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PubMed1992

Depot-medroxyprogesterone acetate (DMPA) and risk of invasive squamous cell cervical cancer. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives.

To determine whether the long-acting progestational contraceptive, depot-medroxyprogesterone acetate (DMPA), alters risk of cervical cancer, 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. Information on prior use of DMPA, screening for cervical cancer, and the suspected risk factors for this disease was ascertained from interviews of 2,009 women with invasive squamous cell cervical cancer and 9,583 controls. For selected subsets of these women, a smoking history was also elicited, blood specimens were collected for measurement of antibodies against herpes simplex and cytomegaloviruses, and information on sexual behavior was obtained from interviews with their husbands. The relative risk (and 95% confidence interval) of invasive squamous cell cervical carcinoma in women who ever used DMPA was estimated to be 1.11 (0.96, 1.29). No trends in risk with duration of use or times since initial or most recent exposure were observed. These results provide reassurance that prolonged use of DMPA does not enhance risk of invasive squamous cell cervical carcinomas, even after a potential latent period of over a decade.

Adult↗
PubMed1992

Use of injectable progestin (medroxyprogesterone acetate) in adolescent health care.

To assess medroxyprogesterone acetate (DMPA) prescription practices in adolescent health care practices, an anonymous questionnaire was distributed to 160 American and Canadian physicians attending the 1991 meetings of either the Society for Adolescent Medicine or the North American Society for Pediatric and Adolescent Gynecology. Of 54 (33.7%) physicians who responded, 33 (61.1%) reported prior prescription of an injectable progestin (DMPA) as a form of birth control. Of those, 15 (45.5%) had prescribed it to 10 or more adolescents. Twelve (57%) pediatricians but only 3 (25%) gynecologists reported prescribing DMPA to 10 or more adolescents (p = 0.074). Female physicians were more likely to have prescribed DMPA to adolescents than male physicians (p = 0.009). Mental retardation was considered the strongest "potential indication" for DMPA administration by 48 physicians responding to a 5-point Likert scale. The study suggests that physicians with interest or expertise in Adolescent Medicine are using DMPA as a form of birth control for selected young women in spite of the lack of Food and Drug Administration approval. A centralized DMPA registry is suggested to monitor adverse outcomes in users.

Adult↗
PubMed1994

Toxicology of depot medroxyprogesterone acetate.

Depo-Provera (depot-medroxyprogesterone acetate or DMPA), administered either subcutaneously or intramuscularly, has undergone a thorough toxicological evaluation in a number of animal species. DMPA has been tested in short- and long-term toxicity studies in rodents, rabbits, and monkeys. It has been examined for its effects on reproduction in mice, rats, and rabbits, and for carcinogenic potential in rats, mice, beagle dogs, and rhesus monkeys. Genotoxicity tests have been performed in vitro and in vivo. This paper describes the toxicology data submitted to the US FDA in support of the New Drug Application (NDA) for Depo-Provera as well as data published in the literature. When interpreted in the light of the available pharmacokinetic information, these data demonstrate that DMPA is not significantly different from other contraceptive progestogens in its toxic and tumorigenic potential.

Animals↗
PubMed1991

Medroxyprogesterone acetate, aggression, and sexual behavior in male cynomolgus monkeys (Macaca fascicularis).

Medroxyprogesterone acetate (MPA) is used clinically to treat male sex offenders, but there are conflicting reports about its effects on aggression. To investigate these matters in a nonhuman primate, four intact male cynomolgus monkeys were studied in a testing paradigm that involved the presence of a caged, aggression-arousing stimulus male either immediately before or during a pair-test with an ovariectomized, untreated female partner. After two 4-week periods of pretreatment baseline, males received weekly injections of 40 mg MPA either alone (two 4-week treatment periods) or in combination with testosterone replacement with sc implants (one period) and additional daily injections of 2 mg testosterone propionate (two periods). MPA was then withdrawn while testosterone replacement continued (three periods). The testing paradigm was effective in maintaining aggression, especially male-male aggression, for many months. Male-male aggression increased with MPA treatment, and increased further with testosterone replacement, whereas male-female aggression tended to change in the opposite direction. As in earlier studies, MPA decreased both plasma testosterone and male sexual activity, but restoring plasma testosterone levels in treated males failed to restore their sexual activity. MPA therefore has behavioral effects that are not mediated primarily by its suppression of circulating androgens.

Aggression↗
PubMed1990

Sequential Gn-RH superagonist and medroxyprogesterone acetate treatment of uterine leiomyomata.

A group of 48 women with symptomatic leiomyomata were treated during 6 months with the short-acting Gn-RH superagonist analog buserelin. The first (group C) was followed up for an additional six months of no medication. The second (group M) was treated for 6 additional months with medroxyprogesterone acetate (MPA) at doses decreasing from 200 to 25 mg/day. Buserelin therapy significantly decreased uterine size (P less than 0.001) in all patients, the average final volume being 48.5% of the original (from 262 +/- 147 ml to 127 +/- 85.4 ml). In group C there was a significant (P less than 0.001) re-growth during the post-treatment observation period (from 120 +/- 81.0 ml to 198 +/- 77.2 ml); a significant (P less than 0.01) re-growth was also observed in group M during MPA medication (from 132 +/- 77.2 ml to 170 +/- 96.0 ml). The agonist had also a marked effect on fibroids: on average they decreased from 75.1 +/- 74.3 ml to 24.7 +/- 23.3 ml (P less than 0.025). In group C during the post-buserelin period of observation without treatment, there was a significant re-growth from 23.7 +/- 21.6 ml to 47.7 +/- 27.5 ml (P less than 0.001), whereas in group M treatment with MPA prevented any significant re-growth (from 25.6 +/- 24.8 to 30.6 +/- 32.9 ml; P greater than 0.3).

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Growth of human aortic smooth muscle cells cultured with human serum is retarded when serum lipids are lowered by medroxyprogesterone.

Human aortic smooth muscle cells were cultured in the presence of sera from 7 normolipidemic women before and after treatment with high-dose medroxyprogesterone acetate, which caused 16% and 25% decreases in serum cholesterol and HDL-cholesterol concentrations, respectively. As assessed by cell counting and by DNA determination the growth of the cells was retarded significantly in the presence of sera taken after the treatment. At the same time, there were no marked changes in the incorporation rate of [3H]proline into collagen or [3H]glucosamine into hyaluronic acid by the cells. The results indicate that: (1) the mitogenicity of human serum can be altered by drug treatment of serum donors, (2) simultaneously with a lowering of serum lipids in man in vivo, a decreased mitogenicity of sera occurs in vitro.

Aged↗
PubMed1983

Interaction of medroxyprogesterone acetate with cytosol androgen receptors in the rat hypothalamus and pituitary.

The binding of medroxyprogesterone acetate (MPA) with cytosol androgen receptors from rat pituitary and hypothalamus was studied. The pituitary and hypothalamic cytosol androgen receptors from adult castrated female rats were in vitro labeled using 3H natural (testosterone (T) and 5 alpha-dihydrotestosterone (DHT] and [3H]synthetic (methyltrienolone) androgens as radioligands. The [3H]androgen-receptor complexes sedimented with a coefficient of 8S in linear sucrose gradients. When incubated with an excess of radioinert MPA, specific binding was abolished indicating interaction of MPA with androgen receptors. Furthermore specific [3H]MPA-androgen cytosol receptor complexes could be identified in these neuroendocrine tissues when a post-gradient receptor labeling technique was used in the absence or presence of radioinert MPA, DHT, and triamcinolone acetonide. A study of binding kinetics disclosed that the equilibrium dissociation constant and saturation binding capacity for the MPA binder, were similar to those exhibited by DHT binding to androgen receptors in both studied tissues under identical experimental conditions. The overall results were interpreted as demonstrating that MPA interacts with cytosol steroid receptors other than those of progesterone in the rat hypothalamus and anterior pituitary. The data are consistent with MPA binding to androgen receptors.

Animals↗
PubMed1984

Studies on the developmental pattern of rat ovarian 3 alpha-hydroxysteroid dehydrogenase: inhibition of the postpubertal activity with medroxyprogesterone acetate in vivo.

The developmental pattern of rat ovarian 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD) activity was determined with respect to age, vaginal opening, ovarian histology and serum 5 alpha-androstane-3 alpha, 17 beta-diol (3 alpha-diol). The enzyme was assayed by the incubation of [3H]dihydrotestosterone with a portion of whole ovarian cytosol in the presence of 5 X 10(-4) M NADPH. Serum levels of 3 alpha-diol declined from 11.1 +/- 1.2 ng/ml on day 22-3.4 +/- 0.3 ng/ml on day 30 (P less than 0.01). There was no significant change in 3 alpha-HSD during that period which fluctuated from 6.0 +/- 4.0 nmol/h/organ on day 22-8.4 +/- 1.9 nmol/h/organ on day 39. A significant increase on day 42 of 21.1 +/- 6.1 nmol/h/organ occurred well after vaginal opening, corpus luteum formation and the presence of ovarian progesterone; the activity plateaued on day 49 at 31.2 +/- 3.7 nmol/h/organ. In an attempt to inhibit the developmental increase in 3 alpha-HSD activity, medroxyprogesterone acetate (MPA), known inhibitor in vitro was administered to three groups of developing rats in vivo. The administration of MPA at doses of 0.1, 1.0 and 10.0 mg/kg to 30 and 36 day did not inhibit activity when assayed on day 44. In 44-day old rats, the administration of MPA failed to inhibit 3 alpha-HSD activity at 24 h (C-21.1 +/- 2.6; 0.1 mg/kg-19.4 +/- 5.5; 1.0 mg/kg-20.7 +/- 3.7; 10.0 mg/kg-21.1 +/- 3.0 nmol/h/organ) yet there was a significant reduction of 3 alpha-HSD activity when assayed at 48 h (C-21.1 +/- 1.5; 01 mg/kg-9.6 +/- 1.3; 1.0 mg/kg-8.5 +/- 1.9; and 10 mg/kg 5.2 +/- 2.0 nmol/h/organ).

3-Hydroxysteroid Dehydrogenases↗
PubMed1985

The effects of medroxyprogesterone acetate on enzyme activities in human endometrial carcinoma.

Creatine kinase (CK), isocitrate (ICDH) and glucose-6-phosphate dehydrogenase (G-6-PD) activities and cytosol oestrogen (REc) and progestin (RPc) receptors have been measured in twenty post-menopausal subjects with endometrial carcinoma. Diagnostic curettage and hysterectomy specimens were obtained from each patient with intervening medroxyprogesterone acetate therapy (MPA). In RPc rich tumours the activity of creatine kinase was significantly increased following MPA and was attributed to an increase in the BB-isoform. There was a similar though less significant increase in ICDH activity. Neither CK nor ICDH were significantly increased following MPA therapy in progesterone receptor poor specimens. There was a small but significant increase in G-6-PD activity following MPA regardless of RPc content. REc was decreased in some but not all RPc rich tumours following MPA and the trend was significant. The highly significant increase in CK activity confirms the apparent response of this enzyme to progesterone in normal human endometrium during the menstrual cycle.

Creatine Kinase↗
PubMed1987

Medroxyprogesterone acetate: receptor binding and correlated effects on steroidogenesis in rat granulosa cells.

Medroxyprogesterone acetate (MPA), a widely used synthetic steroid, was studied to determine both its effects on steroid receptors and steroidogenesis in the well-characterized rat ovarian granulosa cell model. Initial receptor binding studies showed MPA was as potent as progesterone and 10-fold less potent than R-5020 (an active synthetic progestin) in binding to progesterone cytosolic receptors in rat ovarian granulosa cells. MPA was 20-fold less potent than testosterone, and 10-fold less potent than dexamethasone in binding to the androgen and glucocorticoid cytosolic receptors, respectively. The binding of MPA to progestrone, androgen and glucocorticoid receptors predicted direct effects of MPA on FSH-stimulated estrogen (E), progesterone (P), and 20 alpha-dihydroprogesterone (DHP) production by cultured rat ovarian granulosa cells. MPA at 10(-7) to 10(-6) M significantly augmented FSH-stimulated P and DHP production (a previously documented progestin, androgen and glucocorticoid effect). This augmentation was blocked by the concurrent addition to cell culture of 10-fold excess RU-486 (a potent anti-progestin and anti-glucocorticoid). At concentrations greater than 10(-6) M, MPA inhibited the production of P and DHP (a progestin effect), and the production of E (a progestin and glucocorticoid effect). MPA, structurally a progestin, has complex steroid hormone effects predicted by its interaction with progesterone, androgen and glucocorticoid receptors.

20-alpha-Dihydroprogesterone↗
PubMed1988

Inhibitory effects of danazol and medroxyprogesterone acetate on [3H]thymidine incorporation in human endometrial cancer cells.

Effects of medroxyprogesterone acetate (MPA) and danazol (1 nM-10 microM) on cultured cancer cells from human endometrial adenocarcinomas obtained by hysterectomy were simultaneously investigated. Of twenty-four endometrial adenocarcinomas examined, five tumors were successfully maintained in primary cell culture. The addition of MPA as well as danazol in culture of cells from the five tumors resulted in a significant inhibition of [3H]thymidine incorporation in cancer cells from three tumors having progesterone receptors (PR). The minimum effective concentrations of MPA and danazol for the inhibition of [3H]thymidine incorporation were found to be 10 and 100 nM, respectively. The difference in effective concentration could be explained by a higher affinity of MPA to PR than that of danazol in cancer cells. On the other hand, neither danazol nor MPA affected [3H]thymidine incorporation in cultured cells from the remaining two tumors, in which PR was absent in one but present in the other. These findings, together with our previous findings that danazol inhibited the growth of a human endometrial cancer cell line with PR, suggest that a growth-inhibitory effect of danazol on human endometrial cancer cells is mediated through PR in the cells.

Adenocarcinoma↗
PubMed1988

Pharmacokinetics and metabolism of medroxyprogesterone acetate in patients with advanced breast cancer.

The pharmacokinetics and metabolism of medroxyprogesterone acetate (MPA) were studied in patients with advanced breast cancer after i.v. injection and oral administration of [3H]MPA. MPA was distributed very rapidly into three compartments after i.v. injections, revealing half-lives of 4-7 h. Using a nonlinear model fitting metabolic clearance rates (MCR) were found to be 652 1/day before and 601 1/day during MPA treatment, and distribution volumes (V0) 5.9 and 3.41 respectively. The major metabolite of MPA following i.v. injection was a glucuronide of MPA, presumably of the 3-enol form. After oral administration the radioactivity in serum increased rapidly and reached a plateau of about 1% of the dose per litre serum after approx 2 h. About 80-90% of the radioactivity was found in the water phase after hexane extraction, persumably as glucuronides of metabolites more polar than MPA. Radioimmunoassay (RIA) of MPA in untreated serum samples showed 3-8-fold greater MPA values as compared to measurements in hexane extracts of serum. Ethanol extraction did not remove these interfering substances. Extraction of serum with a low polar solvent before RIA of MPA is essential in order to prevent great overestimation, as the glucuronidated polar metabolites most likely will crossreact in an assay with an antiserum raised against a MPA-3-O-carboximethyloxime coupled to bovine serum albumin.

Administration, Oral↗
PubMed1989

The effects of sequential treatment with ethynyloestradiol and medroxyprogesterone acetate on oestrogen and progestogen receptors in breast cancer.

As part of a clinical study designed to modulate oestrogen and progestogen receptor (ER and PR) binding site concentrations prior to chemotherapy ER and PR levels have been estimated immediately before treatment, after ethynyloestradiol (EE, 10 micrograms/day, 1 week) and after medroxyprogesterone acetate (MPA, 500 mg/day i.m., 2 weeks) in tumour tissue from 14 women with advanced breast cancer. There was no consistent change after EE treatment. MPA tended to decrease ER and PR levels, though some increases were also seen. Responses (10 complete and 3 partial remissions) to sequential cyclical hormono-chemotherapy were not related to ER or PR levels prior to chemotherapy.

Aged↗
PubMed1989

The effect of medroxyprogesterone acetate on aromatase and DNA polymerase alpha activities in breast tumours.

The effect of treatment with the progestogen medroxyprogesterone acetate (MPA) on the peripheral conversion of androstenedione to oestrone and tumour aromatase activity has been examined in post-menopausal women with advanced breast cancer. In addition to being a potent progestational compound, MPA also possesses glucocorticoid properties and glucocorticoids have been shown to stimulate in vitro aromatase activity. While some evidence was obtained of an increase in aromatase activity in tumour tissue after treatment with MPA, peripheral conversion of androstenedione to oestrone was similar when measured before (2.12 +/- 0.67%) and after (1.89 +/- 0.16%) treatment. DNA polymerase alpha activity, measured as a marker of cellular proliferation, decreased from 331 +/- 145 to 156 +/- 93 pmol thymidine triphosphate (TTP)/mg protein per h (P less than 0.02) in tumour samples examined before and after treatment. It is concluded that treatment with high doses of MPA has no effect on the peripheral conversion of androstenedione to oestrone but results in a significant reduction in tumour DNA polymerase alpha activity.

Aged↗
PubMed1986

Pre-optic and hypothalamic neurons accumulate [3H]medroxyprogesterone acetate in male cynomolgus monkeys.

Medroxyprogesterone acetate (MPA) is a synthetic progestin that is reported to be effective in the treatment of paraphilic behavior, including paraphilic aggression, in men. The mechanisms and sites of action for its behavioral effects are not known. Thaw-mount autoradiography was used to help identify sites in the brain at which MPA may act in a male primate. Two adult, castrated male cynomolgus monkeys were administered [3H]MPA and killed one hour later. Radioactivity was concentrated in the nuclei of many neurons in the medial preoptic nucleus (n.), anterior hypothalamic area, ventromedial hypothalamic n., and arcuate n. Virtually no labeled cells were observed in the bed n. of the stria terminalis, lateral septal n., or amygdala. Analysis by high performance liquid chromatography of brain samples from the same animals demonstrated that 84% of the extractable radioactivity in cell nuclei from the hypothalamus and preoptic area was in the form of unmetabolized [3H]MPA. The localization of MPA-concentrating neurons in regions of the brain known to be implicated in regulating both sexual behavior and pituitary function suggests that, among other sites of action, MPA may act directly upon the brain.

Animals↗
PubMed1983

High-dose depot-medroxyprogesterone acetate (DMPA) - effects on lipid and lipoprotein metabolism.

Twenty-one women were given depot-medroxyprogesterone acetate (DMPA) 1000 mg/wk for 6 mth as part of the treatment for endometrial carcinoma in either clinical stage I or II. Total and free cholesterol, triglycerides and phospholipids were analysed in serum and in the ultracentrifugally separated lipoprotein fractions VLDL, LDL and HDL (very low, low and high density lipoproteins). Previous studies have shown little effect on lipoprotein metabolism after lower doses of MPA, unlike progestins of the 19-nor-testosterone series, after which an 'androgenic' lipoprotein pattern is seen, i.e., a decrease in HDL-cholesterol and in triglycerides in serum and VLDL. After this massive DMPA dose, only a slight decrease in HDL-cholesterol was seen, as well as a rise in triglycerides in serum and VLDL. We interpret the latter finding as secondary to an influence on carbohydrate metabolism.

Aged↗
PubMed1984

Tamoxifen and medroxyprogesterone therapy for advanced endometrial carcinoma.

We have studied the response rates and survival of a group of 93 patients with Stage III or IV endometrial adenocarcinoma after random allocation to therapy with tamoxifen (TAM) 20 mg twice daily (n = 45) or medroxyprogesterone acetate (MPA) 1 g/wk intramuscularly (n = 48). The patients were examined every 4 months. In the non-responders and in those who relapsed, combination therapy with TAM and MPA was given. Twenty-four of 45 (53.4%) responded to TAM alone, 27 of 48 (56.2%) responded to MPA alone. Of the responders 23 later relapsed in the TAM group and 24 in the MPA group and of these 14 (60.8%) and 15 (62.5%), respectively, responded to the combination therapy. Of the original 21 non-responders to MPA alone, 10 responded to the combination (47.6%) and 11 (52.4%) did not; the comparable figures for the TAM alone group were 13 (61.9%) and 8 (38.1%), respectively. Survival rates were much higher in the differentiated than in the undifferentiated carcinomas. In conclusion, we feel that the efficacy, and the few side-effects of these drugs used alone and particularly when used in sequential combination, make them a very attractive treatment for advanced endometrial adenocarcinoma.

Adenocarcinoma↗
PubMedDate not supplied

Placebo-controlled comparison of hormonal and biochemical effects of danazol and high-dose medroxyprogesterone acetate.

The hormonal and biochemical effects of danazol (600 mg a day) and high-dose medroxyprogesterone acetate (MPA; 100 mg a day) were studied in a placebo-controlled, 6-month trial. Serum gonadotrophins and prolactin levels did not change during danazol and MPA treatments, whereas oestradiol and progesterone levels decreased significantly in relation to placebo without any difference between danazol and MPA. Both drugs significantly suppressed the sex hormone-binding globulin level (SHBG), and consequently, the free-androgen index (serum total testosterone nmol/l per SHBG nmol/l x 100) as compared with placebo, the effect of danazol being significantly stronger than that of MPA. Danazol, but not MPA, significantly increased serum aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT) and haemoglobin levels, and also thrombocyte counts, whereas MPA, but not danazol, increased the serum concentration of albumin in relation to placebo. Serum total bilirubin, conjugated bilirubin, gamma-glutamyl transferase, creatinine, alkaline phosphatase, sodium and potassium levels and leucocyte counts remained unchanged during both treatments. Danazol and high-dose MPA did not differ from each other in their ovarian and anterior pituitary effects, while the increase in androgenic activity induced by danazol was greater than that achieved with MPA. Danazol also had more biochemical effects than MPA. It interfered with the functions of the liver and the production of thrombocytes and haemoglobin, whereas MPA affected only albumin synthesis/release.

Adult↗