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PubMed2004

Medroxyprogesterone acetate attenuates estrogen-induced nitric oxide production in human umbilical vein endothelial cells.

We report the novel observation that medroxyprogesterone acetate (MPA) attenuates the induction by 17beta estradiol (E2) of both nitric oxide (NO) production and endothelial nitric oxide synthase (eNOS) activity in human umbilical vein endothelial cells. Although MPA had no effect on basal NO production or basal eNOS phosphorylation or activity, it attenuated the E2-induced NO production and eNOS phosphorylation and activity. Moreover, we examined the mechanism by which MPA attenuated the E2-induced NO production and eNOS phosphorylation. MPA attenuated the E2-induced phosphorylation of Akt, a kinase that phosphorylates eNOS. Treatment with pure progesterone receptor (PR) antagonist RU486 completely abolished the inhibitory effect of MPA on E2-induced Akt phosphorylation and eNOS phosphorylation. In addition, the effects of actinomycin D were tested to rule out the influence of genomic events mediated by nuclear PRs. Actinomycin D did not affect the inhibitory effect of MPA on E2-induced Akt phosphorylation. Furthermore, the potential roles of PRA and PRB were evaluated. In COS cells transfected with either PRA or PRB, MPA attenuated E2-induced Akt phosphorylation. These results indicate that MPA attenuated E2-induced NO production via an Akt cascade through PRA or PRB in a non-genomic manner.

Animals↗
PubMed2004

Long-term survival of a patient with primarily chemo-resistant metastatic breast cancer treated with medroxyprogesterone acetate.

The prognosis of breast cancer patients with liver metastases is extremely poor. Here we present the case of a 66-year-old female breast cancer patient with multiple liver metastases diagnosed 2 years after a radical modified mastectomy followed by adjuvant tamoxifen. At progression, anthracycline-based chemotherapy was administered, but a CT scan following two cycles of FEC (5-fluorouracil, epirubicin, cyclophosphamide) showed progression of the liver metastases. Chemotherapy was therefore switched to medroxyprogesterone acetate (MPA). After 3 months the patient's general status improved, and disease stabilization was observed at the next CT scan. A further 4 months of MPA treatment resulted in complete response of all liver lesions. Treatment with oral MPA was continued for 4 years. At present, 11 years after the diagnosis of metastatic liver involvement, the patient is alive, free of cancer, and fully ambulatory. Despite bulky visceral disease and chemoresistance, hormonal treatment with MPA resulted in a spectacular and long-lasting response.

Aged↗
PubMed2005

Cytogenetic findings, Trp53 mutations, and hormone responsiveness in a medroxyprogesterone acetate induced murine breast cancer model.

Medroxyprogesterone acetate (MPA)-induced mammary carcinomas express high levels of estrogen (ER) and progesterone receptors (PR) and when transplanted in syngeneic mice they show a progestin-dependent (PD) growth pattern. By successive transplantation, progestin-independent (PI) variants were generated and showed a different response to antihormone therapy. A diploid chromosome number (2n=40) was found in three of five PD tumors, with numbers in the triploid to tetraploid range in the other two. Some PI tumors were diploid, but most were aneuploid (8 of 12 tumors). The most frequent alterations found in PD and PI tumors were gains of chromosomes 3, 4, and 6 and losses of chromosomes 16 and X. Chromosomes 4 and 7 were involved in translocations in three of the four tumor families studied. single-strand conformation polymorphism analysis revealed a point mutation on the Trp53 gene in one of the PD tumors; this showed a stable diploid karyotype, suggesting that mutated Trp53 is not uniquely involved in chromosome instability. We have shown that hormone independence may be acquired without changes in ploidy, suggesting that the increase in ploidy is favored by successive transplantation. In our model, diploid tumors responded to hormone treatment but aneuploid tumors were either responsive or not.

Aneuploidy↗
PubMed2006

Medroxyprogesterone and tamoxifen augment anti-proliferative efficacy and reduce mitochondria-toxicity of epirubicin in FM3A tumor cells in vitro.

We have shown that low doses of medroxyprogesterone acetate (MPA- 2.6 microM) and tamoxifen (TAM- 270 nM) could augment the effectiveness of epirubicin in breast tumor cells. In this study, we monitored early cell kinetics (24-96 h plating and S-phase) and mitochondrial morphology during chemo-endocrine treatments to delineate the epirubicin sensitizing mechanism. S-phase fractions with radioactive thymidine uptake, plating efficacy, and transmission electron microscopic analysis were taken for 24-h periods until the 7th day after drug treatments. Despite strongly enhancing the clonogenic killing, both MPA and TAM did not affect epirubicin induced early cytotoxicity. Instead, they augmented the S-phase inhibition, which was even more pronounced for TAM. Epirubicin induced prominent swelling and crista damage of mitochondria and fragmentation of nuclei. Mitochondria were a normal size during a combination of epirubicin with either MPA- or tamoxifen treatment, despite the persistence of chromatin fragmentation and strong synergism on the clonogenic killing of breast tumor cells. Low dosage endocrine agent-induced anthracycline sensitization may be independent of mitochondrial toxicity. Further studies would be worthwhile, since the uncoupling of mitochondrial toxicity from the anti-neoplastic effect may also mean obviated cardiac toxicity in clinic.

Antibiotics, Antineoplastic↗
PubMed2004

Menstrual pattern and lipid profiles during use of medroxyprogesterone acetate and estradiol cypionate and NET-EN (200 mg) as contraceptive injections.

The objectives of this study were to compare effects of medroxyprogesterone acetate 25 mg + estradiol cypionate 5 mg (Cyclofem) and norethisterone enanthate (NET-EN) upon the menstrual pattern and determine changes in lipoprotein parameters after 12 months of use. One-hundred females were included and 87 (45 with Cyclofem and 42 with NET-EN) women completing 12 months were evaluated. Menstrual changes were the leading complaint among users. At the end of 12 months, 20/45 (44.4%) and 18/41 (43.9%) Cyclofem and NET-EN users, respectively, had normal menstrual pattern. Irregular and infrequent bleeding were the two most important changes that occurred. The discontinuation rate at 12 months due to menstrual disturbances did not show any significant differences between the two preparations, but showed lower incidence compared to other studies. Total cholesterol, high-density, low-density and very low-density lipoprotein cholesterol and triglyceride levels decreased at 12 months in both groups and these changes were statistically significant.

Adolescent↗
PubMed2004

The association between depot medroxyprogesterone acetate contraception and bone mineral density in adolescent women.

Although adolescent women are actively acquiring bone, there has been little study of the possible effects of depot medroxyprogesterone acetate (DMPA) injectable contraception use on bone density in adolescents. We conducted a cross-sectional evaluation of the association between DMPA use and bone mineral density in adolescent women, ages 14-18 years. Of 174 study participants, 81 were DMPA users (range, 1-13 injections, median = 3) and 93 were not. Mean bone density at all anatomic sites (hip, spine and whole body) was lower for DMPA users than nonusers, but differences were not statistically significant (e.g., hip, 0.940 vs. 0.970 g/cm2, p = 0.10; spine, 0.970 vs. 0.992 g/cm2, p = 0.19). Duration of DMPA use showed a trend toward lower spine bone density (p-value for trend = 0.06). This study did not find a strong association between DMPA use and bone density. Further prospective evaluation of bone density changes with DMPA use and after DMPA discontinuation are needed in this age group.

Absorptiometry, Photon↗
PubMed2004

Immediate monthly combination contraception to facilitate initiation of the depot medroxyprogesterone acetate contraceptive injection.

Conventional clinical protocols specify that women initiate depot medroxyprogesterone acetate (DMPA) within 7 days of the onset of menses, and product labeling specifies initiation within 5 days. Women outside of this window should wait until next menses to begin, often leaving them with inadequate interim contraceptive protection. An alternative is for women to initiate monthly hormonal contraception immediately, as a bridge to DMPA, with a scheduled follow-up appointment about 4 weeks later. We evaluated bridge preferences and DMPA initiation among 150 women requesting DMPA who were ineligible for their first injection at the time of clinic visit due to menstrual cycle day. Ninety-eight percent (n = 147) rejected the standard protocol of waiting with condoms or abstinence in favor of a hormonal bridge method. Ninety-seven percent follow-up (n = 146) showed that 86% were satisfied with their bridge method. There were no posttreatment pregnancies, and 55% (n = 81) of participants had initiated DMPA or another long-term contraceptive within 4 weeks of their initial clinic presentation.

Adolescent↗
PubMed2005

A prospective study of immediate initiation of depo medroxyprogesterone acetate contraceptive injection.

Traditional protocols for depo medroxyprogesterone acetate (DMPA) initiation mandate that women start the method during the first 5-7 days of the menstrual cycle. Women who do not have their initial clinic visit during this time period are generally instructed to return to clinic during menses to begin DMPA, which often leaves them insufficiently protected from pregnancy. An alternative approach is to give women the injection immediately during the clinic visit, regardless of menstrual cycle day. In this prospective study, we evaluated a protocol for immediate DMPA initiation among 149 women who presented on cycle day 8 or later. Ninety-two percent (n = 137) of subjects returned for a follow-up pregnancy test, but half of all subjects required multiple reminders to return for the visit. There were three pregnancies. Forty-seven percent (n = 70) continued to a second DMPA injection or another contraceptive method within 14 weeks of their initial clinic visit. Factors associated with returning for repeat injection included satisfaction with DMPA, older age and finding it easy to return for the follow-up pregnancy test visit.

Adult↗
PubMed2005

Bone mineral density in women aged 40-49 years using depot-medroxyprogesterone acetate, norethisterone enanthate or combined oral contraceptives for contraception.

Most studies show that depot-medroxyprogesterone acetate (DMPA) has a negative effect on bone mass. There are conflicting reports with respect to recovery of bone mass with long-term use of DMPA. No information is available on the effect of norethisterone enanthate (NET-EN) on bone mass, and combined oral contraceptives (COCs) have not been found to be associated with loss of bone mass. The aim of this study was to investigate bone mineral density (BMD) in older women (40-49 years) in relation to use of DMPA, NET-EN and COCs for at least 12 months preceding recruitment into the study. One-hundred twenty-seven users of DMPA, 102 NET-EN users and 106 COC users were compared to 161 nonuser controls. Bone mineral density was measured at the distal radius and midshaft of the ulna using dual X-ray absorptiometry. There was no significant difference in BMD between the four contraceptive user groups (p=.26) with and without adjustment for age. Although a small decrease in BMD was noted in the age range of 40-49 years, this was not statistically significant (p=.7). The BMD was found to be significantly associated with body mass index (BMI) (p or=25.8 mIU/mL was associated with a decrease of 0.017 g/cm2 in radius BMD relative to women with FSH <25.8 mIU/mL. Significant interaction between FSH and BMI in their effect on BMD was observed (p=.006). This study found no evidence that long-term use of DMPA, NET-EN and COCs affects BMD in this population.

Adult↗
PubMed2005

Same-day administration of depot-medroxyprogesterone acetate injection: a retrospective chart review.

A chart review of clients administered depot-medroxyprogesterone acetate (DMPA) injection in September of 2000 was performed to assess implementation of a same-day injection administration protocol irregardless of menstrual cycle day. Women were classified into one of the three categories: (1) routine injection (injection given as specified by the package label), (2) same-day start injection (no injection for more than 6 months, did not meet labeled criteria for administration and received an injection the day of the visit) or (3) same-day restart injection (injection given within 6 months prior to receiving an injection at the visit despite being late for their injection). Of the 228 women receiving an injection, 104 (46%) had a nonroutine same-day injection, meaning almost half of the women receiving a contraceptive injection would have had to return for another visit if this protocol had not been in place. Among these women administered a same-day injection, 23 (22%) were also dispensed emergency contraception. Only 1 of the 104 women was subsequently identified to have become pregnant. Other pregnancies are presented to illustrate the importance of adherence to pregnancy testing at the time of injection and revisit, and the need for backup contraception. Using a same-day injection protocol, women can have increased access to injection contraception, and proper adherence to a protocol can assure few pregnancies.

Adult↗
PubMed2005

Concentration of depot medroxyprogesterone acetate and pain scores in adolescents: a randomized clinical trial.

A prospective, single-blinded, randomized trial was initiated to determine whether injection site pain differed in adolescents receiving two concentrations of 150 mg of depot medroxyprogesterone acetate (DMPA). Ninety-five adolescents seeking injectable contraception were randomized to receive 150 mg of DMPA as follows: a deltoid injection of 1.0 mL from a single-unit-dose vial containing 150 mg/mL or 0.38 mL from a multidose vial containing 400 mg/mL of DMPA. A visual analogue scale was measured at each visit and cumulatively compared between the groups. Continuation rates were tabulated. The report of pain for the multidose vial group was significantly higher than for the unit-dose vial group (p<.003). The dropout rates for both groups were high at 1 year and were not statistically different (multidose group=64% and unit-dose group=77%). Twenty percent of the subjects in the multidose group vs. 22% in the unit-dose group discontinued due to bleeding irregularities. The concentrated form of DMPA led to greater pain at the injection site than did the less concentrated form, but this did not lead to higher discontinuation rates among adolescents.

Adolescent↗
PubMed2005

Randomized assignment to copper IUD or depot-medroxyprogesterone acetate: feasibility of enrollment, continuation and disease ascertainment.

OBJECTIVES: We conducted a feasibility study to enroll and follow family planning acceptors who were randomly assigned to use an intrauterine device (IUD) or injectable depot-medroxyprogesterone acetate (DMPA). METHODS: Centers in Brazil, Guatemala, Egypt and Vietnam aimed to enroll 100 participants per site. Enrolled women were randomly assigned to have inserted a TCu 380A IUD, or to receive injections of 150 mg of DMPA every 3 months, and scheduled for up to 12 months of follow-up. We tested for cervical infection at first and final visits, and examined for signs of pelvic inflammatory disease (PID) at each visit. RESULTS: The sites screened 555 women and enrolled 368. Two women (0.5%) had three discomfort signs of PID during follow-up. The prevalence of gonorrhea at each woman's final follow-up visit was 0.5%, and the prevalence of chlamydia at final visit was 5.4%. Sixty-eight percent of women either completed 12 months of observation with their assigned method or were still using their method at the end of the study. CONCLUSION: A larger, definitive clinical trial appears feasible. The majority of women we approached agreed to participate; nearly 400 women were enrolled; two thirds continued to use their assigned method until study closeout; and the STI risk was moderate.

Adolescent↗
PubMed2006

Changes in bleeding patterns with depot medroxyprogesterone acetate subcutaneous injection 104 mg.

OBJECTIVE: This study aims to assess changes in bleeding patterns with the use of depot medroxyprogesterone acetate (DMPA) 104 mg/0.65 ml subcutaneous injection (DMPA-SC 104). STUDY DESIGN: An analysis was conducted using data from two 1-year, noncomparative clinical trials (N=1787) and a 2-year randomized study comparing DMPA-SC 104 (N=266) with DMPA intramuscular injection (DMPA-IM). Bleeding was analyzed per 30-day interval by category and number of days. Analyses also were performed for age and body mass index (BMI) subgroups and for the percentages of women shifting from bleeding/spotting to amenorrhea after each injection. RESULTS: Each study showed decreased incidence of irregular bleeding and increased amenorrhea with continued use of DMPA-SC 104. Rates of amenorrhea at Month 12 (52-64% across studies) and Month 24 (71% in the 2-year trial) were comparable with those originally reported for DMPA-IM. Changes in bleeding patterns showed no consistent differences according to age or BMI. The percentages of subjects shifting from bleeding and/or spotting to amenorrhea increased with each subsequent injection. CONCLUSION: Clinical data show that the incidence of amenorrhea increases over time with the use of DMPA-SC 104.

Adult↗
PubMed2006

Bone mineral density in women aged 25-35 years receiving depot medroxyprogesterone acetate: recovery following discontinuation.

INTRODUCTION: This 7-year, prospective, matched-cohort, clinical study evaluated the effects of intramuscular depot medroxyprogesterone acetate (DMPA) (150 mg/mL) on bone mineral density (BMD) in women aged 25-35 years. METHODS: Bone mineral density changes in new DMPA-IM users (n=248) were compared with those in women using nonhormonal contraception (n=360) for up to 240 weeks of treatment and 96 weeks of posttreatment follow-up (in subjects receiving >or=1 dose). RESULTS: At week 240 of treatment, mean percentage changes from baseline in DMPA-IM vs. nonhormonal subjects were: -5.16% (n=21) vs. +0.19% (n=65), total hip (p<.001); -5.38% (n=33) vs. +0.43% (n=105), lumbar spine (p<.001). At week 96 posttreatment, these values were: -0.20% (n=25) vs. +0.84% (n=43), total hip (p=.047); -1.19% (n=41) vs. +0.47% (n=66), lumbar spine (p=.017). CONCLUSIONS: These results show BMD declines during DMPA-IM use; following discontinuation, significant increases in BMD occur through 96 weeks posttreatment.

Adult↗
PubMed2006

Effects of the long-term use of depot medroxyprogesterone acetate as hormonal contraceptive on bone mineral density and biochemical markers of bone remodeling.

PURPOSE AND METHOD: Our objective is to evaluate the effects of the long-term use of depot medroxyprogesterone acetate (DMPA) as a method of contraception on bone mineral density (BMD) and bone remodeling. Forty women (21-44 years old) who used DMPA for contraception for <1, 1-2 and >5 years, in addition to 20 age-matched healthy women (nonusers), participated in this study. Lumbar spine BMD (LS-BMD) was measured by dual-energy X-ray absorptionmetry. Serum osteocalcin (OC), a bone formation marker, was measured by enzyme amplification sorbent immunoassay. Urinary deoxypyridinoline (DPD), a bone resorption marker, was determined by enzyme immunoassay. RESULTS: Serum OC and urinary DPD levels in women who used DMPA for <1, 1-2 and >5 years were significantly increased compared to the corresponding levels in nonusers. The increase of both biomarkers was more pronounced with longer duration of use. LS-BMD was significantly decreased in women on long-term DMPA use compared to LS-BMD in nonusers. The mean percentage decrease of LS-BMD in women who used DMPA for 1-2 and >5 years was 9% and 11.8%, respectively. LS-BMD was negatively correlated with serum OC and urinary DPD in women who used DMPA. On the other hand, LS-BMD and bone turnover were not significantly different between women who used DMPA for <1 year and nonusers. CONCLUSION: Long-term use of DMPA (>2 years) had a significant adverse effect on BMD and induced increased bone turnover, as evidenced by a significant increase in biochemical indices of bone formation and resorption. The measurement of LS-BMD and of biomarkers of bone turnover may be recommended in women aged above 40 years and who used DMPA for a long duration (2-5 years).

Adult↗
PubMed2006

Adenohypophyseal function in bitches treated with medroxyprogesterone acetate.

The aim of this study was to investigate the effects of treatment with medroxyprogesterone acetate (MPA) on canine adenohypophyseal function. Five Beagle bitches were treated with MPA (10mg/kg, every 4 weeks) and their adenohypophyseal function was assessed in a combined adenohypophyseal function test. Four hypophysiotropic hormones (CRH, GHRH, GnRH, and TRH) were administered before and 2, 5, 8, and 11 months after the start of MPA treatment, and blood samples for determination of the plasma concentrations of ACTH, cortisol, GH, IGF-1, LH, FSH, prolactin, alpha-MSH, and TSH were collected at -15, 0, 5, 10, 20, 30, and 45 min after suprapituitary stimulation. MPA successfully prevented the occurrence of estrus, ovulation, and a subsequent luteal phase. MPA treatment did not affect basal and GnRH-induced plasma LH concentrations. The basal plasma FSH concentration was significantly higher at 2 months after the start of MPA treatment than before or at 5, 8, and 11 months after the start of treatment. The maximal FSH increment and the AUC for FSH after suprapituitary stimulation were significantly higher before treatment than at 5, 8, and 11 months of MPA treatment. Differences in mean basal plasma GH concentrations before and during treatment were not significant, but MPA treatment resulted in significantly elevated basal plasma IGF-1 concentrations at 8 and 11 months. MPA treatment did not affect basal and stimulated plasma ACTH concentrations, with the exception of a decreased AUC for ACTH at 11 months. In contrast, the maximal cortisol increment and the AUC for cortisol after suprapituitary stimulation were significantly lower during MPA treatment than prior to treatment. MPA treatment did not affect basal plasma concentrations of prolactin, TSH, and alpha-MSH, with the exception of slightly increased basal plasma TSH concentrations at 8 months of treatment. MPA treatment did not affect TRH-induced plasma concentrations of prolactin and TSH. In conclusion, the effects of chronic MPA treatment on adenohypophyseal function included increased FSH secretion, unaffected LH secretion, activation of the mammary GH-induced IGF-I secretion, slightly activated TSH secretion, suppression of the hypothalamic-pituitary-adrenocortical axis, and unaffected secretion of prolactin and alpha-MSH.

Adrenocorticotropic Hormone↗
PubMed2006

Continuous versus intermittent tamoxifen versus intermittent/alternated tamoxifen and medroxyprogesterone acetate as first line endocrine treatment in advanced breast cancer: an EORTC phase III study (10863).

BACKGROUND: Continuous ligand depletion of endocrine responsive tumours may enhance resistance to therapy. Intermittent treatment with tamoxifen (T) was considered to mimic (incomplete) ligand depletion and reintroduction. Furthermore it was postulated that alternating tamoxifen with a non-cross resistant endocrine modality could (further) postpone hormone resistance. PATIENTS AND METHODS: Postmenopausal patients with advanced breast cancer who did not progress after 4 months of first line T therapy were randomised to continue T (40 mg daily) or to 2 monthly intermittent T or intermittent/alternated T and medroxyprogesterone acetate (MPA, 300 mg daily). At progression during break or during MPA, T should be reintroduced. Endpoints of the study were progression free survival (PFS), time to resistance to tamoxifen and overall survival (OS). RESULTS: Of 593 registered patients, 276 were randomised. After 8 years follow-up the median PFS for continuous T, intermittent T and intermittent/alternated T and MPA was 11.0 (8.1-15.2), 8.0 (6.2-12.4) and 10.8 (7.1-16.7) months, respectively (NS). Resistance to tamoxifen was established only in 84%, 70% and 55% of patients in the three treatment arms, respectively. The median times from randomisation to resistance to tamoxifen were 12.5 (9.1-21.1), 13.2 (8.8-19.8) and 24.0 (16.9-60.9) months, respectively (p<0.001), without translation in differences in survival times. CONCLUSION: Intermittent T or intermittent/alternated T and MPA had no impact on PFS or OS as compared with classical continuous T in patients with advanced breast cancer. Intermittent/alternated T and MPA resulted in prolonged time to resistance to T, but this might partly be due to bias by omittance of the proof of tamoxifen resistance in a high proportion of the patients in this treatment arm.

Adult↗
PubMed2004

Development and validation of a direct, non-destructive quantitative method for medroxyprogesterone acetate in a pharmaceutical suspension using FT-Raman spectroscopy.

A simple linear regression method was developed and statistically validated for the direct and non-destructive quantitative analysis--without sample preparation--of the active pharmaceutical ingredient (API) medroxyprogesterone acetate (MPA) in an aqueous pharmaceutical suspension (150 mg in 1.0 ml) using FT-Raman spectroscopy. The linear regression was modelled by plotting the highest peak intensity of the vector normalized spectral band between 1630 and 1590 cm-1 against different MPA standard suspension concentrations. At this band, no spectral interferences from additives in the suspension are observed. The validated model was used for the quantification of a commercial suspension (150 mg in 1.0 ml) of the commercialized preparations. The same standards and samples were used, respectively, for the development and validation of a simple linear regression model and for the quantitative determination by means of HPLC-with sample preparation-as described for the related substances of MPA in the Ph. Eur. IV. The quantification results obtained by the FT-Raman method corresponded with the claimed label concentration (150.01+/-0.96 mg/ml (n=6)). Applying the HPLC method, however, a systematic error was observed (157.77+/-0.94 mg/ml (n=6)). The direct FT-Raman method hence appears the most reliable for the quantification of the MPA component in suspension, compared to the HPLC method that requires sample preparation. The latter method provides a systematic error because the exact volume or density of a suspension sample is unknown. A precise isolation of fixed volumes from a suspension is rather unfeasible because of the continuous sagging of the suspended particles and their sticking to the used materials in the isolation process.

Chromatography, High Pressure Liquid↗