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PubMed2006

Inhibitory effect of medroxyprogesterone acetate on human liver cytochrome P450 enzymes.

OBJECTIVE: Medroxyprogesterone acetate (MPA), frequently used in contraception and chemotherapy, was involved in a report of drug-drug interaction (DDI) when co-administrated with phenytoin, doxifluridine and cyclophosphamide. In order to clarify the mechanism of such interaction, an in vitro study was undertaken to evaluate MPA's potential to inhibit cytochrome P450 (CYP) enzymes. METHODS: Inhibitory effects of MPA on seven CYPs, including CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2D6, CYP2E1 and CYP3A4, were conducted in human liver microsomes. Time- and NADPH-dependent inhibitions were also tested. DDI potential was predicted according to the [I]/K ( i ) value. RESULTS: MPA was found to inhibit CYP2C9 and CYP3A4; half inhibition concentration (IC(50)) was 16.1 microM and 31.5 microM, respectively. Slight inhibition was observed on CYP1A2, CYP2A6, CYP2C8 and CYP2D6 with IC(50) of more than 100 microM. MPA exhibited activation rather than inhibition on CYP2E1. Further study revealed that MPA showed a noncompetitive inhibition on CYP2C9 and a competitive inhibition on CYP3A4 with K ( i ) of 9.0 microM and 36 microM, respectively. In addition, MPA was not a mechanism-based inhibitor to any of seven isoforms tested. By using predicted concentration of MPA in liver, [I]/K ( i ) was estimated to be 0.24 and 0.06 for CYP2C9 and CYP3A4, respectively. The concentration of phenytoin co-administrated with MPA was calculated to increase by 24%. CONCLUSION: Based on our results, MPA can possibly cause clinically relevant DDI via the inhibition of CYP2C9.

Adult↗
PubMed1998

A combination chemoendocrine therapy of mitoxantrone, doxifluridine, and medroxyprogesterone acetate for anthracycline-resistant advanced breast cancer.

Between January 1993 and October 1995, 34 patients with anthracycline-resistant advanced breast cancer were treated with a combination chemoendocrine therapy of mitoxantrone (MIT), doxifluridine (5'-DFUR) and medroxyprogesterone acetate (MPA). Of 34 patients, 28 were evaluable for efficacy of this combination therapy, and 30 including 2 for whom data were incomplete were assessed for adverse drug reactions. Adriamycin (ADM) was used for pretreatment in 12 patients, 4'-epi-ADM in 6, and THP-ADM in 12. In the eligible patients, 8.0 mg/m2 MIT was administered intravenously every 4 weeks, and 600 mg MPA and 600 mg 5'-DFUR were given orally every day. The median follow-up period was 25 weeks (range 2-90 weeks). The median cumulative dose of mitoxantrone was 66 mg (range 12-121 mg). Of the 28 patients, 11 (39.3%) responded to this combination therapy. As for response in relation to predominant site of lesion, 1 of 5 soft tissue lesions (20%) and 8 of 12 bone metastases (66.7%) showed a partial response, and one complete response and one partial response (25.0%) were seen in eight lung lesions. None of three pleural lesions responded to this therapy. The median duration of response was 31 +/- weeks (range 12-82 weeks). Adverse drug reactions were controllable or tolerable. Combined chemoendocrine therapy with a low dose of MIT is a well-tolerated and moderately effective regimen for the treatment of anthracycline-resistant advanced breast cancer.

Adult↗
PubMed1998

Pharmacokinetic study of low- versus high-dose medroxyprogesterone acetate (MPA) in women.

The present study was conducted to compare the pharmacokinetics (PK) of low-dose versus high-dose medroxyprogesterone (MPA) as a once-daily oral administration. Of 32 patients, all women, enrolled in this PK study, 18 received 600 mg MPA daily and 14 received 1200 mg daily. Detailed PK data were obtained on day 1 and after more than 4 weeks of MPA treatment. In addition, multiple data for the minimum steady-state concentration (Css min) were analyzed. The MPA serum concentrations were measured by high-performance liquid chromatography. Wide interpatient variability was found in the PK parameters obtained both on day 1 and after more than 4 weeks. There were no clear relationships between the oral dose and the MPA peak concentration (Cmax), area under the time versus concentration curve (AUC), or mean Css min. Weight gains of 10% or more were demonstrated more frequently in the high-dose group (P < 0.01). Liver dysfunction (n = 5) did not influence the PK of MPA. Five patients demonstrated extremely low AUC and Cmax (< 10 ng/ml) values on day 1. Phenobarbital, dexamethasone and betamethasone were being taken concomitantly with the MPA each by one patient. The serum MPA concentrations were markedly increased after the discontinuation of phenobarbital in that patient, suggesting a drug interaction. At present we cannot recommend the high dose of MPA, except in clinical studies, from a PK or a pharmacodynamic points of view.

Adult↗
PubMed1998

Multidrug-resistant recurrent breast cancer which responded to medroxyprogesterone acetate showing a remarkable improvement in the quality of life: report of a case and the role of team medical care.

We herein report the case of a patient with recurrent breast cancer who showed a remarkable improvement in her quality of life (QOL) as a result of a good response to medroxyprogesterone acetate (MPA). A 43-year-old Japanese woman developed bone metastases 3 years after surgery. Subsequent radiotherapy and chemoendocrine therapy with CAF (cyclophosphamide, adriamycin, 5-fluorouracil) and tamoxifen all failed, and she could not sit up because of bone metastases. The performance status (PS) on admission was grade 4. After admission, delirium accompanied with sensory and visual hallucination caused by intense anxiety occurred, and a continuous consultation by psychiatrists was necessary. MPA treatment at the dose of 1200 mg/day alleviated the bone pain, thus improving her PS to grade 1. Her appetite also improved, while her mental state stabilized. A bone scintigram revealed an improvement of bone metastases, and the tumor markers also returned to normal values. The patient thus showed a pronounced improvement in her QOL due to both MPA treatment and team medical care. The role of the medical staff as well as the importance of their cooperation in achieving an improvement in the QOL of cancer patients is also discussed.

Adult↗
PubMed2001

Successful management of breast cancer with liver metastases with medroxyprogesterone acetate treatment.

A 38-year-old woman with cancer in the left breast underwent standard radical mastectomy. The estrogen receptor and progesterone receptor status of the primary tumor was unknown. Ten years after the surgery, a metastatic liver tumor was detected, and chemoendocrine therapy, consisting of cyclophosphamide, epirubicin, 5-fluorouracil (CEF) and medroxyprogesterone acetate (MPA) was initiated. The metastatic liver tumor showed a partial response after 11 cycles of such chemoendocrine therapy. Subsequently, MPA alone was given daily as maintenance therapy, and the disease has remained stable for 6 years. For women with metastatic breast cancer, complete remission is uncommon, and stable disease is a reasonable goal of successful therapy. In this respect, chemoendocrine therapy with CEF and MPA, followed by MPA alone as maintenance therapy, was successful in the patient reported here. Importantly, the patient's quality of life has remained favorable for several years after the partial response was achieved.

Adult↗
PubMed2005

In vivo assessment of the regulation of transforming growth factor alpha, epidermal growth factor (EGF), and EGF receptor in the human endometrium by medroxyprogesterone acetate.

PURPOSE: The present study evaluated the in vivo effect of medroxyprogesterone acetate (MPA) on the localization of immunoreactive transforming growth factor alpha (TGFalpha), epidermal growth factor (EGF), and their common receptor (EGF-R) in the human endometrium. METHODS: The study design was a randomized clinical trial enrolling 36 healthy women with regular menstrual cycles. The participants were randomly assigned into three groups: groups 1 (n = 11) and 2 (n = 17) received placebo and were submitted to endometrial biopsy during the proliferative and secretory phases of menstrual cycle, respectively; group 3 (n = 8) received MPA (10 mg/day) for 10 days followed by endometrial biopsy, which was performed during the secretory phase. Immunohistochemistry was used to localize TGFalpha, EGF, and EGF-R in the endometrial tissue. RESULTS: TGFalpha was present markedly in the luminal and glandular epithelia but also in the periglandular stroma, with a distribution pattern similar in the three experimental groups. EGF immunostaing was equally distributed in epithelial and stromal layers of the endometrium and remained unchanged in endometrial samples from women treated with MPA compared to placebo. EGF-R was expressed only in the epithelium. The intensity of EGF-R immunostaining was higher in secretory than in proliferative endometrium and was further increased by administration of MPA (p < 0.05, chi-square test). CONCLUSION: The present results suggest that the progestogen-induced in vivo differentiation of secretory endometrium does not require dramatic changes in the expression of EGF or TGFalpha, whereas EGF-R may be up regulated.

Adult↗
PubMed2006

Rapid determination of time-resolved fluoroimmunoassay for medroxyprogesterone acetate residues in pork tissues and comparison with liquid chromatography and tandem mass spectrometry.

A competitive time-resolved fluoroimmunoassay (TR-FIA) was developed for the determination of medroxyprogesterone acetate (MPA) residues in pork tissues. The limits of detection (LOD) was determined to be 0.06 ng g-1 and the limits of quantification (LOQ) was less than 0.8 ng g-1. The intra-assay variations were below 10% and the interassay variations ranged between 9.7 and 12.7%. The mean recoveries established at six concentration levels varied from 87.3 to 108.3%. The results obtained by the TR-FIA and ELISA showed a good correlation. The established TR-FIA was validated for the determination of incurred pork tissues and confirmed by high-performance liquid chromatography and tandem mass spectrometry (LC-MS-MS). This proposed technique could be applied to routine residue analysis.

Animals↗
PubMed2006

Reproductive response in suckling Corriedale ewes to the ram effect during the non-breeding season: effect of postpartum condition and the use of medroxyprogesterone priming.

The response to the ram effect and the use of progestagen priming was studied in postpartum suckling Corriedale ewes. Two experiments were carried out during the non-breeding season. In experiment 1, the effectiveness of the ram effect to induce fertile oestrus in postpartum ewes was determined. While no significant differences in the frequency of ewes in oestrus were found, the overall conception rate was significantly higher in ewes that were weaned at least 6 months before the study started (63.3%) than in 60-90 days postpartum ewes (45.3%, p < 0.01). In experiment 2, the influence of medroxyprogesterone acetate priming on the response to the ram effect in suckling Corriedale ewes was determined. The frequency of ewes in oestrus and conception rate between ewes that remained unprimed and 6-days-primed ewes were similar. We conclude that it is possible to induce oestrus in postpartum suckling Corriedale ewes using the ram effect during the non-breeding season and that the use of progestagen priming seems to be ineffective in improving the response of postpartum ewes to the ram effect.

Animals↗
PubMed1980

Binding of medroxyprogesterone acetate in human breast cancer.

Human mammary tumor cytosol containing macromolecules which bound 3H-MPA (3H-medroxyprogesterone acetate or 1,2-3H-6 Alpha-methyl-17 alpha-acetoxy-pregn-4-ene-3,20-dione) and 3H-R5020 (6,7-3H-17,21-dimethyl-19-nor-pregna-4,9-diene-3,20-dione) similarly with high affinity (Ka approximately equal to 2 nM-1) and specificity. The progestin-binding components had sedimentation coefficients of about 4S and 7S in sucrose gradients and had approximately the same number of binding sites for Ma and R5020 as revealed by gradient centrifugation and saturation analysis. Among the steroids tested, these components had the highest affinities for progestins and were probably progesterone receptors of human breast cancer. A 4S component of human serum bound 3H-R5020 but not 3H-MPA. With 3H-MPA and 3H-estradiol used as the tracers, the concentrations of progesterone and estrogen receptors have been determined in 236 human breast cancers by saturation analysis. Our results on the receptor content and response of 31 of these tumors to endocrine therapy suggest that progesterone receptor may be a better marker of a hormonally responsive breast cancer.

Binding, Competitive↗
PubMed1986

The effect of ventilatory stimulation with medroxyprogesterone on exercise performance and the sensation of dyspnoea in hypercapnic chronic bronchitis.

Seven male patients with hypercapnic chronic bronchitis were given the ventilatory stimulant drug medroxyprogesterone acetate (MPA) 20 mg t.d.s. orally for 4 weeks preceded by a control period of one week. The patients were assessed at the beginning and end of the control period, at 2-weekly intervals while they took the drug and 2 weeks to 5 months after they stopped it. Arterial blood gases, spirometry and a 12-minute walking test were performed on each occasion. During treatment with MPA, arterial Pco2 fell in all patients from a mean control of 50.6 (+/- 1 SEM) mmHg to 44.4 (+/- 1) mmHg (P less than 0.001) and Po2 rose in all patients from a mean control of 53 (+/- 1.9) mmHg to 61 (+/- 3.2) mmHg (P less than 0.05). These effects were achieved without changes in PEFR, FEV1 or FVC. In spite of this, there was no improvement in the sensation of dyspnoea on visual analogue scales at rest or after exercise, and no significant increase in the 12-minute walking distance. The only side effect associated with MPA was slight fluid retention. Ventilatory stimulation with MPA improves arterial blood gases in hypercapnic chronic bronchitis but there is no accompanying improvement in symptoms or exercise tolerance.

Aged↗
PubMed1995

Cervical carcinoma in situ and use of depot-medroxyprogesterone acetate (DMPA). WHO Collaborative Study of Neoplasia and Steroid Contraceptives.

The relationship of depot-medroxyprogesterone acetate (D-MPA) use to risk of cervical carcinoma in situ was investigated using data from a large multi-national, hospital-based case-control study. To avoid possible detection bias from Pap smear screening, final analyses were restricted to a subset of cases with symptoms at the time of their diagnosis of cervical carcinoma in situ. Relative to nonusers, the risk was elevated in women who had ever used DMPA and increased with duration of use. Decreasing trends in relative risk with times since first and last uses were observed in long-term users. Results from another portion of this same study did not show a relationship of invasive cervical cancer to DMPA use. These findings suggested that if DMPA increases the risk of cervical carcinoma in situ then either this is a reversible effect, or the cervical lesions induced by DMPA tend not to progress to invasive disease.

Adult↗
PubMed1994

Breast cancer and depot-medroxyprogesterone acetate: a review.

Depot-medroxyprogesterone acetate (DMPA) has been used world-wide since 1964 as a contraceptive in spite of the fact that it was only in 1992 licensed for contraceptive use in the USA due to concern about a possible breast cancer risk. Two recent studies have considered DMPA use and risk of breast cancer and these and earlier studies are reviewed here. Overall, the results are reassuring but there is some evidence that breast cancer risk may be increased in women using DMPA when very young and particularly in recent users. Current knowledge of the biology of human breast cancer is such that it is difficult to judge the biological plausibility of this evidence. There is no doubt that DMPA is a highly effective form of contraception and any overall assessment must take into account all the relevant risks and benefits. Thus, the risk-benefit equations in developed and developing countries must allow for different levels of maternal mortality and morbidity, as well as differing underlying cancer rates.

Breast Neoplasms↗
PubMed1994

Depot-medroxyprogesterone acetate, other injectable contraceptives, and cervical neoplasia.

The relationship between depot-medroxyprogesterone acetate (DMPA), and other injectable contraceptives and cervical neoplasia was reviewed mainly on the basis of three studies: the WHO Collaborative Study of Neoplasia and Steroid Hormone Contraceptives (2,009 cases and 9,583 controls collected in several, mainly developing, countries); a study of 369 cases of carcinoma in situ, 133 of invasive cancer and 646 controls collected by the National Tumor Registry of Costa Rica; and a cooperative study of 759 cases of invasive cervical cancer and 1,430 controls from four countries in Latin America (Costa Rica, Peru, Mexico and Colombia). There was no evidence of an appreciably elevated risk since most relative risks for ever users ranged from between 0.8 and 1.4, nor of consistent duration-risk relationship which was observed only in one study. The relative risk estimates for longest duration of use ranged from between 0.9 and 2.4. The data are still compatible with the absence of a causal association and with a moderately increased risk (up to a factor 1.5), which finds some biological plausibility as it is in agreement with the overall evidence of the relation between oral contraceptives and cervical neoplasia.

Carcinoma in Situ↗
PubMed1994

Risk of cervical dysplasia in users of oral contraceptives, intrauterine devices or depot-medroxyprogesterone acetate. The New Zealand Contraception and Health Study Group.

Three cohorts of women aged 20-39 attending medical practitioners or family planning clinics in New Zealand for contraceptive advice were followed prospectively for five years. The three cohorts were defined by use (or at least prescription) of one of three study contraceptive methods at the time of beginning of follow-up--oral contraceptives (OC), intrauterine devices (IUD) or depot-medroxyprogesterone acetate (MPA)--and numbered 2469, 2072 and 1721 women, respectively. Follow-up was intended to be annual and included cervical smear as well as interim contraceptive and medical histories. A positive outcome (referred to here as 'dysplasia') was any degree of definite dysplasia or carcinoma of the cervix diagnosed cytologically by a central study laboratory, and confirmed by histology or analysis of DNA ploidy. In the three cohorts (OC, IUD and MPA, respectively), 12,839, 10,774 and 8,984 person-years of follow-up were accumulated and 125, 92 and 101 cases of dysplasia were confirmed. Crude annual rates of dysplasia per 1,000 person-years were approximately the same in the OC (9.6) and IUD (8.4) cohorts. Crude rates were higher in the MPA cohort (11.3 per 1,000 person-years). However, important confounding factors, principally smoking and sexual behavior, were identified with rate ratios ranging between 1 and 3 over the range of the potentially confounding variables, and multivariate analyses revealed no evidence of increased risk for the MPA cohort when these factors were taken into account. At least over the short term, there appears to be no difference in risk of cervical dysplasia between women using these three methods of contraception if differences between groups in respect to known confounding factors are taken into account.

Adolescent↗
PubMed1994

History of long-term use of depot-medroxyprogesterone acetate in patients with cervical dysplasia; case-control analysis nested in a cohort study. The New Zealand Contraception and Health Study Group.

Histories of use of depot-medroxyprogesterone acetate (MPA) given by women entering a previously-reported prospective study of risk of cervical dysplasia, including carcinoma, have been evaluated. Over a six-year follow-up period, 348 of the 7199 enrolled women developed cervical dysplasia diagnosed by cytology and confirmed by histology or DNA analysis. Use of MPA prior to entry into the study was reported somewhat more commonly and for somewhat longer periods by the women who developed confirmed dysplasia than by those who did not. However, this association was accounted for entirely by the fact that women who reported use of MPA, particularly at an early age, tended to carry a number of known strong risk factors for dysplasia, specifically, first intercourse at an early age, multiple sex partners and cigarette smoking. These findings indicate that the lack of relationship of MPA use to risk of cervical dysplasia, noted previously for women whose median duration of use within the formal study period was about 2 years, extended to the same women who used MPA prior to the study period--even to those whose duration of prior use was 4 years or more.

Adult↗
PubMed1995

Depression in users of depo-medroxyprogesterone acetate.

Prevalence of depression is high among poor, young, Hispanic inner city women. Depot-medroxyprogesterone acetate (DMPA) is a popular contraceptive choice in this group. DMPA labelling suggests that depression may worsen with use. In order to identify any association of DMPA use with worsening depression, we surveyed an English-speaking subset of DMPA users in a Title-X funded family planning clinic. Eighty women completed the CES-D scale on two occasions: once about four weeks after a DMPA injection when the subject would have been exposed to the highest blood levels, and once immediately prior to an injection when recent blood levels of the drug would be somewhat lower (or absent preceding the first injection). The median CES-D score was 14. The scores were not related to timing of the test (pre- or post-injection). The depression scores were somewhat higher among those women receiving their first DMPA injection during the study period (i.e., unexposed women) and among those women who had received four or more injections. Scores were unrelated to age or parity, but were somewhat higher in women who reported fewer years of education or a recent adverse pregnancy outcome. These data provide little evidence of increasing depression with long-term use of DMPA and no evidence of a short-term effect of dose (within the contraceptive range) on mood. Women at risk of depression should not be denied DMPA as a contraceptive choice.

Adolescent↗
PubMed1995

Depot-medroxyprogesterone acetate (DMPA) and risk of invasive adenocarcinomas and adenosquamous carcinomas of the uterine cervix. WHO Collaborative Study of Neoplasia and Steroid Contraceptives.

A hospital-based case-control study was conducted in two hospitals in Bangkok, Thailand, and in one hospital each in Chiang Mai, Thailand, Mexico City, Mexico and Nairobi, Kenya. One purpose of this study was to determine whether the long-acting progestational contraceptive, depot-medroxyprogesterone acetate (DMPA), alters risk of invasive cervical carcinomas with adenomatous histological features. Information on prior use of DMPA, screening for cervical cancer, and the suspected risk factors for this disease was ascertained from interviews of 239 women with adenocarcinomas and 85 women with adenosquamous carcinomas, as well of from a large pool of controls, 2534 of whom were matched to the cases included in this report. For selected subsets of these women, a smoking history was also elicited, blood specimens were collected for measurement of antibodies against herpes simplex and cytomegalovirus, and information on sexual behavior was obtained from interviews of their husbands. The relative risk (and 95% confidence interval) of adenomatous cervical carcinomas in women who ever used DMPA was estimated to be 0.75 (0.51, 1.11). No trends in risk were observed with duration of DMPA use, times since first or last use, or age at first use. The results provide reassurance that use of DMPA for over four years does not enhance risk of adenomatous cervical carcinomas, and risk is not increased after a potential latent period of over 12 years since initial exposure.

Adenocarcinoma↗
PubMed1996

Effect of pretreatment counseling on discontinuation rates in Chinese women given depo-medroxyprogesterone acetate for contraception.

The study examined the effect of pretreatment counseling upon discontinuation of 150 mg depo-medroxyprogesterone acetate (Depo-Provera (DMPA)), given for contraception. A total of 421 Chinese women participated, 204 receiving detailed structured pretreatment and ongoing counseling on the hormonal effects and probable side effects of DMPA and 217 receiving only routine counseling. The primary study endpoint was termination rate; secondary endpoints were frequency of medical events and reasons for termination. Study termination rates were significantly lower in the intensive structured counseling group than in the routine counseling group. At one year, the total cumulative termination rates were 11% (23/204) and 42% (92/217), respectively (p < 0.0001). The most common reasons for terminating DMPA were menstrual changes. No pregnancy, serious or unexpected medical events were reported, nor were statistically or clinically significant changes in vital signs observed. We conclude that pretreatment counseling on expected side effects increases the acceptability of DMPA.

Adolescent↗