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PubMed1981

Tamoxifen and aminoglutethimide in the management of patients with advanced endometrial carcinoma not responsive to medroxyprogesterone.

Eleven patients with advanced endometrial carcinoma not responsive to medroxyprogesterone were entered into a trial of therapy with tamoxifen, aminoglutethimide or both in combination. Two patients had a complete response, 1 to aminoglutethimide and 1 to tamoxifen. One patient who initially had a partial response to tamoxifen but then relapsed, had a partial response to aminoglutethimide. Two patients had stable disease for 8 and 6 months on aminoglutethimide, and 1 patient who initially showed no response to tamoxifen has had stable disease for 14 months since addition of aminoglutethimide to therapy. The relative lack of toxicity of these drugs make their use attractive in the management of such patients.

Adenocarcinoma↗
PubMedDate not supplied

Significance of p27 as a predicting marker for medroxyprogesterone acetate therapy against endometrial endometrioid adenocarcinoma.

We reported that p27 induced by medroxyprogesterone acetate (MPA) may be involved in the progestin-induced growth suppression of human endometrial adenocarcinoma cells. This study aimed at investigating whether p27 expression could be a predicting marker to evaluate the effectiveness of MPA therapy. The clinical responses of 15 patients with endometrial carcinoma treated with MPA were examined. p27 expression was evaluated by immunohistochemical staining. Percentage of positive nuclear staining was expressed as a strongly positive (SP) labeling index (LI). Before MPA treatment, SP LIs in the effective and noneffective groups were 22.6 +/- 14.3% and 9.1 +/- 9.2%. At 1-6 weeks in the MPA treatment, SP LIs increased in both groups and were significantly higher than those before the therapy. At 7-12 weeks, SP LIs in both groups decreased to the level of pretherapy. At 13-18 weeks, SP LIs in the effective group were 14.9 +/- 5.7%, whereas in the noneffective group, 1.1 +/- 2.0%. The former was significantly higher than the latter. p27 expression could predict the effectiveness of MPA treatment for endometrial carcinoma at an early stage of the 4-month period in MPA therapy and could be a useful predicting marker for MPA.

Adult↗
PubMed1988

Treatment of sex offenders with imaginal desensitization and/or medroxyprogesterone.

Thirty sex offenders were randomly allocated: 10 to receive medroxyprogesterone therapy (M), 10, imaginal desensitization (ID) and 10 both (ID + M). Twenty-four responded for one year though 3 subsequently relapsed. There were no significant differences in response to the 3 treatments. Four patients who did not respond to the initial treatment and the 3 who relapsed responded to further treatment. Most treated with M maintained heterosexual intercourse at pretreatment frequency. Self-reported reduction in anomalous sexual urges in patients receiving M correlated with reduced testosterone levels one month following treatment, demonstrating that the response was specific and validating the assessment by patients' self-reports. Where cost-effectiveness or time constraints are factors influencing treatment of sex offenders, one of these therapies warrants consideration.

Adolescent↗
PubMed1997

A population-based case-control study of canine mammary tumours and clinical use of medroxyprogesterone acetate.

We investigated whether or not an association could be found between mammary tumours and prior clinical use of medroxyprogesterone acetate (MPA) in bitches. A population-based retrospective age-matched case-control study was designed based on interviews with the owners of the bitches. The proportion of bitches with diagnosed mammary tumours (group MT+, n = 98) that had received progestin injections was compared with the proportion in a control group without mammary tumours (group MT-, n = 98). In the case group 39%, and in the control group 21% of the bitches had been treated with MPA. A significantly higher number of bitches with mammary tumours had been exposed to progestins, compared with the control group without mammary tumours (odds ratio = 2.32, Chi-square = 7.01, p = 0.008). Bitches treated clinically with low doses of MPA to avoid oestrus were at a greater risk of developing mammary tumours, the majority of which were histologically malignant (91%).

Age Factors↗
PubMed2004

Bone mineral density in adolescent women using depot medroxyprogesterone acetate.

PURPOSE: To present current data on bone mineral density (BMD) in adolescent women using the long-acting contraceptive depot medroxyprogesterone acetate (DMPA) and also to discuss the importance of developing maximal bone mass during adolescence to offset bone demineralization later in life. DATA SOURCES: Research-based articles in the medical literature, review articles, and recommendations from the American Academy of Pediatrics and the National Osteoporosis Foundation. CONCLUSIONS: Osteoporosis is a preventable disease that affects millions of Americans, particularly older women. Factors influencing the attainment and maintenance of peak bone mass during childhood and adolescence affect the future risk of fractures. Although longitudinal studies conducted on adolescent women using DMPA are very limited, findings suggest that adolescents are losing bone density during a time of expected bone accretion. IMPLICATIONS FOR PRACTICE: Clinicians must consider all the risks and benefits when prescribing contraceptives to adolescents. By themselves, the findings related to BMD and DMPA use by adolescents are not sufficient to limit the use of DMPA as a contraceptive method. However, clinicians must take into account the addition of other modifying factors associated with BMD that may contribute to overall bone loss in adolescent females. More prospective data on the long-term use of DMPA by adolescents are needed to determine DMPA's effect on bone loss and to determine if bone loss is transient in adolescents.

Adolescent↗
PubMed1993

The relationship between the prevalence of uterine lesions and the use of medroxyprogesterone acetate for canine population control.

The prevalence of uterine disease was established during desexing of 175 bitches in the Torres Strait and Cape York, 42 of which had been treated with injectable medroxyprogesterone acetate (MPA) for oestrus postponement. The prevalence of uterine lesions was 45% for treated bitches, 5% for untreated bitches, and 14.9% for the sample population. A highly significant relationship (P < 0.01) between MPA treatment and uterine lesions was established. A significant association (P < 0.05) between age (> 2 years old) and uterine lesions was found, most likely attributable to a significantly higher proportion (P < 0.01) of MPA-treated bitches in the older population. There was no significant difference in the effect of MPA on the prevalence of uterine lesions between older and younger bitches. There was no effect of parity on the prevalence of uterine lesions.

Animals↗
PubMed2005

Medroxyprogesterone acetate binds the glucocorticoid receptor to stimulate alpha-ENaC and sgk1 expression in renal collecting duct epithelia.

Medroxyprogesterone acetate (MPA), a widely used synthetic progestational contraceptive, occasionally leads to Cushingoid side effects such as hypertension, fluid retention, and centripetal obesity. We investigated the effect of MPA on classic mineralocorticoid target genes, alpha-epithelial Na channel (ENaC) and sgk1, in the collecting duct. In adrenalectomized mice, aldosterone, dexamethasone, and MPA increased alpha-ENaC mRNA levels in kidney cortex. MPA and dexamethasone, but not progesterone, dose dependently increased alpha-ENaC and sgk1 mRNA in M-1 and in Madin-Darby canine kidney-C7 cells, both collecting duct cell lines. The stimulatory effect of MPA and dexamethasone on alpha-ENaC expression was inhibited by RU-38486, a combined glucocorticoid receptor (GR) and progesterone receptor (PR) antagonist, but not by Org31710, a pure PR antagonist. MPA and dexamethasone dose dependently increased alpha-ENaC promoter-driven luciferase activity in M-1 cells, which was not inhibited by Org31710, indicating that MPA regulates alpha-ENaC in a PR-independent manner. When tested in HT29 cells, MPA could only stimulate alpha-ENaC-driven reporter activity when GR was coexpressed, confirming the requirement for functional GR in the transcriptional effect of MPA. The activation of steroid receptors such as GR can explain the apparent glucocorticoid effects of MPA, independent of PR activation.

5' Flanking Region↗
PubMed1978

Ventilatory response to medroxyprogesterone acetate in normal subjects: time course and mechanism.

The time course of ventilatory adaptation to medroxyprogesterone acetate (MPA) and potential mediators of this response in plasma and lumbar CSF were determined in five healthy adult males. A significant decrease in arterial PCO2 (PACO2) at rest and exercise was noted within 48 h of drug administration with the maximum effect reached within 7 days and amounting to a 5-Torr decrement in PACO2. Blood and lumbar cerebrospinal fluid pH because significantly alkaline to control as soon as the ventilatory resporse was noted and remained alkaline during the treatment period. The ventilatory and dP/dt max response to exogenous CO2 was unchanged but their response to moderate exercise was increased after MPA. MPA-rlated materials were detected in both the plasma and CSF as soon as the ventilatory response was noted. The increase in CSF MPA-related materials approximated the unbound fraction determined in plasma. We conclude that [H+] in plasma and CSF is a function rather than a cause of ventilator acclimatization to MPA. MPA-related materials are capable of crossing the blood-brain barrier and could potentially exert their ventilatory stimulant effect by some central mechanism.

Adult↗
PubMed2005

Decreased androgen receptor levels and receptor function in breast cancer contribute to the failure of response to medroxyprogesterone acetate.

Previously, we reported that androgen receptor (AR), but not estrogen receptor (ER) or progesterone receptor (PR), is predictive of response to the synthetic progestin, medroxyprogesterone acetate (MPA), in a cohort of 83 patients with metastatic breast cancer. To further investigate the role of AR in determining response to MPA in this cohort, we analyzed AR levels by immunohistochemistry with two discrete antisera directed at either the NH2 or the COOH termini of the receptor. Compared with tumors that responded to MPA (n = 31), there was a significant decrease in the intensity and extent of AR immunoreactivity with both AR antisera in tumors from nonresponders (n = 52). Whereas only a single AR immunostaining pattern was detected in responders to MPA, reflecting concordance of immunoreactivity with the two AR antisera, tumors from nonresponders exhibited four distinct AR immunostaining patterns: (a) concordance with the two antibodies (31%), (b) staining only with the COOH-terminal antibody (33%), (c) staining only with the NH2-terminal antibody (22%), or (d) no immunoreactivity with either NH2- or COOH-terminal antibody (14%). DNA sequencing and functional analysis identified inactivating missense gene mutations in the ligand-binding domain of the AR in tumors from two of nine nonresponders positive with the NH2-terminal AR antisera but negative for COOH-terminal immunoreactivity and lacking specific, high-affinity dihydrotestosterone binding in tumor cytosol fractions. Tumors with more AR than the median level (37 fmol/mg protein) had significantly lower levels of PR (30 fmol/mg protein) than tumors with low AR (PR; 127 fmol/mg protein) despite comparable levels of ER. Ligand-dependent activation of the AR in human T47D and MCF-7 breast cancer cells resulted in inhibition of estradiol-stimulated cell proliferation and a reduction in the capacity of the ER to induce expression of the PR. These effects could be reversed using a specific AR antisense oligonucleotide. Increasing the ratio of AR to ER resulted in a greater androgen-dependent inhibition of ER function. Collectively, these data suggest that reduced levels of AR or impaired AR function contribute to the failure of MPA therapy potentially due to abrogation of the inhibitory effect of AR on ER signaling.

Animals↗
PubMed1998

Effects of Ringer's lactate, medroxyprogesterone acetate, gonadotropin-releasing hormone analogue and its diluent on the prevention of postsurgical adhesion formation in rat models.

Fifty adult female rats were randomly divided into five groups. Before the standard surgical procedure which consisted of creating a lesion with electrocautery over the uterus, leuprolide acetate (LA) together with its diluent, the diluent alone and medroxyprogesterone acetate (MPA) were injected to the third, fourth, and fifth groups, respectively. Ringer's lactate (RL) solution was applied intraperitoneally to the second group at the end of the surgery. Group I received no medication. Relaparotomy was performed 3 weeks later to evaluate the adhesions. The mean adhesion scores were (mean +/- SD) 2.6 +/- 0.7, 1.4 +/- 0.8, 0.9 +/- 0.6, 2.3 +/- 0.8, and 0.8 +/- 0.6 in groups I, II, III, IV, and V, respectively. The postsurgical adhesions were significantly less in the groups treated with RL, LA, and MPA.

Animals↗
PubMed1999

Carboplatin, methotrexate and 5-fluorouracil in combination with medroxyprogesterone acetate (JMF-M) in the treatment of advanced or recurrent endometrial carcinoma: A Hellenic cooperative oncology group study.

Twenty-three patients with advanced or recurrent endometrial carcinoma entered a prospective study of chemotherapy which consisted of carboplatin (300 mg/m2), methotrexate (30 mg/m2), and 5-fluoruracil (500 mg/m2) given on day 1, in a 3-weekly schedule, in combination with medroxyprogesterone acetate (MPA): 300 mg daily, p. o., until progression (JMF-M regimen). None had received prior chemotherapy and/or hormonotherapy for metastatic disease. Ten patients had received radiotherapy. Response to treatment was evaluated every two courses. Objective response was seen in 17 of the 23 patients (74%, 95% confidence interval = 52-90%), with 2 long-lasting complete responses (9%). The median response duration was 10+ months (3-45+). The median survival was 16+ months (2-45+). The 2 complete responders, the first in the lung and the second in groin nodes, are without evidence or recurrence after 32 and 45 months, respectively. The regimen was given on an outpatient basis and was well tolerated. The major toxic effects were myelosuppression (less than 14% leukopenia, anemia and thrombocytopenia). The MPA-related side effects were: weight gain (22%), hypertension (17%) and thromboplebitis (17%). In 2 patients, consolidation treatment with MPA was discontinued because of thromboplebitis. In conclusion, the JMF-M regimen is highly active with an acceptable toxicity in patients with recurrent or metastatic endometrial carcinoma.

Adult↗
PubMed1999

A randomized controlled comparative study of oral medroxyprogesterone acetate 1,200 and 600 mg in patients with advanced or recurrent breast cancer.

A randomized controlled comparative study of oral medroxyprogesterone acetate (MPA) 1,200 mg (arm I) and 600 mg (arm II) was conducted in 80 patients with advanced or recurrent breast cancer. There were no significant differences between arm I and arm II in terms of response rate, duration of response and survival, or in terms of incidence and severity of adverse reactions. The lowest serum MPA concentration in responders tended to be higher than that in nonresponders. In the cohort of this study, the lowest concentration in partial response was 17.4 ng/ml, suggesting that this level may be the required minimum serum concentration.

Antineoplastic Agents, Hormonal↗
PubMed2000

An analysis of serum interleukin-6 levels to predict benefits of medroxyprogesterone acetate in advanced or recurrent breast cancer.

Treatment of advanced or recurrent breast cancer with medroxyprogesterone acetate (MPA) shows high response rates and the accessory effects of appetite stimulation, improvement in performance status (PS) and bone marrow protection. In recent years, interleukin-6 (IL-6) has been reported to cause cachexia. In this study, to clarify the significance of IL-6 in advanced or recurrent breast cancer, the relationship between the IL-6 level and clinical findings or effect of MPA was investigated. Sixty-five patients with recurrent or advanced breast cancer participated in a prospective study. The age of patients ranged from 28 to 79 years with an average age of 51.3 years. IL-6 level was investigated in these patients dosed with 800 mg/day of MPA and in 17 postoperative nonrecurrent patients. Serum MPA level was measured by high-performance liquid chromatography and IL-6 level was measured prior to MPA administration, 4 weeks (in 59 cases) and 12 weeks (in 32 patients) after MPA administration by ELISA. Serum IL-6 level was significantly higher in recurrent cases, especially in those with visceral metastasis. Further, in patients for whom MPA therapy was effective, the IL-6 level prior to the treatment was clearly low. The IL-6 level was significantly increased after 4 weeks. However, response to MPA was significantly higher and PS was improved in those cases demonstrating less increased IL-6 levels after 4 weeks. In addition, the effect of MPA was significantly related to a higher serum concentration of MPA-positive ER, and longer disease-free interval, although there was no significant predictive factor for the clinical effect of MPA therapy in multivariate analysis. In conclusion, MPA therapy was effective in cases demonstrating a low IL-6 level and less increased IL-6 levels after 4 weeks. PS was improved in those cases in which the degree of IL-6 increase was suppressed by MPA, and many such cases showed low IL-6 levels prior to MPA therapy. Furthermore, PS was improved even in nonresponders to MPA. Therefore, it is suggested that MPA therapy might be useful in treating recurrent breast cancer, and its benefits might be mediated by IL-6.

Adult↗
PubMed2001

Autophagy and nuclear changes in FM3A breast tumor cells after epirubicin, medroxyprogesterone and tamoxifen treatment in vitro.

OBJECTIVE: Autophagy is a form of physiological programmed cell death which is observable after hormonal withdrawal. In this study, the FM3A murine breast tumor cell line was treated with epirubicin alone and with medroxyprogesterone acetate (MPA) or tamoxifen, to determine if structural and kinetic signs of autophagy may also occur in an enhanced manner during epirubicin sensitization via hormonal agents. METHODS: One-week soft agar colony growth, 96-hour values of plating and pulse thymidine labeling and electron microscopical examinations were performed following treatment with MPA and tamoxifen alone or with epirubicin. RESULTS: Tamoxifen induced signs of autophagy, which was enhanced when it was combined with MPA. Epirubicin also induced autophagy of secretory granules, which coalesced to form an intracytoplasmic lumen. Combining MPA with epirubicin enhanced the formation of apoptotic blebs and chromatin fragmentation. When epirubicin was combined with tamoxifen, peculiar nuclear structures were formed. CONCLUSIONS: Hormonal agents may modulate anthracycline activity towards specific patterns in eliciting cell death, via autophagy and/or as yet unknown nucleolus-specific interactions.

Antibiotics, Antineoplastic↗
PubMed2001

Efficacy of every-other-day administration of conjugated equine estrogen and medroxyprogesterone acetate on gonadotropin-releasing hormone agonists treatment in women with endometriosis.

We performed a randomized controlled study to determine the efficacy of add-backed therapy by every-other-day administration of 0.625 mg conjugated equine estrogen (CEE) and 2.5 mg medroxyprogesterone acetate (MPA) on GnRH agonists (GnRH-a) treatment in Japanese women with symptomatic endometriosis. At the end of treatment, serum estrone and estradiol levels in the add-back group (n = 11) were significantly higher than those in the control group (n = 10). The assessment of Beecham classification by bimanual examination, serum CA-125 levels, and the frequency of genital bleeding revealed no significant differences between the two groups. The add-back group showed reduced Kupperman indices relative to those of the control group, and could prevent the loss of bone density. These findings led to a conclusion that GnRH-a therapy added back by every-other-day administration of 0.625 mg CEE and 2.5 mg MPA was a safe and effective treatment for Japanese women with endometriosis.

Adult↗
PubMed2003

The effects of Medroxyprogesterone acetate on apoptosis of CD34+ cells.

BACKGROUND: Medroxyprogesterone acetate (MPA) is widely used in oncology practice, especially in the treatment of gynecological malignancies and cachexia of cancer. Some studies have demonstrated that high-dose MPA might reduce hematological toxicity in patients receiving chemotherapy for solid tumors. The underlying mechanism of this action is still unknown. We aimed to investigate the in vitro effects of MPA on CD34+ cells. METHODS: We investigated the in vitro effects of two different doses of MPA (10 and 100 ng/ml) on acidic pH-induced apoptosis of CD34+ cells derived from 12 healthy volunteers. RESULTS: Compared with the control group, we found that MPA at the dose of 100 ng/ml has a negative effect on apoptosis (6.7 +/- 3.8 and 12.5 +/- 5.0% apoptosis, respectively; p = 0.038) and a positive effect on the number of CD34+ cells (680 +/- 294 and 350 +/- 131 x 10(3)/ml, respectively; p = 0.009). CONCLUSION: Our results indicate that further studies are needed on larger populations in order to assess the relationship between MPA and its myeloprotective effect.

Antigens, CD34↗
PubMed2006

Progesterone and medroxyprogesterone acetate effects on central and peripheral allopregnanolone and beta-endorphin levels.

The increased use of hormonal therapies has led to the study of the properties of different progestin molecules and their effects on the central nervous system. The central and peripheral levels of neurosteroid allopregnanolone and the opioid peptide beta-endorphin (beta-END) are regulated by estrogens. The aim of the present study was to investigate the effects of a 2-week oral treatment with micronized progesterone or medroxyprogesterone acetate (MPA) alone or in addition to estradiol valerate (E2V) on central and peripheral allopregnanolone and beta-END levels in ovariectomized (OVX) female rats. Thirteen groups of Wistar OVX rats received one of the following treatments: oral progesterone (2, 4 or 8 mg/kg/day); oral MPA (0.05, 0.1 or 0.2 mg/kg/day); E2V (0.05 mg/kg/day); E2V + progesterone (0.05 mg/kg/day + 2, 4 or 8 mg/kg/day), or E2V + MPA (0.05 mg/kg/day + 0.05, 0.1 or 0.2 mg/kg/day) for 14 days. One group of fertile and one group of OVX rats were used as controls. The concentration of allopregnanolone was assessed in the frontal and parietal lobes, hypothalamus, hippocampus, anterior pituitary, adrenals and serum, while the beta-END content was assessed in the frontal and parietal lobes, hypothalamus, hippocampus, anterior and neurointermediate pituitary, and plasma. E2V administration reverted the ovariectomy-induced reduction in allopregnanolone and beta-END. Progesterone and MPA increased allopregnanolone levels in all tissues except in the adrenal gland. The combined administration of progesterone or MPA and E2V determined a further increase in allopregnanolone levels with respect to E2V alone except in the adrenal gland and hippocampus only after MPA treatment. Progesterone did not affect beta-END levels in the frontal and parietal lobes, hippocampus and anterior pituitary, while it caused an increase plasma, hypothalamic and neurointermediate pituitary beta-END levels. MPA only affected beta-END levels in the hippocampus and in the neurointermediate lobe. The combined administration of progesterone or MPA and E2V did not alter the effect of estradiol or it determined a further dose-dependent increase in beta-END levels. In conclusion, this study demonstrates that progesterone and MPA have a similar but not identical effect on central and peripheral allopregnanolone and beta-END levels. Their association with an estrogenic compound does not interfere with the positive effects produced by estrogen on allopregnanolone and beta-END brain content.

Administration, Oral↗
PubMed1984

Effects of medroxyprogesterone acetate on hepatic glucose metabolism and microsomal enzyme activity in rats with normal and altered liver.

Effects of medroxyprogesterone acetate (MPA) on hepatic glucose handling and drug metabolism were investigated in female rats with intact and damaged liver. Hepatic glucose-6-phosphatase activity, glycogen content and fasting blood glucose were assessed as indices of glucose metabolism. Cytochrome P-450 content and NADPH-cytochrome P-450 reductase activity were assayed to reflect liver drug metabolism. Liver injury was induced by dimethylnitrosamine and carbon tetrachloride. The results demonstrate that hepatic glucose handling and drug metabolism were changed in a parallel fashion in intact, damaged and induced liver. The MPA-induced changes in glucose metabolism were slight in intact animals, whereas the compound has an increasing effect on glucose and drug metabolism in rats with damaged liver. The findings demonstrate the MPA enhances the normallization of hepatic glucose and drug metabolism in damaged liver.

Animals↗