Managing vasomotor symptoms in women after cancer.

Women with estrogen-sensitive cancer or survivors of these neoplasms are generally not candidates for systemic menopausal hormone therapy or tibolone for the treatment of bothersome vasomotor symptoms (hot flashes or night sweats). However, menopausal symptoms negatively affect quality of life and need to be addressed by clinicians. For mild vasomotor symptoms, optimizing lifestyle changes or mind-brain behavior may be sufficient. For women with moderate to severe vasomotor symptoms unresponsive to these measures, non-hormone pharmacologic therapy may be needed. Randomized controlled trials have shown efficacy for vasomotor symptoms with selective serotonin reuptake inhibitors (paroxetine, citalopram, and escitalopram) and serotonin-norepinephrine reuptake inhibitors (venlafaxine and desvenlafaxine), as well as gabapentin, pregabalin, and clonidine. Therapies in development include neurokinin B inhibitors (neurokinin 3 receptor), stellate ganglion blockade, and a natural estrogen, estetrol. Individualizing therapy is important. As the physiology of menopausal hot flashes becomes better understood, it will drive development of future non-hormone pharmacotherapies.

Beyond estrogen: advances in tissue selective estrogen complexes and selective estrogen receptor modulators.

Selective estrogen receptor modulators (SERMs) are synthetic non-steroidal agents which have variable estrogen agonist and antagonist activities in different target tissues. Tamoxifen is an anti-estrogen in the breast used for treatment and prevention of breast cancer, with estrogen agonist activity in the uterus. Raloxifene prevents and treats osteoporosis and prevents breast cancer, and can be safely combined with vaginal but not systemic estrogen. The tissue selective estrogen complex combines conjugated equine estrogens (CEE) with the SERM bazedoxifene (BZA). The five Selective Estrogen Menopause and Response to Therapy studies, with up to 2 years of data, demonstrated that CEE/BZA 0.45 mg/BZA 20 mg improved vasomotor symptoms and vulvovaginal atrophy, prevented bone loss, and was neutral on breast tenderness, breast density, with breast cancer incidence similar to placebo. Protection against estrogen-induced endometrial hyperplasia and cancer was found, with similar amenorrhea rates to placebo. Ospemifene is approved to treat dyspareunia, with potential benefits on bone and the breast, while lasofoxifene is being developed to treat resistant estrogen receptor-positive breast cancer in women. Estetrol is an estrogen synthesized exclusively during pregnancy by the human fetal liver and initially considered a weak estrogen, but it appears to have dual weak estrogenic/anti-estrogenic features.

Revised global consensus statement on menopausal hormone therapy.

The following Consensus Statement is endorsed by The International Menopause Society, The North American Menopause Society, The Endocrine Society, The European Menopause and Andropause Society, The Asia Pacific Menopause Federation, The International Osteoporosis Foundation and The Federation of Latin American Menopause Societies.

Treatment of symptoms of the menopause: an Endocrine Society Clinical Practice Guideline

OBJECTIVE: The objective of this document is to generate a practice guideline for the management and treatment of symptoms of the menopause. PARTICIPANTS: The Treatment of Symptoms of the Menopause Task Force included six experts, a methodologist, and a medical writer, all appointed by The Endocrine Society. EVIDENCE: The Task Force developed this evidenced-based guideline using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe the strength of recommendations and the quality of evidence. The Task Force commissioned three systematic reviews of published data and considered several other existing meta-analyses and trials. CONSENSUS PROCESS: Multiple e-mail communications, conference calls, and one face-to-face meeting determined consensus. Committees of The Endocrine Society, representatives from endorsing societies, and members of The Endocrine Society reviewed and commented on the drafts of the guidelines. The Australasian Menopause Society, the British Menopause Society, European Menopause and Andropause Society, the European Society of Endocrinology, and the International Menopause Society (co-sponsors of the guideline) reviewed and commented on the draft. CONCLUSIONS: Menopausal hormone therapy (MHT) is the most effective treatment for vasomotor symptoms and other symptoms of the climacteric. Benefits may exceed risks for the majority of symptomatic postmenopausal women who are under age 60 or under 10 years since the onset of menopause. Health care professionals should individualize therapy based on clinical factors and patient preference. They should screen women before initiating MHT for cardiovascular and breast cancer risk and recommend the most appropriate therapy depending on risk/benefit considerations. Current evidence does not justify the use of MHT to prevent coronary heart disease, breast cancer, or dementia. Other options are available for those with vasomotor symptoms who prefer not to use MHT or who have contraindications because these patients should not use MHT. Low-dose vaginal estrogen and ospemifene provide effective therapy for the genitourinary syndrome of menopause, and vaginal moisturizers and lubricants are available for those not choosing hormonal therapy. All postmenopausal women should embrace appropriate lifestyle measures.

Tissue selective estrogen complex combinations with bazedoxifene/conjugated estrogens as a model.

The tissue selective estrogen complex (TSEC) pairs a selective estrogen receptor modulator (SERM) with one or more estrogens. Different TSECs are associated with distinct gene expression profiles in mammary gland and endometrial tissue according to the individual SERM and estrogen components. Few TSECs have been evaluated outside the laboratory. In preclinical trials, bazedoxifene (BZA) was distinct from other SERMs, with a neutral effect on mammary gland and endometrial tissue, and an antagonist effect on these tissues when combined with conjugated estrogens (CE). The only TSEC in an advanced stage of clinical development pairs BZA with CE. In large, randomized clinical trials, two doses, BZA 20 mg/CE 0.45 and 0.625 mg, reduced menopausal symptoms and prevented bone loss in postmenopausal women with a favorable safety profile on the breast, endometrium, and ovary, and with cardiovascular and venous thrombosis events similar to placebo. Improvements were seen in sleep, health-related quality of life, and treatment satisfaction. Compared with traditional, progestogen-containing hormone therapy, BZA/CE had higher rates of amenorrhea and reduced breast pain, with changes in breast density from baseline similar to placebo. Future TSECs identified in preclinical studies need to be tested in rigorous phase-3 clinical trials for effectiveness, safety and tolerability.

Bazedoxifene/conjugated estrogens for menopausal symptom treatment and osteoporosis prevention.

Postmenopausal women with vasomotor and vaginal symptoms are commonly treated with estrogens or combined estrogen/progestin therapy (hormone therapy). However, hormone therapy is associated with some safety and tolerability concerns and its benefit/risk profile may vary for women based on their time since menopause. The tissue selective estrogen complex (TSEC) pairs a selective estrogen receptor modulator with one or more estrogens, with the goal of relieving menopausal symptoms and preserving bone mineral density without stimulating the breast or endometrium. Bazedoxifene/conjugated estrogens (BZA/CE) is the first TSEC in clinical development. BZA 20 mg/CE 0.45 and 0.625 mg have been shown in phase-3 clinical trials to significantly improve hot flushes and vulvar/vaginal atrophy measures in symptomatic postmenopausal women and to prevent bone loss in postmenopausal women at risk for osteoporosis while ensuring endometrial safety. These doses of BZA/CE have also demonstrated significant improvements in quality-of-life scores, sleep parameters, and treatment satisfaction compared with placebo. BZA 20 mg/CE 0.45 and 0.625 mg showed high cumulative rates of amenorrhea and low rates of breast pain, similar to those with placebo. The favorable treatment effects seen with BZA/CE were generally consistent in women < 5 or ≥ 5 years since menopause. Based on its demonstrated efficacy and safety in women both closer to or further from menopause, BZA/CE may be an appropriate alternative to hormone therapy for the treatment of menopausal symptoms and the prevention of osteoporosis.

Use of alternatives to estrogen for treatment of menopause.

Women frequently chose alternatives to hormone replacement therapy (HRT) for treatment of menopause even though medical indications for estrogens may be present. Prior breast cancer or fear of breast cancer is a major consideration. This review of alternatives to estrogen discusses the evidence linking breast cancer to HRTs and compares potential risks and benefits of HRT to nonHRT alternatives for relief of vasomotor symptoms, vaginal atrophy, neurocognitive changes and prevention of heart disease and osteoporosis. Practical guidelines are suggested for use of alternatives for each problem.

Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate.

OBJECTIVE: To evaluate the efficacy of lower doses of conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) for relieving vasomotor symptoms and vaginal atrophy. DESIGN: A randomized, double-blind, placebo-controlled trial (the Women's Health, Osteoporosis, Progestin, Estrogen study). SETTING: Study centers across the United States. PATIENT(S): Two thousand, six hundred, seventy-three healthy, postmenopausal women with an intact uterus, including an efficacy-evaluable population (n = 241 at baseline). INTERVENTION(S): Patients received for 1 year (13 cycles; in milligrams per day) CEE, 0.625; CEE, 0.625 and MPA, 2.5; CEE, 0.45; CEE, 0.45 and MPA, 2.5; CEE, 0.45 and MPA, 1.5; CEE, 0.3; CEE, 0.3 and MPA, 1.5; or placebo. MAIN OUTCOME MEASURE(S): Number and severity of hot flushes and Papanicolaou smear with vaginal maturation index (VMI) to assess vaginal atrophy. RESULT(S): In the efficacy-evaluable population, reduction in vasomotor symptoms was similar with CEE of 0.625 mg/d and MPA of 2.5 mg/d (the most commonly prescribed doses) and all lower combination doses. CEE of 0.625 mg/d alleviated hot flushes more effectively than the lower doses of CEE alone. VMI improved in all active treatment groups. CONCLUSION(S): Lower doses of CEE plus MPA relieve vasomotor symptoms and vaginal atrophy as effectively as commonly prescribed doses.

Ethical theory and principles: do they have any relevance to problems arising in everyday practice?

This review of ethical theories with application to two difficult obstetric cases will allow the practicing obstetrician and gynecologist to use these theories to help resolve difficult ethical dilemmas. In the first case a pregnant human immunodeficiency virus-infected woman refuses to take triple preventive therapy, with potential fetal harm. In the second case a couple with a quintuplet multifetal pregnancy needs assistance to decide about selective termination to effect fetal reduction.

Cerebral arteriovenous malformation in pregnancy: presentation and neurologic, obstetric, and ethical significance.

Cerebral arteriovenous malformations infrequently complicate pregnancy. We sought to determine the neurologic, obstetric, and ethical significance of such malformations. We present the clinical course of 2 pregnant women with arteriovenous malformations who experienced cerebral hemorrhage and a loss of capacity for decision making. We also review the neurologic and obstetric significance of arteriovenous malformations in pregnancy. Various treatment options with concern for pregnancy and the prognosis for arteriovenous malformations are outlined. The ethical issues involved for pregnant patients whose decisional capacity is compromised as a result of cerebral injury are explored. A review of persistent vegetative state and brain death (death by neurologic criteria) occurring in pregnancy allows us to explore many issues that are applicable to decisionally incapacitated but physiologically functioning pregnant women. We outline a document, the purpose of which is to obtain advance directives from pregnant women regarding end-of-life decisions and to appoint a surrogate decision maker. We believe that evaluation and treatment of the arteriovenous malformation may be undertaken without regard for the pregnancy and that the pregnancy should progress without concern for the arteriovenous malformation.

Patient satisfaction with psychiatric treatment of menopausal women in a multidisciplinary women's midlife center.

OBJECTIVE: Menopause may be associated with new onset psychiatric symptoms or may exacerbate or heighten preexisting psychiatric problems in women. We present a model center for midlife women, with a multidisciplinary approach to treating this population, and patients' perceptions of satisfaction with treatment received during referral visits to an outpatient psychiatry clinic. DESIGN: In this study, 59 patients were referred from their primary care provider at the midlife center for evaluation by a faculty psychiatrist in an outpatient setting. A brief telephone interview was administered within 1 year of initial evaluation, using items from the Client Satisfaction Questionnaire-8 (CSQ-8) to assess patient satisfaction with psychiatric services received during the referral visits. Findings were based on responses provided by 50 women who were successfully contacted by telephone for the follow-up assessment. RESULTS: For this sample, the mean total client satisfaction score was 27.8 (s = 5.4) of a possible score of 32, which indicated that most women who were referred for psychiatric services reported a positive experience with the services provided by outpatient psychiatrists and reported being very satisfied with their treatment. CONCLUSIONS: We feel that this model center represents a unique way to identify and treat psychiatric disorders in a patient population that may be at high risk for depression and other psychiatric disorders.

Parental rights at the birth of a near-viable infant: conflicting perspectives.

OBJECTIVE: Our purpose was to clarify the roles of parents and caregivers in making decisions for resuscitation of near-viable infants. STUDY DESIGN: We present two cases and review ethical and legal issues involved in making decisions for near-viable infants. RESULTS: Medical responsibility for the infant shifts at birth from obstetrics to neonatology. Neonatologists will "opt for life" when prognosis is uncertain. As surrogate decision makers, parents have rights to make decisions about initiation of resuscitation, but these parental rights are limited by the infant's best interests. If caregivers believe parents are not acting in the infant's best interests, they may persuade parents, challenge parental refusal by petitioning the courts, or treat without consent with possible legal risk. CONCLUSIONS: Effective communication is essential to prevent misunderstanding and conflicts. In most instances parents are the best decision makers for a near-viable infant. Parental rights are limited by best interests of the infant.

Resolving the clinical and ethical dilemma involved in fetal-maternal conflicts.

A serious ethical dilemma occurs when a pregnant woman refuses a medically indicated intervention. Should respect for her autonomy preclude any approach other than to accept her decision? Should the caregivers have recourse to "gentle persuasion"? Is there ever a justification for invoking the power of court-ordered intervention? The societal views on this subject are first developed from an ethical perspective. The pertinent court cases that reflect on this topic are reviewed. The process of developing guidelines within our institution is related. Finally, the guidelines that were eventually developed are offered.

Ethical considerations of managed care.

Universal health care will soon be here. This paper presents the basic models of managed care as well as a glossary of terms to allow discussion of the basic plans. Three cases are discussed to illustrate the dilemmas of managed care utilizing Dr. Fletcher's ethical model. Basic concepts are derived from these cases to assist physicians to work within the constraints of the new health care systems and enable them to respond to the sometimes unavoidable conflicts between medical benefit and cost containment.