New protocol of clomiphene citrate treatment in women with hypothalamic amenorrhea.

OBJECTIVE: To determine if a new protocol of administration of clomiphene citrate (CC) is effective in menstrual cycle recovery in women with hypothalamic secondary amenorrhea. DESIGN: This was an open-label study. PATIENTS: Patients comprised a group of eight women with secondary amenorrhea. Interventions. An oral preparation containing CC (50 mg/day) was administered for 5 days followed by a double dose (100 mg/day) for another 5 days, initiated on day 3 after estrogen/progestogen-induced withdrawal bleeding. If ovulation and vaginal bleeding occurred, treatment continued in the two next months with 100 mg/day from day 3 to day 7 day of the cycle. MAIN OUTCOME MEASURES: Cycle control was evaluated at each visit, when patients recorded bleeding patterns and tablet intake. Data on the intensity and duration of bleeding were collected. RESULTS: Six patients responded to the first cycle of CC administration, resuming normal menstrual cycles. The other two patients failed to menstruate after the first 10 days of treatment with CC and repeated the same protocol. After the second administration, these two women also had normal menstrual bleeding. CONCLUSIONS: The present data show that this new protocol of CC treatment may be useful to restore normal menstrual cycles in young women with hypothalamic amenorrhea.     

Effect of supplementary oral estrogen on long-acting injectable progestogen contraception

To test the effectiveness of daily oral doses of estrogen in regulating the menstrual cycle of women receiving 150 mg of depo-medroxyprogesterone acetate (DMPA), 32 women were administered 1 mg of stilbestrol daily in conjunction with their DMPA injections for 90 days. A control group of 31 women received DMPA with a placebo for the same period of time. After the first 90 days, 28 women were chosen from both the stilbestrol group and placebo group, and were instructed to take 1 mg of stilbestrol daily for 3 weeks of each of the 3 subsequent 4 week periods, with 22 women receiving no medication. Continuous daily doses during the first 90 days failed to diminish the incidence of uterine bleeding of the silbestrol group when compared to the controls. Supplemental administration of estrogen did not significantly alter the appearances of endometrial biopses or kayopyknotic indices. Cyclic administration of oral estrogen for 3 weeks of a 4 week period caused regular withdrawal uterine bleeding. It was concluded that there was very little advantage to the administration of supplemental oral estrogen to women using DMPA, except in the case of a women who psychologically needs a bleeding period.     

Ovulation induction with luteinizing hormone--releasing hormone in amenorrheic, infertile women.

Thirteen women with infertility thought due to anovulation were treated with LRH. Etiologic diagnoses of amenorrhea included hypothalamic or "idiopathic" and PCOD. All patients had normal gonadotropins and otherwise normal endocrinologic and infertility evaluations; none had ovulated with clomiphene. Patients were studied for six 35 day cycles, single blind, and received LRH or placebo by subcutaneous injections for 28 days/cycle (LRH dosage 1.0 mg 2 or 3 times each day). Frequent assessments of physical status, cervical mucus, vaginal cytology, and serum LH, FSH, estrogen, and progesterone were performed. Ovulation was documented by basal temperature, serum progesterone and, on occasion, endometrial biopsy. Follow-up was continued for 6 months after therapy. Of the 13 patients treated, eight have ovulated and five have conceived. There were no complications of therapy.     

Endometrial histology and bleeding patterns after 8 years of continuous combined estrogen and progestogen therapy in postmenopausal women.

Continuous combined estrogen and progestogen preparations enable the postmenopausal woman to enjoy the benefits of estrogen replacement without the inconvenience of regular progestogen-induced withdrawal bleeding. The endometrium appears to be adequately protected in the short term, but no published data are available on the bleeding patterns or endometrial response after more than 18 months of therapy. Therefore, we reviewed 41 patients who continued on such preparations for up to 10 years (mean duration of use 8.0 years). Six women had experienced episodes of breakthrough bleeding after achieving amenorrhea, two of whom had benign endometrial polyps and two with adenocarcinoma of the endometrium. The remaining 35 women each had prolonged amenorrhea and were found to have an atrophic inactive endometrium. It is too early to comment on the long-term endometrial effects of these preparations because the numbers are too small; however, any breakthrough bleeding occurring after a period of prolonged amenorrhea must be investigated by means of endometrial biopsy.     

Reversible hypogonadism induced by a luteinizing hormone-releasing hormone (LH-RH) agonist (Buserelin) as a new therapeutic approach for endometriosis

Ten women with endometriosis (stages I to IV) were treated with twice-daily subcutaneous injections of 200 micrograms of (D-Ser[TBU]6-des-Gly-NH2(10] luteinizing hormone-releasing hormone ethylamide (Buserelin) for 5 days followed by 400 micrograms intranasally three times daily for 25 to 31 weeks. Serum follicle-stimulating hormone levels returned to basal values on the second day of treatment, and serum luteinizing hormone levels progressively decreased to normal within 4 weeks. Serum estradiol decreased below early follicular phase levels within 7 to 30 days and continued to decrease to castrate levels. Light to moderate estrogen withdrawal bleeding was followed by amenorrhea with occasional bleeding or spotting in four women. Abdominal pain and dyspareunia disappeared or were ameliorated after 2 months of treatment. Resorption of endometrial implants was demonstrated by laparoscopy, and endometrial biopsy revealed atrophy or weak proliferation. Ovulation returned within 45 days, and two of four sexually active women became pregnant during cycles 3 and 5. The treatment was well accepted in spite of the expected hot flushes and vaginal dryness. Safety laboratory tests during and after treatment did not reveal any abnormalities. Reversible down-regulation of pituitary/ovarian function using repetitive luteinizing hormone-releasing hormone agonist administration can be a worthwhile approach to medical treatment of endometriosis.     

Low incidence of endometrial hyperplasia with acceptable bleeding patterns in women taking sequential hormone replacement therapy with dydrogesterone.

A meta-analysis was undertaken to assess the incidence of endometrial hyperplasia during sequentially combined oral 17 beta-estradiol and dydrogesterone (Femoston) treatment in postmenopausal women. Bleeding pattern was assessed separately in each study. Two studies were double-blind, 6-month studies and two were open, long-term (1- or 2-year) studies. 17 beta-estradiol 2 mg daily was combined with dydrogesterone 10 mg for 14 days per 28-day cycle. Endometrial safety was assessed by endometrial biopsy in 369 women treated. In 236 women treated for one year or more, one simple hyperplasia was diagnosed (success rate: 99.61%; lower limit of one-sided 95% confidence interval: 98.16). The last observation carried forward analysis in 369 women also revealed one simple hyperplasia (success rate: 99.73%; lower limit of one-sided 95% confidence interval: 98.72). Cyclic bleeding occurred in approximately 90% of women; the duration and day of onset was highly predictable between cycles and the severity of bleeding was generally rated as slight. In conclusion, sequentially combined 17 beta-estradiol 2 mg and dydrogesterone 10 mg has very good endometrial safety and is associated with light and predictable bleeding of short duration.     

Amenorrhea following the administration of oral contraceptives

It is estimated that about 2.2% of women experience amenorrhea and anovulatory cycles after discontinuing use of oral contraceptives (OCs), although exact figures are lacking due to differences of definition and problems of diagnosis. Several possible mechanisms to explain the occurrence of postpill amenorrhea have been suggested, including endometrial atrophy and fibrosis, changes in the ovaries similar to those found in Stein-Levanthal syndrome, hypothalamic disorder, late menarche, irregular cycles, and periods of amenorrhea before or during OC use. Previous pregnancies, duration of pill use, and formulation utilized are apparently not related to occurrence of post-pill amenorrhea. Clinical diagnosis requires detection of ovulation by means of basal body temperature, cervical mucus changes, and vaginal smears. If amenorrhea persists after administration of a progestagen to induce bleeding, more complete examinations must be done to exclude pituitary tumor, Cushing's syndrome, thyroid problems, and possible precocious menopause or anorexia nervosa. X-rays, administration of thyroid or suprarenal hormones, gonadotropins, or estrogens, an endometrial biopsy, or laparoscopy may be necessary. Generally all test values are normal except that levels of estrogens, follicle stimulating hormone, and luteinizing hormone are usually reduced. Treatment of post-pill amenorrhea can take various forms. About 5% of cases appear to resolve spontaneouusly; efforts should therefore be made to detect ovulation through basal body temperature, cervical mucus and vaginal smears. Corticosteroids including prednisone and dexametasone may administrered, or if estrogen levels are low and the patient fails to respond to progestagens with withdrawal bleeding, clomiphene may be used. Human menopausal gonadotropin or human chorionic gonadotropin can be in patients with low estrogen levels who do not respond to clomiphene. Ergocriptine derivatives may be used in cases with associated galactorrhea due to basal hyperprolactinemia. Palliative treatment with OCs may be used in patients who wish to avoid pregnancy. The prognosis is always poor in the presence of galactorrhea or if progestagen administration is not followed by withdrawal bleeding or estrogen levels are low. Treatment is usually futile in cases of polycystic ovaries that have sclerosed. The most significant feature of such amenorrhea is its role in infertility. If the patient wishes to become pregnant after some period of OC use, it is advisable to interrupt treatment periodically until 1-2 normal menstrual cycles have reappeared, especially in young patients who had irregular cycles before initiating hormonal contraception.     

Magnetic field profiles in normal human breast during the menstrual cycle

OBJECTIVE: To investigate the subtle magnetic fields produced by living normal breast tissue during the menstrual cycle. METHODS: The magnetic activity of the breast was recorded in four young women, 26-28 years old; two had regular and two irregular menstrual cycles. The recordings were accomplished with a biomagnetometer and covered two complete menstrual cycles. The results were correlated with estrogen and progesterone levels on days 7, 14 and 21 of the menstrual cycle. RESULTS: The magnetic breast recordings in the two young women with the regular cycling endometrium showed a biphasic magnetic curve, apparently corresponding to the proliferative and secretory phase of the menstrual cycle. By contrast, the two young women with irregular menstrual cycles showed a monophasic magnetic curve. CONCLUSION: It is suggested that a biphasic, but not a monophasic, pattern of magnetic activity in the breast is indicative of an ovulatory endometrial cycle.     

Lipid effects of hormone replacement therapy with sequential transdermal 17-beta-estradiol and oral dydrogesterone

OBJECTIVE: To assess the effects on lipid and lipoprotein levels of a combination therapy of matrix patch and oral sequential dydrogesterone. METHODS: The lipid effects of transdermal estradiol (E2) (80 microg/day continuously) and oral dydrogesterone (10 mg from days 15-28 of each cycle) were assessed in a multicenter, prospective, open, baseline-controlled study. Subjects were 42 healthy, postmenopausal women who had not had hysterectomies. Fasting blood samples were taken at baseline, day 14 of cycle 3 (estrogen alone), and day 25 of cycle 6 (estrogen and progestogen). The main outcome measures were changes from baseline in total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides after six cycles. RESULTS: Thirty-six subjects completed six cycles and in the 28 with complete data, HDL cholesterol increased by 10.6% from 65.25 to 72.2 mg/dL (95% confidence interval [CI] 2.32, 11.58, P = .005) and LDL cholesterol fell by 5.1% from 130.9 to 124.3 mg/dL (95% CI 13.9, 1.16, P = .07). There was a nonsignificant decrease in LDL cholesterol from 130.9 at baseline to 124.3 mg/dL at 6 months and in triglycerides from 110.6 to 107.1 mg/dL. CONCLUSION: Sequential treatment with transdermal E2 and oral dydrogesterone increased HDL cholesterol, without the accompanying increase in triglycerides that occurs with oral estrogen replacement therapy.     

1 and 2 mg 17beta-estradiol combined with sequential dydrogesterone have similar effects on the serum lipid profile of postmenopausal women.

OBJECTIVES: The aim of this study was to assess the effects of 1 and 2 mg 17beta-estradiol on serum lipid profile. Beneficial effects have been clearly established in previous studies with a 2 mg dose; further evidence was required to confirm the beneficial effects of a 1 mg dose. METHODS: This double-blind, placebo-controlled study involved 579 postmenopausal women randomized to oral treatment with placebo, 1 mg/day 17beta-estradiol sequentially combined with 5 or 10 mg/day dydrogesterone for the last 14 days of each 28-day cycle, or 2 mg/day 17beta-estradiol sequentially combined with 10 or 20 mg/day dydrogesterone for the last 14 days of each 28-day cycle. Treatment was continued for 26 cycles. RESULTS: High density lipoprotein (HDL) cholesterol levels were significantly (p<0.05) increased after 26 cycles in all active treatment groups compared with placebo. In addition, low density lipoprotein (LDL) cholesterol and lipoprotein(a) levels were significantly reduced, and apolipoprotein A1 and triglyceride levels were significantly increased, in all active treatment groups after 13 and 26 cycles. CONCLUSIONS: The results of this study clearly indicate that sequential combinations of either 1 or 2 mg 17beta-estradiol with dydrogesterone are associated with long-term, favorable changes in the serum lipid profile. There was no evidence that dydrogesterone compromised the 17beta-estradiol-induced improvements in lipid profile.     

Effectiveness and safety of dydrogesterone in regularization of menstrual cycle: a post-marketing study

Oral administration of dydrogesterone during second half of menstrual cycle has been shown to reduce menstrual irregularities. This prospective, observational study aimed to determine continued effectiveness of dydrogesterone (prescribed between 1 and 6 cycles or longer) in menstrual cycle regularization in Indian women aged ≥18 years with irregular menstrual cycle for at least 3 months. Those achieving regular cycles (21 to 35 days, inclusive) during treatment were followed up for 6 months after cessation of dydrogesterone treatment. Of the 910 women completing dydrogesterone treatment, 880 (96.7%) achieved cycle regularization (p<0.0001 for 90% success rate) at end of treatment (EOT). Of the 788 subjects available for follow up at 6 months, 747 (94.8%) reported cycle regularity (p<0.0001 for 90% success rate). At EOT, the mean cycle duration reduced by 16.14 (±24.04) days and mean amount of menstrual bleeding decreased by 0.45 (±1.20) pads/day. While five subjects reported worst pain at baseline, none experienced it at EOT. One serious adverse event (appendicitis) and three non-serious adverse events were reported. Dydrogesterone regularizes and improves the duration of the menstrual cycle, reduces the amount of bleeding, relieves menstrual pain and prevents relapse of irregular cycles at six months after discontinuation of treatment.     

The comparison of bleeding patterns with high-dose and low-dose hormone replacement therapy in postmenopausal women.

Our objective was to compare vaginal bleeding patterns with lower doses of conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA), in a randomized, double-blind, placebo-controlled trial. A total of 112 healthy, postmenopausal women were divided into three groups. Group A received CEE 0.625 mg/day plus MPA 2.5 mg/day; group B received CEE 0.3 mg/day, plus MPA 1.25 mg/day; and another group received placebo. All medications were continued for 13 months and bleeding data were analyzed in each group. The percentage of patients who experienced no bleeding in cycle one was 45.2% in group B. These values were significantly greater than the figure for group A (18.2%) and lower than in the placebo group (66.7%). A linear trend between time since menopause and cumulative amenorrhea was observed in cases in group B and the placebo group in all cycles (p < 0.05). This finding was significant in only cycle 13 in group A. In conclusion, a higher rate of amenorrhea was observed with a lower-dose regimen of CEE/MPA, which may be the appropriate regimen.     

The comparison of bleeding patterns with high-dose and low-dose hormone replacement therapy in postmenopausal women

Our objective was to compare vaginal bleeding patterns with lower doses of conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA), in a randomized, double- blind, placebo-controlled trial. A total of 112 healthy, postmenopausal women were divided into three groups. Group A received CEE 0.625 mg/day plus MPA 2.5 mg/day; group B received CEE 0.3 mg/day, plus MPA 1.25 mg/day; and another group received placebo. All medications were continued for 13 months and bleeding data were analyzed in each group. The percentage of patients who experienced no bleeding in cycle one was 45.2% in group B. These values were significantly greater than the figure for group A (18.2%) and lower than in the placebo group (66.7%). A linear trend between time since menopause and cumulative amenorrhea was observed in cases in group B and the placebo group in all cycles (p <?0.05). This finding was significant in only cycle 13 in group A. In conclusion, a higher rate of amenorrhea was observed with a lower-dose regimen of CEE/MPA, which may be the appropriate regimen.     

Endometrial blood flow measured by xenon 133 clearance in women with normal menstrual cycles and dysfunctional uterine bleeding

Endometrial blood flow was measured through the menstrual cycle in nonpregnant women (28 studies of 17 women with normal menstrual cycles and 32 studies of 20 women with dysfunctional uterine bleeding) with use of a clearance technique in which 100 to 400 microCi of the gamma-emitting isotope, xenon 133 in saline solution was instilled into the uterine cavity. The mean (+/- SEM) endometrial blood flow in normal cycles was 27.7 +/- 2.6 ml/100 gm/min, with a significant elevation in the middle to late follicular phase, followed by a substantial fall and a secondary slow luteal phase rise that was maintained until the onset of menstruation. There was a significant correlation between plasma estradiol levels and endometrial blood flow in the follicular but not the luteal phase. Blood flow patterns in women with ovulatory dysfunctional bleeding were similar to normal, except for a significantly lower middle follicular rate. Women with anovulatory dysfunctional bleeding exhibited exceedingly variable flow rates.     

Clinical and metabolic responses of menopausal women to sequential versus continuous estrogen and progestin replacement therapy

To minimize the cyclic menstrual bleeding associated with the sequential administration of estrogen and progestin in menopausal women, medroxyprogesterone acetate at the daily dose of 10 mg orally was administered, either sequentially for ten days of each 25-day treatment cycle or continuously with conjugated equine estrogen for three months. Cyclic menstrual bleeding occurred in all ten patients on sequential therapy; their endometrial histology was secretory in six, proliferative in two, and adenomatous hyperplasia in one. Of the ten patients on continuous therapy, four were amenorrheic and six experienced acyclic bleeding, but the endometrial histology was atrophic or inactive in all ten. The continuous treatment group experienced a statistically significant decrease in the mean serum levels of total cholesterol, whereas the serum levels of both low- and high-density cholesterol fractions decreased slightly. However, the sequential group experienced no change in serum levels of total cholesterol, a slight rise in high-density lipoprotein, and a significant decrease in low-density lipoprotein cholesterol fractions. Our data suggest that the combined and continuous use of conjugated equine estrogen and medroxyprogesterone acetate effectively relieves menopausal symptoms, decreases the frequency of uterine bleeding, induces endometrial atrophy, and significantly decreases serum levels of total cholesterol.     

Endometrial, physical and psychological effects of postmenopausal oestrogen therapy with added dydrogesterone

Sixteen postmenopausal women receiving conjugated equine oestrogens 1.25 mg/day, continuously, were randomly allocated to add dydrogesterone 20 mg/day for 12 days each calendar month for 3 months and then 10 mg/day in an identical fashion for a further 3 months, or to receive the dydrogesterone doses in reverse sequence. The effects of the two dydrogesterone doses on endometrial histology, vaginal bleeding, and the symptomatic and psychological status were compared. Endometrial samples were obtained around day 10 of progestogen addition. Dydrogesterone, 20 mg, induced uniform, late secretory transformation in all samples; with 10 mg one sample showed mixed early and late secretory features and another demonstrated late secretory changes associated with atypical hyperplasia. Both dydrogesterone doses induced an acceptable withdrawal bleed; most bleeding episodes were 'spotting' or normal in amount, and heavy bleeding was reported infrequently. There was one episode of breakthrough bleeding. There were no differences in bleeding patterns between the two dose regimens. Anxiety, and the physical and psychological status were significantly improved after 3 months of therapy. Significant benefits on depression were observed less clearly. There were no differences between the two dydrogesterone doses on anxiety, depression and the physical and psychological status, and, overall, the addition of the progestogen did not antagonize oestrogen benefits.     

Endometrial, physical and psychological effects of postmenopausal oestrogen therapy with added dydrogesterone

Summary. Sixteen postmenopausal women receiving conjugated equine oestrogens 1.25 mg/day. continuously, were randomly allocated to add dydrogesterone 20 mg/day for 12 days each calendar month for 3 months and then 10 mg/day in an identical fashion for a further 3 months, or to receive the dydrogesterone doses in reverse sequence. The effects of the two dydrogesterone doses on endometrial histology, vaginal bleeding, and the symptomatic and psychological status were compared. Endometrial samples were obtained around day 10 of progestogen addition. Dydrogesterone, 20 mg, induced uniform, late secretory transformation in all samples; with 10 mg one sample showed mixed early and late secretory features and another demonstrated late secretory changes associated with atypical hyperplasia. Both dydrogesterone doses induced an acceptable withdrawal bleed; most bleeding episodes were 'spotting' or normal in amount, and heavy bleeding was reported infrequently. There was one episode of breakthrough bleeding. There were no differences in bleeding patterns between the two dose regimens. Anxiety, and the physical and psychological status were significantly improved after 3 months of therapy. Significant benefits on depression were observed less clearly. There were no differences between the two dydrogesterone doses on anxiety, depression and the physical and psychological status, and, overall, the addition of the progestogen did not antagonize oestrogen benefits.     

Effects of initiation day of clomiphene citrate on the endometrium of women with regular menstrual cycles

OBJECTIVE: To investigate the effects of initiation time of clomiphene citrate (CC) on the endometrium of women with regular menstrual cycles. DESIGN: Randomized, double-blind, cross-over study. SETTING: Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. PATIENT(S): Thirty-three healthy female volunteers with regular menstrual cycles. INTERVENTION(S): The volunteers were randomized to receive either 100 mg of CC on days 1-5 and placebo on days 5-9 (study group) or placebo on days 1-5 and CC on days 5-9 (control group). After a wash-out period of 1 month of CC treatment, the medication was switched in each group. Ultrasonography was performed daily after day 10 of the cycle to detect ovulation. Ultrasonography for endometrial appearance and thickness, endometrial sampling, and blood samples obtained for determination of E(2) and P levels were performed 7 days after ovulation in both groups. MAIN OUTCOME MEASURE(S): Morphometric analysis, histologic dating, and ultrasonographic appearance and thickness of the endometrium. RESULT(S): Morphometric parameters, histologic dating, and ultrasonographic appearance and thickness of the endometrium were similar in both groups. CONCLUSION(S): Starting CC on either day 1 or day 5 of the menstrual cycle did not have any differential effects on the endometrium of women with regular menstrual cycles, particularly regarding the morphometric analysis, histologic dating, or ultrasonographic appearance.     

Dose-response evaluation of cyclic estrogen/gestagen in postmenopausal women: Placebo-controlled trial of its gynecologic and metabolic actions

In order to study dose-response relationships of estrogen in normal postmenopausal women, 100 volunteers were randomized to 12 months' treatment with placebo or one of three different doses (high, medium, or low) of natural estrogens (17β-estradiol and estriol), sequentially combined with norethisterone acetate for 10 of the 28 cycle days. A total of 87 women completed the trial with examinations every 3 months. Relief of climacteric symptoms was dose related, being 70%, 56%, and 33% in the high, medium, and low estrogen groups and unchanged in the placebo group. Regular vaginal bleeding occurred in 78% receiving high-dose in 64% receiving medium-dose, and in 40% receiving low-dose estrogen. Bone mass increased in the high and medium groups, was unchanged in the low group, and declined in the placebo group. Dose-related decreases in serum cholesterol of 10%, 5%, and 3% occurred in the three respective estrogen groups. Serum triglyceride levels, blood pressure, and body weight remained unchanged in all groups.     

Endometrial effects of bazedoxifene acetate, a novel selective estrogen receptor modulator, in postmenopausal women

OBJECTIVE: To assess the endometrial effects of bazedoxifene acetate in healthy postmenopausal women. METHODS: The endometrial effects of bazedoxifene 2.5, 5.0, 10, 20, 30, and 40 mg/d were evaluated in a 2-part, 6-month, double-blind, randomized, active- and placebo-controlled study among a total of 497 healthy postmenopausal women. Conjugated estrogens (0.625 mg)/medroxyprogesterone acetate (2.5 mg) served as the active control. Patients underwent transvaginal ultrasonography to measure double-wall endometrial thickness and endometrial biopsy at baseline and at 6 months of treatment. The incidence of amenorrhea was assessed from self-reported daily diaries. RESULTS: Bazedoxifene treatment at 2.5-20 mg/d resulted in mean changes from baseline in endometrial thickness that were no different than those seen with placebo treatment. Changes in endometrial thickness for the bazedoxifene 30 and 40 mg groups were significantly smaller than for placebo. The change from baseline in endometrial thickness was significantly and inversely related to dose (P < or = .001). None of the endometrial biopsy specimens demonstrated endometrial hyperplasia. Subjects in the 2.5-20 mg bazedoxifene groups experienced amenorrhea rates of 57-74%, comparable with the 59% seen in placebo. Over 90% of subjects treated with bazedoxifene 30 or 40 mg/d were amenorrheic at 6 months. CONCLUSION: Bazedoxifene at dosages up to 40 mg/d was well tolerated and did not stimulate the endometrium. The significant decreases in endometrial thickness and decreased uterine bleeding observed with doses of 30 and 40 mg/d as compared with placebo suggest endometrial antagonism, representing a novel characteristic not previously associated with any selective estrogen receptor modulator.