promising. Traditional recommendations to maintain skeletal integrity, such as weight-bearing exercise; a diet rich in calcium and limited in caffeine, alcohol, and protein; avoidance of smoking; and measures to minimize trauma have been expanded to include the use or investigation of drugs (either alone or in combination). These drugs include progestins, vitamin D metabolites, injectable and intranasal synthetic salmon calcitonin, bisphosphonates, sodium fluoride, parathyroid hormone, growth factors, tamoxifen, etc. Strict control of the known risk factors, such as smoking, dyslipidemia, and hypertension as well as exercise, weight control, and the use of tamoxifen, are employed for the prevention and treatment of cardiovascular complications.(ABSTRACT TRUNCATED AT 250 WORDS)

The combined effects of physical, sexual, and emotional abuse during childhood: long-term health consequences for women.

The long-term health effects of physical, sexual, and emotional abuse during childhood were studied in a sample of 668 middle class females in a gynecologic practice who responded to a self-administered, anonymous questionnaire covering demographic information, family history, physical and psychological health, as well as stressful events and abusive experiences as a child. Half (53%) of the sample reported childhood abuse, with 28.9% recounting exposure to one type of abuse, 18.7% to two types of abuse, and 5.4% to all three types of abuse. In comparison to women not abused during childhood, the abused reported significantly more hospitalizations for illnesses, a greater number of physical and psychological problems, and lower ratings of their overall health. The greater the number of childhood abuses, the poorer one's adult health and the more likely one was to have experienced abuse as an adult. Thus, in addition to the deleterious psychological consequences of abuse described in the literature, physical health also appears to be adversely affected in women abused as children.