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PubMed1984

Pharmacokinetic and pharmacodynamic basis for the treatment of metastatic breast cancer with high-dose medroxyprogesterone acetate.

Postmenopausal patients with metastatic breast cancer were treated with medroxyprogesterone acetate (MPA) (Clinovir) in dosages between 500 and 1500 mg orally per day. The relation of MPA plasma concentrations and endocrine effects were studied in a longitudinal fashion. MPA exerted suppressive effects on the basal and gonadotropin-releasing hormone (GnRH) stimulated gonadotropin secretion, cortisol, dehydroepiandrosterone (DHEA), and estradiol (E2) in a dose-dependent manner leading to a complete suppression with 1500 mg orally per day. The depression of thyroid hormones (T3 and T4) coincided with a depression of the thyroxine-binding index (TBI). MPA did not affect human growth hormone (hGH), basal and thyrotropin-releasing hormone (TRH) stimulated thyroid-stimulating hormone (TSH) and aldosterone. Basal and TRH-stimulated prolactin (PRL) secretion showed a slight but distinct elevation. From these data it is concluded that in postmenopausal patients MPA exerts its antitumor activity by an interference with the hypothalamo-pituitary adrenal axis in the sense of a selective pharmacologic hypophysectomy leading to complete suppression of adrenal steroid secretion. Additionally, MPA inhibits tumor cell growth through the progesterone receptor. A dual mechanism for the antitumor activity of high dose is postulated MPA: ablative through suppression of the hypothalamo-pituitary-adrenal axis and subsequent estrogen deprivation, and additive via the progesterone receptor directly on the tumor cell. The significance of gonadotropin suppression in the postmenopause for breast cancer growth is unclear. The depression of T3 and T4 is due to a depression of thyroid hormone-binding proteins. The elevation of PRL secretion may be explained by a slight estrogenic activity of MPA metabolites.

Adrenocorticotropic Hormone↗

PubMed1985

A phase III trial of oral high-dose medroxyprogesterone acetate (MPA) versus mepitiostane in advanced postmenopausal breast cancer.

A randomized controlled trial was performed to compare the therapeutic results of oral high-dose medroxyprogesterone acetate (HD-MPA) versus mepitiostane (MS) in the treatment of postmenopausal breast cancer. MPA was given at three doses of 400 mg orally daily to 47 patients and produced objective responses in 19 cases (40.4%). An objective response was seen in 14 of the 40 control patients given MS at two doses of 10 mg orally daily (35.0%). Among patients with bone metastases, 6 of 19 (31.6%) for HD-MPA and 2 of 13 (15.4%) for MS showed objective responses. The other merits of HD-MPA suggested in the study were improvement in performance status, increase in appetite, and myeloprotective effect.

Adult↗

PubMed1986

Oral high-dose medroxyprogesterone acetate versus tamoxifen. A randomized crossover trial in postmenopausal patients with advanced breast cancer.

In a prospective randomized multicenter study in previously untreated postmenopausal patients with advanced breast cancer, the response to treatment with oral medroxyprogesterone acetate (MPA) 300 mg three times daily was compared with tamoxifen (TAM) 20 mg twice daily. Of 61 patients treated with MPA, 27 (44%) had a partial or complete remission, 6 showed no change, and 28 had progressive disease. Of 68 patients treated with TAM, 24 (35%) showed a remission, 15 no change, and 29 progression. The difference in response rate is not significant. However, 11 of 25 patients with osseous metastases as predominant site, responded to MPA and 7 of 31 to TAM (P = 0.05). Moreover, in patients older than age 70 years, 13 of 26 responded to MPA and 6 of 31 to TAM (P less than 0.05). Median duration of remission of all patients in the MPA arm was 17 months and in the TAM arm, 23 months (not significant). Median survival was 20 months for MPA and 26 months for TAM (not significant). After cross-over from TAM to MPA 8 of 31 patients responded and after cross-over from MPA to TAM, no response was seen in 27 patients. These data indicate that the response rate and duration to MPA and TAM are comparable, except in patients with osseous metastases and in patients older than age 70 years. MPA has more side effects, but seems to be more effective after cross-over, and may thus be reserved for second-line treatment.

Aged↗

PubMed1986

Aminoglutethimide and medroxyprogesterone acetate in the treatment of patients with advanced breast cancer. A phase II study of the Association of Medical Oncology of the German Cancer Society (AIO).

One hundred twenty-eight women with advanced metastatic breast cancer were treated with a combination of aminoglutethimide (AG) (1000 mg orally, daily) and medroxyprogesterone acetate (MPA) (1500 mg orally, daily for six weeks and thereafter 500 mg orally, daily; omitting cortisone substitution). AG/MPA did not lead to side effects other than those described under AG or MPA monotherapy. Mental and personality changes seem to be more severe and frequent under combined therapy than under monotherapy. Impairment of mental functions, depressive syndromes, fatigue, ataxia, skin rash, and transient increase of gammaglutamyl transferase appeared and disappeared within the first 4 to 6 weeks of treatment. Objective remissions of at least 3 months duration from initiation of therapy were seen in 21 of 128 patients (21.9%) (3.9% complete remission [CR], 18% partial remission [PR]). A no change (NC) status occurred in an additional 25.8%. The remission duration (mean and range) was 19 (10.5-54) for CR, 16.5 (4.5-52+) for PR and 6 (3-27) months for NC patients. The highest response rate was registered for patients with only bone involvement (PR, 11; and NC, 11 of 26 patients). There was a distinct correlation of response to prior systemic treatment, receptor status of the primary tumor, disease-free interval, menopausal status, age and condition of the patient. PR was obtained in 4 of 20 patients with receptor-negative primary tumors. These results justify a prospective trial comparing AG/MPA with other forms of endocrine therapy in selected patient subgroups.

Adult↗

PubMed1988

Clinical trial of high-dose oral medroxyprogesterone acetate in the treatment of metastatic breast cancer and review of the literature.

Recent studies have suggested that there are benefits from the use of high-dose parenteral medroxyprogesterone acetate (MPA) in the treatment of metastatic breast cancer. The present study was designed to assess the efficacy and toxicity of high-dose oral MPA in women with clinical parameters suggesting potentially hormonally sensitive metastatic breast cancer. The first 28 patients received 800 mg/day, and 11 of them had received no previous hormone (NPH) therapy. The response rate (complete plus partial) was 63% for those receiving NPH and 12% for those receiving previous hormone (PH) therapy. Toxicity was significant at these doses, especially for women treated for more than 5 weeks. Toxic effects included excessive weight gain, Cushingoid facies, worsening of diabetes mellitus, and other stigmata suggestive of hypercorticism. Nineteen other patients were treated at 400 mg/day with a 60% response rate for 10 NPH patients and 44% for patients with PH treatment. Toxicity was less severe in these patients. The median time to treatment failure was 23 weeks, and to survival, 119 weeks for all treated patients. Moderately high (400 mg/d) and higher dose (800 mg/d) oral MPA are capable of inducing reasonable response rates in patients with NPH treatment. The toxicity of these regimens was significant--profound weight gain was dose limiting in some patients. While effective, high-dose oral MPA is unlikely to supplant tamoxifen as first-line therapy in metastatic breast cancer.

Administration, Oral↗

PubMed1989

High-dose medroxyprogesterone acetate in advanced breast cancer. Clinical and pharmacokinetic study with a combined oral and intramuscular regimen.

Seventy-five patients with advanced and intensively pretreated breast cancer received high-dose medroxyprogesterone acetate (MPA) using a schedule consisting of an intramuscular (IM) loading dose (1 g MPA IM days 1 to 10) and an oral maintenance treatment (200 mg/day three times a day) thereafter. A reinduction was performed in part of the responding patients at time of early relapse (1 g MPA IM for 10 consecutive days). MPA serum levels above 100 ng/ml were achieved during induction treatment and maintained for 3 to 4 months during the oral phase of therapy before decreasing to approximately 50 ng/ml. Two complete remissions (duration, 17.2 and 62 months), 15 partial remissions (median duration, 7 months), and 21 cases of disease stabilization (median duration, 5.5 months) were achieved. The median survival time was significantly longer for responders (19.9 months) than nonresponders (4.8 months). Although a higher proportion of postmenopausal patients responded, the remission duration in premenopausal women was remarkably long. Favorable sites of response were soft tissue, lymph nodes, and bone lesions. Reinduction treatment yielded a second response (two partial remissions, three no change) in five of six patients indicating that high-dose conditions were necessary to maintain response. This schedule allows to restrict higher doses of MPA on a long-term basis to responding patients.

Administration, Oral↗

PubMed1990

Inability of medroxyprogesterone acetate to down regulate estrogen receptor level in human breast cancer.

The influence of medroxyprogesterone acetate (MPA) on estrogen receptor (ER) and progesterone receptor (PR) levels was studied in 20 postmenopausal patients with ER-positive and PR-positive primary breast cancers. Each patient underwent drill biopsy and subsequently mastectomy. The drill biopsy and surgical specimens were assayed for the total ER and PR levels (cytosolic plus nuclear fraction) by enzyme immunoassay. Between the drill biopsy and mastectomy, ten patients received no treatment (control group) and the other ten patients were given MPA (1200 mg/day) for 7 days. In the control group, the total ER and PR levels of the surgical specimens decreased by 68.2 +/- 7.3% and 60.7 +/- 8.4%, respectively, taking the receptor values of the drill biopsy specimens as 100%, although no treatment was given preoperatively. This decrease seems to be attributable to the receptor degradation due to damages occurring during mastectomy. In the MPA group, the total ER and PR levels of the surgical specimens decreased by 64.2 +/- 8.0% and 23.3 +/- 7.6%, respectively. The decrease in PR, but not ER, was statistically significant between the control and MPA groups (P less than 0.01). These results demonstrate that MPA down regulates PR but not ER in human breast cancer and challenge the conventional idea, extrapolated from the results on the endometrium and endometrial cancer, that MPA antagonizes endogenous estrogens by down regulating ER.

Antineoplastic Agents↗

PubMed1990

Medroxyprogesterone acetate lowers plasma corticotropin and cortisol but does not suppress anterior pituitary responsiveness to human corticotropin releasing factor.

The endocrine action of medroxyprogesterone acetate (MPA) has been claimed to be of a glucocorticoid-like nature. Upon clinical observation, MPA has been shown to improve life quality and overall well-being in patients with advanced breast cancer, renal carcinoma, prostatic carcinoma, and uterine adenocarcinoma. The authors have evaluated MPA endocrine action by the administration of human corticotropin releasing factor (hCRF) in a 90-minute assay in 15 patients with advanced breast cancer or renal cell carcinoma both, before the initiation of oral high-dose MPA treatment (1000 mg MPA) as well as after at least 10 days of therapy. The curves for corticotropin, beta-endorphin, and cortisol responses to hCRF of tumor patients who were tested before the initiation of MPA treatment were parallel to the curves of a healthy control group of probands tested under equal conditions, although at significantly higher respective hormone levels. In patients with malignant disorders assayed after MPA administration, both basal and peak hormone levels were found to be comparable with values obtained in healthy controls. In conclusion, MPA appeared to act at a suprapituitary level since pituitary responsiveness to hCRF was preserved under MPA treatment. Moreover, it appeared that MPA brought the hormonal stress state found in patients with malignant tumors back to normal.

Administration, Oral↗

PubMed1991

Sequentially administered ethinyl estradiol and medroxyprogesterone acetate in the treatment of refractory epithelial ovarian carcinoma in patients with positive estrogen receptors.

The activity of sequentially administered hormonal therapy was investigated over 25 days in 25 patients with epithelial ovarian carcinoma who had estrogen receptor (ERc)-positive tumors. Patients received ethinyl estradiol (EE) (50 micrograms/d) on days 1 to 7 and medroxyprogesterone acetate (MPA) (400 mg/d) on days 8 to 25. Twenty-three patients completed one or more courses of treatment. There were no complete responses (CR). Four partial responses (PR) with durations of 9, 4, 3, and 1 months were seen. Two incomplete responses with durations of 6 and 4 months were also seen. Six patients had stable disease (SD), and 11 patients had progression. The overall response rate was 17% and may represent a modest improvement in response over those in previously published studies conducted with MPA alone. No significant toxic effects were noticed, and some patients reported an improved sense of well-being. However, two patients experienced depression with this treatment. The mean ERc values in responders, patients with SD, and nonresponders were 70.0, 36.7, and 47.9 fmol/mg cytosolic protein, respectively. Future studies of hormonal therapy in patients with ovarian carcinoma should attempt to identify more reliable indices for determining sensitivity to these agents.

Administration, Oral↗

PubMed1985

Short-term effects of danazol and medroxyprogesterone acetate on cytosol and nuclear estrogen and progestin receptors, 17 beta-hydroxysteroid dehydrogenase activity, histopathology, and ultrastructure of human endometrial adenocarcinoma.

We measured concentrations of cytosol and nuclear estrogen, as well as progestin receptors and activities of 17 beta-hydroxysteroid dehydrogenase (17-HSD), and examined histopathology and ultrastructure of endometrial carcinoma specimens taken before and after one-week danazol (200 mg, 3 times daily) or medroxyprogesterone acetate (MPA, 100 mg daily) treatments in 14 and 16 patients, respectively. A typical progestin effect, a significant increase in the activity of 17-HSD, was observed after both treatments. The post-therapy 17-HSD activities correlated significantly with the pretreatment cytosol progestin receptor concentrations in both treatment groups. Both MPA and danazol decreased the proliferative activity and increased the secretory activity of the malignant epithelial endometrial cells. These biochemical and morphological results support the concept that danazol has progestin-like actions on the human endometrium, and might therefore be an alternative for hormonal treatment of endometrial carcinoma.

17-Hydroxysteroid Dehydrogenases↗

PubMed1989

Actions of medroxyprogesterone acetate on the efficacy of cytotoxic drugs: studies with human breast cancer cells in culture.

Human breast cancer cells (MCF-7) showed increased responses to methotrexate and vincristine after a 48-hr pre-treatment with medroxyprogesterone acetate. The effect of the hormone, which was detectable at concentrations of between 10 and 100 nM, was independent of its growth-inhibitory action. These findings confirm a previous clinical study and have important implications with regard to the management of advanced breast cancer.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1989

Adriamycin action on human breast cancer cells: enhancement by medroxyprogesterone acetate.

Exposure of cultured human breast cancer cells (MCF-7) to medroxyprogesterone acetate (MPA) prior to treatment with adriamycin (ADR) enhanced the effect of the cytotoxic drug on cell yield after further growth of viable cells. Pretreatment with oestradiol (E2) produced similar synergism, but no such effect was observed using dexamethasone. Exposure to ADR before MPA led to an additive effect, but not to synergism. When cells resistant to the growth-inhibitory action of MPA were examined, progestogen/drug synergism could still be demonstrated. We conclude that the effects of ADR, like those of methotrexate and vincristine, can be enhanced by pre-treatment with MPA and that further clinical trials of such a regimen are needed.

Antineoplastic Agents↗

PubMed1989

Medroxyprogesterone acetate, an anti-cancer and anti-angiogenic steroid, inhibits the plasminogen activator in bovine endothelial cells.

Medroxyprogesterone acetate (MPA) is an anti-cancer drug for mammary carcinomas and an angiostatic steroid. The effects of MPA on the growth and plasminogen activator (PA) activity of bovine endothelial cells were investigated to elucidate the inhibitory mechanism observed in angiogenesis. MPA did not suppress the growth of capillary endothelial cells, even at high concentrations. On the other hand, in bovine endothelial cells of 3 types (adrenal cortical capillary, aortic and pulmonary artery endothelial cells), MPA inhibited extracellular and cell-associated activity of PA, which might be a protease involved in the neovascular response. MPA also greatly inhibited the high level of PA induced by basic fibroblast growth factor (FGF). The same result was obtained when PA production was induced by 4 beta-phorbol-12-myristate-13-acetate (PMA) in endothelial cells. These findings suggest that one of the points of inhibitory action of MPA in the process of angiogenesis may be the suppression of PA activity, and that inhibition of this protease might be useful for reduction of tumorigenic or excessive angiogenesis in vivo.

Animals↗

PubMed1991

Depot-medroxyprogesterone acetate (DMPA) and risk of liver cancer. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives.

A hospital-based case-control study was conducted to assess the possible relationship between use of depot-medroxyprogesterone acetate (DMPA), an injectable progestational contraceptive, and the development of liver cancer in 2 developing countries where hepatitis B is endemic. Information about prior DMPA use and potential confounders was ascertained during personal interviews with 71 cases and 530 controls from 3 hospitals in Thailand and 1 hospital in Kenya. No significant association between liver cancer and DMPA use was observed in Kenya (RR = 1.64, 95% Cl = 0.4-0.6) or Thailand (RR = 0.33, 95% Cl = 0.1-1.0). No consistent changes in risk were observed with duration of use, time since last use, or time since first use. No significant associations were observed between DMPA use and risks of either hepatocellular carcinoma or cholangiocarcinoma. These findings suggest that risk of liver cancer in areas where hepatitis B is endemic is not appreciably altered by the use of DMPA.

Adolescent↗

PubMed1992

The effect of endocrine therapy with medroxyprogesterone acetate, 4-hydroxyandrostenedione or tamoxifen on plasma concentrations of insulin-like growth factor (IGF)-I, IGF-II and IGFBP-1 in women with advanced breast cancer.

Tamoxifen treatment of women with advanced breast cancer has previously been reported to reduce plasma insulin-like growth factor-type I (IGF-I) concentrations. In this study we have examined the effect of treatment with Tamoxifen, medroxyprogesterone acetate (MPA) or 4-hydroxyandrostenedione (4-OHA) on plasma IGF-I and IGF-II concentrations. As IGF-binding proteins (IGFBPs) can modulate the biological effects of IGF-I, plasma IGFBP-I levels were also measured. Treatment with Tamoxifen for 2 weeks resulted in a small, but significant, decrease in IGF-I levels, but increase in the plasma concentration of IGFBP-I. In contrast, treatment with MPA increased levels of IGF-I, but significantly reduced plasma IGFBP-I concentrations. Treatment with 4-OHA had no significant overall effect on plasma IGF-I or IGFBP-I levels, although changes were detected for some subjects. Plasma IGF-II concentrations were not altered by treatment with Tamoxifen, MPA or 4-OHA. It is concluded that although treatment with Tamoxifen or MPA produced significant changes in plasma IGF-I concentrations, any physiological effects of such changes are likely to be modulated by the corresponding alterations in plasma IGFBP-I concentrations.

Aged↗

PubMed1991

Improved bioavailability of a new oral preparation of medroxyprogesterone acetate.

Medroxyprogesterone acetate (MPA) is widely used in the hormonal therapy of breast cancer. So far, oral formulations of MPA commercially available present a very low bioavailability, with a less than 10% extent of oral absorption. A new oral preparation of MPA has been recently developed. Based on a pilot study, an open, randomized, crossover trial has been performed on 22 breast and endometrial cancer patients to evaluate the relative bioavailability of this new oral formulation (200-mg sachet, twice daily) as compared with a standard formulation (Farlutal, 500-mg tablet, twice daily). The bioavailability evaluation was mainly based on the area under the curve measured between two administrations at steady state, after 15 days of continuous therapy. Wide interpatient variability of MPA plasma levels after oral MPA administration was confirmed. The MPA plasma levels were higher in patients treated with the new formulation than in patients treated with Farlutal. The relative bioavailability of the new preparation was 3.5 times higher than that of the standard. This new formulation represents a great improvement in the extent of oral absorption of MPA and could lead to better management of hormone-responsive tumors by hormonal therapy.

Administration, Oral↗

PubMed1989

Cyclic and sequential therapy with tamoxifen and medroxyprogesterone acetate in metastatic breast cancer.

A clinical trial of sequential tamoxifen and medroxyprogesterone acetate (MPA) was carried out in 36 women with metastatic breast cancer in order to evaluate the therapeutic efficacy of this regimen and to determine if tamoxifen would increase progesterone receptor (PR) levels and thereby increase response to MPA. Fourteen patients (39%) responded to this treatment, with the duration of remission ranging from 2 to 24 + months (the mean and median were 11 months). In 22 patients, PR levels were measured both before and after 7 days of tamoxifen administration. In PR-positive patients, PR changes induced by tamoxifen did not appear to increase the response rate. In PR-negative patients, PR became positive in 3 patients following tamoxifen treatment, with 2 of 3 responding to treatment, whereas in 11 others whose PR levels remained negative, only one response was observed. Our results suggest that potentiation by tamoxifen was not observed, since in our previous study, MPA alone was equally effective. Thus, tamoxifen and MPA should be given independently for palliation of metastatic breast cancer, and MPA should be administered following therapy with tamoxifen.

Adult↗

PubMed1982

Teratogenic effects of cyproterone acetate and medroxyprogesterone treatment during the pre- and postimplantation period of mouse embryos. I.

Pregnant mice were treated with a single subcutaneous injection of either cyproterone acetate (CA) or medroxyprogesterone acetate (MPA). In the first experiment the animals received 5-900 mg/kg of the hormone before implantation (day 2 of pregnancy). CA treatment on day 2 caused a dose-dependent decrease in fetal weight and a significant dose-dependent increase in the rates of cleft palate and urinary tract abnormalities. Exencephaly and heart abnormalities were also significantly more frequent, but this increase was not dose-dependent. MPA treatment on day 2 was followed by sporadic increases in dead and resorbed fetuses, a decrease in fetal weight and an increase in the rates of cleft palate, and malformed or abnormally developed fetuses. None of these effects, however, was dose-dependent. In the second experiment the mice were given one single injection (30 mg/kg) of CA or MPA on any one of days 1-12 of gestation. Treatment with CA on one day between days 1 and 12 revealed that the specific sensitivity for abnormalities of the urinary tract was on days 5 and 6, for the respiratory tract on days 8 and 9, and for cleft palate on days 10 and 11. Treatment with MPA on one day between days 1 and 12 only revealed a high rate of respiratory and urinary tract abnormalities on day 9. After treatment with MPA cleft palate was again significantly more frequent in all treated groups, however, days of peak sensitivity were not detected. The long half-life of CA (60 hours) explains the teratogenic effect of high doses of this progestin after treatment on day 2 and also the pattern of abnormal development found after treatment with a single dose of CA on one of the days between day 1 and day 12.

Abnormalities, Drug-Induced↗