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Comparison of norethindrone and medroxyprogesterone acetate with natural progesterone and estradiol in stimulating prolactin production from cultured endometrial stromal cells.

Progestins stimulate prolactin production from endometrial stromal cells in culture. We compared the potencies of the synthetic progestins norethindrone and medroxyprogesterone acetate to natural progesterone in inducing stromal prolactin production. Modifications of the culture system provided an increase in stromal cell yield, thus permitting multiple comparisons from the treatment of cells from a common endometrial sample. The effects of high-dose estradiol also were evaluated in this system. The findings suggest relative potencies of 50:1 for medroxyprogesterone acetate and progesterone. Norethindrone gave intermediate and more variable responses. Estradiol potentiated prolactin production from only submaximal progestins doses. The differences between the progestin effects, in large measure, were due to differential culture growth as reflected by culture mass. Compared to controls and estradiol alone, all the progestins induced much greater prolactin production. Thus during decidualization, progestins probably promote both stromal growth and intracellular prolactin production. High-dose estradiol may not interfere with these events.

Analysis of Variance↗

A study of the mechanism of weight gain in medroxyprogesterone acetate users.

Twelve non-lactating Thai women using the injectable contraceptive medroxyprogesterone acetate (DMPA) were studied in order to elucidate the mechanism of weight gain frequently seen among DMPA users. The study design included repeated estimations of body fluid compartments (total, extracellular and intravascular) and of nitrogen metabolism, as well as anthropometric measurements. The mean weight remained constant in this group of women after one year of treatment. But 25% of them demonstrated a mean weight gain of 6.05 kilograms, while another 25% showed a mean weight loss of 3.50 kilograms. None of the subjects (including those who gained and lost weight) showed significant changes in her fluid compartmental size, creatinine excretion rate, or nitrogen metabolism. However, skin-fold thicknesses were positively correlated to body weight changes. It can be concluded that medroxyprogesterone acetate when used as injectable contraceptive does not appear to have significant anabolic or fluid retaining properties, and that weight gain appears to be associated mainly with fat deposition.

Adolescent↗

High-dose depot-medroxyprogesterone acetate--effects on the fatty acid composition of serum lecithin and cholesterol ester.

Twenty-one women were treated with high doses of depot-medroxyprogesterone acetate (1000 mg/week im) for 6 months as part of the treatment of endometrial carcinoma. The relative fatty acid composition of serum lecithin and cholesterol ester were analyzed. In previous studies low doses of medroxyprogesterone acetate (MPA), in contrast to progestins of the 19-nor-testosterone series, have been shown not to affect the fatty acid composition of serum lecithin and cholesterol ester. However, the high doses of MPA used in this study increased linoleic acid and decreased arachidonic and di-homogammalinolenic acids in serum lecithin. The ability of a steroid to induce this shift has been ascribed to its androgenicity. MPA is considered to have weak, if any, such properties. The findings of this study emphasize the necessity to delineate effects on metabolism of different doses and administrative routes of any particular steroid.

8,11,14-Eicosatrienoic Acid↗

High dose versus low dose medroxyprogesterone acetate: a randomized trial in advanced breast cancer.

One hundred and twenty-four patients with advanced breast cancer were randomly allocated to treatment with either low dose (300 mg/day) or high dose (1000 mg/day) oral medroxyprogesterone acetate. The objective response rate was 24% for both treatment groups. For premenopausal patients, responses were achieved in two out of four on low dose and three out of six on high dose therapy (overall 5 out of 10 responders). No significant differences in response were seen in relation to previous endocrine therapy or site of disease. Both treatments were associated with a high incidence of bone pain relief (43 and 52%) but a low objective response rate (13%) in bone. Median response duration (10 vs. 11 months) and survival (13 vs. 11 months) were not significantly different for the two treatments. Both treatments were in general well tolerated, but toxicity was greater with the high dose treatment. Low dose oral medroxyprogesterone acetate is as effective as high dose therapy in the treatment of advanced breast cancer, and is cheaper and less toxic.

Adult↗

Sequential combination of tamoxifen and high dose medroxyprogesterone acetate: therapeutic and endocrine effects in postmenopausal advanced breast cancer patients.

A sequential combination of tamoxifen and medroxyprogesterone acetate has been evaluated in 42 postmenopausal untreated patients with metastatic breast cancer. Patients received tamoxifen 10 mg b.i.d., days 1-14, followed by medroxyprogesterone acetate 500 mg b.i.d., days 15-28, orally in an alternating sequence until progression. Twenty-two out of 40 evaluable patients showed an objective response to treatment (55%, 95% confidence limits 38-75%). A significantly higher response rate was observed in patients with age greater than or equal to 70 years, with soft tissue dominant lesions and with only one metastatic site. Median time to progression was 41 weeks and the median survival time 88 weeks. In 4 cases treatment was discontinued because of severe toxicity while in the remaining patients no toxicity (20 patients) or mild side effects (17 patients) have been observed. After 2 months of therapy, this combination showed a progestogenic effect on the endocrine parameters inducing a significant decrease of SHBG, gonadotropins, testosterone and cortisol. These preliminary clinical results and the moderate toxicity of the sequential combination support the need to further investigate this approach.

Adult↗

Specific and sensitive determination of medroxyprogesterone acetate in human serum by gas chromatography-mass spectrometry.

The mass fragmentographic determination of medroxyprogesterone acetate (MPA) in serum, using as internal standard medroxyprogesterone propionate (MPP) synthesized from MPA, is described. After addition of MPP, the sera are extracted on Sep-Pak C18 cartridges and MPA and MPP are detected as their respective 3-enol trifluoroacyl esters. Serum samples from 84 patients with breast cancer, daily receiving MPA orally, were determined showing a large variation in MPA concentrations (4-349 ng/ml). Our proposed gas chromatographic-mass spectrometric (GC-MS) method, which can be considered as a reference, was compared with a radioimmunoassay (RIA) method showing a correlation coefficient of 0.73 (n = 69; p much less than 0.001). The assay was also used to determine sequential serum levels of patients receiving a single oral dose of MPA. With only minor adjustments, the GC-MS method allows the determination of serum concentrations of related steroids such as megestrol acetate and cyproterone acetate.

Biological Availability↗

A chemiluminescence enzyme immunoassay (CLEIA) for the determination of medroxyprogesterone acetate in human serum.

An enzyme immunoassay with chemiluminescence detection (CLEIA) for measuring serum levels of medroxyprogesterone acetate (MPA), a synthetic progestational agent currently used in fertility control and hormonal cancer, is reported. The polyclonal antiserum was obtained by immunizing rabbits with the synthetized 17-hemisuccinate derivative of medroxyprogesterone (MPS) coupled to serum albumin. This antiserum does not display any cross reactivity with extracted metabolites or with corticosteroid analogs with modifications at positions 11 and 16. The same MPS coupled to alkaline phosphatase is used as tracer. For the chemiluminescent detection system, adamantyl-1,2-dioxetane phosphate is selected as substrate. The typical standard curve ranges from 18.5 to 1182 pg per well and displays a slope factor of 0.74, with an ED50 of 143.8 pg of MPA per well and a minimum detectable and maximal level of 0.83 and 12,400 pg per well respectively. The assay has been validated on spiked serum samples in terms of precision (intra- and interassay coefficient variations of less than 8% and 13%, respectively), and of accuracy (mean recovery 105%). The validation on clinical samples demonstrates a good correlation of MPA serum values obtained both by radioimmunoassay and CLEIA. This specific and sensitive CLEIA, which requires less than 100 microliters of serum sample, appears to be an interesting alternative for the monitoring of serum levels of MPA in humans.

Administration, Oral↗

Lunelle monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension): assessment of return of ovulation after three monthly injections in surgically sterile women.

The pharmacodynamic effects of medroxyprogesterone acetate (MPA) and estradiol cypionate (E2C) (MPA/E2C) (Lunelle Monthly Contraceptive Injection) on ovarian function were assessed through changes in serum progesterone concentrations. The data described here were obtained simultaneously with pharmacokinetic data presented in another article in this issue. Sixteen surgically sterile women with regular menstrual cycles were studied for one control cycle, three consecutive treatment months, and 3-5 months of follow-up. Suppression, followed by resumption of ovulation (the dynamic end point), was assessed by serum progesterone levels. Return of ovulation was presumptive based on progesterone concentrations > or = 4.7 ng/mL, as ultrasound was not used to determine the follicular/ovulatory status of these subjects. Luteal-like serum progesterone peaks were observed in all 16 women before drug administration, confirming the presence of ovulatory cycles. After the third monthly injection of MPA/E2C, progesterone concentrations were measured until demonstration of ovulation. Two women discontinued and three were lost to follow-up before this objective was achieved. Serum progesterone levels and, consequently, ovulation were suppressed beyond the entire dosing interval, indicated by the absence of any luteal-like progesterone peaks (serum progesterone concentrations did not exceed 1 ng/mL). The first normal ovulatory cycle, based on progesterone concentrations > or = 4.7 ng/mL, was observed in 11 women between days 63 and 112 after the third injection. Select medroxyprogesterone acetate parameters (i.e., area under the curve and minimum concentration) were correlated with return of ovulation. The correlation coefficients (r) were 0.757 and 0.492 for area under the curve and minimum concentration, respectively, indicating that return of ovulation is dependent, in part, on area under the curve and on the magnitude of the serum MPA trough level. In general, the higher the minimum concentration levels, the longer the time to return of ovulation. In conclusion, the return of ovulation, as confirmed by serum progesterone concentrations > or = 4.7 ng/mL, was observed as early as 63 days after the third and final monthly intramuscular injection of MPA/E2C, suggesting that consistent suppression of the hypothalamic-pituitary-ovarian axis is reversible after discontinuation of dosing.

Contraceptive Agents, Female↗

Adjuvant medroxyprogesterone acetate and steroid hormone receptors in category M0 renal cell carcinoma. An interim report of a prospective randomized study.

From July 1, 1979 to June 30, 1983, 136 consecutive patients with category M0 renal cell cancer who had undergone transperitoneal radical nephrectomy at 5 centers entered a prospective randomized trial to compare 500 mg. adjuvant medroxyprogesterone 3 times a week for 1 year to no treatment. Sex steroid hormone receptors also were studied in the renal tumor and in the surrounding healthy parenchyma with the dextran-coated charcoal technique. After a median followup period of 3 years (range 13 to 60 months) 30 of 121 evaluable patients (24.8 per cent) experienced relapse, usually in the lung or bones. Relapses occurred in 15 of 58 evaluable patients in the adjuvant treatment group (25.8 per cent) and 15 of 63 evaluable controls (23.8 per cent). The disease recurred more frequently (35.1 per cent) in the 57 patients with no receptors in the tumor than in the 45 with at least 1 receptor (17.8 per cent). These results were independent of adjuvant therapy. After a median 3-year followup, adjuvant medroxyprogesterone acetate was of no therapeutic benefit in patients who had undergone radical nephrectomy and the side effects of the therapy were evident in more than 50 per cent of the patients.

Antineoplastic Agents↗

Cardiovascular side effects of diethylstilbestrol, cyproterone acetate, medroxyprogesterone acetate and estramustine phosphate used for the treatment of advanced prostatic cancer: results from European Organization for Research on Treatment of Cancer trials 30761 and 30762.

Two randomized trials were started in 1976 by the European Organization for Research on Treatment of Cancer urological group. Trial 30761 compared 1 mg. diethylstilbestrol orally 3 times daily to 250 mg. oral cyproterone acetate daily and to 500 mg. medroxyprogesterone acetate intramuscularly 3 times weekly for 8 weeks, then 200 mg. orally daily. Trial 30762 compared 3 mg. diethylstilbestrol to 560 mg. estramustine phosphate orally for 8 weeks and then 280 mg. daily. The 239 patients in study 30761 and 226 in study 30762 were evaluated for cardiovascular toxicity during treatment. Various types of side effects (fluid retention, hypertension, electrocardiographic changes, myocardial infarction and thromboembolic disease) and their degrees of severity were analyzed. In both studies the most frequent type of cardiovascular toxicity was represented by fluid retention. Cardiovascular toxicity as a whole was higher with diethylstilbestrol than with estramustine phosphate or medroxyprogesterone acetate therapy, and was the lowest with cyproterone acetate therapy. The risk of severe cardiovascular complications developing was the highest during the first 6 months of treatment. Increasing age, body weight greater than 75 kg. and, especially, the presence of previous cardiovascular disease represented adverse factors in the development of cardiovascular toxicity.

Aged↗

The effect of past use of the injectable contraceptive depot medroxyprogesterone acetate on bone mineral density in normal post-menopausal women.

OBJECTIVE: Depot medroxyprogesterone acetate (DMPA), an injectable progestogen, is a widely used contraceptive acting primarily by inhibiting secretion of pituitary gonadotrophins, thus producing oestrogen deficiency. Cross-sectional and prospective studies in pre-menopausal women have shown DMPA use to be associated with reduced bone density, but bone density increases following discontinuation of the drug. Because fracture rates are low in pre-menopausal women, the principal concern arising from the effects of DMPA on bone is that there may be residual osteopenia in former users such that their post-menopausal fracture risk is increased. The present study addresses this question. DESIGN: Cross-sectional study of bone density in post-menopausal former users of DPMA and controls. SUBJECTS: Three hundred and forty-six normal post-menopausal women, of whom 34 had previously used DMPA. The median age at which DMPA use began was 41 years and the median duration of use was 3.0 years. MEASUREMENTS: Bone density was measured in the spine, proximal femur and total body by dual-energy, X-ray absorptiometry. RESULTS: There were no significant differences in bone density at any site between the women who had previously used DMPA and the others in the cohort. However, in those who had used DMPA for > 2 years there was a trend towards bone densities being lower in the former users, the differences from non-users being 1.6% in the lumbar spine (P = 0.6), 3.1% in the femoral neck (P = 0.4) and 0.5% in the total body (P = 0.8). There was no correlation between bone densities and the duration of DMPA use, the age at discontinuation of DMPA, or the time between DMPA discontinuation and the menopause. CONCLUSIONS: Any residual effects of depot medroxyprogesterone acetate use on post-menopausal bone density are small and therefore unlikely to have a substantial impact on fracture risk in the post-menopausal years.

Bone Density↗

Effects of cortisone acetate, methylprednisolone and medroxyprogesterone on wound contracture and epithelization in rabbits.

Standardized flank wounds were made on 20 rabbits divided into the following five groups: Group 1 served as controls, Group 2 were given cortisone acetate 6.25 mg/kg/day (I.M.), Group 3--methylprednisolone (Solu-Medrol) 1 mg/kg/day, Group 4--medroxyprogesterone (Depo-Provera) 35 mg/kg/day, Group 5--methylprednisolone 1 mg/kg/day and medroxyprogresterone 35 mg/kg/day. Wound contracture and epithelization was measured by planimetry of photographs taken twice weekly; weekly weights were recorded, and the maturation phase of wound healing followed in the control and methylprednisolone groups. All three steroids prolonged the latent phase of wound healing, slowed the rate and decreased the total amount of contracture. Cortisone showed the most inhibition of wound contracture and was the only steroid to inhibit epithelization suggesting it may have a slightly different or more potent mode of action. When the methylprednisolone group was followed for seven weeks on daily injections, the maturation phase of wound healing was inhibited, and this inhibition persisted during the next nine weeks after the drug was withdrawn. Only the control and the medroxyprogesterone group gained weight. Combining medroxyprogesterona and methylprednisolone resulted in the severest weight loss of 20% with a 60% mortality.

Animals↗

Fertility of male rabbits during oligozoospermia induced by injections of medroxyprogesterone acetate and testosterone enanthate.

Spermatogenesis of male rabbits was completely suppressed by weekly injection of medroxyprogesterone acetate (10 mg) combined with testosterone enanthate (5 mg) for 6 weeks. However, the fertility of the medicated animals was not abolished during the induced oligozoospermia objectively determining by artificial insemination. Besides reduction in sperm density, the drugs did not cause any significant change in neither sperm motility nor morphology. If the combination of medroxyprogesterone acetate and testosterone enanthate is to be effectively used as a male contraceptive it must be given at such a dose that azoospermia is induced and continuously maintained with some consequent undesirable side effects.

Animals↗

Medroxyprogesterone induced Cushing's syndrome.

A 74-year old female taking medroxyprogesterone acetate (MPA) presented with Cushing's syndrome together with low serum cortisol and plasma ACTH and an impaired response to synthetic ACTH (Synacthen, CIBA). When the medroxyprogesterone therapy was ceased the cushingoid features resolved and serum cortisol, ACTH and ACTH responsiveness all returned to normal. The MPA was acting as an exogenous glucocorticoid causing Cushing's syndrome.

Adrenocorticotropic Hormone↗

Medroxyprogesterone acetate in the treatment of pelvic pain due to venous congestion.

Ovarian function was suppressed with 30 mg of medroxyprogesterone acetate, daily for 6 months, in 22 women with lower abdominal pain due to pelvic congestion. There was reduction in pelvic congestion demonstrated by venography in 17 of the 22 women, and in 16 this was associated with induction of amenorrhoea which suggests that effective ovarian suppression is an important component of successful treatment. In the 17 women who showed a reduction in venogram score, the median change in pain score was 75% compared with only 29% in the five women with no change in venogram score (P less than 0.01). This significant association between reduction in pelvic congestion and pain indicates that pelvic congestion is likely to be the cause of pain in these women and that treatment with medroxyprogesterone acetate could be of value.

Adult↗

No effect of high-dose medroxyprogesterone acetate on the frequency of sister chromatid exchange in lymphocytes of cancer patients.

Sister chromatid exchange observed in metaphase chromosomes has been shown to be a sensitive assay for the detection of possible mutagenic and/or carcinogenic agents. The semisynthetic progestin medroxyprogesterone acetate is a drug used in high doses for the treatment of advanced breast cancer. We studied the frequency of sister chromatid exchange in PHA-stimulated peripheral lymphocytes of 11 patients who received medroxyprogesterone acetate in high doses. Overall results disclosed no significant effect of this drug on the frequency of sister chromatid exchange (SCE) and cell proliferation in sister chromatid differentiation patterns. Considering sex differences a slight tendency towards SCE increase and growth delay was observed in females.

Breast Neoplasms↗

High-dose medroxyprogesterone in the treatment of advanced therapy-resistant prostatic carcinoma.

In a preliminary study we have administered medroxyprogesterone acetate to 20 patients with advanced metastatic prostatic cancer, who no longer responded to previous therapy. The dose used was 1,000 mg intramuscularly three times a week for 5 weeks, followed by 1,000 mg weekly until progression. All patients had undergone orchidectomy or had been treated with estrogens. 15 patients also had received estramustine, and another 3 patients, chemotherapy. A partial response occurred in 4 patients for periods of up to 18 months, and stable disease was seen in 2 patients. 7 more patients reported subjective response lasting less than 2 months. The disease progressed in the remaining 7 patients. Adverse reactions were tolerable. Our results are promising and indicate that medroxyprogesterone in high doses may have an effect in therapy-resistant cases of prostatic carcinoma.

Aged↗

Treatment of sex offenders with medroxyprogesterone acetate.

Forty-eight male patients with long-standing histories of deviant sexual behavior received medroxyprogesterone acetate and milieu therapy for up to 12 months. Forty subjects responded positively, all within 3 weeks, with diminished frequency of sexual fantasies and arousal, decreased desire for deviant sexual behavior, increased control over sexual urges, and improvement in psychosocial functioning. Improvement in deviant sexual behavior and psychosocial functioning was maintained after treatment ended, and there was no evidence of permanent physiological changes. The author suggests that medroxyprogesterone acetate associated with counseling may be the treatment of choice for patients with long-term deviant sexual behavior. He discusses the ethical issues involved.

Antisocial Personality Disorder↗