Medroxyprogesterone Acetate Levels Research Articles

253 Relation between plasma levels of medroxyprogesterone acetate and suppression of adrenal androgens

253 Relation between plasma levels of medroxyprogesterone acetate and suppression of adrenal androgens

Transfer of contraceptive steroids in milk of women using long-acting gestagens

Levels of norethisterone and medroxyprogesterone acetate were measured in serum and milk of women receiving the injectable contraceptive formulations Norigest and DepoProvera, respectively, throughout complete injection intervals. In 5 of 10 women receiving Norigest, serum norethisterone levels were undetectable by 8 weeks after injection and only 2 women had detectable levels of norethisterone in milk at this time. In contrast, 8 of 10 women receiving DepoProvera had detectable levels of medroxyprogesterone acetate in both serum and milk 12 weeks after injection. The ratio of the milk:serum concentrations of norethisterone varied from 0.12 to 0.92 (mean 0.34) and for medroxyprogesterone acetate from 0.12 to 2.60 (mean 0.88). It is unlikely that these differences between the two formulations are due entirely to differences between the binding of norethisterone and medroxyprogesterone acetate to serum proteins. The area under the curve of serum steroid concentrations plotted against time was only 50% higher for women injected with DepoProvera than for those injected with Norigest but the area under the curve for milk values was 400 times higher. Assuming the infant ingests 600 ml milk daily, the daily intake of steroids in the first week after injection would be 0.5 to 2.4 μg for norethisterone and 1 to 13 μg for medroxyprogesterone acetate. By 8 weeks after injection, the amount of norethisterone ingested would be small but that of medroxyprogesterone acetate would still be significant.

Plasma levels of medroxyprogesterone acetate (MPA), sex-hormone binding globulin, gonadal steroids, gonadotrophins and prolactin in women during long-term use of depo-MPA (Depo-Provera®) as a contraceptive agent

The aim of the study was to evaluate the functional state of the hypothalamo-pituitary-gonadal axis and to assess the concentrations of MPA in the peripheral blood during very long-term use of depo-medroxyprogesterone acetate (DMPA) as a contraceptive agent. The concentrations of MPA, sex-hormone binding globulin (SHBG) and the different pituitary and gonadal hormones in the peripheral blood were measured in nine 26-41 year old women. They had for 4.4-10.6 years (mean 8.9 years) been receiving DMPA im in a dose of 150 mg every 12th week as a contraceptive. Blood samples were obtained immediately before an injection of DMPA, 2 weeks later, and again immediately before the next injection. SHBG was measured by radio-electro-immunoassay; MPA, gonadal and pituitary hormones by RIA. The investigation showed that the oestradiol levels - even after very long-term use of DMPA - were still within the normal range for the early follicular phase. Gonadotrophins and prolactin were within the normal range for eumenorrhoeic women as well as the concentration of SHBG. MPA did not accumulate in the plasma. The changes in the plasma levels of oestradiol, MPA and SHBG after each injection disappeared within 12 weeks. The study appearts to warrant the conclusion that even up to 10 years' use of DMPA in a dose of 150 mg im every 12th week as a contraceptive agent, does not induce hormonal changes different from those seen after the very first injection.

Influence of medroxyprogesterone acetate (Provera) on plasma growth hormone levels and on carbohydrate metabolism. II. Studies in the ovariohysterectomized, oestradiol-primed bitch.

The combined effects of oestradiol and medroxyprogesterone acetate on growth hormone (GH) levels and carbohydrate metabolism were studied in 6 ovariohysterectomized dogs, which previously had shown moderate increments in GH after medroxyprogesterone acetate (MPA) administration. Oestradiol (Oe2) implants were administered 5 months after the last MPA injection, when MPA and GH levels tended to decrease. Following Oe2 administration GH levels rose significantly. Single MPA injections (100 mg) given 20 days after Oe2-priming were followed by still further increased GH levels. These GH levels were several-fold higher than GH levels achieved by previous MPA administration alone. GH levels decreased in 3 dogs after 35 days and remained elevated in the other 3 dogs as long as 70 days after MPA administration with Oe2 priming. Glucose assimilation became impaired and insulin response to a glucose load increased in relation to elevated GH levels. Oe2-primed control dogs, which received no MPA, failed to develop elevated GH levels. These findings indicate (1) that Oe2 and MPA induce overproduction in ovariohysterectomized dogs synergistically (2) that GH levels of the magnitude evoked are associated with glucose intolerance and insulin resistance.

Effect of medroxyprogesterone acetate on serum levels of LH, FSH, cortisol, and estrone in patients with endometrial carcinoma.

Medroxyprogesterone acetate (MPA) was administered orally for at least 6 months to 25 patients with endometrial adenocarcinoma starting 1 week after hysterectomy and bilateral ovariectomy. We measured serum concentrations of MPA during treatment and serum levels of LH, FSH, cortisol, and estrone before and during treatment with MPA. The serum levels of MPA 3--5 h after ingestion of a daily 100-mg dose of MPA at 08.00 h, varied considerably, the mean value (+/- SE) being 43 +/- 3.6 nmol/l range 15--119 nmol/l. Serum FSH levels rose after operation in the five premenopausal patients and remained elevated despite MPA treatment. In the 20 postmenopausal patients, however, initially high serum FSH and LH levels declined to half the starting values as a result of MPA treatment. After the administration of MPA for 6 months the mean serum cortisol and estrone concentrations at 08.00 a.m. had fallen to 78% and 82% of the mean values before treatment.

Experimental study on the anabolic and androgenic/antiandrogenic activity of different dose levels of medroxyprogesterone acetate (MAP) in rats.

The authors treated three groups of rats with medroxyprogesterone acetate (MAP) at different dosages (0, 2.5, 5, 10, 20, 40, 80 mg/kg) i.p. and orally for 7 days to evaluate its anabolic and its androgenic/antiandrogenic effect. 70 rats had been previously castrated and 35 were intact. The anabolic effect is evident in all groups of animals which were treated. The androgenic action predominates in castrated animals, while the antiandrogenic action predominates in intact animals. The above-mentioned actions are more marked when very high doses are used. After suggesting the possible mechanism of action of MAP, the authors point out that the anabolic effect confirms what has already been reported in clinical oncology after treatment with very high doses of MAP (1,000-2,000 mg orally or i.m. for 30 days) in different types of tumors (breast, kidney, prostate).

Medroxyprogesterone acetate (MPA) plasma levels after oral and intramuscular administration in a long-term study.

In a long-term study (1 year) the plasma concentration of medroxyprogesterone acetate (MPA, Depo-Provera, Provera, Upjohn) was measured in 30 patients with endometrial carcinoma treated with MPA in the following dosages: 1) MPA 1 000 mg i.m. weekly; 2) MPA 1 000 mg i.m. once every second week, and; 3) MPA 100 mg orally twice daily. In the orally treated group the blood samples were taken just before the next tablet. The plasma concentration in the orally treated group rapidly reached steady state, while the i.m. treated group showed gradually increasing levels that had a tendency to level off after 6 months. The mean concentration at the end of the year was about three times higher for MPA 1000 mg i.m. weekly than for MPA 100 mg orally twice daily. This does not take into consideration the peak MPA level that occurs 2-4 hours after each tablet. MPA i.m. has a very good depot effect, with release of MPA from the injection site for up to 9 months. The steady initial increase in MPA plasma concentration seen in the i.m. treated groups is probably due to the additions of new depots rather than accumulation in the body generally.

A Preliminary Pharmacokinetic and Pharmacodynamic Evaluation of Depot-Medroxyprogesterone Acetate and Norethisterone Oenanthate

A comparative pilot study was carried out in two World Health Organization Collaborating Centers on Research and Training in Human Reproduction (New Delhi and Stockholm) to assess the pharmacokinetic and pharmacodynamic properties of two injectable steroidal contraceptives, depot-medroxyprogesterone acetate (DMPA) and norethisterone oenanthate (NET-OEN). The assessment also included a variety of biochemical and hematologic indices. The period during which NET was detectable in the blood following injection of NET-OEN was significantly shorter in Indian women than in Swedish women. No difference was apparent with DMPA. None of the four Swedish women ovulated until more than 156 days after injection of DMPA and until plasma medroxyprogesterone acetate (MPA) levels were undetectable. The four Indian women ovulated within 73 days of injection of DMPA, and MPA levels at this time were above 0.6 ng/ml. There was no difference between the two centers in the time of return of ovulation for subjects receiving NET-OEN. For women receiving DMPA, the number of days on which bleeding and spotting occurred and the number of episodes of bleeding were significantly higher than those of women receiving NET-OEN. There were no significant changes in any of the biochemical or hematologic analyses as a result of injection of the gestagens. This preliminary study suggests that responses to the two injectable contraceptives may vary in different populations and emphasizes the need for more detailed comparative investigations in those countries where the formulations are expected to be in widespread use.

Blood levels of medroxyprogesterone acetate after multiple injections of DepoProvera or CycloProvera

Mean levels of MPA in blood taken 90 days after injection were not significantly different between women who had received a single injection of DepoProvera and those who had received eight injections at 90-day intervals. There was a wide variation in plasma MPA concentration in the two groups of women. In women who had received 31 to 45 injections of CycloProvera, plasma levels of MPA 28 days after injection were significantly higher than those of women who had received a single injection. The levels were also higher than those found in women 90 days after injection of DepoProvera. The results suggest that the dose of MPA in CycloProvera could be reduced.

Plasma medroxyprogesterone acetate levels following intramuscular or oral administration in patients with endometrial adenocarcinoma

The concentration of medroxyprogesterone acetate (MPA) in plasma samples taken 24 h after intramuscular or oral administration of 100 mg daily doses of the drug to patients with endometrial adenocarcinoma was measured by radioimmunoassay. In general, a plasma level of about 4 ng/ml was found 24 h after the dose, independent of the route of drug administration. However, in three of the patients to whom intramuscular MPA was given, considerably higher values were found. A maximal plasma level was achieved three hours after ingestion of 100 mg MPA. This was followed by a rapid decline to 20-25% of the peak value after about 12 h. A rather small day-to-day intraindividual variation was found in daily blood samples taken just before administration of the next dose. However, considerable differences were found between individuals and it is concluded that this variation in plasma levels may be reflected in the clinical efficacy of the treatment. Thus further studies in which plasma values and clinical effectiveness are correlated seem to be indicated.

The monthly injectable contraceptive: a two-year clinical trial.

A contraceptive regimen of monthly im injections of a combination of 25 mg of medroxyprogesterone acetate and 5 mg of estradiol cypionate (Cyclo-Provera) was studied in 111 Thai women through 2356 cycles. During the first 2 years of treatment more than 80% of the patients had only 1 bleeding episode per cycle. Average cycle length and duration of bleeding were similar to the pretreatment values. High continuation rates (79% at 12 months) indicated good patient acceptance of the method. There were no contraceptive failures or serious side effects. Return of fertility was relatively prompt. Among 21 patients who had discontinued treatment in order to plan pregnancy 10 were pregnant within 6 months and 3 others conceived during the succeeding 3 months. In 5 volunteers serum medroxyprogesterone acetate levels were below 5 ng/ml (with 1 exception) after a single injection of cyclo-Provera given at intervals up to 56 days.(AUTHORS)

Role of Hormones in Growth Kinetics of Renal Cell Carcinoma in Vitro

Medroxyprogesterone acetate has been used to treat metastatic renal cell carcinoma largely because of its observed inhibitory effects on the growth of estrogen-induced tumors in male Syrian golden hamsters. The absence to date of any successful, established chemotherapeutic regimen in the management of metastatic renal cell carcinoma has led to the continued application of medroxyprogesterone acetate in the majority of patients with this disease because of the occasional regression witnessed (particularly in male patients) and the absence of untoward side effects. To examine the mechanism of action of medroxyprogesterone acetate renal cell carcinoma tumor cells from a patient who had responded to medroxyprogesterone acetate therapy were established in tissue culture. Cells were cultured in control medium, and in the presence of therapeutic and pharmacologic levels of medroxyprogesterone acetate. Tumor cell growth kinetics were determined by the incorporation of 3H thymidine. There was no growth inhibition effected by medroxyprogesterone acetate at therapeutic or pharmacologic levels. Therefore, the proposed salutary effect of medroxyprogesterone acetate in regression of metastatic renal cell carcinoma results from factors other than direct inhibition of renal cell carcinoma growth.

Serum medroxyprogesterone acetate (MPA) concentrations and ovarian function following intramuscular injection of depo-MPA.

A sensitive radioimmunoassay measuring serum medroxyprogesterone acetate (MPA) has been developed in order to measure and correlate serum MPA concentrations and ovarian function in women following im administration of deop-MPA (DMPA), employing goat anti-MPA-3-(O-carboxymethyl) oxime-bovine serum albumin and MPA-3-(O-carboxymethyl) imino-125I-iodohistamine. In the 3 women studied, im injection of 150 mg of DMPA yielded brief initial serum MPA concentrations ranging from 1.5 to 3 ng/ml for a few days. Serum MPA concentrations gradually declined and remained relatively constant at about 1 ng/ml for 2 to 3 months, declined gradually thereafter reaching 0.2 ng/ml during the 6th month and became undetectable (less than 0.02 ng/ml) about 7-1/2 to 9 months following administration. Serum estradiol remained at early to midfollicular phase levels for 4 to 6 months after DMPA injection and rose to preovulatory levels when serum MPA levels fell below 0.5 to 0.25 ng/ml. Ovulation, however, as evidenced by serum progesterone concentrations did not occur, apparently due to suppression of the LH peak by positive feedback inhibition. Prolonged inhibition of cyclic ovarian function following DMPA injection is caused by slow MPA absorption and persists until serum MPA levels have decreased below 0.1 ng/ml or become undetectable about 7 to 9 months after DMPA administration.

Medroxyprogesterone acetate, estradiol, FSH and LH in peripheral blood after intramuscular administration of depo-provera® to women

The peripheral blood levels of medroxyprogesterone acetate (MPA), estradiol, FSH and LH were measured after an intramuscular injection of 150 mg and 300 mg of Depo-Provera® in three women. The radioimmunoassay used measured levels of medroxyprogesterone 5 — 10 times lower than previously reported following intramuscular injection of 150 mg Depo-Provera. No evidence for accumulation of the drug was found. Ovulation was suppressed during treatment. The levels of estradiol remained in the range of the early follicular phase of the untreated cycle, as did FSH and LH. The levels of LH were lower than those of FSH. MPA at levels ranging from 0.5 to 10 ng/ml suppresses ovulation by inhibition of the development of follicles.

Plasma levels of medroxyprogesterone acetate (MPA), estradiol and progesterone in the rhesus monkey after intramuscular administration of depo-provera®

Intramuscular injection of medroxyprogesterone acetate (MPA) 150 mg to four mature cycling rhesus monkeys resulted in initially high blood levels of MPA until 3 weeks after injection. Thereafter the concentrations decreased gradually during the remainder of the experiment. MPA concentrations reached below 0.5 ng/ml 70, 83, 90 and 105 days after injection. Ovulatory rises in peripheral plasma levels of progesterone were detected 101, 113, 123 and 233 days after injection, respectively. Despite a 10-fold difference in weight, the same dose of MPA as used in humans (150 mg), resulted in similar peripheral concentrations and duration in the rhesus monkey as in women, as found in a parallel study. The estrogen levels remained within those levels reported for the early follicular phase of the menstrual cycle of untreated monkeys. A significant rise in plasma estrogen levels was found at the end of the experiment. The patterns of plasma MPA, estradiol and progesterone concentrations in the rhesus monkey appear to be related to each other in a similar manner as in women. The metabolism of MPA in rhesus monkey appears to be considerably faster than in women.

Pharmacokinetic observations on medroxyprogesterone acetate administered orally and intravaginally

Plasma levels of medroxyprogesterone acetate (MPA) were determined by radioimmunoassay in five women after oral administration of 10 mg of MPA and during treatment with intravaginal rings homogenously impregnated with 100 mg of MPA. Peak plasma levels of MPA of 1.15–5.15 ng/ml were reached within two hours after oral administration. The levels thereafter rapidly declined being 0.09–0.35 ng/ml at twelve hours. During IVR treatment rather stable plasma levels between 0.37 and 0.63 ng/ml were reached. Vaginal absorption of MPA was found to be very rapid with plasma levels between 0.29 and 0.47 ng/ml already three hours after insertion of the IVR. The plasma levels found are lower than previously reported probably due to methodological differences. The plasma levels of MPA are much lower than the d-norgestrel levels found after administration of smaller amounts of d-norgestrel. This is probably explained by differences in compartmentalization of the drugs. The elimination halflife of MPA was found to be about 30 hours which is longer than for d-norgestrel (20 hours).