Reduced vaginal bleeding in postmenopausal women who receive combined norethindrone acetate and low-dose ethinyl estradiol therapy versus combined conjugated equine estrogens and medroxyprogesterone acetate therapy

OBJECTIVE: The purpose of this study was to compare the effects on vaginal bleeding patterns of continuous combined hormone replacement therapy with norethindrone acetate and ethinyl estradiol versus conjugated equine estrogens and medroxyprogesterone acetate. STUDY DESIGN: Three hundred fifty-seven postmenopausal women were selected randomly (in a blinded manner) to 12 months of treatment with 1 mg norethindrone acetate/5 microg ethinyl estradiol, placebo, or open-label 0.625 mg conjugated equine estrogens/2.5 mg medroxyprogesterone acetate (conjugated equine estrogens/medroxyprogesterone acetate [CEE/MPA]; Prempro). The incidence and duration of vaginal bleeding were assessed throughout the study. Statistical analyses used Cochran-Mantel-Haenszel methodology and analysis of variance. RESULTS: At 3 months, 1 mg norethindrone acetate/5 microg ethinyl estradiol therapy reduced the incidence of bleeding (12% vs 23%; P <.029) and bleeding and/or spotting (22% vs 44%; P <.001), compared with conjugated equine estrogens/medroxyprogesterone acetate therapy. The mean duration of bleeding and bleeding and/or spotting were also reduced with 1 mg norethindrone acetate/5 microg ethinyl estradiol therapy versus conjugated equine estrogens/medroxyprogesterone acetate (P =.004 and P <.001, respectively). The incidence of cumulative amenorrhea at every monthly interval was significantly better with 1 mg norethindrone acetate/5 microg ethinyl estradiol therapy versus conjugated equine estrogens/medroxyprogesterone acetate therapy (P <.05). Associated adverse event (ie, headache, breast pain) incidence rates were similar in the 2 active treatment groups. CONCLUSION: The 1 mg norethindrone acetate/5 microg ethinyl estradiol therapy provides significantly better control of vaginal bleeding than conjugated equine estrogens/medroxyprogesterone acetate therapy at all time points investigated in this 12-month study.     

A study of combined continuous ethinyl estradiol and norethindrone acetate for postmenopausal hormone replacement

In a blinded, prospective, dose-response pilot study of continuous estrogen-progestin replacement therapy, 77 thin, nonsmoking, white women, who were 12 to 60 months postmenopausal and had normal medical histories, were randomly assigned to receive one of five dose combinations of daily ethinyl estradiol and norethindrone acetate (20 micrograms and 1.0 mg, 10 micrograms and 1.0 mg, 10 micrograms and 0.5 mg, 5 micrograms and 1.0 mg, and 5 micrograms and 0.5 mg) or conjugated estrogens 0.625 mg on days 1 to 25 and medroxyprogesterone acetate 10 mg on days 16 to 25. An additional 10 women meeting the same criteria served as a comparison group by taking calcium only. During 12 months of therapy, continuous users had significantly less vaginal bleeding and spotting than did sequential users. As compared with baseline values, bone metabolism and computerized tomographic measurements of vertebral trabecular bone density at month 12 indicated reduced bone turnover and increased density in hormone users. Endometrial biopsy specimens were negative for hyperplasia and neoplasia. The continuous ethinyl estradiol-norethindrone acetate tablet, even at the lowest doses studied, provided the same salutary effects on bone, endometrium, and postmenopausal symptoms as sequential therapy while minimizing annoying vaginal bleeding and spotting.     

Contrasting effects of two hormone replacement therapies on the cardiovascular and mammary gland outcomes in surgically postmenopausal monkeys

OBJECTIVE: The purpose of this study was to compare the effects of two hormone replacement therapies on the intermediate end points of coronary heart disease and mammary gland hyperplasia in postmenopausal monkeys.Study Design: Surgically postmenopausal cynomolgus monkeys were fed an atherogenic diet for 12 months while receiving no treatment (control, n = 19), conjugated equine estrogens plus continuous medroxyprogesterone acetate (n = 19), or ethinyl estradiol plus norethindrone acetate (n = 21) at doses that were scaled from those doses taken by women. RESULTS: Quantitative coronary angiography revealed that the arteries of the control group and the conjugated equine estrogens plus continuous medroxyprogesterone acetate-treated animals constricted in response to acetylcholine (-5.4% +/- 1.4% and -6.2% +/- 1.5%, respectively), whereas those arteries in the animals in the ethinyl estradiol plus norethindrone acetate group did not (P =.002). The incidence of dobutamine-induced ST-segment depression in the ethinyl estradiol plus norethindrone acetate group (10.5%) was significantly less than in the control group (68.8%, P =.001) or the conjugated equine estrogens plus continuous medroxyprogesterone acetate group (50%, P =.01). Conjugated equine estrogens plus continuous medroxyprogesterone acetate, but not ethinyl estradiol plus norethindrone acetate, induced diffuse epithelial tissue proliferation in the mammary glands (P =.0006). CONCLUSION: Ethinyl estradiol plus norethindrone acetate protected against atherosclerosis-induced endothelium-mediated vasoconstriction of coronary arteries and heart rate-induced myocardial ischemia and did not induce epithelial tissue proliferation (tissue density) in the mammary gland.     

Effects of two different regimens of continuous hormone replacement therapy on endometrial histopathology and postmenopausal uterine bleeding

Objective: To compare the effects of frequently used two different regimens of combined continuous hormone replacement therapy; 0.625 mg conjugated equine estrogen (CEE) + 2.5 mg medroxyprogesterone acetate (MPA) and 1 mg 17β estradiol (E2) + 0.5 mg norethindrone acetate (NETA), on endometrial histopathology and postmenopausal uterine bleeding. Materials and methods: Two hundred and forty-six outpatient subjects aged 41–57 years were enrolled in the study conducted at the menopause clinic between November 2003 and November 2004. One hundred and thirty-nine patients were assigned to receive 0.625 mg conjugated equine estrogen + 2.5 mg medroxyprogesterone acetate (CEE/MPA), whereas 107 patients were to receive 17β estradiol + 0.5 mg norethindrone acetate (E2/NETA). Inclusion criteria of the study were: normal values of endometrial thickness at basal evaluation, women with intact uterus, at least 12 months of amenorrhea, normal vaginal smear, bilateral mammography and biochemical blood parameters. All women were questioned every 3 months for vaginal bleeding/spotting. Endometrial sampling was performed by Pipelle catheter in the 12th month of therapy. Results: For the first 3 months, vaginal bleeding/spotting rate for the CEE/MPA group was 38.7%, whereas it was higher (45%) in the E2/NETA group. For the second 3-month period, vaginal bleeding/spotting frequencies were 41.1 and 37.8%, respectively. In the third 3-month period 30.6 and 29.6%, and in the fourth 3-month period, 18.5 and 12.5% of the patients reported vaginal bleeding or spotting. None of the results of endometrial sampling have shown findings of cancer histopathology. Conclusion: Compared to CEE/MPA regimen, E2/NETA therapy has not shown more favorable effects on postmenopausal bleeding abnormalities. Irregular endometrial proliferation was seen more with the E2/NETA regimen.     

Menopausal hormone replacement therapy with continuous daily oral micronized estradiol and progesterone

The safety and efficacy of a daily combination of micronized estradiol (E2) (0.7-1.05 mg) and progesterone (200-300 mg) were evaluated in ten menopausal women with moderate to severe vasomotor symptoms and/or vaginal atrophy over a 12-month study interval. For comparison, five similar women were placed on conjugated estrogens, 0.625 mg daily, and medroxyprogesterone acetate, 10 mg daily, for the first 10 days of each calendar month for 12 months. Patients were evaluated at 0, 1, 3, 6, and 12 months. Estrogens rose significantly from baseline in both groups (P less than .01). Progesterone increased significantly above baseline in the E2 and progesterone group (P less than .01), but did not change in the conjugated estrogens and medroxyprogesterone acetate users. All women on E2 and progesterone had a decrease in total cholesterol and an increase in high-density lipoprotein cholesterol from baseline (P less than .01). Those on conjugated estrogens and medroxyprogesterone acetate had no significant change from baseline in total cholesterol; however, they did have an increase in high-density lipoprotein cholesterol values (P less than .01). In the E2 and progesterone group, the endometrial histology became completely quiescent and there was no uterine bleeding after 6 months of observation. Four of five women on conjugated estrogens and medroxyprogesterone acetate continued regular withdrawal bleeding throughout the study period, but no endometrial hyperplasia was encountered. This study demonstrates that the daily administration of a combination of micronized E2 and progesterone results in symptomatic improvement, minimal side effects, an improved lipid profile, and amenorrhea without endometrial proliferation or hyperplasia in menopausal women.     

Endometrial effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate.

OBJECTIVE: To determine the endometrial safety of lower doses of continuous combined conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA). DESIGN: Randomized, double-blind, placebo-controlled study (the Women's Health, Osteoporosis, Progestin, Estrogen study). SETTING: Study centers across the United States. PATIENT(S): Healthy, postmenopausal women (n = 2,673) with an intact uterus. INTERVENTION(S): Patients received CEE 0.625 mg/day, CEE 0.625/MPA 2.5 mg/day, CEE 0.45 mg/day, CEE 0.45/MPA 2.5 mg/day, CEE 0.45/MPA 1.5 mg/day, CEE 0.3 mg/day, CEE 0.3/MPA 1.5 mg/day, or placebo for 1 year. Endometrial biopsies were evaluated at baseline, cycle 6, and year 1 using a centralized protocol.MAIN OUTCOME MEASURE(S): Efficacy of lower doses of CEE/MPA in reducing the incidence of endometrial hyperplasia rates associated with unopposed CEE. RESULT(S): Endometrial hyperplasia rates ranged from 0 to 0.37% for all CEE/MPA doses. Twenty-nine of the 32 cases of endometrial hyperplasia developed in women who were administered CEE 0.625 mg or CEE 0.45 mg. The incidence of endometrial hyperplasia increased with age for patients administered CEE alone. As expected, there were some inconsistencies among pathologists' ratings in the numbers of hyperplasias and incidence rates for the CEE-alone regimens. There were too few cases of hyperplasia in the combination groups to evaluate consistency among pathologists. CONCLUSION(S): One year of treatment with lower doses of CEE/MPA provides endometrial protection comparable to commonly prescribed doses. These regimens may be used by clinicians to individualize hormone replacement therapy in postmenopausal women.     

Vaginal bleeding in postmenopausal women taking low-dose norethindrone acetate and ethinyl estradiol combinations. The FemHRT Study Investigators

OBJECTIVE: To determine the effect of continuous combined treatment with norethindrone acetate and ethinyl estradiol (E2) on vaginal bleeding, spotting, or bleeding and/or spotting in postmenopausal women. METHODS: Two randomized clinical trials were conducted in which participants recorded information on the daily occurrence of vaginal bleeding or spotting. In study 1, 219 postmenopausal women reporting at least ten hot flushes per week were randomized to placebo or one of four treatment groups (0.2 mg norethindrone acetate/1 microg ethinyl E2, 0.5 mg norethindrone acetate/2.5 microg ethinyl E2, 1 mg norethindrone acetate/5 microg ethinyl E2, or 1 mg norethindrone acetate/10 microg ethinyl E2). In study 2, 266 postmenopausal women reporting at least 56 moderate to severe hot flushes were randomized to placebo or one of three treatment groups (0.5 mg norethindrone acetate/2.5 microg ethinyl E2, 1 mg norethindrone acetate/5 microg ethinyl E2, or 1 mg norethindrone acetate/10 microg ethinyl E2). The total duration of treatment was 16 weeks in study 1 and 12 weeks in study 2. In both studies, subjects reported in daily diaries whether they had either bleeding or spotting.Results: In study 1, there was a significantly greater relative risk (RR) for bleeding in the group receiving 1 mg norethindrone acetate/10 microg ethinyl E2 at study weeks 4 and 8 (RR = 1.36 and 95% confidence interval [CI] 1.01, 1.83; RR = 1.37 and 95% CI 1.1, 1.72; respectively) compared with placebo, but not at study weeks 12 or 16. The group receiving 1 mg norethindrone acetate/5 microg ethinyl E2 also had a significantly greater risk at weeks 4 and 8 (RR = 1.5 and 95% CI 1.15, 1.96; RR = 1.33 and 95% CI 1.00, 1.77; respectively), whereas the other dose combinations did not differ from placebo. Results from study 2 were similar to those of study 1.Conclusion: Although there was a greater risk for bleeding and/or spotting at the higher doses of norethindrone acetate and ethinyl E2, this risk declined over time. If compliance with hormone replacement therapy regimens is influenced at least in part by vaginal bleeding, the combined norethindrone acetate/ethinyl E2 regimen investigated in these studies may provide a treatment option.     

Effects of conjugated equine estrogen with and without three different progestogens on lipoproteins, high-density lipoprotein subfractions, and apolipoprotein A-I.

The effects of conjugated equine estrogen and subsequent cyclical progestogen supplementation on lipoprotein and apolipoprotein A-I levels were investigated in three groups of postmenopausal women. Unopposed conjugated equine estrogen (0.625 mg) lowered total cholesterol 4-8% and low-density lipoprotein (LDL) cholesterol 12-19% below pre-treatment levels in all three groups. Levels of high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I were increased 9-13 and 9-18%, respectively, with unopposed estrogen. The increase in HDL cholesterol was mainly due to increases in the high-density lipoprotein2 (HDL2) subfraction. Addition of medroxyprogesterone acetate, norethindrone acetate, or d,l-norgestrel at doses shown previously to provide protection against endometrial hyperplasia reversed some of the beneficial estrogen effects, reducing levels of HDL cholesterol 14-17%, HDL2 cholesterol 22-37%, and apolipoprotein A-I 11-15% from those obtained with unopposed estrogen. The LDL cholesterol levels fell 12-19% with unopposed estrogen but remained 7-12% below baseline when progestogens were added. These observations demonstrate that after 3 months of treatment, all three progestogens reversed some of the favorable effects of unopposed estrogen on lipoproteins but permitted a continued modest reduction in LDL cholesterol.     

Biochemical and histologic effects of sequential estrogen/progestin therapy on the endometrium of postmenopausal women

Medroxyprogesterone acetate in doses of 10, 5, and 2.5 mg was administered sequentially to three groups of postmenopausal women receiving 0.3 mg, 0.625 mg, and 1.25 mg of conjugated equine estrogens, respectively. Serial endometrial biopsies were performed on these women before therapy, during estrogen therapy alone, and during sequential estrogen-progestin therapy. Endometrial histology and estrogen receptor concentrations were assessed. A linear increase of cytosolic estrogen receptor concentration occurred over the dosage range of conjugated equine estrogen. When medroxyprogesterone acetate was added to the estrogen therapy, the concentrations of estrogen receptors fell. Within the groups of women receiving 0.3 mg and 0.625 mg of conjugated equine estrogen, all doses of medroxyprogesterone acetate were equally effective in reducing the levels of cytosolic receptor to pretreatment levels. However, at the conjugated equine estrogen dose of 1.25 mg, only 5 mg and 10 mg doses were effective in reducing the cytosolic receptor concentration to pretreatment levels. Histologically, little effect was observed from the lowest doses of either drug. However, even though 5 and 10 mg of medroxyprogesterone acetate were identical biochemically, the 10 mg dose was the only one producing a homogeneous, secretory pattern within the endometrium.     

Norethindrone acetate and estradiol-induced endometrial hyperplasia

OBJECTIVE: To identify the lowest effective continuous dose of norethindrone acetate that significantly reduces 12-month incidence of endometrial hyperplasia associated with unopposed 17beta-estradiol (E2), 1 mg. METHODS: In a double-masked, randomized, multicenter study, 1176 healthy postmenopausal women 45 years of age or older without evidence of endometrial abnormalities were given 12 months of treatment with unopposed E2, 1 mg, or continuous-combined regimens of E2, 1 mg, and norethindrone acetate, 0.1 mg, 0.25 mg, or 0.5 mg. Endometrial histology was evaluated at the end of the treatment period. RESULTS: Continuous-combined E2-norethindrone acetate regimens significantly reduced 12-month incidence of endometrial hyperplasia compared with unopposed E2 1 mg (P <.001). Endometrial hyperplasia occurred in 14.6% of women treated with unopposed E2 1 mg, whereas in all continuous-combined groups, the rate decreased to less than 1%. Among patients who received E2-norethindrone acetate 0.1 mg, incidence was 0.8%; among those who received 0.25 mg and 0.5 mg, it was 0.4%. CONCLUSION: Continuous norethindrone acetate at doses as low as 0.1 mg combined with E2 1 mg effectively negated risk for endometrial hyperplasia associated with unopposed E2 1 mg, at least for the first year of therapy.     

Endometrial effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate: two-year substudy results

OBJECTIVE: To determine the endometrial safety of 2 years of treatment with lower doses of continuous combined conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA). DESIGN: Randomized, double-blind, placebo-controlled, multicenter metabolic and osteoporosis substudy of the Women's Health, Osteoporosis, Progestin, Estrogen (Women's HOPE) study. SETTING: Nineteen study centers across the United States. PATIENT(S): Healthy, postmenopausal women (n = 822) with an intact uterus were recruited. INTERVENTION(S): Patients received CEE 0.625, CEE 0.625/MPA 2.5, CEE 0.45, CEE 0.45/MPA 2.5, CEE 0.45/MPA 1.5, CEE 0.3, CEE 0.3/MPA 1.5 (all doses mg/day), or placebo for 2 years. Endometrial biopsies were evaluated at baseline and years 0.5, 1, 1.5, and 2 using a centralized protocol. MAIN OUTCOME MEASURE(S): Efficacy of lower doses of CEE/MPA in reducing the incidence of endometrial hyperplasia rates associated with unopposed estrogen (E). RESULT(S): No cases of endometrial hyperplasia were seen in the four CEE/MPA groups. For the CEE-alone groups, a dose-related increase in incidence rates from 3.17% (CEE 0.3 mg) to 27.27% (CEE 0.625 mg) was seen at 2 years. The number of cases increased from year 1 to year 2. For the CEE-alone groups, the incidence rates and types of hyperplasia diagnosed varied among the pathologists. CONCLUSION(S): Two years of treatment with lower doses of CEE/MPA provided endometrial protection comparable to that seen with commonly prescribed doses. These regimens should be considered for postmenopausal women who are candidates for hormone therapy.     

Add-back therapy and gonadotropin-releasing hormone agonists in the treatment of patients with endometriosis: can a consensus be reached? Add-Back Consensus Working Group

OBJECTIVE: To reach a consensus on the role of add-back therapy for patients with endometriosis administered GnRH agonists (GnRH-a). DESIGN: Results of consensus conference reviewing MEDLINE search of English language abstracts of both prospective and retrospective series. SETTING: Consensus conference of 31 specialists in gynecologic surgery and reproductive endocrinology. PATIENT(S): Patients with symptomatic endometriosis who were candidates for GnRH-a therapy in treatment courses ranging in duration from 6 to 12 months. INTERVENTION(S): Oral steroidal and nonsteroidal add-back regimens. MAIN OUTCOME MEASURE(S): Alteration in painful symptoms, extent of disease, vasomotor symptoms, bone mineral density, and serum lipid profile. RESULT(S): When added to GnRH-a for 6 months, both 2.5 mg of norethindrone and 0.625 mg of conjugated equine estrogens with 5 mg/d of medroxyprogesterone acetate provide effective relief of vasomotor symptoms and decrease but do not eliminate bone mineral density loss. During 12 months of GnRH-a therapy, bone mineral density loss is eliminated effectively with an add-back of 5 mg of norethindrone acetate alone or in conjunction with low-dose conjugated equine estrogens. Organic bisphosphonates also may play a role. CONCLUSION(S): In patients with symptomatic endometriosis, the efficacy of GnRH agonists may be preserved and therapy prolonged while overcoming hypoestrogenic side effects with the use of appropriate add-back regimens.     

Uterine effects of raloxifene in comparison with continuous-combined hormone replacement therapy in postmenopausal women

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.     

Continuous combined conjugated equine estrogen-progestogen therapy: effects of medroxyprogesterone acetate and norethindrone acetate on bleeding patterns and endometrial histologic diagnosis.

OBJECTIVES: This study was designed to assess the incidence of amenorrhea with continuous combined therapy by using two different progestogens and to determine whether early bleeding predicts subsequent bleeding and endometrial response. STUDY DESIGN: Seventy-nine postmenopausal women on sequential estrogen-progestogen treatment were switched to continuous combined estrogen-progestogen therapy comprising conjugated equine estrogens 0.625 mg daily with either norethindrone acetate 0.35 mg twice daily or medroxyprogesterone acetate 2.5 mg twice daily added continuously for 78 weeks. All bleeding was recorded, and endometrial biopsies were performed at 26 and 78 weeks. RESULTS: Only one third of the women who starting the study had amenorrhea by week 78, but 46 (62%) of these women had withdrawn, mainly because of chronic irregular bleeding. Endometrial atrophy was observed in the majority of biopsy specimens. The two progestogens had similar effects. Bleeding patterns were useful predictors of subsequent bleeding, but not of endometrial response. CONCLUSIONS: Persistent irregular bleeding is common with continuous combined estrogen-progestogen therapy. Women with persistent early bleeding should probably revert to sequential treatment. Regular endometrial sampling is advised.     

Effects of trimonthly progestin administration on the endometrium in elderly postmenopausal women who receive hormone replacement therapy: a pilot study

OBJECTIVE: The purpose of this study was to determine the effect of trimonthly progestin administration on the endometrium in elderly postmenopausal women who receive hormone replacement therapy. STUDY DESIGN: This was a prospective, randomized, double-blind, placebo-controlled study at a university teaching program. Twenty-five postmenopausal women who were >or=75 years old with an intact uterus were assigned randomly to receive conjugated equine estrogens (0.625 mg/d plus medroxyprogesterone acetate 5 mg/d for 13 days every 3 months (n = 13) or placebo (n = 12) for 9 months). At the end of the 9 months, patients in the hormone replacement therapy arm continued therapy for an additional 9 months. Statistical analysis was performed with the Student t test, the chi(2) test, and the Fisher exact test. RESULTS: Transvaginal sonography was performed at baseline and at 9 and 18 months. Endometrial biopsy was performed if the endometrial thickness was >4 mm or as clinically indicated at 18 months. Patients in the hormone replacement therapy group demonstrated a significant increase in endometrial thickness between baseline (3.9 + 0.8 mm) and 9 months (8.0 + 4.8 mm). There were no cases of endometrial hyperplasia at the 18-month endometrial biopsy. CONCLUSION: Trimonthly progestin administration in elderly postmenopausal women who receive hormone replacement therapy may be a reasonable alternative to the monthly administration of progestin in hormone replacement therapy.     

Bleeding patterns in postmenopausal women using continuous combination hormone replacement therapy with conjugated estrogen and medroxyprogesterone acetate or with 17beta-estradiol and norethindrone acetate

OBJECTIVE: We studied bleeding patterns in postmenopausal women who were using 2 types of continuous combination regimens. STUDY DESIGN: A prospective, double-blind, randomized study of 208 postmenopausal women treated with conjugated estrogen, 0.625 mg, and medroxyprogesterone acetate, 5 mg, or with 17beta-estradiol, 2 mg, and norethindrone acetate, 1 mg. RESULTS: The mean number of bleeding days decreased during the first 4 months of treatment (P <.002) but not thereafter. The number of bleeding days was fewer (P <.002) and the time until amenorrhea was shorter (P <.02) in patients receiving conjugated estrogen and medroxyprogesterone acetate than in patients receiving 17beta-estradiol and norethindrone acetate. The odds ratio for progression to amenorrhea with the use of conjugated estrogen and medroxyprogesterone acetate was 1.58, in comparison with the use of 17beta-estradiol and norethindrone acetate. A thick endometrium at the start of treatment resulted in more bleeding days than were found for a thin endometrium (P <.03). Body mass index, age, and blood pressure had no predictive value for bleeding problems. CONCLUSIONS: Treatment with continuous combined conjugated estrogen and medroxyprogesterone acetate resulted in fewer bleeding problems than did treatment with 17beta-estradiol and norethindrone acetate. Endometrial thickness may help to predict the chance of achieving amenorrhea during early hormone replacement therapy.     

Is Provera the ideal progestogen for addition to postmenopausal estrogen therapy?

In a dose-ranging study, medroxyprogesterone acetate, 2.5, 5, or 10 mg daily, was given for 12 days of each calendar month to postmenopausal women also receiving conjugated estrogens, 0.625 mg daily, continuously. Endometrial biopsy specimens were taken on the sixth day of combined therapy for histologic, ultrastructural and biochemical evaluation. Medroxyprogesterone acetate induced secretory and ultrastructural changes within the endometrium, but the responses were variable and inconsistent. Suppression of epithelial deoxyribonucleic acid synthesis appeared dose-dependent. The levels of nuclear estradiol receptor, although reduced to within the secretory phase range, were not significantly lower than the values observed during the estrogen-only phase of treatment. Induction of both estradiol and isocitrate dehydrogenase activities was to within the secretory phase ranges, but the magnitude of these responses appeared less than those observed previously with other progestogens. Both morphologically and biochemically, medroxyprogesterone acetate, even at high dosage, produced suboptimal responses. Further studies are required to establish whether this is a dose-related effect.     

Effects of tibolone on plasma homocysteine levels in postmenopausal women

OBJECTIVE: To investigate the effects of tibolone on levels of plasma homocysteine, an independent risk factor for cardiovascular disorders, in postmenopausal women. DESIGN: Prospective, randomized clinical study. SETTING: University hospital. PATIENT(S): Postmenopausal healthy women. INTERVENTION(S): Tibolone (2.5 mg/d) or calcium (1250 mg/d) and conjugated equine estrogens (0.625 mg/d) plus medroxyprogesterone acetate (5 mg/d) were administered orally for 6 months. Blood samples were collected at the start and the end of therapy. MAIN OUTCOME MEASURE(S): Plasma homocysteine levels. RESULT(S): Administration of tibolone and calcium caused only a 4% decrease in plasma homocysteine levels compared with initial levels. In contrast, conjugated equine estrogens plus medroxyprogesterone acetate caused a 29% decrease in plasma homocysteine levels. CONCLUSION(S): Despite the reported beneficial effect of tibolone on the serum lipid profile, tibolone had no statistically significant effect on serum homocysteine levels in postmenopausal women. The possible cardiovascular protective role of tibolone might be unrelated to its effects on homocysteine levels.     

Efficacy of a continuous estrogen-progestin regimen in the menopausal patient

The major concern with the use of unopposed estrogen is its neoplastic effect on the endometrium. Progestins used to oppose the estrogen may be associated with vaginal bleeding and reversal of estrogen's protective changes in serum lipoprotein concentrations. A study was performed in which all postmenopausal women received conjugated equine estrogen for days 1-28; with group I receiving 2.5 mg medroxyprogesterone acetate for days 1-28, group II receiving 5 mg medroxyprogesterone acetate for days 1-28, and group III receiving 5 mg medroxyprogesterone acetate for days 17-28. Pre- and postdrug evaluations of the endometrium revealed atrophic changes after therapy with continuous combined estrogen-progestin. Pre- and poststudy evaluation of serum lipoprotein concentrations demonstrated significant declines in cholesterol and low-density lipoprotein cholesterol within groups I and III, and no change in group II. All patients kept a weekly diary recording any vaginal bleeding or change in vasomotor symptoms. The results suggest that a continuous regimen of 0.625 mg conjugated equine estrogen with 2.5 mg medroxyprogesterone acetate is beneficial as a primary hormonal replacement therapy for the postmenopausal patient.     

The effects of hormone replacement on the biomechanical properties of the uterosacral and round ligaments in the monkey model

OBJECTIVE: The purpose of this study was to determine effects of ovariectomy (OVX) and conjugated equine estrogens plus medroxyprogesterone acetate (CEE/MPA), or ethinyl estradiol plus norethindrone acetate (EE/NA) on biomechanics of uterosacral (USL) and round (RL) ligaments in postmenopausal (PMP) monkeys. STUDY DESIGN: This was a randomized, triple blind, placebo-controlled study. OVX monkeys received 12 months no treatment (Pbo) (n = 19), CEE/MPA (n = 19), or EE/NA (n = 21). USL and RL step strains and stress-relaxation data were curve-fitted, giving strain-dependent tensile modulus (TM) from 0% to 30%. RESULTS: (1) USL: TM for both treatment groups was greater than Pbo for strains from 0% to 12% (P < .04). (2) RL: TM for both treatment groups was smaller than Pbo for strains from 12% to 30% (P < .05). No differences were found between treatment regimens. CONCLUSION: CEE/MPA and EE/NA both affect functional biomechanical properties by increasing tensile stiffness in the USL and decreasing it in the RL.