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Effect of medroxyprogesterone acetate on the quality of life of the oncologic patient: a multicentric cooperative study.

Anorexia and cachexia, major problems in patients with cancer, lead to decreased caloric intake and weight loss. Successful treatment of these conditions has a positive effect on patients' quality of life. Among the pharmacologic treatments, partial effects have been observed following administration of corticosteroids, anabolizing drugs and synthetic progestogens such as megestrol acetate and medroxyprogesterone acetate (MPA). The aim of the present study was to evaluate whether MPA is able to influence the quality of life of neoplastic patients undergoing different chemotherapeutic regimens and/or radiotherapy for different tumor types. A series of 279 cancer patients undergoing either chemotherapy and/or radiotherapy treatment for different tumor types was randomly allocated to receive either MPA or no treatment. We explored the effect of MPA oral suspension at the daily dose of 1000 mg for 12 weeks (group A) or no treatment (group B). Our data show an increase of body weight in group A patients and improvement in performance status. The outcome of the present study strongly demonstrates that therapy with MPA plays a fundamental role in ameliorating the complex symptomatology of cancer patients in intermediate or advanced stage of the disease undergoing casual treatment with chemotherapy and/or radiotherapy.

Adult↗

Mifepristone for the prevention of breakthrough bleeding in new starters of depo-medroxyprogesterone acetate.

Depo-medroxyprogesterone acetate (DMPA) is an effective injectable contraceptive with worldwide availability. However, it is associated with a high incidence of breakthrough bleeding (BTB) during the first 6 months of use which often leads to discontinuation. Mifepristone is a progesterone receptor antagonist that has been demonstrated to decrease BTB caused by the levonorgestrel subdermal implant (Norplant). The purpose of this study was to determine if mifepristone would decrease BTB in new starters of DMPA. Twenty regularly cycling women who were new starters of DMPA were randomized to receive 50 mg of mifepristone or placebo every 2 weeks for 24 weeks. Percent days of BTB and number of cycles with bleeding intervals > or =8 and > or =14 days were evaluated using daily bleeding diaries. Ovulation was determined by measuring thrice-weekly urinary metabolites of estrogen and progesterone. Endometrial concentrations of ER and PR were determined by immunohistochemistry. Mifepristone significantly decreased the percent days of BTB and the number of cycles with prolonged bleeding intervals when compared to placebo. No subject ovulated in either group. ER immunostaining increased and PR immunostaining decreased after mifepristone treatment. In conclusion, a 50 mg dose of mifepristone taken every 2 weeks decreases the incidence of BTB in new starters of DMPA. This effect may be due to modulation of endometrial estrogen and progesterone receptors.

Adult↗

Genotoxic potential of medroxyprogesterone acetate in cultured human peripheral blood lymphocytes.

Medroxyprogesterone acetate was studied at three different concentrations (1, 5 and 10 microM), for its genotoxic effects in human peripheral blood lymphocyte culture using chromosomal aberrations and sister chromatid exchanges as parameters. Duplicate peripheral blood cultures were treated with three different concentrations (1, 5 and 10 microM) of medroxyprogesterone acetate. The study was carried out both in the absence as well as in the presence of metabolic activation (S9 mix) with and without NADP. Medroxyprogesterone acetate was found genotoxic at 5 and 10 microM in the presence of S9 mix with NADP. To study the possible mechanism of the genotoxicity of medroxyprogesterone acetate, superoxide dismutase and catalase at different doses were used separately and in combination with 10 microM of medroxyprogesterone at different doses in the presence of S9 mix with NADP. Superoxide dismutase treatment results in an increase of the genotoxic damage but catalase treatment reduce the genotoxic damage of medroxyprogesterone acetate. Catalase treatment in combination with superoxide dismutase also results in the further reduction of the genotoxic damage. The results of the present study reveal that medroxyprogesterone acetate is genotoxic only in the presence of metabolic activation (S9 mix) with NADP. Treatments with superoxide dismutase and catalase suggests the possible generation of reactive oxygen species by redox cycling of various forms of quinones, similar to estrogens, that are the results of aromatic hydroxylation by cytochrome P450s.

Antioxidants↗

Decline in bone mineral density with stress fractures in a woman on depot medroxyprogesterone acetate. A case report.

BACKGROUND: Depot medroxyprogesterone acetate is a popular contraceptive among young, physically active women. However, its administration has been linked to a relative decrease in estrogen levels. Since bone resorption is accelerated during hypoestrogenic states, there has been growing concern about the potential development of osteoporosis and fractures with the use of this contraceptive method. CASE: A physically active, 33-year-old woman demonstrated a 12.4% drop in femoral neck bone mineral density (BMD), 6.4% drop in lumbar BMD and 0.8% drop in total BMD with the subsequent development of a tibial stress fracture while on depot medroxyprogesterone acetate. Bone mineralization rapidly improved, and the stress fracture resolved with discontinuation of the medication. CONCLUSION: The long-term effects of depot medroxyprogesterone acetate on bone mineralization in physically active women should be evaluated more thoroughly.

Adult↗

The effect of medroxyprogesterone acetate on premature labor in the sheep.

The ability of medroxyprogesterone acetate to delay premature delivery was investigated in nine chronically catheterized pregnant sheep (125 to 130 days' gestation). Catheters were placed for measurement of intrauterine pressure and uterine vein concentrations of progesterone, 17 beta-estradiol, and 15-keto-13,14-dihydroxyprostaglandin F2a. Premature parturition was induced in all animals by infusion of dexamethasone (1 mg/24 hours) to the fetus. Three ewes served as controls, three ewes received oral medroxyprogesterone acetate (5 mg/kg/day) 48 hours prior to the start of and during dexamethasone (early medroxyprogesterone acetate), and the remaining three animals received oral medroxyprogesterone acetate 12 hours after the onset of dexamethasone infusion (late medroxyprogesterone acetate). The lengths of time from dexamethasone until the onset of labor and from dexamethasone until delivery were compared, and were significantly longer for each group compared to control times. Of all endocrine events analyzed, the fall in plasma progesterone was the most consistent in all groups, showing that animals with rapid falls in progesterone levels (control group) tended to deliver earlier. These results demonstrate that medroxyprogesterone acetate can delay premature parturition in the sheep. Also medroxyprogesterone acetate appears to delay the endocrinologic events that normally occur at this time.

Animals↗

Effect of antiandrogens and medroxyprogesterone acetate on testicular morphometry in mice.

Administration to albino mice of cyproterone (C), cyproterone acetate (CA) and medroxyprogesterone acetate (MPA) for one week produced a marked decrease in volume, surface area and length of the seminiferous tubules besides inhibiting spermatogenesis. This response was elicited by all the three treatments but was assessed as mild in "C", moderate in "MPA" and severe in "CA" groups. On the basis of present work it is concluded that inhibition of spermatogenesis occurred even with low dose schedule of the two antiandrogens and MPA. The possible mechanism of action has been discussed in the light of available literature.

Androgen Antagonists↗

Evaluation of oral medroxyprogesterone acetate in the treatment of endometriosis.

Medroxyprogesterone acetate was administered orally at the daily dose of 50 mg for four months to 21 symptomatic women with moderate to severe endometriosis, staged according to the American Fertility Society classification. The efficacy of the therapy was evaluated prospectively by the patients' symptomatology, monthly pelvic examinations, and by restaging the disease at second-look laparoscopy during the last week of treatment. The effects of therapy on the serum gonadotropin and ovarian steroid levels and on the endometrium and the implants of endometriosis were also evaluated. Improvement of symptoms, pelvic nodularity, and tenderness occurred in 80% of the patients. The mean stage score of disease by the American Fertility Society classification decreased from 18.2 +/- 2 before therapy to 5.9 +/- 1 after therapy (P less than .005). Amenorrhea, breakthrough bleeding, and persistent cyclic bleeding occurred in 75, 20, and 10% of the patients, respectively. Ovulation was inhibited in all patients, but serum hormone changes were statistically significant only for LH, which decreased from 9.5 +/- 4 to 5.2 +/- 2 IU/L (P less than .001), and estradiol (E2), which decreased from 80 +/- 30 to 46 +/- 26 pg/mL (P less than .02). Atrophic changes and pseudodecidualized reaction occurred in both the endometrium and the implants of endometriosis. In summary, oral medroxyprogesterone acetate is effective in relieving symptoms and objectively improving endometriosis. Besides inducing a pseudodecidualized reaction and atrophic changes in the endometrium and ectopic implants, medroxyprogesterone acetate also suppresses ovulation and the serum levels of both LH and E2.

Administration, Oral↗

[Comparative study between estradiol valerate combined with cyproterone acetate, and conjugated equine estrogens combined with medroxyprogesterone acetate as hormone replacement therapy in climacteric].

OBJECTIVE: To compare the effectiveness in the control of climacteric symptoms, the tolerability and the uterine bleeding pattern between two types of hormone replacement therapy. MATERIAL AND METHODS: 81 postmenopausal women between 40 and 60 years age with vasomotor symptoms were studied. Randomly it was administered: I. Conjugated equine estrogens (CEE)-Medroxyprogesterone acetate (MPA): 21 tablets with 0.625 mg of CEE and 10 tablets with 5 mg of MPA which were taken with the last ten tablets of CEE in each cycle (n = 3 7). II. E2V-CPA: 11 tablets with 2 mg of E2V and 10 tablets with 2 mg of E2V and 1 mg of CPA (n = 44). Each cycle comprised 28 days. The treatments were compared with squared Chi and Mann-Whitney U test. RESULTS: The hot flushes presence was significantly greater in the group with CEE-MPA (p < 0.03). Severe throbs at the end of the study had a trend to be more frequent in the group with EC-MPA (p < 0.06). At the end of the study there was a greater frequency of breast tenderness in the group with CEE-MPA (P = 0.009). CONCLUSIONS: Both treatments have good effectiveness, tolerability and same bleeding pattern. Only the frequency of hot flushes, the presence of severe throbs and breast tenderness were lower in the group with E2V-CPA, that makes this preparation an option that can have a better acceptance by the women.

Adult↗

Antiproliferative effect of leuprorelin acetate, alone or combined with tamoxifen or medroxyprogesterone acetate, on human breast cancer cell lines.

We have investigated the antiproliferative action of leuprorelin acetate (TAP-144) on human breast cancer cells, cultured in medium supplemented with charcoal-treated fetal calf serum. The analogue had no effect on cell growth of oestrogen receptor-negative MDA-MB-231 cells. Although ineffective when used alone, TAP-144 inhibited in a dose-dependent fashion the oestradiol-induced cell growth in oestrogen receptor-positive and oestrogen-sensitive MCF-7, ZR-75-1 and CG-5 cells. TAP-144 did not modify the growth inhibitory activity of tamoxifen on CG-5 cells. A high concentration of TAP-144 (10(-6) M) seemed to increase the antioestrogenic effect of medroxyprogesterone acetate (MPA) (10(-7) M) in the same model. The data reported indicate that, in our culture conditions, TAP-144 has a direct antitumour effect on breast tumour cells. Our findings concerning the promotion of the antiproliferative effect of MPA merit further investigation.

Antineoplastic Agents↗

[The weakest link: medroxyprogesterone acetate in pig feed].

Medroxyprogesterone acetate (MPA)-contaminated feed arrested the onset of farrowing, and induced post-lactational anoestrus in sows. Sixty percent of the sows developed cystic ovaries after weaning following exposure to pharmaceutical waste of MPA in glucose syrup. This waste ended up in acidified feed of by-products of a sow farm, and proved to be the cause of the disorders. Analysis by thin layer chromatography and Gas Chromatography/Mass Spectrometry of renal fat from 10 slaughter sows demonstrated residues of 2.5-8 ppb of MPA. Within the European Union use of MPA is illegal as growth promoter in production animals, and therefore MPA-exposed farms were placed under official control by the general inspection service. Clinical signs and diagnostic procedures of the initial case are presented and the role of the veterinary practitioner in detecting potential food safety hazards is discussed.

Anestrus↗

Endometrial progesterone and estrogen receptors and bleeding disturbances in depot medroxyprogesterone acetate users.

BACKGROUND: Depot medroxyprogesterone acetate (DMPA) is a very popular hormonal contraceptive. Unpredictable bleeding disturbances are the main reasons for discontinuation and may be mediated through endometrial hormone receptors. This study was aimed to compare the expression of progesterone and estrogen receptors in the endometrium of bleeding DMPA users with that of amenorrhoeic DMPA users. METHODS: Subjects were recruited between April 2000 and January 2001. On the day of the third DMPA injection, 42 amenorrhoeic DMPA users and 42 DMPA users who had frequent or prolonged endometrial bleeding and were bleeding on that day were matched by age and body mass index. Endometrial biopsies were collected for immunohistochemical study of progesterone receptor A plus B (PRAB) and B alone (PRB) and estrogen receptor alpha (ERalpha) and beta (ERbeta) expression. RESULTS: There were 23 adequate endometrial samples from each group. There were no differences in any of a series of comparisons of PRAB, PRB, ERalpha and ERbeta expression in glands or stroma between the groups. Serum estradiol and progesterone levels were also not different between the groups. CONCLUSIONS: Endometrial PRAB, PRB, ERalpha and ERbeta expression in glands and stroma was not different between DMPA users who had frequent or prolonged bleeding and amenorrhoeic DMPA users.

Adult↗

Initiation of parturition and lactation in the sow: effects of delaying parturition with medroxyprogesterone acetate.

The synthetic progestagen, medroxyprogesterone acetate (MPA), was administered to sows in late pregnancy with the objective of slightly delaying the time of farrowing and thereby providing more marked associations between hormonal changes and the termination of pregnancy, and the initiation of farrowing and lactation in this species. MPA was administered orally (140 mg, twice daily) to eight sows in late pregnancy on days 112, 113 and 114 of gestation. Parturition was then induced to occur on day 116 by injecting 200 micrograms cloprostenol i.m. on day 115 of gestation. The peripartum changes in the plasma concentrations of progesterone, cortisol, oestradiol-17 beta, relaxin, prolactin, lactose and 13,14-dihydro-15-keto prostaglandin F2 alpha (PGFM) were measured in these sows together with a group of untreated sows. The gestational length for the MPA-treated sows (116.3 +/- 0.3 days, mean +/- S.E.M.) was significantly (P less than 0.01) greater compared with the untreated sows (114.9 +/- 0.3 days). Plasma progesterone declined earlier (P less than 0.05) with respect to the time of parturition in the treated sows compared with the untreated group. With respect to the timing of parturition, the time at which maximal concentrations of relaxin were attained and the timing of the subsequent decline were earlier in the MPA-treated sows. In both groups of sows, the concentration of relaxin increased before the decline in plasma progesterone. In the untreated sows, the concentration of PGFM increased either slightly before or at the same time as the decline in plasma progesterone, whereas in sows treated with MPA, progesterone concentrations began to decline before any significant increase in the plasma concentration of PGFM. The profiles of cortisol, oestradiol-17 beta and PGFM were similar in both groups of sows. In both groups of sows, the timing of the initial increase in the concentration of plasma prolactin coincided with a similar rise in plasma lactose (P less than 0.01). Plasma progesterone either declined earlier or at the same time as the rise in plasma lactose (P less than 0.01) in the treated group of sows only. We conclude that since the prepartum changes in the concentration of progesterone and relaxin occurred before significant changes in the concentration of PGFM in the MPA-treated sows, the nature of the luteolytic factor and the mechanism by which it exerts its action remains obscure. The higher concentration of lactose in the mammary secretion at birth in the MPA-treated sows compared with the untreated group suggested that lactogenesis was initiated earlier with respect to parturition following MPA treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

A double-blind randomised controlled trial of the effects of medroxyprogesterone acetate on bone density of women taking oestrogen replacement therapy.

OBJECTIVE: To assess the effects of medroxyprogesterone acetate on bone density in women who have had a hysterectomy. DESIGN: Randomised, double-blind, placebo-controlled trial of medroxyprogesterone acetate 10 mg, 20 mg or placebo as an adjunct to oestrogen therapy. PARTICIPANTS: One hundred and twenty-three women, aged 18 to 45 years and currently receiving daily oestrogen, who presented at a university-based rheumatology practice. INTERVENTIONS: The women were randomly assigned to receive either medroxyprogesterone acetate 10 mg, 20 mg or placebo daily beginning on day 15 of each month for one year. Forty-one women were randomised into each group. MAIN OUTCOME MEASURE: The primary outcome measurement was the percentage of change from baseline in bone mineral density of the lumbar spine (L2-L4). Secondary outcome measures included differences in femoral neck bone density, cholesterol and triglyceride levels between groups. RESULTS: At one year, change in bone mineral density did not differ between either the treatment or placebo groups. Medroxyprogesterone acetate 20 mg and 10 mg led to statistically significant reductions in very low density lipoprotein cholesterol, total triglycerides, and very low density lipoprotein triglycerides when compared with placebo. Medroxyprogesterone acetate 20 mg also led to a statistically significant reduction in high density lipoprotein cholesterol, high density lipoprotein-2 cholesterol, and high density lipoprotein-2 triglycerides. CONCLUSIONS: Medroxyprogesterone acetate at either dose as an adjunct to oestrogen did not improve bone mineral density at one year when compared with placebo. Medroxyprogesterone acetate 10 mg may not adversely affect lipids. Medroxyprogesterone acetate 20 mg, however, did reduce high density lipoprotein cholesterol and therefore may increase cardiovascular risk.

Adolescent↗

Spermatogenesis in men treated with injections of medroxyprogesterone acetate combined with testosterone enanthate.

The effects of a combination of medroxyprogesterone acetate and testosterone enanthate, on the exocrine and endocrine testicular function were examined in adult men. The treatment was carried out with 2 different regimens and lasted for 8 months. Group I received an initial injection of 1000 mg medroxyprogesterone acetate and 500 mg testosterone enanthate followed by monthly maintenance dose of 150 mg medroxyprogesterone acetate and 500 mg testosterone enanthate. In group II, after an initial high dose of 1000 mg medroxyprogesterone acetate and 250 mg testosterone enanthate treatment was given as biweekly injections of 75 mg medroxyprogesterone acetate and 250 mg testosterone enanthate. Complete spermatogenic arrest of variable duration was achieved in all 9 subjects enrolled. Restoration of spermatogenesis occurred in both groups, in a few cases during the treatment, and there was a delay of full recovery of sperm counts up to 5 months after cessation of therapy. None of the subjects enrolled in this study complained of decrease in libido or change in sexual behaviour. Clinical evaluation and measurements of various urine and serum components revealed no significant changes during the treatment period. The dosage and the different administration schedule of the hormone combination described here was inadequate to maintain azoospermia in all subjects during treatment.

Adult↗

The effect of medroxyprogesterone acetate and heparin in the prevention of postsurgical adhesion formation in the rat uterine model.

OBJECTIVE: To evaluate the effects of depot medroxyprogesterone acetate and heparin in preventing postsurgical adhesion formation in the rat model. METHODS: A hundred and five female Wistar rats were divided into 7 groups. Groups 1 and 2 were injected with intramuscular 15 mg medroxyprogesterone acetate 3 weeks before surgery and at the end of laparotomy. Groups 3 and 4 were given 15 mg medroxyprogesterone acetate by intramuscular injection, 3 weeks before surgery. An equal volume of intramuscular sterile saline was injected to control groups, 3 weeks before and at the end of surgery. Before abdominal closure, 2 ml of Ringer's lactate was instilled into the peritoneal cavity of all rats, except group 7. Groups 1, 4, and 5 were given 2 ml of intraperitoneal Ringer's lactate containing 500 U heparin/ml. A standardized surgical injury was performed in all rats. Two weeks after surgery, the adhesions were scored on a scale of 0 to 3 according to their thickness-tenacity and vascularity. Kruskall-Wallis and Mann-Whitney U statistical test were used. RESULTS: The preoperative and postoperative administration of medroxyprogesterone acetate resulted in the least number of and the least severe adhesions, when compared with single dose medroxyprogesterone acetate treated rats and controls (p < 0.05). However, the combination of medroxyprogesterone acetate and intraperitoneal heparin did not enhance the adhesion reducing capacity of medroxyprogesterone acetate. CONCLUSIONS: Concurrent preoperative and postoperative administration of medroxyprogesterone acetate results in the most significant reduction of postsurgical adhesions. The combination treatment of medroxyprogesterone acetate and heparin does not show any additional effect in the reduction of adhesion formation, when compared with medroxyprogesterone acetate treatment alone.

Animals↗

Bone mineral density in women using depot medroxyprogesterone acetate for contraception.

OBJECTIVE: To evaluate the possible effects of depot medroxyprogesterone acetate injectable contraception on bone mineral density in reproductive-age women. METHODS: We conducted a population-based cross-sectional comparison of bone mineral density levels in women using depot medroxyprogesterone acetate contraception and in women of similar age not using this method. The study recruited 457 nonpregnant women aged 18-39 years who were enrollees of a Washington state health maintenance organization. One hundred eighty-three women were receiving injections and 274 were not. Bone mineral density at several anatomic sites (spine, femoral neck, greater trochanter, and whole body) was measured using dual-energy x-ray absorptiometry. Data on other factors potentially related to bone density were collected through questionnaire and examination. RESULTS: Overall, age-adjusted mean bone density levels were lower for users of this method than for nonusers at all anatomic sites: The mean difference was 2.5% for the spine (P = .03) and 2.2% for the femoral neck (P = .12). Exposure to depot medroxyprogesterone acetate continued to be significantly (P < .01) associated with decreased bone density at the femoral neck, spine, and trochanter after multivariate adjustment for other risk factors related to bone density. Age-specific comparisons indicated that the major differences in bone density between users and nonusers occurred in the youngest age group (women 18-21 years); the mean femoral neck bone density was 10.5% lower (P < .01) for the exposed women, and differences were consistent (P < .01) across all anatomic sites. We also noted a significant dose-response relation between longer use of depot medroxyprogesterone acetate and decreased bone density levels in this age group (P < .01 for all sites). CONCLUSION: These results provide evidence that contraception with depot medroxyprogesterone acetate, particularly long-term use, may adversely affect bone mineral density levels in young women aged 18-21 years. The implications for future bone health need further study.

Absorptiometry, Photon↗

Evaluation of the mutagenicity of medroxyprogesterone acetate in vitro and in vivo.

Medroxyprogesterone acetate (CAS 71-58-9) is used for cyclic hormone substitution during the menopause and in hormone therapy of breast cancer. The test substance was investigated for its mutagenic potential in a series of test systems according to the current EC guidelines. There were no indications for a mutagenic potential of medroxyprogesterone acetate.

Animals↗