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PubMed1990

A randomized comparison of megestrol acetate (MA) and medroxyprogesterone acetate (MPA) in patients with advanced breast cancer.

The efficacy and side-effects of megestrol acetate and medroxyprogesterone acetate in postmenopausal patients with advanced breast cancer were compared in a prospectively randomized study. The dosage of MA was 2 X 80 mg p.o. or MPA 2 X 500 mg p.o. daily, given as a secondary hormonal treatment, mostly after previous treatment with tamoxifen. Ninety-eight patients entered the study and 92 were evaluable for effect, 48 patients on MA and 44 on MPA. Age, main tumor site and prior treatment were not different, but there was a preponderance of ER-negative tumors in the MA group. Responses appeared to be more frequent in the MPA-treated group (25% vs. 43%), predominantly in bone lesions, 12% for MA and 45% for MPA. Median progression-free survival was comparable, 15 vs. 10 months, and overall survival was not different (20 vs. 16 months). Toxicity was frequent, occurring in 83% vs. 74% of patients: increased appetite, nausea and dizziness in more than 20%, and a preponderance of pyrosis and breathlessness on MA and hot flashes, sweating and tremors on MPA. Cushingoid symptoms were present in about a quarter of the patients treated for more than 3 months. The occurrence of thrombo-embolic episodes and cardiovascular events was evenly distributed. Patients on MPA had more often increase in body weight, systolic blood pressure and serum creatinine than those treated with MA. It is concluded that MPA may be more effective for treatment of bone metastases, at the expense of more progestational side-effects. The occurrence of Cushingoid effects is frequent but similar in both arms, while the incidence of cardiovascular or thrombo-embolic events cannot be related to the use of either compound.

Aged↗

PubMed1990

Comparison of mass spectrometry and radioimmunoassay to measure medroxyprogesterone acetate in patients with endometrial cancer.

Serum medroxyprogesterone acetate (MPA) was measured by radioimmunoassay (RIA) and gas chromatography-mass spectrometry (GC-MS) in patients with endometrial cancer. Samples were obtained 3, 6 and 24 h after the oral administration of 100 or 200 mg MPA once a day. The levels obtained by GC-MS were lower (median 16-29%) than those obtained by RIA, which is probably attributable to the presence of metabolites interfering with the RIA. Two commercial MPA formulations gave different MPA serum levels by both RIA and GC-MS. The levels obtained by GC-MS were so low that frequently only partial saturation of the endometrial progesterone receptor may be achieved which may explain why high oral doses are needed to produce optimum therapeutic response.

Aged↗

PubMed1986

Induction of mammary adenocarcinomas by medroxyprogesterone acetate in BALB/c female mice.

In a previous paper we reported that medroxyprogesterone acetate (MPA) decreased the incidence of foreign body tumorigenesis in BALB/c mice but that mammary adenocarcinomas appeared in some of the females. The experiment was repeated in 245 virgin females as follows: (1) 40 mice treated with 40 mg of MPA depot s.c. every 2 months during a whole year; (2) 117 mice bearing a foreign body (FB) and treated with MPA; (3) 46 mice bearing a FB; (4) 42 non-treated mice. Mammary adenocarcinomas developed in 16/40 in group 1 and 30/117 in group 2; no mammary tumors appeared in either control groups. The tumors were infiltrating adenocarcinomas often affecting more than one mammary gland; metastases were occasionally observed. Animals killed after 1 year of MPA treatment presented deciduomas. MPA also decreased the incidence of FB-induced sarcomas, confirming previous results.

Adenocarcinoma↗

PubMed1992

Modulatory influence of injectable contraceptive steroid medroxyprogesterone acetate on methylcholanthrene-induced carcinogenesis in the uterine cervix of mouse.

Methylcholanthrene (approximately 300 micrograms) plus beeswax-impregnated thread, when placed inside the canal of the uterine cervix of virgin female adult mice for 30, 60 and 90 days produced cervical tumors in 0.0, 10 and 30% of mice, respectively. Employing this experimental cervical carcinogenesis model system, the present study evaluated the modulatory influence of medroxyprogesterone acetate (MPA) on the incidences of precancerous and cancerous lesions in the cervical epithelium as well as on phase I and phase II drug metabolizing enzymes and acid soluble sulfhydryl level in the liver. Intramuscular administration of MPA (50 micrograms every 5th day) to the carcinogen-thread inserted mice for 30, 60 and 90 days produced cervical tumors respectively in 0.0, 13.3 and 60.5% (P less than 0.05) of mice. A significant increase (P less than 0.05) in hyperplasia was also observed in the present study. A significant decrease in cytochrome b5 was found after 30 days.

Administration, Intravaginal↗

PubMed1986

Time course of hepatic changes produced by medroxyprogesterone acetate in the rat.

The time course of the effects of medroxyprogesterone acetate (MPA) treatment (100 mg/kg, i.p.) on hepatic drug metabolism was investigated in female rats. The findings demonstrate that the maximum effects of MPA on the microsomal enzyme systems, liver weight and protein content were attained within 3-7 days depending on the measured parameter. The blood concentration of MPA reached a constant level of about 120 ng/ml in 3 days. After cessation of MPA administration the induced values decreased to the control level within about 11 days.

Animals↗

PubMed1988

Medroxyprogesterone acetate (MPA) enhances liver NADPH-generating enzyme activities in normal rats.

The aim of the present study was to evaluate the effects of medroxyprogesterone acetate (MPA), an inducer of liver drug metabolism, on the ability of liver to generate NADPH, a reducing cofactor for drug oxidation reactions in normal rats and to compare these results with those obtained in rats receiving phenobarbital (PB), a well known inducer of liver drug metabolism. The results showed that: 1. Administration of MPA (100 mg/kg body wt) for a week increased liver wt and NADPH cytochrome P-450 reductase activity, suggesting that the compound induced liver drug metabolism. 2. The regimen also increased the activities of two NADPH generating enzymes, isocitrate dehydrogenase and malic enzyme, suggesting that MPA enhanced the capacity of normal liver tissue to produce NADPH. 3. Phenobarbital treatment increased the activities of three NADPH generating enzymes, glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase and malic enzyme, suggesting that MPA and PB differ in their effects on the liver NADPH-producing system.

Animals↗

PubMed1987

Medroxyprogesterone acetate- and ethinylestradiol-induced changes in biliary bile acids of the rat studied by high-performance liquid chromatography.

The effects of subcutaneous administration (5 mg/kg per day) for seven days of medroxyprogesterone acetate (MPA) or 17 alpha-ethinylestradiol (EE) on bile flow, total bile acid output and individual biliary acids have been studied in adult male Wistar rats. Biliary bile acid composition was quantitated by a simple isocratic high-performance liquid chromatographic technique using a C18 reversed-phase radial compression column and refractive index detection. This method revealed that muricholic acids, analysed as taurine and glycine conjugates, constituted a higher proportion of biliary bile acids in the rat than previously observed with gas chromatographic techniques. Marked cholestasis was produced by EE while MPA had little effect on bile flow or total bile acid output. Despite this, both steroids significantly increased the proportion of taurine-conjugated muricholic acids relative to taurocholic acid, although the estrogen had the more pronounced effect. Further study of the hepatobiliary consequences of high doses of MPA would seem warranted in view of the important use of this progestogen for cancer therapy.

Animals↗

PubMed1991

Mass spectrometric and high-performance liquid chromatographic studies of medroxyprogesterone acetate metabolites in human plasma.

Medroxyprogesterone acetate (MPA) treatment has been shown to exert several beneficial effects in cancer patients. It has been suggested that such effects are due in part to the metabolites derived from MPA in vivo. The first results are reported on the identification of 2 alpha-hydroxy- and 21-hydroxy-MPA, 20-dihydro-MPA, 17 alpha-acetoxy-2 alpha,3 beta-dihydroxy-6 alpha-methylpregn-1,4-dien-20-one and two X,21-dihydroxy-MPAs, one of them presumably being 6 alpha-hydroxymethyl-21-hydroxy-MPA, in patient's plasma by high-performance liquid chromatographic (HPLC), gas chromatographic-mass spectrometric and NMR methods. Additionally, the presence of other metabolites such as di- and tetrahydro-MPAs and 6,21-dihydroxy-MPA, found in urine and other samples, was demonstrated in plasma. For routine clinical examinations an HPLC method is described for determination of, e.g., the unreduced MPA metabolite group in Sep-Pak-ODS column extracts of patients' plasma.

Chromatography, High Pressure Liquid↗

PubMed1986

Interactions of medroxyprogesterone acetate with estrogen on the calcium-parathyroid axis in post-menopausal women.

We studied the effect of medroxyprogesterone acetate (MPA) as a single agent and in combination with conjugated equine estrogens (E), on the calcium-parathyroid axis in healthy post-menopausal women. Twenty-six subjects, 2-22 yr post-menopause, were studied under basal conditions, and then following 10 days of MPA (10 mg/day), 30 days of E (0.625 or 1.25 mg/day), and an additional 10 days of E + MPA. As predicted, E decreased urinary excretion of calcium and hydroxyproline. MPA did not alter these excretion variables, either when given alone, or when added to E. Cyclic administration of MPA for 10 days is currently advocated to avoid the adverse endometrial consequences of unopposed estrogen. These data indicate that such a program does not interfere with the beneficial effect of estrogen on the calcium-parathyroid axis.

Adult↗

PubMed1992

Clinical and laboratory evaluation of the myeloprotective effect of medroxyprogesterone acetate in head and neck cancer.

The action of high-dose medroxyprogesterone acetate (MPA) was studied by analysing the behaviour of colony-forming-unit granulocyte-macrophage (CFU-GM) during chemotherapy. 21 non-pretreated men with locally advanced carcinoma of the head and neck were randomised into two arms: A (11 patients) received three alternating cycles of cisplatin, 5-fluorouracil (CF)/cisplatin, methotrexate, bleomycin, vincristine and then CF every 4 weeks and B (10 patients) were treated with the same schedule plus 1000 mg per day of MPA. MPA was administered 14 days before the start of chemotherapy (day 0) and continued daily up to the 90th day. Bone marrow was harvested in arm A on days 0, +14 and +90, and in B, also on day -14. There was diverse CFU-GM behaviour in the two arms on the 14th day. These data support the hypothesis that the myeloprotective effect of MPA is due to induction of a mitotic rest in the stem cells, which protects them from drug action.

Antineoplastic Agents↗

PubMed1991

Medroxyprogesterone acetate and the nuclear uptake of testosterone and its metabolites by brain, pituitary gland and genital tract in male cynomolgus monkeys.

The synthetic progestin, medroxyprogesterone acetate (MPA), is used to treat male sex offenders, and it is also suppresses sexual activity in male monkeys. To examine the possibility that MPA may act as an anti-androgen in the primate brain, 4 intact male cynomolgus monkeys were given MPA (40 mg i.m.) once a week for 16 weeks, while 4 control males received i.m. injections of vehicle. All males were then castrated and 3 days later were given 3 mCi [3H]testosterone ([3H]T) i.v.; 1 h after injection males were killed, and radioactivity in nuclear pellets obtained from the hypothalamus (HYP), preoptic area (POA), amygdala (AMG), septum, pituitary gland and genital tract was analyzed by HPLC. Concentrations of [3H]T and [3H]dihydrotestosterone in nuclear pellets were 65-96% lower in MPA-treated males than in controls (P less than 0.001), but the aromatized metabolite, [3H]estradiol, which was the major form of radioactivity present in nuclear pellets from HYP, POA and AMG, was unchanged. There were no differences in concentrations of [3H]T in supernatants from the tissues of MPA-treated and control males. Because the reduced nuclear uptake of androgen in brain occurred in males whose androgen-dependent behavior had been suppressed by MPA treatments, it is proposed that MPA may have anti-androgenic effects at the level of the cell nucleus in brain regions that control behavior.

Animals↗

PubMed1992

An enzyme linked immunosorbent assay (ELISA) for plasma medroxyprogesterone acetate (MPA).

A single extraction fixed antigen enzyme-linked immunosorbent assay (ELISA) that can be completed in less than 24 h is described for the measurement of medroxyprogesterone acetate (MPA) in plasma. MPA is covalently coupled to bovine thyroglobulin and passively adsorbed in guanidine hydrochloride to a standard 96-well microtitre plate where it competes with MPA in the extracted plasma sample for goat anti-MPA. Antibody binding to the solid phase is determined via binding of a horse-radish peroxidase second antibody which reacts colorimetrically with its substrate. The reaction is stopped by addition of 1.25 M H2SO4 and absorbance read at 492 nm. All steps except for sample addition and extraction can be performed on an automatic ELISA processing machine. The assay is sensitive, specific and precise, with intra- and inter-assay coefficients of variation of less than 10 and 15%, respectively. Assay sensitivity is 0.08 ng/ml. The assay follows established methodology for other assays in this laboratory which assists standardization, cost structure and sample throughput and thus is a useful alternative to radioimmunoassays for the determination of MPA in plasma.

Animals↗

PubMed1980

The combined use of oral medroxyprogesterone acetate and methyltestosterone in a male contraceptive trial programme.

A male contraceptive trial was undertaken in 23 men using a combination of oral medroxyprogesterone acetate (MPA) and oral methyltestosterone (MeT). The men were divided into four groups according to varying drug dosages and were followed for 15 months (control - 3 months, treatment - 6 months, follow-up - 6 months). The parameters assessed included sperm count and motility, serum gonadotropins and sex steroids, and several biochemical and hematological tests. A questionnaire dealing with side-effects and changes in sexual function was administered intermittently. Although sperm count was suppressed (most dramatically at the highest drug doses, MPA 20mg,MeT 20mg), it was not suppressed to infertile levels. Sperm motility was unaltered; LH was modestly suppressed, FSH was not suppressed; testosterone was suppressed even at low doses; dihydrotestosterone responses were inconsistent. No significant biochemical abnormalities or side-effects occurred although some men experienced mild transient acne, gynecomastia and decreased testicular size. We conclude that in the doses used in this trial, the combination of MPA and MeT is not effective for male contraceptive, purposes and that higher doses may induce severe and undesirable side-effects.

Clinical Trials as Topic↗

PubMed1983

Multinational comparative clinical trial of long-acting injectable contraceptives: norethisterone enanthate given in two dosage regimens and depot-medroxyprogesterone acetate. Final report.

Final results are presented from a two-year WHO multinational comparative trial of three regimens: depot-medroxyprogesterone acetate (DMPA) given at 90-day intervals, norethisterone enanthate (NET-EN) given at 60-day intervals for the entire study period (NET-EN (60-day)), and NET-EN given at 60-day intervals for six months and thereafter at 84-day intervals (NET-EN (84-day)). 1587 DMPA subjects were observed for 20,550 woman-months, 789 NET-EN (60-day) subjects were observed for 10,361 woman-months, and 796 NET-EN (84-day) subjects were observed for 10,331 woman-months. This clinical trial represents the largest clinical trial undertaken on injectable contraceptives. After two years, the pregnancy rate with NET-EN (84-day) was 1.4 (+/- 0.6 S.E.) per 100 women, as compared with the two-year rates of 0.4 (+/- 0.3 S.E.) per 100 women observed with DMPA and 0.4 (+/- 0.2 S.E.) with NET-EN (60-day). Both discontinuation rates for amenorrhea and the prevalence of amenorrhea lasting more than 90 days were significantly higher with DMPA than with either NET-EN regimen. Terminations for bleeding problems were similar with the three treatments, despite a better cyclic pattern for the first six months with the NET-EN regimens. The three treatments were comparable with respect to discontinuation rates for other medical or personal reasons, and for all reasons combined. For family planning programs, NET-EN (60-day) has the advantage of low pregnancy rates compared to NET-EN (84-day), and a schedule of administration that does not change. Both NET-EN regimens produce less amenorrhea than DMPA. However, the NET-EN (60-day) regimen has the logistic and economic disadvantage of requiring more frequent injections. All three injectable regimens compare favourably with oral contraceptives in terms of pregnancy and total continuation rates observed in clinical trial settings.

Adult↗

PubMed1987

A multicentered phase III comparative clinical trial of depot-medroxyprogesterone acetate given three-monthly at doses of 100 mg or 150 mg: II. The comparison of bleeding patterns. World Health Organization. Task Force on Long-Acting Systemic Agents for Fertility Regulation Special Programme of Research, Development and Research Training in Human Reproduction.

A multicentered phase III clinical trial was conducted in seven countries to compare two dosages of depot-medroxyprogesterone acetate (DMPA), 100mg and 150mg, given every 90 days. Contraceptive efficacy and side-effects of both regimens were reported previously. Their effect on vaginal bleeding patterns is the object of this paper. A total of 1216 women were randomly assigned to a dose group and 1156 of them provided a menstrual diary. The comparison of the bleeding patterns is made using a 90-day reference period approach and following the guidelines published by WHO. In addition, the longest bleeding/spotting episode and the longest bleeding/spotting-free interval are calculated over the entire diary length. The only difference found between the two dose groups is a higher incidence of amenorrhea with the 150mg regimen. Overall, there is a high degree of consistency between the reasons given by individual women for discontinuing the contraceptive method and their vaginal bleeding pattern during the 90 days preceding discontinuation. However the data revealed large between-centre differences, both in the incidence of specific patterns, and in the identification by women of bleeding problems as reasons for discontinuation. This last point suggests that the life-table analysis underestimates the true incidence of menstrual irregularities. Comments on the reference period analysis method are made.

Amenorrhea↗

PubMed1996

Comparative phase III clinical trial of two injectable contraceptive preparations, depot-medroxyprogesterone acetate and Cyclofem, in Vietnamese women.

A multicenter clinical trial was conducted in Viet Nam, comparing two injectable contraceptive preparations: the three-monthly injectable depot-medroxyprogesterone acetate (DMPA) and the once-a-month injectable Cyclofem. A total of 600 volunteers were randomized to the two treatment groups and followed for one year. No pregnancy occurred during the trial. Approximately one quarter of the women in each group discontinued early from the trial. In the DMPA group, this was mostly because of amenorrhea and vaginal bleeding irregularities. In the Cyclofem group, an equal number discontinued because of menstrual problems and personal reasons. These personal reasons are probably related to the inconvenience of having to return to the clinic for injection on a monthly basis. Thus, Vietnamese women experience less side effects with Cyclofem than with DMPA, and once Cyclofem is made more widely available and is more accessible, it may better meet their needs than does DMPA.

Adult↗

PubMed1997

Depot medroxyprogesterone acetate pioneers. A retrospective study at a North Carolina Health Department.

This article examines the characteristics of the first group of depot medroxyprogesterone acetate (DMPA) acceptors after US Food and Drug Administration (FDA) approval of the method and evaluates their continuation rates and factors associated with discontinuation. This was a population based retrospective study based on 12 months of clinic data for 510 women who began using DMPA in 1993 at a large county health department. Cumulative 12 month life table rates were calculated for the entire group and were then stratified by selected characteristics. The 4, 8, and 12 month continuation rates were 67%, 46%, and 35%, respectively. More than half of these women discontinued because of bleeding and nonbleeding side effects (25% and 28%, respectively). Almost 20% of these women were considered discontinuers because they waited longer than 16 weeks to return for an injection. As measured in this study, continuation rates for this first group of DMPA acceptors were low. The next step is to determine if the characteristics and patterns of use of these "pioneer" acceptors are representative of more recent acceptors, and if lessons learned from this group will lead to higher continuation rates.

Adolescent↗

PubMed1998

Effectiveness of Cyclofem in the treatment of depot medroxyprogesterone acetate induced amenorrhea.

A total of 100 women who were using depot medroxyprogesterone acetate (DMPA) for contraception and who had experienced at least 6 months of drug induced amenorrhea, were randomized to either switching their method of contraception to Cyclofem, or continuing with DMPA. At the end of 6 months, 82% of the Cyclofem users had experienced some vaginal bleeding, compared with 10% of DMPA users. Time to resumption of vaginal bleeding was related to the duration of DMPA use to the duration of DMPA induced amenorrhea, and to the body mass index of the user. Over the 6 months of follow-up, 94% of Cyclofem users complained of some side effects, compared with 22% of DMPA users. The most frequently cited problems among Cyclofem users included breast tenderness, abdominal pain, and dysmenorrhea; yet a third of these women opted to stay on Cyclofem at the end of the study. It is concluded that switching to Cyclofem is a new option for DMPA users who are concerned about amenorrhea. Although using Cyclofem in this setting will not meet the needs of all such women, its effectiveness in inducing vaginal bleeding justifies a trial in those who have no contraindication to estrogen treatment.

Adult↗