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PubMed2007

A comparative study of the effect of continuous combined conjugated equine estrogen plus medroxyprogesterone acetate and tibolone on blood coagulability.

BACKGROUND: Hormone therapy (HT) after the menopause is associated with increased risk of venous thromboembolism (VTE). Tibolone has pharmacodynamic properties different from other hormone preparations. We compared the effect of a combined HT and tibolone on the inhibition of haemostasis. METHODS: Thirty-eight post-menopausal women were randomly assigned to 1.25 or 2.5 mg per day of tibolone or oral continuous combined conjugated equine estrogen plus medroxyprogesterone acetate (CEE/MPA). Inhibitors of haemostasis were measured at baseline and after 12 months. RESULTS: Results from the two groups of women receiving tibolone were not significantly different and, to improve the power of the study, the two groups were merged. Higher concentration of protein S (1.16 versus 1.00 IU ml(-1); P = 0.005) and higher activated protein C resistance ratio (APC-R) (4.2 versus 3.65; P = 0.04) were observed in the tibolone group than in the CEE/MPA group. Both doses of tibolone increased APC-R significantly (P < 0.01). Tissue factor pathway inhibitor (TFPI) was lower in the CEE/MPA group than in the tibolone group (67.8 versus 79.9 ng ml(-1); P = 0.03). CEE/MPA reduced the concentration of antithrombin (P = 0.002), protein S (P < 0.001) and TFPI (P < 0.001). Both preparations reduced the concentration of plasminogen activator inhibitor 1 (P < 0.05). CONCLUSIONS: Tibolone induces fewer pharmacological alterations on blood coagulability than CEE/MPA and has a potentially favourable effect on APC-R. This may translate into a corresponding low risk of VTE, as also indicated from the existing clinical data.

Aged↗
PubMed2003

The myeloprotective effect of medroxyprogesterone acetate in an irradiated animal model.

BACKGROUND: In this study we evaluated the effect of medroxyprogesterone acetate (MPA) and its major ingredients on protection of the hematopoietic organs against radiation damage. METHOD: One group of mice was given saline as placebo and the other groups were given MPA. Mice were injected with MPA (10 mg/kg) or saline 10 days before or after a single 8 Gy whole body cobalt irradiation. On day 14 the mice were sacrificed and their bone marrow transplanted to recipient mice. Ten days after the transplantation, spleen colony formation was investigated in mice. RESULTS: Administration of MPA with irradiation increased the formation of the spleen colony. Statistically significant enhancement of the spleen colony formation was found in mice treated with MPA repeatedly, as compared with those treated with placebo (P < 0.001). No significant difference in Spleen Colony Forming Unit (CFU-S) numbers was observed between pre-and post-radiotherapy administration of MPA (P = 0.216). CONCLUSION: It is an important observation that no significant difference was observed in CFU-S numbers between pre- and post-irradiation administration of MPA.

Animals↗
PubMed2005

Medroxyprogesterone acetate elevation of Nm23-H1 metastasis suppressor expression in hormone receptor-negative breast cancer.

BACKGROUND: Reestablishment of metastasis suppressor gene expression may constitute a therapeutic strategy for high-risk breast cancer patients. We previously showed that medroxyprogesterone acetate (MPA), a progestin that has been tested as treatment for advanced breast cancer, elevates expression of the Nm23-H1 metastasis suppressor gene in hormone receptor-negative metastatic human breast carcinoma cell lines in vitro via a glucocorticoid receptor-based mechanism. Here, we tested whether MPA treatment inhibits metastatic colonization of a hormone receptor-negative breast cancer cell line in vivo. METHODS: We tested the soft-agar colony-forming efficiency of untransfected MDA-MB-231T human breast carcinoma cells and MDA-MB-231T cells transfected with antisense Nm23-H1 in the presence and absence of MPA. Pharmacokinetic studies were used to establish dose and injection schedules that led to MPA serum levels in mice similar to those achievable in humans. For in vivo studies, nude mice were injected intravenously with MDA-MB-231T cells. After 4 weeks, mice were randomized to control or MPA arms. Endpoints included incidence, number, and size of gross pulmonary metastases; Nm23-H1 protein expression in gross metastases; and side effects. All statistical tests were two-sided. RESULTS: MPA reduced colony formation of MDA-MB-231T cells by 40%-50% but had no effect on colony formation of Nm23-H1 antisense transfectants. Metastases developed in 100% (95% confidence interval [CI] = 78% to 100% and 77% to 100%, respectively) of control mice injected with MDA-MB-231T cells. In two independent experiments, only 73% (95% CI = 45% to 92%) and 64% (95% CI = 35% to 87%) of mice injected with 2 mg of MPA developed metastases. Mice injected with 2 mg of MPA showed reductions in the mean numbers, per mouse, of all metastases and of large (>3 mm) metastases (P = .04 and .013, respectively). Nm23-H1 was expressed at high levels in 43% of pulmonary metastases in MPA-treated mice but only 13% of metastases in untreated mice. Mice receiving at least 1-mg doses of MPA gained more weight than control-treated mice but exhibited no bone density alterations or abnormal mammary fat pad histology. CONCLUSION: Our preclinical results show that MPA appears to elevate Nm23-H1 metastasis suppressor gene expression, thereby reducing metastatic colonization. The data suggest a new use for an old agent in a molecularly defined subset of breast cancer patients.

Animals↗
PubMed1993

Adjuvant chemohormonal therapy with cyclophosphamide, doxorubicin and 5-fluorouracil (CAF) with or without medroxyprogesterone acetate for node-positive breast cancer patients.

BACKGROUND: The Comprehensive Cancer Center trial 82-01 is a prospective randomized study to investigate the value of the addition of high-dose medroxyprogesterone acetate (MPA) to chemotherapy in patients with node-positive operable breast cancer. MPA may be of advantage in this setting because of its activity in estrogen receptor ER-positive as well as ER-negative tumors and since it may protect against chemotherapy-induced myelosuppression and thus enable maintenance of the appropriate chemotherapeutic scheduling. PATIENTS AND METHODS: Four hundred eight evaluable patients with node-positive (N+) operable breast cancer (T1-3, N1) were entered in a multicenter randomized trial. Two hundred nine patients were randomized in the MPA- arm and 199 in the MPA+ arm. CAF chemotherapy was given as a short i.v. bolus infusion: cyclophosphamide 500 mg/m2 i.v. day 1, doxorubicin 40 mg/m2 i.v. day 1, and 5-fluorouracil 500 mg/m2 i.v. day 1, q 4 wks x 6. MPA was given intramuscularly (i.m.) 500 mg q d x 28 days, followed by 500 mg i.m. twice weekly during 5 months. RESULTS: The main side effects of MPA were weight gain with a mean of 5.5 kg as opposed to 1.8 kg in the control group (p = 0.01) and vaginal bleeding in 30/199 in the MPA+ group and 0 in the MPA- group. MPA ameliorated vomiting grade III, IV (45% vs. 28%, p < 0.001), nausea grade III, IV (50% vs. 34%, p < 0.001) and leucocyte nadir grade III, IV (20% vs. 11%, p = 0.003). Disease-free survival (DFS) after 5 years was 59% in the MPA+ and 49% in the MPA- group (p = 0.12). Patients > or = 60 years benefitted most from MPA treatment, in particular if freedom from distant metastases was taken as the endpoint (p = 0.02). Overall survival (OS) was not significantly different between the two treatment groups (p = 0.18), but within subgroups analysed there was an advantage for MPA+ in patients > or = 55 years (p = 0.002) and in pT1 patients (p = 0.045). CONCLUSIONS: High-dose MPA ameliorates CAF side effects and reduces the risk of metastatic disease, especially in elderly breast cancer patients.

Aged↗
PubMed1993

Primary endocrine therapy for advanced breast cancer: to start with tamoxifen or with medroxyprogesterone acetate?

BACKGROUND: The availability of compounds effective against metastatic disease and at the same time excellently tolerated even in long-term administration has determined the choice of tamoxifen as primary treatment for palliation in metastatic breast cancer. Other drugs or other hormonal approaches were hardly tested against tamoxifen, especially as first-line treatment. PATIENTS AND METHODS: 119 patients with metastatic breast cancer and no prior endocrine therapy were randomized to receive either tamoxifen (TAM) 20 mg/day orally (64 patients), or medroxyprogesterone acetate (MAP) 1g/day i.m. 5 days/week for 4 weeks and then 500 mg twice a week (55 patients). The subsequent endocrine therapy was also prospectively defined at study entry. RESULTS: A total of 111 events, contributing to the endpoint 'time to progression' have so far been observed: a study of similar size would have a 90% power to detect a hazard ratio of 1.85. Initial MAP was associated with a significantly higher remission rate (50% versus 30% for tamoxifen; p = 0.023) and a marginally significantly longer median time to progression (8.8 versus 5.4 months; p = 0.051). Overall survival was also longer for the MAP group (28 versus 20 months; p = 0.384). The use of MAP was associated with a significantly higher toxicity, mainly hypertension, weight gain and tremor. CONCLUSIONS: The implications of these results are that initial endocrine therapy in postmenopausal patients with metastatic disease should be MAP if the patient is willing to accept the side effects of high-dose progestins. Progestins should be tested in the adjuvant setting for postmenopausal women, especially those with no tendency to hypertension or obesity.

Adult↗
PubMed2002

Effects of a 6-day treatment with medroxyprogesterone acetate after prostaglandin F2 alpha-induced luteolysis at midcycle on antral follicular development and ovulation rate in nonprolific Western white-faced ewes.

Medroxyprogesterone acetate (MAP) from intravaginal sponges prolongs the lifespan of large ovarian follicles when administered after prostaglandin F2alpha (PGF2alpha)-induced luteolysis early in the luteal phase of ewes. The present study was designed to determine whether a PGF2alpha/MAP treatment applied at midcycle would alter the pattern of antral follicle growth and increase ovulation rate in nonprolific ewes. A single injection of PGF2alpha (15 mg, i.m.) was given, and an intravaginal MAP (60 mg) sponge was inserted for 6 days, on approximately Day 8 after ovulation, in 7 (experiment 1), 8 (experiment 2) or 11 (experiment 3) ultrasonographically monitored, cycling Western white-faced ewes; seven ewes (experiment 1) served as untreated controls. Blood samples were collected each day and also every 12 min for 6 h, halfway through the period of treatment with MAP (experiment 1), or every 4 h, from 1 day before to 1 day after sponging (experiment 2). Seventeen of 26 treated ewes (experiment 1, n = 6; experiment 2, n = 5; experiment 3, n = 6) ovulated 1 to 6 days after PGF2alpha, but this did not affect the emergence of ensuing follicular waves (experiments 1 and 2). These ovulations, confirmed by laparotomy and histological examinations of the ovaries (experiment 3), were not preceded by an increase in LH/FSH secretion and did not result in corpora lutea, as evidenced by transrectal ultrasonography and RIA of serum progesterone (experiments 1 and 2). Following the removal of MAP sponges, the mean ovulation rate was 3.1 +/- 0.4 in treated ewes and 2.0 +/- 0.3 in control ewes (experiment 1; P < 0.05). In experiments 1 and 2, the ovulation rate after treatment (3.1 +/- 0.4 and 2.8 +/- 0.4) was also greater than the pretreatment rate (1.9 +/- 0.3 and 1.9 +/- 0.1, respectively). Ovulations of follicles from two consecutive waves before ovulation were seen in five treated but only in two control ewes (experiment 1), and in seven ewes in experiment 2. There were no significant differences between the MAP-treated and control ewes in mean daily serum concentrations of FSH and estradiol, and no differences in the parameters of LH/FSH secretion, based on frequent blood sampling. Treatment of nonprolific Western white-faced ewes with PGF2alpha and MAP at midcycle changed follicular dynamics and increased ovulation rate by approximately 50%. These effects of MAP, in the absence of luteal progesterone, may not be mediated by changes in gonadotropin secretion.

Animals↗
PubMed1990

The clinical effect of medroxyprogesterone (MPA) in elderly patients with lung cancer.

Eighty-nine patients over 70 years old with untreated lung cancer, of various cell type and in various stages, were randomly assigned to chemotherapy (CT) alone or CT combined with medroxyprogesterone acetate (MPA). CT consisted of cisplatin, 60 mg/m2 i.v., along with etoposide (VP-16), 150 mg/m2 i.v., on day 1. The VP-16 was increased to 200 mg/m2, orally, on day 3. The entire regimen was given every 4 weeks for a maximum of six cycles. MPA was administered in daily 500-mg doses, i.m., 5 days a week for 1 month, followed by 1000 mg i.m., once a week, for 5 months. Changes in body weight and appetite were documented. After two cycles of CT, 64 patients were found to be evaluable for response. Forty-five had non-small-cell lung cancer (NSCLC) and 19 had small-cell lung cancer (SCLC). Thirty-seven patients had received CT alone and 27 CT plus MPA. In NSCLC, the objective response to CT alone was 36% versus 37% with CT plus MPA. In SCLC, the corresponding figures were 63% and 22%. The overall objective response rate was 60% in NSCLC and 48% in SCLC. Median survival using CT alone was 10 months for NSCLC patients and 11 months for SCLC patients. Using CT plus MPA, it was 10 months for NSCLC patients and 7 months for SCLC patients. In the control arm, 1-year survival was 42% for NSCLC patients and 48% for SCLC patients; in those who were given MPA, it was 48% for NSCLC patients and 9% for SCLC patients. Improved appetite and weight gain were reported more frequently by MPA patients, and they did not complain of CT's usual side effects. The fact that MPA had no significant effect on CT response or survival in patients also treated with a combination of cisplatin and VP-16, along with the small survival advantage for the control group in SCLC patients, suggests that combining MPA and CT may result in improved quality of life.

Aged↗
PubMed1993

A randomized trial of mitomycin-C (M) versus mitomycin-C plus high-dose medroxyprogesterone acetate (MMPA) in the treatment of patients with advanced breast cancer.

Seventy-six women with previously treated breast cancer were randomized to receive mitomycin (M) or M plus high-dose oral medroxyprogesterone acetate (MMPA). Patients were balanced with respect to age, performance status, hormone receptor status, previous treatment, and number of metastatic sites. There were more patients with visceral metastases in the M arm of the study. Side effects were tolerable and not significantly different for the two regimens. No life-threatening toxicity occurred. Objective response was documented in 4 of 37 patients on M and 11 of 39 on MMPA. On M the median time to treatment failure (TTF) was 3 months, and median survival was 7.8 months. On MMPA the median TTF was 4.4 months, and median survival was 9.7 months. There was a tendency for higher response and longer TTF and survival on MMPA, but statistical significance was not reached (p = 0.09).

Adult↗
PubMed1993

A phase II trial of medroxyprogesterone acetate in epithelial ovarian cancers. A Gynecologic Oncology Group study.

Twenty-four evaluable patients with advanced or recurrent epithelial ovarian carcinoma who progressed on platinum-containing combination chemotherapy were treated with medroxyprogesterone acetate (C.T. Provera) 50 mg orally three times a day until progression of disease. One patient had a partial response (4.2%), 9 patients had stable disease (37.5%), and 14 (58.3%) had increasing disease. The 95% upper confidence limit for response is less than or equal to 18.3%. There was no toxicity associated with its use. C.T. Provera has limited activity in patients with epithelial ovarian cancer who have failed combination chemotherapy.

Adult↗
PubMed1995

Epirubicin plus medroxyprogesterone as second-line treatment of advanced prostatic cancer. A study by the Italian Trials in Medical Oncology Group.

The evaluation of drug efficacy in patients with advanced prostatic cancer who have progressed to hormonal therapy is difficult, although palliation of the pain related to bone involvement still represents an important endpoint. In this study, epirubicin (EpiADM) plus medroxyprogesterone acetate (MPA) were given to advanced prostatic cancer patients with symptomatic bone involvement who had progressed to hormonal therapy. EpiADM was administered at a dose of 30 mg/m2 i.v. weekly and MPA at a daily dose of 1,000 mg p.o. for the first month and 500 mg thereafter. Fifty-four patients entered the trial, all of whom were evaluable. Amelioration of pain and a > or = 50% reduction in analgesic intake were observed in 52% of cases, with a mean duration of 4 months. Of the 28 responsive patients, 26 had already received two lines of hormonal therapy or were resistant to first-line therapy. Of the 23 patients with measurable lesions, 6 obtained a > or = 50% tumor shrinkage at these sites. The treatment was well tolerated, and no cardiac toxicity was observed up to a total cumulative EpiADM dose of 660 mg/m2. In conclusion, this regimen seems to have a palliative effect in patients with advanced prostatic cancer who have progressed to hormonal therapy, and it is feasible in an outpatient setting.

Aged↗
PubMed1993

Bioavailability of a new oral formulation of medroxyprogesterone acetate compared with the standard formulation: a single dose randomized study.

Twenty-six female patients with breast cancer participated in an open, randomized, cross-over study comparing single dose bioavailability of a recently developed oral medroxyprogesterone acetate (MPA) formulation (200 mg sachet where MPA is loaded in a polyvinylpyrrolidone cross-linked polymer, MPA/PVP) with the standard formulation (500 mg tablet). Blood tests were performed under standardized conditions for 120 h in all patients and MPA plasma concentrations determined by means of HPLC. Dose-normalized AUC(0-tz), AUC (0-infinity) and Cmax were all significantly higher for the MPA/PVP formulation than for the standard formulation. The relative bioavailability of the MPA/PVP formulation was on average three times superior to that of the standard formulation. This new MPA formulation might have important clinical implications for the treatment of hormone-sensitive cancer.

Administration, Oral↗
PubMed1997

Effect of medroxyprogesterone acetate on the quality of life of the oncologic patient: a multicentric cooperative study.

Anorexia and cachexia, major problems in patients with cancer, lead to decreased caloric intake and weight loss. Successful treatment of these conditions has a positive effect on patients' quality of life. Among the pharmacologic treatments, partial effects have been observed following administration of corticosteroids, anabolizing drugs and synthetic progestogens such as megestrol acetate and medroxyprogesterone acetate (MPA). The aim of the present study was to evaluate whether MPA is able to influence the quality of life of neoplastic patients undergoing different chemotherapeutic regimens and/or radiotherapy for different tumor types. A series of 279 cancer patients undergoing either chemotherapy and/or radiotherapy treatment for different tumor types was randomly allocated to receive either MPA or no treatment. We explored the effect of MPA oral suspension at the daily dose of 1000 mg for 12 weeks (group A) or no treatment (group B). Our data show an increase of body weight in group A patients and improvement in performance status. The outcome of the present study strongly demonstrates that therapy with MPA plays a fundamental role in ameliorating the complex symptomatology of cancer patients in intermediate or advanced stage of the disease undergoing casual treatment with chemotherapy and/or radiotherapy.

Adult↗
PubMed1998

Additive effects of medroxyprogesterone acetate and 5-fluorouracil derivative on 7,12-dimethylbenz[a]anthracene-induced rat mammary tumors.

Chronic oral administration of 1-(2-tetrahydrofuryl)-5-fluorouracil in combination with uracil suppressed thymidylate synthetase (TS) gene expression followed by reduction of TS activity in rat mammary tumors induced with 7,12-dimethylbenz[a]anthracene. Addition of medroxyprogesterone acetate (MPA) to the anticancer drug caused an additional decrease in TS and thymidine kinase activities in the tumor growth and restoration of bone loss. These results suggest that the simultaneous administration of MPA and anticancer drugs causes increased inhibition of mammary tumor growth and also diminishes the bone loss.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2003

Melting after keratoprosthesis implantation: the effects of medroxyprogesterone.

PURPOSE: This study was conducted to evaluate the effect of topical medroxyprogesterone (MPG) following KPro implantation in human subjects in whom donor tissue grafts had been contraindicated by high risk of failure. METHODS: Outcomes of implantation of the Chirila KPro, now known as AlphaCor, were reviewed with respect to postoperative MPG therapy. Ten of 45 (22%) patients had received MPG for a period of 12 months, while 35/45 (78%) had not. MPG treatment was halted because the drug is not approved as an adjunctive treatment of KPro patients. The main outcome measures were the incidence and timing of corneal stromal melting and visual acuity. RESULTS: Of those untreated with MPG, 34% developed a melt (mean follow-up 9.7 months), whereas of those who received MPG, 60% developed a melt (mean follow-up 28.4 months). However, mean time to melt onset for untreated cases was 8.8 months, whereas mean time to melt onset for treated cases was 23.2 months. There is a statistically significant association between time to melt onset, where melts occurred, and MPG therapy (chi2 = 0.001). In both groups, melts were strongly associated with a history of ocular HSV, which represented 17.1% of untreated and 20% of treated cases and is now considered a contraindication for AlphaCor. Preoperative visual acuities were in the range Perception Light (PL)-Count Fingers (CF) in all cases, whereas mean best postoperative best corrected visual acuity was 20/200 (range PL-20/30) in untreated cases and was 20/120 [range Hand Movements (HM)-20/30)] in MPG-treated cases. CONCLUSIONS: Although MPG may not influence the underlying incidence of melt-related complications, which are likely to be associated with other risk factors especially HSV, it may have a protective effect with regard to melt onset and severity. Controlled studies would assist evaluation of its use in this indication.

Administration, Topical↗
PubMed1986

Melphalan, 5-fluorouracil, and medroxyprogesterone acetate in metastatic endometrial carcinoma.

Fifty consecutive patients with recurrent and metastatic endometrial carcinoma were treated with melphalan, 5-fluorouracil, and medroxyprogesterone acetate with or without tamoxifen as first-line chemotherapy. The objective response rate was 48%, with 20% complete responses. The estimated median progression-free survival time was only five months (0.5 to 65 months) with estimated two- and five-year progression-free survival rates of 16 and 13%, respectively. The estimated median progression-free survival time was 24 months for complete responders; the progression-free survival times were significantly longer than the survival times (median = four months) for all other patients (P = .0002). Whether or not the addition of cytotoxic chemotherapy to progesterone hormonal therapy for metastatic endometrial carcinoma lengthens survival time is still open to question.

Adult↗
PubMedDate not supplied

Effect of medroxyprogesterone acetate and norethisterone on serum-stimulated and estradiol-inhibited proliferation of human coronary artery smooth muscle cells.

OBJECTIVE: The addition of progestogen to estrogen replacement therapy is thought to antagonize, at least in part, the beneficial effects of estrogens on the vasculature. The aim of this study was to investigate the effect of two progestogens mostly used in clinical practice on the proliferation of vascular smooth muscle cells, which has been demonstrated to be a crucial step in the development of atherosclerosis. MATERIAL AND METHODS: The effect of medroxyprogesterone acetate (MPA) and norethisterone (NET), which represent the two different classes of C21- and C19-progestogens, respectively, was investigated on proliferation of smooth muscle cells from human coronary artery in vitro. The steroids were tested in the concentration range 10(-8) to 10(-5) M, which is in the upper range of that reached during hormonal replacement therapy, and compared with control values. RESULTS: Estradiol significantly inhibited serum-stimulated cell growth at the concentrations 10(-6) and 10(-5) M by 18% and 34%, respectively. MPA significantly enhanced serum-stimulated growth at the concentrations 10(-6) and 10(-5) M by 29% and 47%, respectively. In equimolar combinations of MPA and estradiol, proliferation of the cells was significantly stimulated at the concentrations 10(-6) and 10(-5) M by 26% and 44%, respectively. In contrast, NET had no significant effect on serum-stimulated cell growth and had no impact on the estradiol-inhibited proliferation. CONCLUSIONS: These data suggest that MPA may antagonize beneficial antiatherosclerotic estradiol effects on the vasculature, whereas NET may be neutral in this respect. However, these effects occurred at supraphysiological concentrations. Because these concentrations might be reached in the target tissues, the clinical relevance for treatment of patients with cardiovascular risk cannot be excluded.

Blood↗
PubMedDate not supplied

Unscheduled bleeding during initiation of continuous combined hormone replacement therapy: a direct comparison of two combinations of norethindrone acetate and ethinyl estradiol to medroxyprogesterone acetate and conjugated equine estrogens.

OBJECTIVE: To determine whether there are differences between continuous combined hormone replacement therapies on bleeding control. DESIGN: Nine hundred and forty-five postmenopausal women were randomized to one of seven double-blind treatment groups (placebo, 0.25 mg norethindrone acetate (NA)/5 microg ethinyl estradiol (EE), 1 mg NA/5 microg EE, 0.5 mg NA/10 microg EE, 1 mg NA/10 microg EE, 5 microg EE, and 10 micro EE) or unmasked 0.625 mg conjugated equine estrogens (CEE)/2.5 mg medroxyprogesterone acetate (MPA). Treatment was for 12 months; subjects kept daily diaries recording whether they had bleeding and/or spotting. RESULTS: The results focused on currently commercially available hormone replacement therapy products (femhrt [1 mg NA/5 microg EE] and Prempro [0.625 mg CEE/2.5 mg MPA]) as well as a high-dose NA/EE dose combination (1/10) over the first 6 months of use, the most critical period in establishing treatment adherence. At the end of month 6 there was a greater incidence of amenorrhea with both NA/EE dose combinations compared with CEE/MPA (p = 0.009 for 1 mg NA/5 microg EE and p = 0.006 for 1 mg NA/10 microg EE). Statistically significantly more women were amenorrheic at every month based on cumulative amenorrhea for 1 mg NA/5 microg (p < 0.05) compared with CEE/MPA; at months 3 and 6 more women were amenorrheic on 1 mg NA/10 microg EE compared with CEE/MPA using the cumulative amenorrhea parameter. CONCLUSIONS: The results indicate that statistically significantly more women attained amenorrhea based on various parameters when administered continuous combined NA/EE compared with CEE/MPA. The potential for long-term treatment compliance based on better bleeding control may optimize the opportunity to prevent osteoporosis as well as other associated health benefits.

Drug Combinations↗
PubMedDate not supplied

Comparative effects of tibolone and conjugated equine estrogens with and without medroxyprogesterone acetate on the reproductive tract of female cynomolgus monkeys.

OBJECTIVE: To measure the effects of 2 years' treatment with tibolone on the reproductive tract of female monkeys (Macaca fascicularis) in comparison with conventional hormone replacement therapy. DESIGN: Ovariectomized adult female monkeys were randomized for 2 years of treatment into five groups: controls (n = 31); tibolone at 0.05 mg/kg (LoTIB group; n = 30); tibolone at 0.2 mg/kg (HiTIB group; n = 31); conjugated equine estrogens (CEE) at 0.042 mg/kg (CEE group; n = 28); or CEE + medroxyprogesterone acetate (MPA) at 0.167 mg/kg (CEE + MPA group; n = 29). Endpoints included vaginal cytology; uterine weight; histopathologic evaluation of the uterus, vagina, and cervix; histomorphometry of the endometrium; and immunohistochemical detection of the proliferation marker Ki67 and progesterone receptor in endometrial tissue. RESULTS: Endometrial atrophy was found in 29 of 30 and 23 of 31 animals in the LoTIB and HiTIB groups, respectively, compared with 0 of 28 and 11 of 29 in the CEE and CEE + MPA groups, respectively. All ovariectomized control animals had atrophic endometria. No complex or atypical hyperplasia was seen. Simple endometrial hyperplasia of a significant degree was seen in 3 of 31 HiTIB-treated animals, 1 of 30 LoTIB-treated animals, 26 of 28 CEE-treated animals, and 16 of 29 CEE + MPA-treated animals, and in none of the control animals. Marked simple endometrial hyperplasia and Ki-67 expression was induced by CEE and partially antagonized by MPA. LoTIB and HiTIB slightly increased endometrial thickness, whereas CEE and CEE + MPA induced a marked increase of 350% and 200%, respectively. Neither LoTIB nor HiTIB increased endometrial proliferation (Ki67 labeling) or induced vaginal keratinization. Endometrial bleeding was not seen in tibolone-treated animals but was present in 10 of 29 animals given CEE + MPA. CONCLUSIONS: The effect of tibolone on the uterus and lower reproductive tract was minimal. The lack of a proliferative response of the endometrium to tibolone, coupled with the lower incidence of endometrial bleeding, suggests that tibolone may have advantages over CEE and CEE + MPA regarding endometrial safety and efficacy.

Analysis of Variance↗