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PubMed1987

Radiochemical detection of dihydrodiol dehydrogenase: distribution of the enzyme in male Sprague-Dawley rat tissues and its sensitivity to inhibition by indomethacin and 6-medroxyprogesterone acetate.

Dihydrodiol dehydrogenase (EC 1.3.1.20) catalyzes the NADP+-dependent oxidation of (-)-7R,8R-dihydroxy-dihydro-benzo(a)pyrene and (+)-7S,8S-dihydroxy-dihydro-benzo(a)pyrene, which are potent proximate carcinogens (Smithgall, Harvey, and Penning, J. Biol. Chem., 261: 6184-6191, 1986). Using benzenedihydrodiol [(+)-trans-1,2-dihydroxy-3,5-cyclohexadiene] as a model substrate for these reactions, dihydrodiol dehydrogenase can be assayed in rat liver cytosol by measuring the change in absorbance of the pyridine nucleotide. This method lacks the sensitivity to detect the enzyme in extrahepatic tissues. Here we describe a sensitive radiochemical assay for dihydrodiol dehydrogenase in which the oxidation of benzenedihydrodiol to pyrocatechol is coupled to O-methylation catalyzed by catechol-O-methyltransferase (EC 2.1.1.6). In this manner the pyrocatechol formed in the oxidation step can be radiolabeled using S-adenosyl[methyl-3H]methionine as methyl donor. The resulting tritiated product, guaiacol, is readily extracted into toluene and quantified by scintillation counting. Using S-adenosyl[methyl-3H]methionine at a specific activity of 0.1 microCi/nmol, the assay provides a 5000-fold increase in sensitivity over the existing spectrophotometric method. The radiochemical assay was validated by comparing the Km and Vmax values obtained for the 40-75% (NH4)2SO4 fraction of rat liver cytosol with those measured spectrophotometrically. There was close agreement between values determined radiochemically (Km = 0.77 +/- 0.11 mM, Vmax = 2.14 +/- 0.13 nmol/min/mg protein) and determined spectrophotometrically (Km = 0.96 +/- 0.10 mM, Vmax = 6.31 +/- 0.50 nmol/min/mg protein). Using the radiochemical method, dihydrodiol dehydrogenase activity was detected in extrahepatic sites of polycyclic aromatic hydro-carbon metabolism: lung greater than small intestine greater than testis greater than bladder greater than prostate. Specific activities varied over 50-fold (0.866-0.017 nmol/min/mg protein) and did not show a strict inverse correlation with organ susceptibility to PAH-induced chemical carcinogenesis. Four tissues predominantly concerned with trans-dihydrodiol oxidation (liver, lung, small intestine, and testis) contain dihydrodiol dehydrogenase which is potently inhibited by indomethacin, two of these tissues (liver and small intestine) contain dehydrogenase sensitive to inhibition by 6-medroxyprogesterone acetate. These observations suggest that indomethacin and 6-medroxyprogesterone acetate may prevent the oxidation of trans-dihydrodiol proximate carcinogens in major tissues involved in their further metabolism and activation.

Alcohol Oxidoreductases↗
PubMed1984

Cytochemistry of cell surface sialoglycoconjugates in endometrial adenocarcinoma. Effects of medroxyprogesterone therapy.

Ferritin- and rhodamine-conjugated Limulus polyphemus agglutinin was used to localize, by electron microscopy, and to quantify, by microfluorometry, the cell surface sialoglycoconjugates in human endometrial adenocarcinoma before and after medroxyprogesterone acetate therapy. In the untreated tumor the lectin labelling was irregularly distributed on the cell surface, with a maximum density at the apical area and at the intercellular border; high values of the density-binding sites on cell surface were also detected by cytofluorometry. The binding pattern in both electron microscopy and microfluorometry on normal tissue and on tumor tissue submitted to medroxyprogesterone acetate stimulation appeared clearly modified; the lectin labelling concerned the apical areas only (also after treatment with chelating agents), with low fluorometric values of the reactive site density. The differences found in the lectin binding to the cellular sialic acid residues may be due to sialoglycoconjugate quantitative changes and/or to their different reactivity resulting from alterations of the cell membrane architecture. The data appear also correlated with a different proliferative activity and ploidy level of the three situations analyzed.

Adenocarcinoma↗
PubMed1980

Melphalan, 5-fluorouracil, and medroxyprogesterone acetate in metastatic or recurrent endometrial carcinoma. Preliminary report.

The purpose of this study was to evaluate therapy with melphalan, 5-fluorouracil (5-FU), and medroxyprogesterone acetate combination (MFP) in women with metastatic or recurrent endometrial carcinoma not amenable to surgery or radiation therapy, as compared to progesterone therapy alone. Previously, the authors have treated 114 women with progesterone therapy and achieved a 15.8% objective response rate; 7.0% were complete responders. Thirteen women with documented recurrent or metastatic endometrial carcinoma were entered into the MFP study. Thirteen were evaluable for toxicity and 11 for response (2 had no measureable parameter). Treatment consisted of melphalan 0.2 mg/kg/day for 4 days every 4 weeks; 5-FU 15 mg/kg/day for 4 days every 4 weeks; and medroxyprogesterone acetate 1.0 g intramuscularly weekly. Two of the first 3 patients who were treated with this regimen developed severe thrombocytopenia (platelets, 25,000 and 17,000/mm3). Therefore, the remaining 10 patients received 5-FU at a dose of 10 mg/kg/day for 4 days every 4 weeks. Except for 1 patient who devloped thrombophlebitis, there was no other significant toxicity in the 90 courses of therapy received by the 13 women. Of the 11 women evaluable for respone, 6 (54.5%) responded (2 complete responders, 4 partial responders), 2 for stationary disease, and 3 progressed after having had stationary disease for 3, 6, and 9 months, respectively. Of special interest was that the 2 women with adenosquamous carcinoma responded and 1 additional patient with adenocarcinoma maintained a complete response with 5-FU therapy alone.

Adenocarcinoma↗
PubMed1995

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↗
PubMed1993

Long-term effects of transdermal estradiol with and without medroxyprogesterone acetate.

OBJECTIVE: To study the long-term biological and metabolical effects of estradiol (E2) administered by transdermal therapeutic systems with and without the addition of medroxyprogesterone acetate (MPA). DESIGN: Open, randomized, comparative trial. SETTING: The reproductive endocrine unit of a tertiary care university-affiliated hospital. PATIENTS: Fifty-seven postmenopausal women were given E2 transdermally, whereas 28 were randomized to take MPA by mouth. Fifteen premenopausal women were studied for comparison. INTERVENTIONS: Estradiol, 0.1 mg, was administered by a transdermal therapeutic system for 24.5 of 28 days and was cycled for 96 weeks. Medroxyprogesterone acetate, 10 mg, was given for days 13 to 25 of each 28-day cycle (E+P group), whereas the remainder received E2 only. MAIN OUTCOME MEASURES: Serum E2, estrone (E1), luteinizing hormone, follicle-stimulating hormone, low-density, high-density, very low-density, and total cholesterol, triglycerides, blood pressure, renin substrate, plasma renin activity, and serum aldosterone levels were measured in all subjects at baseline and in the postmenopausal women every 24 weeks until the end of study. RESULTS: Mean +/- SE levels of E2 rose significantly from baseline at 24 weeks to 426 and 355 pmol/L for the E only and E+P groups, respectively. Smaller increases of estrone (E1) were observed to 263 and 244 pmol/L for the same respective groups. As expected, baseline levels of both gonadotropins were elevated, fell significantly with E2 administration, but remained increased in comparison with values observed in younger women. Decreases of total and low-density lipoprotein (LDL) cholesterol were observed in both groups that reached statistical significance at 48 weeks or later with the exception of LDL cholesterol in the E only group. No significant change of high-density lipoprotein or very low-density lipoprotein cholesterol or triglycerides was observed. There were reductions of mean systolic and diastolic blood pressures in both groups that reached significance at 72 weeks. Mean baseline plasma renin substrate, plasma renin activity, and serum aldosterone levels were within the ranges observed in younger, healthy women and did not change significantly with E2 administration in either group. CONCLUSION: These data support the long-term efficacy and safety of this form of replacement therapy, particularly in combination with MPA, in women with a uterus.

Administration, Cutaneous↗
PubMed1996

Pharmacokinetics of depot medroxyprogesterone acetate contraception.

Depot medroxyprogesterone acetate (DMPA) is an aqueous suspension of 17-acetoxy 6-methyl progestin administered by intramuscular injection for long-term contraception. This highly effective injectable formulation of medroxyprogesterone acetate (MPA) has a prolonged duration of action since the progestin is released slowly from the muscle. MPA is detected in the serum within 30 minutes after an injection of 150 mg. Serum concentrations vary between individual women but generally plateau at about 1.0 ng/mL for about three months, after which there is a gradual decline. In some women, MPA can be detected in the serum for as long as nine months after a single injection of 150 mg. The circulating MPA initially inhibits the midcycle leutinizing hormone (LH) peak, but LH and follicle stimulating hormone (FSH) levels remain in the range of those for the luteal phase of a pretreatment control cycle. Since ovulation is inhibited, serum progesterone levels remain low (< 0.4 ng/mL) for several months following an injection of DMPA. When MPA levels fall below 0.1 ng/mL, ovulation resumes. Thus, return to fertility is delayed for several months if a woman wishes to conceive after receiving one or more injections of DMPA. Following an injection of DMPA, serum estradiol levels initially are in the early to midfollicular phase range (mean approximately 50 pg/nL). Serum estradiol levels begin to rise about four months after a single injection when MPA levels fall below 0.5 ng/mL. For women who have used DMPA for several years, serum estradiol levels range between 10 and 92 pg/mL, with mean levels of about 40 pg/mL. Despite these low levels of estradiol, hot flushes are a rare event, and the vaginal epithelium remains moist and well rugated. Women using DMPA for several years do not observe a change in breast size. DMPA causes the endometrium to become atrophic, with small, straight endometrial glands and decidualized stroma. The cervical mucus remains thick and viscid. DMPA is a very effective form of contraception because of its multiple mechanisms of action and slow release into the circulation.

Contraceptive Agents, Female↗
PubMed1998

Estradiol inhibits LDL oxidation: do the progestins medroxyprogesterone acetate and norethisterone acetate influence this effect?

Estrogen replacement therapy in postmenopausal women must be combined with progestin to avoid endometrial cancer. However, progestin addition could antagonize cardioprotective effects of estradiol. Therefore we investigated the effect of the two most commonly used progestins--medroxyprogesterone acetate (progesterone-derivative) and norethisterone acetate (nortestosterone-derivate)--alone and in combination with 17 beta-estradiol on copper-mediated oxidation of low density lipoprotein (LDL). Whereas 17 beta-estradiol alone inhibited the onset of LDL oxidation at the concentrations 0.5, 1.0, 5 and 10 microM, the progestins alone did not demonstrate any significant effect. In the estrogen-progestin combinations of 0.5 microM 17 beta-estradiol with 0.5, 1.0, 5 and 10 microM progestin, respectively, the estradiol effect was not changed. These results suggest that medroxyprogesterone acetate as well as norethisterone acetate do not counteract the beneficial effect of 17 beta-estradiol on LDL oxidation when used in hormone replacement therapy.

Drug Interactions↗
PubMed1991

Long-term effects of depot-medroxyprogesterone acetate on lipoprotein metabolism.

To assess the effects of depot-medroxyprogesterone acetate (DMPA) upon serum lipids and lipoproteins, a comparative study in chronic users and new acceptors was undertaken. Two groups of women of reproductive age were included in the study; group I (n = 8) was formed by new acceptors whereas, group II (n = 14) constituted DMPA users of more than five continuous years (7.0 + 2.1 years). Blood samples were taken on the day of injection and 15, 29, 57 and 92 days after the i.m. administration of 150 mg of DMPA for the measurement of total triglycerides (TG), cholesterol (CHOL) and phospholipids (PHL). In addition, the TG and CHOL content in the very low density (VLDL), low density (LDL) and high density (HDL) lipoprotein fractions obtained by ultracentrifugation were also determined. The results demonstrated a moderate increase in the serum total TG concentrations at the expense of the VLDL fraction in the group of chronic DMPA users. In both groups, the administration of DMPA induced a moderate, though not significant, decrease in total CHOL and HDL-chol, an effect that was noticed at the end of the treatment interval; the serum LDL-chol content remained unchanged. In addition, a decrease in the total serum phospholipids content was noticed after DMPA injection in both groups, which resembled the fluctuations observed in the luteal phase of normal ovulating women. The overall data indicate that acute and/or chronic DMPA administration at the dose currently employed for contraception does not induce major abnormalities in lipoproteins in serum.

Adult↗
PubMed1977

Radioimmunoassays of ethinyl-norgestrienone (R-2323) and medroxyprogesterone acetate (MPA) and their clinical applicability.

Radioimmunoassays for 2 synthetic progestins (Ethinyl-norgestrienone, R 2323 and medroxyprogesterone acetate, MPA) are demonstrated. 10 patients aged 31 to 72 years were treated with ethinyl-norgestrienone with different schedules and 3 men suffering from benign prostatic hypertrophy were treated with medroxygesterone acetate. Plasma levels of testosterone, LH, FSH were monitored before, during and after treatment.

Adult↗
PubMed1975

Radioimmunoassay of serum medroxyprogesterone acetate (Provera) in women following oral and intravaginal administration.

A radioimmunoassay (RIA) method for measuring medroxyprogesterone acetate (MPA, Provera) in serum has been developed utilizing benzene:iso-octane extraction, 3H-MPA to assess procedural losses, goat anti-MPA-3-(0-carboxymethyl) oxime-bovine serum albumin serum and dextran-coated charcoal separation. Control serum blanks were undetectable, 200 pg/ml of MPA was measurable with a high reliability, and intra- and interassay coefficients of variation were 6 and 13 percent, respectively. MPA added to control serum was quantitatively recovered. Serum MPA levels measured in 2 women after ingestion of 10 mg MPA rose to 3.4 to 4.4 ng/ml within 1 to 4 hours after oral intake and fell rapidly thereafter to 0.3 to 0.6 ng/ml within 24 hours. Insertion of Silastic intra-vaginal rings (IVRs), containing 100 or 200 mg of MPA, into 4 women for periods of 3 weeks resulted in a rapid rise of serum MPA after insertion, rather stable MPA levels of 0.9 to 1.6 ng/ml while the IVRs were in place, and a rapid decline of serum MPA following IVR removal. Serum estradiol-17beta and progesterone concentrations, measured about 3 times a week in these patients, indicated that ovulation was consistently inhibited. The serum MPA levels observed in this study were approximately 5 times lower than those reported by other investigators using a double-antibody RIA of MPA in unextracted serum.

Administration, Oral↗
PubMed1980

The mechanism of action of an antifertility vaccine in the rhesus monkey: reversal of the effects of antisera to the beta-subunit of ovine luteinizing hormone by medroxyprogesterone acetate.

Active immunization of female rhesus monkeys with the beta-subunit of ovine luteinizing hormone )oLH beta) significantly reduced their fertility. To determine whether the major action of the vaccine was interruption of pregnancy, by suppression of "corpus luteum rescue," or inhibition of ovulation, we administered the progestational agent medroxyprogesterone acetate (MPA) from day 4 through day 40 after mating. In the untreated immunized group, the pregnancy rate was significantly below that of control monkeys. MPA treatment restored the fertility rate of immunized animals to that of the control group. These results strongly support the assumption that the antifertility action of antibodies of oLH beta is due to prevention of corpus luteum rescue. Whether the lack of corpus luteum rescue resulted because of neutralization of rhesus monkey chorionic gonadotropin or from a defective corpus luteum, as is found in animals with short luteal phases, cannot be determined from these studies. The successful reversal of the antifertility effect, however, suggests that the circulating antibodies do not interfere with normal ovulation or with the normal development and implantation of the blastocyst.

Animals↗
PubMed1979

Antipyrine metabolism and liver function in patients treated with high-dose medroxyprogesterone.

The effect of high-dose medroxyprogesterone acetate (MPA, 250 mg intramuscularly for six days) on hepatic drug-metabolism and liver function was investigated in eleven females with endometrial carcinoma. Antipyrine plasma clearance, an index of hepatic drug-metabolizing ability, improved significantly during this treatment, and the serum total bilirubin level was lowered, whereas other liver function tests, including alkaline phosphatase, and albumin values in the serum, remained unchanged. The results demonstrate that therapy with MPA has an inducing effect on hepatic enzyme activity and antipyrine metabolism. The findings may be of importance when prescribing drugs for females receiving large doses of MPA.

Adult↗
PubMed1980

[Oral high doses of medroxyprogesterone acetate (MPA) in the treatment of advanced phases of breast and endometrial cancer].

The results of a pilot study on the use of oral medroxyprogesterone acetate (Provera-Upjohn) at high dose in a series of 50 consecutive women with advanced breast (30 cases) and endometrial carcinoma (20 cases) are reported. Patients with progressive disease, non liable to further conventional treatments, received MPA (500 mg/day orally) for 90 days. The evaluation of results have shown only partial responses: in 9/30 (30%) of women with disseminated breast carcinoma (median duration of response 10 months, median survival 15 months), and in 6/20 (30%) of patients with advanced endometrial carcinoma (median duration of response 15 months, median survival not reached at 28 months of follow-up). Even if with a lower response rate, as compared to the results obtained with parenteral formulation, the oral MPA maintains its therapeutic effectiveness in these hormonodependent tumors: easy to handle during the long term treatments, oral MPA could be a useful alternative also for maintenance therapy.

Administration, Oral↗
PubMed1994

Long-acting injectable contraception with depot medroxyprogesterone acetate.

Depot medroxyprogesterone acetate (DMPA) is the only injectable contraceptive available in the United States. After more than 20 years of regulatory review, the Food and Drug Administration approved DMPA for contraceptive use in 1992 after the publication of reassuring data about its possible association with breast cancer. It has been used by 30 million women in more than 90 countries. The recommended dosage, 150 mg intramuscularly every 3 months, has a contraceptive efficacy exceeding 99%. After a 150 mg dose, ovulation is inhibited for at least 14 weeks. Almost all users experience menstrual changes, typically episodes of unpredictable irregular spotting and bleeding, particularly during the first year of use. With continued use, spotting and bleeding decrease, and amenorrhea becomes common. Although ovulation suppression may rarely persist for as long as 18 months after the last injection, DMPA does not permanently affect fertility. Long-term DMPA use reduces menstrual blood loss, has been associated with a decreased incidence of candidal vulvovaginitis and pelvic inflammatory disease, and dramatically lowers the risk of endometrial cancer. Prolonged DMPA use may be associated with reversible reduction in bone density, probably related to suppression of endogenous production of estrogen. The most recently published data suggest that long-term use of DMPA induces moderate changes in lipid metabolism that are unfavorable in terms of risk of atherosclerosis. DMPA should be considered a highly effective, safe, convenient, and reversible contraceptive option for appropriately selected patients.

Delayed-Action Preparations↗
PubMed1980

The use of medroxyprogesterone acetate for relief of climacteric symptoms.

Climacteric symptoms in the menopausal woman are perplexing to the physician. Recent literature concerning the relationship of estrogen to carcinogenesis has caused many women to discontinue this medication; thus, there is a need for an alternative therapy for the relief of these symptoms. The drug medroxyprogesterone acetate (Depo-Provera) was assessed in a double-blind, randomized, placebo-controlled study involving 48 subjects. Only one of the placebo-treated patients claimed any relief from climacteric symptoms while only two of the patients who received the study drug noted little or no relief (P < 0.0001). Relief from climacteric symptoms began at 4 to 7 days after entry into the study and extended for 8 to 20 weeks. The only side effects were withdrawal bleeding and a slight, transient weight gain. Depo-Provera appears to be a reliable substitute for estrogen in the treatment of climacteric symptoms. Further investigations with this medication seem indicated.

Adult↗
PubMed1980

A randomized, single blind comparative trial of norethindrone enanthate and depo-medroxyprogesterone acetate in Bangladesh.

A randomized, single blind comparative trial of norethindrone enanthate (NET-ENT) and depo-medroxyprogesterone acetate (DMPA) was conducted in the Model Clinic, Decca, Bangladesh, to determine if there were differences in reported side effects, reasons for discontinuation and discontinuation rates of these two injectables. On all follow-up visits the proportion of women reporting no bleeding (amenorrhea) was higher for the DMPA clients compared to the NET-ENT clients. Concurrent with these findings, the proportion of women reporting irregular bleeding was consistently higher for the NET-ENT clients. Concurrent with these findings, the proportion of women reporting irregular bleeding was consistently higher for the NET-ENT clients compared to those receiving DMPA. By the fourth injection, less than 15% of the clients in both drug groups still reported having regular cyclic bleeding (4 of the 26 DMPA clients and 4 of the 28 NET-ENT clients). Five of the 133 women on DMPA and 6 of the 106 women on NET-ENT became pregnant while using the injectables. At the end of one year of follow-up, 14 of the 133 DMPA and 14 of the 106 NET-ENT clients were still continuing (came back for a fifth injection).

Adult↗
PubMed1981

Studies on ovarian and adrenal steroids at different phases of the menstrual cycle. III. Steroid and lutropin levels before and after the administration of a single contraceptive dose of depot-medroxyprogesterone acetate (DMPA).

Ovarian and adrenal steroids and biologically active lutropin were measured in peripheral plasma samples obtained from 5 normally menstruating women. Plasma samples were collected every 3 h for a period of 39 hours in the periovulatory period of a pretreatment (control) cycle and then 16 and 54 days after a single i.m. injection of 150 mg of depot-medroxyprogesterone acetate (DMPA). Sixteen days after DMA administration, the levels of estradiol, progesterone, 17-hydroxyprogesterone, and lutropin were reduced to early follicular phase levels. No further decrease was found in 17-hydroxyprogesterone and lutropin levels; however an additional decrease occurred in the levels of estradiol and in the "morning" levels of progesterone 54 days after the administration of DMPA. Furthermore, the levels of pregnenolone, androstenedione, testosterone and dihydrotestosterone were significantly diminished in all samples collected after the administration of DMPA. Fifty-four days following the administration of DMPA, the levels of cortisol and 17-hydroxypregnenolone were significantly reduced. The administration of DMPA did not interfere with the circadian rhythm of cortisol, pregnenolone, 17-hydroxypregnenolone, dehydroepiandrosterone, 17-hydroxyprogesterone, and androstenedione levels. A significant circadian rhythm was also found in testosterone (after 16 days) and lutropin (after 54 days) levels. No circadian variation was found in estradiol, progesterone and dihydrotestosterone levels.

Adrenal Glands↗
PubMed1982

Effect of depo-medroxyprogesterone acetate on serum progesterone levels when administered on various cycle days.

Depo-medroxyprogesterone acetate (DMPA) in the conventional dose of 150 mg, was administered intramuscularly to 49 healthy, already sterilized, Thai women on cycle day 5 (13 subjects), day 7 (12 subjects), day 9 (13 subjects) and day 11 (11 subjects) of normal menstrual cycles. Serum progesterone levels were then monitored in order to ascertain the latest follicular phase day in the cycle (up to day 11) when ovulation would be inhibited in the first month after injection. Among the 25 subjects who received DMPA on day 5 and 7, no longitudinal serum progesterone level rises indicative of ovulation were detected. When DMPA was given on day 9 and 11, 2 out of 13 subjects (15.39%) and 3 out of 11 subjects (27.28%), respectively, had serum progesterone levels characteristic of ovulation. It is concluded that the initial cycle's ovulation can also be inhibited when DMPA is administered on day 7 of that cycle. However, DMPA administered on day 9 and 11 failed to inhibit ovulation of that cycle in some of the subjects.

Adult↗