Impact of estetrol (E4) on hemostasis, metabolism and bone turnover in postmenopausal women.

OBJECTIVE: This study aimed to determine the effects of estetrol (E4) on hemostasis, lipids, carbohydrate metabolism and bone turnover in postmenopausal women. METHODS: This study was a multicenter, randomized, double-blind placebo-controlled phase 2 trial. Participants (n = 180, age 43-64 years) received E4 2.5 mg, 5 mg, 10 mg and 15 mg or placebo once daily for 12 weeks. Changes from baseline at week 12 were evaluated versus placebo for hemostasis parameters, sex hormone binding globulin (SHBG), lipids, carbohydrate metabolism and bone markers. RESULTS: Changes for hemostasis parameters were minimal with a small increase only in the normalized activated protein C sensitivity ratio in the E4 15 mg group versus placebo. SHBG increased in the E4 5 mg, 10 mg and 15 mg groups versus placebo. High-density lipoprotein cholesterol increased in all E4 groups; changes were not consistent for other lipids. Significant decreases versus placebo were seen for insulin resistance (E4 10 mg group), hemoglobin A1c (E4 15 mg group) and type 1 collagen C-terminal telopeptide (E4 10 mg and 15 mg groups). Small decreases in osteocalcin in the E4 5 mg, 10 mg and 15 mg groups were significant versus the increase observed in placebo. CONCLUSION: E4 had limited impact on hemostasis and potentially beneficial effects on lipids, carbohydrate metabolism and bone turnover.

Menopausal hormone therapy for primary prevention: why the USPSTF is wrong.

The US Preventive Services Task Force (USPSTF) Draft Recommendation statement on Menopausal Hormone Therapy: Primary Prevention for Chronic Diseases, released in May 2017, perpetuates a major disconnect between the primary population affected, women within roughly 10 years of menopause, and the data cited. Furthermore, major elements of the evidence relied upon have been misinterpreted or misstated, particularly in regard to coronary heart disease and breast cancer, for which there is no statistically significant evidence of harm. As currently drafted, the recommendations reiterate the USPSTF statements of 2012, 2005 and 2002, and will perpetuate egregious harm to the public health. In an attempt to avoid that outcome and to facilitate a return to rational discourse regarding menopausal hormone therapy, an ad hoc group of experts in menopausal health submitted this comprehensive response to the USPSTF.

Attitudes and approaches to vaginal atrophy in postmenopausal women: a focus group qualitative study.

OBJECTIVE: The impact of postmenopausal vaginal atrophy and women's coping strategies were evaluated through international focus groups. METHODS: Three-hour focus groups of three to five postmenopausal women who had symptoms of vaginal atrophy but had not sought treatment were conducted in Canada, Sweden, the United States, and the United Kingdom. Participants were asked about their experience with menopause and vaginal atrophy, including use of non-prescription treatments and their interactions with health-care providers. Women were classified as one of five personality types, based on their interaction with the world (individualism or belonging) and strategies for coping with stress (control or liberation). RESULTS: Vaginal atrophy was not recognized as a medical condition by focus group participants, and women had not used treatments for vaginal atrophy apart from non-prescription lubricants. Women who had discussed vaginal atrophy symptoms with their doctor felt their concerns were dismissed as a normal part of aging, and they did not receive counseling about treatment options such as low-dose estrogen therapy. Those whose coping strategy involved dominance, combatting, or individualism were more likely to seek treatment than those whose strategy involved submission, acceptance, or belonging. Women who used control to cope with menopausal changes were more likely to respond to information validated by perceived experts than were those who used a strategy of release. CONCLUSIONS: Women's reactions to their vaginal atrophy varied according to personality. Use of a personality-based approach to patient counseling may encourage patients to discuss vaginal atrophy with their health-care provider and seek treatment.

A decade post WHI, menopausal hormone therapy comes full circle--need for independent commission.

The sudden decision by the National Heart, Lung, and Blood Institute of the National Institutes of Health to terminate the estrogen-progestogen therapy arm of the Women's Health Initiative (WHI) Study a decade ago now begs two questions:--has women's health after menopause been helped or harmed as a result of the findings and the way in which they were presented, and, if harmed, what needs to be done to put things right? Time and multiple reviews of specific publications from the WHI lead to the serious question whether a project designed to be of benefit to women's health has boomeranged, and instead may have resulted in significant impairment to both the quality of life and physical health of postmenopausal women. It is therefore urgent to confirm whether this is so and whether corrective action needs be taken to prevent even more harm. There are two obvious and immediate actions to be called for: (1) The Food and Drug Administration (FDA) needs to revisit the black-box warnings on postmenopausal hormones. Specifically, there needs to be a separation of the advisories for estrogen alone from estrogen and progestogen combined usage. (2) Justification is given to call for an independent commission to scrutinize every major WHI paper to determine whether the data justified the conclusions drawn. Women progressing through and beyond menopause in the next decade need to be spared the unnecessary harm that may have been inflicted on their sisters of the previous decade.

Sex steroids and growth factors differentially regulate the growth and differentiation of cultured human endometrial stromal cells.

We have studied the interaction between growth factors and sex steroids in regulating human endometrial stromal cell growth and differentiation using an in vitro serum-free cell culture model system. None of the growth factors [epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), insulin, insulin-like growth factor-I (IGF-I), IGF-II, or platelet-derived growth factor] stimulated the growth of human endometrial stromal cells grown in progestin-free medium. However, the growth of progestin-treated cultures was dramatically increased by EGF, bFGF, or platelet-derived growth factor, but not by insulin, IGF-I, or IGF-II. Estrogen could not substitute for progesterone in this protocol, and coadministration of estrogen with progestin did not enhance the response over that to progesterone alone. In contrast to their positive effects on growth, only EGF, not bFGF, stimulated stromal cell differentiation, as measured by an increase in PRL, laminin, and fibronectin production; moreover, stimulation of differentiation was dependent upon the presence of progestin in the culture medium. Thus, human endometrial stromal cell growth is 1) regulated by a discrete set of growth factors, only a subset of which regulates stromal cell differentiation; and 2) regulation of stromal cell growth and stromal cell differentiation by growth factors is progestin dependent. Our results provide direct evidence for interaction between growth factors and sex steroids in the regulation of stromal cell growth and differentiation in vitro and suggest that growth factors may be absolutely required in conjunction with progesterone for the decidual response in vivo.

Myometrial oxytocin receptors levels in the pregnant rat are higher in distal than in proximal portions of the horn and correlate with disparate oxytocin responsive myometrial contractility in these segments.

Distal (D) segments of the pregnant rat uterine horn express myometrial oxytocin receptors (MORs) earlier than proximal (P) segments (day 18 vs. 20, respectively); the levels in D segments remain higher than in P segments throughout days 21-22 and correlate with the segment-specific myometrial sensitivity to oxytocin. While progesterone (P4) had no effect on MOR levels, RU486 increased (t1/2 6-12 h) MOR levels both in D and P segments, particularly in days 12-17, and the levels in the P segment equaled those in the D segment. Estradiol had no effect on MOR levels in days 20-22; in days 16-19 estradiol increased MOR levels particularly in the P segment, and the levels in the latter were higher than in the D segment. Capillary plasma P4 levels were higher in P vs. in D myometrial segments. These results indicate, in the pregnant rat, a local uterine control of D greater than P MOR expression by P4 withdrawal beginning in day 18. We hypothesize that the D greater than P MOR expression determines a role for oxytocin in initiating myometrial contractions in the D segment, while in active labor another class of agent(s) assume that function in more proximal segments.

Maintenance of in vivo-like keratin expression, sex steroid responsiveness, and estrogen receptor expression in cultured human ectocervical epithelial cells.

In the present manuscript we demonstrate that ectocervical epithelial cells (ECE cells) retain a high degree of differentiated function when cultured using feeder layers. We characterize the cultured cells with respect to morphology, expression of cytokeratins, responsiveness to sex steroids, and the presence of estrogen-binding sites. Like ectocervical cells in vivo, the cultured cells display a typical epithelial cell morphology and undergo extensive stratification and envelope (superficial cell) formation. Like the in vivo ectocervical epithelium, the cultured ECE cells express type I cytokeratins K13, K14, K16, K17, and K19 and type II cytokeratins K5 and K6. Under normal culture conditions, however, cytokeratins K1, K2, K4, K11, and K15, which are expressed in vivo, are not expressed. An interesting finding is that ECE cells, in contrast to endocervix and epidermis in vivo and cultured epidermal keratinocytes, express very abundant levels of K13. In fact, K13 appears to be a specific marker of ECE cells in the female reproductive tract. When incubated with 10 nM diethylstilbestrol, ECE cell envelope production increased 3-fold, while incubation with 100 nM progesterone decreased envelope formation 3.4-fold. Simultaneous incubation with progesterone antagonized the diethylstilbestrol stimulation. Thus, in vivo-like sex steroid regulation of ECE cell differentiation is maintained in culture. In addition, the cells possess a high affinity, limited capacity binding site for estradiol that has a Kd of 1.2 +/- 0.1 nM. This system is likely to provide a useful model for the study of sex steroid regulation of normal ectocervical epithelial cell function.

Cultured human ectocervical epithelial cell differentiation is regulated by the combined direct actions of sex steroids, glucocorticoids, and retinoids.

During the menstrual cycle, the ectocervical epithelium undergoes a cyclic change in differentiation that is correlated with changes in the circulating levels of estrogens and progestins. To better understand the mechanisms underlying this regulation, we have developed an ectocervical epithelial cell (ECE cell) culture system that responds in a physiological manner to stimulation by estrogens and progestins. We have recently proposed that four classes of hormones (retinoids, estrogens, progestins, and glucocorticoids) may play an important role in regulating differentiation. In the present paper we test this hypothesis directly by making detailed dose-response curves. Our results demonstrate that estrogen increases ECE cell differentiation, as measured by release of cornified envelopes (superficial cells), while progesterone decreases envelope production. The effects are dose dependent and within the expected physiological range (0.01-10 nM estrogen; 0.1-100 nM progesterone). Very low concentrations of Ro 13-6298 (0.01-10 nM), a synthetic retinoid, decreased envelope production, while hydrocortisone (0.1-50 nM) increased envelope production and cell growth. Importantly, agents that enhance envelope production are neutralized by agents that reduce envelope formation and vice versa. Based on these findings we conclude 1) that the differentiation-enhancing actions of glucocorticoids and estrogens can be antagonized by either progestins or retinoids, and 2) that glucocorticoids and retinoids are likely to determine the ECE cell differentiation set-point in vivo, with the sex steroids directly modulating the phenotype of the ECE cells around this set-point during the menstrual cycle. Moreover, these results appear to explain some of the clinical descriptions of changes in ectocervical cell morphology resulting from hyper- and hypoestrogenic stimulation.

Ovarian function, therapy-oriented definition of menopause and climacteric.

The lack of uniformity in descriptive terminology applied to the cessation of human female menstruation and events related thereto has retarded scientific progress and resulted in confusion and, perhaps, therapeutic mismanagement. Inevitably, many published clinical studies do not clearly define the population being tested, and conclusions drawn are misleading or invalid. Although menopause refers to the final menstrual period (often defined retrospectively by 6-12 months amenorrhea) and climacteric to the transition from reproductive to nonreproductive stage of life, the event is not necessarily associated with any obvious symptom except amenorrhea. When symptoms do occur, collectively referred to as the climacteric syndrome, they are generated by an interaction between endocrine, sociocultural, and psychological factors, and perhaps concurrent aging phenomena as well. Based on the premise that some women with intact ovaries demonstrate endocrine compensatory mechanisms after menopause (i.e., that there are two types of postmenopausal ovary--one active and one essentially inert) and that women whose menses cease because of surgery (ovariectomy) or chemotherapy, they should not be included with those undergoing a natural menopause (i.e., represent an atypical group), an ovarian function, therapy-oriented definition for climacteric is proposed.

Clinical utility of bone mass measurements in adults: consensus of an international panel. The Society for Clinical Densitometry.

Low bone mass predicts future fracture risk as well as high cholesterol or high blood pressure can predict the risk of heart disease or stroke. Prevention of the first fracture should be a clinical goal. In patients without fractures, osteopenia and osteoporosis can be diagnosed based on the extent of reduction in bone mass below mean peak bone mass of young healthy individuals. As bone mass decreases, fracture risk increases exponentially. Clinical situations in which an assessment of bone mass and fracture risk affects therapeutic decisions include estrogen deficiency, vertebral abnormalities, radiographic osteopenia, asymptomatic primary hyperparathyroidism, and long-term corticosteroid therapy. Serial measurements can also be used to monitor the effects of osteoporosis treatments. The appropriate technique and skeletal site for bone mass measurements should be chosen based on the patient's circumstances and the precision of measurement. A clinical interpretation can enhance the value of computer-generated bone mass measurement reports and improve decision making.

The North American Menopause Society 1998 Menopause Survey. Part I: Postmenopausal women's perceptions about menopause and midlife.

OBJECTIVE: To collect information relevant to the mission of The North American Menopause Society (NAMS)--i.e., increasing understanding of menopause--by assessing perceptions held by postmenopausal women in the United States aged 50 to 65 years regarding their menopause transition and early postmenopausal years. DESIGN: During the period from June to July 1998, The Gallup Organization conducted 752 telephone interviews with a randomly selected sample of postmenopausal women aged 50 to 65 years from across the United States, based on questions developed by NAMS. In Part I of this survey, women were asked about their personal experiences with menopause, their health-related lifestyle changes since premenopause, their frequency of discussing menopause, and their rating of preparedness for menopause. Part II of this survey, including use of hormone replacement therapy as well as use of healthcare services, will be reported in a future communication from NAMS. RESULTS: The majority (51%) of the postmenopausal women surveyed reported being happiest and most fulfilled between the ages of 50 to 65 years, compared with when they were in their 20s (10%), 30s (17%), or 40s (16%). Many areas of their lives had improved since menopause, including family/home life, sense of personal fulfillment, ability to focus on hobbies or other interests, relationship with spouse/partner, and friendships. A majority (51%) said their sexual relationships had remained unchanged. Approximately three-quarters of women surveyed reported making some type of health-related lifestyle change, such as stopping smoking, at menopause/midlife. Women who had undergone hysterectomy expressed more improvement than women with an intact uterus, especially in the areas of sexual relationships, spouse/partner relationships, personal fulfillment, and physical health; data are not available regarding the health state of these women before surgery or whether they experienced surgical menopause, but this improvement did not appear to be the result of hormone replacement therapy. Women tended to look to women from their own generation for menopause-related information and believed that they have prepared the younger generation for menopause better than they were prepared by their mothers' generation. Those surveyed advised younger women to engage in healthful activities and become knowledgeable so that they could make informed health decisions. CONCLUSIONS: Although the postmenopausal women surveyed had differing views of menopause as well as their perceptions of postmenopause compared with premenopause, the majority viewed menopause and midlife as the beginning of many positive changes in their lives and health. Hysterectomy was a factor associated with improved sexual relationships, spouse/partner relationships, sense of personal fulfillment, and physical health.

The North American Menopause Society develops consensus opinions.

Considerable consultation with experts in the field has led to the conclusions reached in the article entitled "NAMS Consensus Opinion." Both published literature and clinical experience were evaluated by a panel of distinguished experts who convened to prepare their recommendations for the NAMS Board of Trustees. The article may not express the only valid approach to the topic, but readers can be assured that, like all official NAMS materials, it has been drafted and reviewed with the full benefit of the Society's considerable expertise. The Society is grateful to the panelists, and to Novartis Pharmaceuticals Corporation, whose unrestricted educational grant helped to defray costs associated with the conference. We also wish to clarify that although the term "NAMS consensus" is used, one should not assume that every single member of the Society agrees with the published findings. Such a constraint would necessarily prevent any organization from publishing its opinions. The Society hopes that the advice offered will be of assistance to the many different specialists charged with providing health care for the 4,000 women (in the U.S. alone) who are reaching menopause every day. We encourage your comments. You, our readers, will determine the way that future Society opinions will be presented.

Women and menopause: beliefs, attitudes, and behaviors. The North American Menopause Society 1997 Menopause Survey.

OBJECTIVE: The main purpose in organizing this survey was to collect information relevant to The North American Menopause Society's (NAMS) educational mission and to document women's knowledge of, and attitudes toward, menopause. DESIGN: During June-July 1997, The Gallup Organization conducted 750 telephone interviews with a randomly selected sample of women 45-60 years of age from across the United States. Women were asked about their sources of information on menopause, what changes in health they anticipated as a result of menopause, why they used hormone therapy, and their attitudes toward menopause as a natural or a medical event. RESULTS: Women are more likely to believe that depression and irritability are associated with menopause than heart disease, but only a few associate menopause with an increasing vulnerability to either memory loss or Alzheimer's disease. Relief of physical symptoms of menopause was mentioned as the reason for starting hormone therapy more often than to protect against osteoporosis (25% relative to 15%), or to prevent stroke or a heart attack (10%), or to reduce the risk of developing Alzheimer's disease (2%). The single main source of women's information on menopause was a health professional (49%). The majority of women who were already menopausal or experiencing menstrual changes expressed an attitude toward menopause that was either neutral (42%) or positive (36%). CONCLUSIONS: Women are divided in their views of menopause, some seeing it as a medical condition requiring medical treatment, whereas others see it as a natural transition to be managed by "natural" means. Providing women with accurate, up-to-date information and enhancing communication between healthcare providers and menopausal women remain the challenges for NAMS.

The menopause in perspective. From potions to patches.

This article attempts to survey our current understanding of the human female climacteric and the role of hormone replacement in its treatment. As a potential endocrinopathy, the climacteric deserves appropriate diagnostic recognition and selective preventive pharmacotherapy. The impact of sometimes conflicting influences such as nutritional, dietary or lifestyle changes, exercise, smoking, drugs, alcohol and other medications, all need differentiation from true hormonal responses. The climacteric, one syndrome occurring over a period of time, has potentially lethal effects, notably coronary heart disease and complications of osteoporotic fractures. However, therapy itself carries major problems, the cancer question being the most important. The dilemma of risk-benefit planning is reviewed and likely future developments are outlined. The role of the new North American Menopause Society is explained.

A risk-benefit appraisal of transdermal estradiol therapy.

Estrogen replacement therapy (ERT) is very effective in relieving many menopausal symptoms such as hot flushes, night sweats, urogenital atrophy and psychological disturbances. Moreover, it is effective in the prevention of postmenopausal osteoporosis and has a favourable effect on some risk factors for cardiovascular disease in the long term, via several mechanisms including mediating effects on the lipid profile. Most of these beneficial effects are maintained with transdermal estradiol therapy, involving the use of a cutaneous delivery system attached to the skin which delivers a controlled rate of estradiol over a period of up to 4 days. However, the clear demonstration of a favourable effect on some risk factors for cardiovascular disease remains to be established. Transdermal administration of estradiol appears to be at least as effective as oral conjugated estrogen therapy on most of the end-points which have been evaluated, but allows a lower dose to be used, avoiding some of the metabolic adverse effects experienced with oral treatment. Endocrinological adverse effects, such as breast tenderness, breakthrough bleeding and fluid retention, are similar in both treatments, and can be minimised by dose adjustments in most cases. The most common adverse effects related to transdermal therapy are local skin reactions at the site of application. These are usually mild and transient in nature, and can be overcome by changing the site of application. Serious risks of transdermal therapy appear to be the same as those for other forms of ERT, namely an increased risk of endometrial hyperplasia and cancer with estrogen therapy alone. However, combination therapy involving the sequential administration of a progestogen has been shown to substantially reduce the risk of endometrial proliferation. The potential increased risk of breast cancer has been controversial and appears to be minimal with ERT. The role of progestogens on breast cancer risk remains controversial, but the data to date do not indicate any significant change in risk when progestogens are added to ERT.

Microscopic versus macroscopic tubal anastomosis in rabbit fallopian tubes.

The importance of the operating microscope in rabbit tubal anastomosis was assessed by operating on 36 rabbits, half with the aid of the operating microscope and half with the aid of low-magnification loupes. The surgeons' operating comfort and sense of assuredness that the anastomoses were being done properly were increased by the operating microscope. However, the outcome of the anastomoses as measured by pregnancy rates, adhesion scores, and microscopic pathologic findings were not significantly different in the two groups.

Role of dextran 70 in microtubal surgery.

Pelvic adhesion formation represents a major problem following fallopian tube surgery for infertility. Intraperitoneal dextran may prevent pelvic adhesions. Extensive personal clinical experience (W. H. U.) with intraperitoneal dextran organ-flotation on completion of tubal and ovarian surgery has appeared to limit adhesions. A specific study was designed to test the validity of this theory. Four randomized groups of rabbits were subjected to bilateral tubocornual division and microsurgical reanastomosis with total hemostasis and pelvic lavage. Routine peritoneal closure was performed on one group, but followed instillation of 30 to 50 ml of normal saline into the peritoneal cavities of the second group, and 30 to 50 ml of 6% dextran 70 into those of the third. Study of fourth group, which received 32% dextran 70 in the peritoneal cavity, was discontinued because of complications. A second laparotomy was performed 4 weeks later for precise assessment and photography of adhesion formation. Each animal was mated 4 weeks after the second operation in order to determine fertility rates. Reduced adhesion formation and increased fertility rates following the instillation of dextran are reported. A role for dextran 70 in infertility surgery is recommended.

PIP: The role of microsurgical techniques and the use of low-molecular-weight Dextran 70 on adhesion formation and fertility rates were investigated in 4 randomized groups of rabbits which were subjected to bilateral tubocornual division and microsurgical reanastomosis with total hemostasis and pelvic lavage. The experiment with 1 group of rabbits using 32% Dextran 70 in the peritoneal cavity postoperatively was discontinued, but the 3 other groups were treated, respectively, with routine peritoneal closure following instillation of 30-50 ml of normal saline, 2) instillation of 30-50 of 6% Dextran 70 and then routine closure, or 3) simple, routine closure with no treatment. 4 weeks later a second laparotomy was performed to assess and photograph adhesive lesions. Then, within 4 weeks after the second operation, each animal was mated to determine fertility rates. Dextran 70 instilled prior to closure seemed to raise fertility rates and lessen the number of and degree of adhesion formation; therefore, use of Dextran in microsurgery is recommended.

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.

Preliminary experience with in vitro fertilization-surrogate gestational pregnancy.

This report documents the medical details and 3-year follow-up evaluation of the infertile and surrogate couples involved in the first successful in vitro fertilization gestational surrogate pregnancy and summarizes clinical experience and outcome of all patients treated to date. Results of the first 28 couples treated are presented. The pregnancy rate for 39 cycles reaching attempts at oocyte retrieval is 18%. The procedural aspects, ethical issues, legal issues, and subsequent program development are summarized. Recommendations are of a similar program. There are numerous potential pitfalls and traps for the unwary, but our experience has thus far been gratifyingly positive, and we endorse the further provision, observation, and documentation of this controversial approach to the care of the infertile couple.

Beneficial effects of estrogen on cardiac stunning in female rabbits.

OBJECTIVE: To determine the effect of estrogen treatment on the contractile, relaxation, and chronotropic responses of hearts of female rabbits to cessation of perfusion. METHODS: Adult female rabbits were treated either with estradiol or with the vehicle (control). The hearts were then isolated and perfused at constant pressure by the Langendorff technique. A saline-filled balloon connected to a pressure transducer was inserted in the left ventricle in order to assess the mechanical function of the isolated heart. Cardiac stunning was induced by halting the perfusion of the coronary vasculature for four successive periods of 1, 3, 5, and 5 minutes, followed by reperfusion between nonperfusion periods. Changes in cardiac function induced by the cessation of perfusion were assessed by monitoring the changes in heart rate and in left ventricular pressure ([dP/dt]max as an index of ventricular contractility and [dP/dt]min as an index of ventricular relaxation). Changes in coronary flow were determined at baseline and following reperfusion. RESULTS: Halting coronary perfusion decreased (dP/dt)max, and (dP/dt)min and slowed left ventricular contractions both in control and in estrogen-treated hearts. The depressant effects of flow cessation on left ventricular (dP/dt)max and (dP/dt)min were smaller in estrogen-treated hearts than in control hearts. Treatment with estrogen had no effect on the changes on the heart rate in responses to cessation of flow and to reperfusion. Treatment with estrogen increased coronary flow by 40%. Coronary reperfusion increased coronary flow transiently, but the effects did not differ significantly between control and estrogen-treated hearts. CONCLUSION: Short-term treatment of adult female rabbits with doses of estrogen that are physiologic for the rabbit exerts a protective effect on cardiac contractility from repetitive periods without perfusion.