Serum Medroxyprogesterone Acetate Research Articles

Ovulation suppression following subcutaneous administration of depot medroxyprogesterone acetate

ObjectivesTo characterize the relationship between serum medroxyprogesterone acetate (MPA) concentrations and ovulation suppression, and to estimate the risk of ovulation for investigational subcutaneous regimens of Depo-Provera CI (Depo-Provera) and Depo-subQ Provera 104 (Depo-subQ). Study DesignWe performed a secondary analysis of 2 studies that assessed the pharmacokinetics and pharmacodynamics of MPA when Depo-Provera is administered subcutaneously rather than by the labeled intramuscular route. Each woman received a single 45 mg to 300 mg subcutaneous injection of Depo-Provera, a single 104 mg subcutaneous injection of Depo-subQ, or 2 injections of Depo-subQ at 3-month intervals. We used an elevation of serum progesterone ≥4.7 ng/mL as a surrogate for ovulation and non-parametric statistical methods to assess pharmacokinetic and pharmacodynamic relationships. ResultsThis analysis included 101 women with body mass index (BMI) 18 to 34 kg/m2. Return of ovulation occurred at a median MPA concentration of 0.07 ng/mL (95% CI: 0.06–0.08) and the 90th percentile was 0.10 ng/mL (95% CI: 0.09–0.14). Neither age, race, nor BMI significantly influenced this relationship. The estimated probabilities of ovulation within 4 months of a 104 mg subcutaneous injection and within 7 months of a 150 mg subcutaneous injection (6 plus a 1-month grace) were each below 2.2%. ConclusionsThe typical MPA concentration associated with loss of ovulation suppression is substantially less than the commonly cited threshold of 0.2 ng/mL. Based on our results, MPA levels would rarely be low enough to permit ovulation if the Depo-subQ reinjection interval were extended to four months or if 150 mg Depo-Provera were injected subcutaneously every 6 months. ImplicationsExtending the three-month Depo-subQ reinjection interval by one month would result in a 25% reduction in yearly MPA exposure, with little risk of pregnancy. Off-label subcutaneous administration of 150 mg Depo-Provera every 6 months would be a highly effective repurposing of an excellent product, with a similar reduction in cumulative exposure.

Clinical trial to evaluate pharmacokinetics and pharmacodynamics of medroxyprogesterone acetate after subcutaneous administration of Depo-Provera

ObjectiveTo evaluate the pharmacokinetics and pharmacodynamics of medroxyprogesterone acetate after a single subcutaneous injection in the abdomen of 150 or 300 mg Depo-Provera and compare results to two injections of Depo-SubQ Provera 104 given 3 months apart.DesignPartially randomized, multicenter, parallel-group study.SettingResearch unit.Patient(s)Forty-two women of reproductive age with confirmed ovulatory cycle and body mass index of 18–35 kg/m2.Intervention(s)Women received a single subcutaneous injection of 150 mg (n = 24) or 300 mg (n = 9) of Depo-Provera or two injections of Depo-SubQ Provera 104 (n = 9).Main Outcome Measure(s)Suppression of ovulation as measured by progesterone, serum medroxyprogesterone acetate concentrations, and estimated pharmacokinetics parameters.Result(s)No ovulations were observed during 7 months after a single injection of 150 or 300 mg Depo-Provera. The 150 mg group had a similar Cmax as observed over two injection cycles of Depo-SubQ Provera 104 and a similar 6-month trough concentration as the 3-month trough of Depo-SubQ Provera 104.Conclusion(s)Our pharmacodynamics and pharmacokinetics data provide proof of concept that Depo-Provera (150 mg) may be an effective contraceptive method when injected subcutaneously every 6 months, with up to a 4-week grace period for reinjections.Clinical Trial Registration NumberNCT02456584.

Suppression of ovulation and pharmacokinetics following subcutaneous administration of various doses of Depo-Provera®: a randomized trial

Objectives: To identify the lowest dose of Depo-Provera that, when administered off-label subcutaneously, suppressed ovulation and had a pharmacokinetic profile consistent with a 4-month contraceptive effect.Study Design: We conducted a randomized, multicenter, parallel-group study to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of medroxyprogesterone acetate (MPA) after subcutaneous injection of three different doses of Depo-Provera. We randomized sixty women between 18 and 40 years of age at low risk of pregnancy with confirmed ovulation and body mass index of 18 to 35 kg/m2 to receive a single injection of 45, 75 or 105 mg of Depo-Provera, or a single injection of Depo-subQ provera 104 as a reference drug (15 women per group) and followed them for 7.5 months. We evaluated suppression of ovulation as the primary outcome, and MPA concentrations, pharmacokinetic parameters, safety, and local tolerability as secondary outcomes.Results: Five women ovulated within four months of treatment initiation (three in the 45 mg group and two in the 75 mg group). MPA levels associated with ovulation were in general low, largely ≤ 0.2 ng/mL (the presumed contraceptive threshold). No women in either the 105 mg group or the Depo-subQ provera 104 group ovulated within four months. The PK parameters including Cmax, C119, and AUC0−119 for these 2 groups were similar but not equivalent.Conclusion: A dose of 105 mg of Depo-Provera injected subcutaneously was the lowest tested dose that consistently suppressed ovulation and maintained serum MPA levels consistent with contraceptive effect for at least 4 months. The PK and PD results for the 105 mg dose were similar to Depo-subQ provera 104 over this period.

The potential for intramuscular depot medroxyprogesterone acetate as a self-bridging emergency contraceptive

ObjectiveTo examine the rate of ovulatory disruption when intramuscular depot medroxyprogesterone acetate (DMPA) is administered across graded stages of dominant follicle development. Study designWe assigned enrolled participants to one of three preassigned dominant follicle size groups: 12-14 mm, 15–17 mm and ≥18 mm. We followed dominant follicles via serial transvaginal ultrasound (TVUS) until the follicles reached their assigned size, at which time we administered DMPA. For 5 consecutive days thereafter, we followed the follicles via TVUS to observe follicle rupture and obtained serum luteinizing hormone (LH), estradiol, and progesterone concentrations. In the following 2 weeks, we collected serum progesterone concentrations twice weekly to detect possible ovulatory delay or dysfunction. We also collected serum medroxyprogesterone acetate (MPA) concentrations at 1 and 24 h after DMPA administration to examine against ovulatory outcomes. ResultsTwenty-six of 29 enrolled women completed the study. DMPA suppressed ovulation in 17/26 (65%) and caused ovulatory dysfunction in 1/26 (4%) participants. Larger follicles were more likely to rupture despite DMPA (12–14 mm: 0/10 (0%); 15–17 mm: 3/10 (30%); ≥18 mm: 6/6 (100%); p < .01). Pre-DMPA LH concentrations ranged from 13.8 to 93.7 IU/L (mean 49.0 IU/L) in cases of follicle rupture. We observed no cases of follicle rupture when DMPA was administered through cycle day 12. All 24-h MPA concentrations exceeded those needed for ovulation suppression. ConclusionDMPA suppressed and additionally disrupted ovulation in 65% and 4% of observed cycles, respectively. DMPA may provide effective emergency contraception as well as ongoing contraception if administered prior to an expected ovulation and specifically before the LH surge. ImplicationsDMPA may be an alternative form of emergency contraception that can also self-bridge to ongoing contraception. As ovulation was not observed among any follicles when DMPA was given through cycle day 12, women who initiate DMPA up through cycle day 12 may not require backup contraception.

HIV risk associated with serum medroxyprogesterone acetate levels among women in East and southern Africa.

Some observational studies have found increased HIV risk associated with self-reported use of injectable depot medroxyprogesterone acetate. Testing blood samples for medroxyprogesterone acetate (MPA), the progestin in depot medroxyprogesterone acetate, permits validation of self-reported data, and exploration of whether potential HIV risk is correlated with MPA levels, which are highest soon after injection. We conducted a case-control study testing archived serum from women who participated in three longitudinal studies of HIV prevention in East and southern Africa. Case samples, from women who acquired HIV, were from visits that occurred at or immediately prior to the first evidence of HIV infection. Secondary analyses restricted to case samples collected within 15 and 30 days of the estimated date of HIV infection. Matched control samples were from women who remained HIV uninfected. We used multivariable conditional logistic regression to compare exogenous hormone levels, quantified through mass spectrometry, among cases and controls. When restricted to cases with samples collected within 15 days or less of estimated date of HIV infection, MPA detection was more frequent among women who acquired HIV (adjusted odds ratio = 2.75, 95% confidence interval 1.22-6.19). In this subset, the increase in HIV risk was only among samples with MPA detected at a low level of 0.02-0.50 ng/ml: 36.7% of cases and 9.4% of controls, adjusted odds ratio = 6.03, 95% confidence interval 2.50-14.54. Detection of MPA at low levels close to the estimated time of HIV acquisition was significantly more frequent among women who acquired HIV. Studies are needed that explore biological mechanisms elicited by any MPA level and HIV risk.

Homologous ELISA for measurement of medroxyprogesterone acetate in serum

In order to develop ELISA for medroxyprogesterone acetate, medroxyprogesterone acetate-3-carboxymethyloxime (MPA-3-CMO) was coupled to bovine serum albumin (BSA) for immunogen preparation and to horseradish peroxidase (HRP) for enzyme conjugate preparation by N-hydroxysuccinimide mediated carbodiimide reaction. The immunogen was used to raise the antiserum in New Zealand white rabbit. The immunoreactivity of MPA-3-CMO-BSA-antibody and MPA-3-CMO-HRP enzyme conjugate was checked by checkerboard assay. The MPA-3-CMO-HRP enzyme conjugate and MPA-3-CMO-BSA-antibody were used for further development, standardization and validation of the assay. Sensitivity, ED50 and affinity of the assay were found to be 0.114 ng/mL, 2.75 ng/mL and 9.9 × 10⁻⁸ L/mol respectively. The % cross-reaction of analogous steroids with MPA-3-CMO-BSA-antibody was less than 0.025%. The recovery of the exogenously spiked MPA serum pools were in the range of 96.83–105.47%. The intra- and inter-assay coefficients of variation was less than 7.02%. The correlation coefficient of the serum level of MPA measured by the developed assay with the commercially available kit was found to be 0.95 (n = 37). This developed ELISA was further validated by measuring serum level of MPA in rat after administering them different doses of MPA intramuscularly.

Medroxyprogesterone acetate levels among Kenyan women using depot medroxyprogesterone acetate in the FEM-PrEP trial

ObjectiveTo describe medroxyprogesterone acetate (MPA) levels among Kenyan depot medroxyprogesterone acetate (DMPA) users in the FEM-PrEP HIV prevention trial, and to compare MPA levels between ARV for HIV prevention (treatment) and placebo groups. Study DesignWe measured MPA in previously collected plasma samples from 63 Kenyan trial participants who used DMPA for one or two complete intervals. We separately assessed MPA levels among the nine DMPA users who became pregnant at this site. ResultsMean MPA levels at the end of each 12week injection interval were 0.37ng/ml (95% CI: 0.25, 1.99) and 0.28ng/ml (95% CI: 0.19, 1.22) among participants assigned TDF/FTC and 0.49 (95% CI: 0.40, 1.27) and 0.39 (95% CI: 0.31, 1.17) among those assigned placebo. The difference between groups was not statistically significant overall, or in an analysis which adjusted for the observed low adherence to TDF/FTC. Unanticipated findings of this analysis were low 12-week MPA levels among DMPA users in both study arms. Of 61 women who contributed data for the first DMPA injection interval, 26.2% had MPA levels<0.1ng/ml and 9.8% had levels below the detection level (0.02ng/ml) at 12weeks post-injection. Levels were similar at the end of the second injection interval. Five of nine women who became pregnant had levels below 0.15ng/mL at the time of their last negative pregnancy test. ConclusionsUse of TDF/FTC did not appear to affect serum MPA levels, however we found lower than expected MPA concentrations at the end of the dosing interval among DMPA users in the FEM-PrEP trial, the cause of which are unknown. ImplicationsThis study presents some of the few available data on MPA levels among DMPA users in Africa. The low levels among users described here, together with a number of pregnancies among DMPA users, are potentially concerning and require further investigation.

Medroxyprogesterone acetate and estradiol cypionate injectable suspension (Cyclofem) monthly contraceptive injection: steady-state pharmacokinetics

BackgroundCyclofem is a combined injectable contraceptive, containing medroxyprogesterone acetate (MPA) and estradiol cypionate. The objective was to characterize the steady-state pharmacokinetics (PK) using tandem liquid chromatography/mass spectrometry and compare these data to a previous PK study of this formulation in US women. Study DesignFifteen ovulatory, surgically sterile women received three Cyclofem injections, once every 28 days, with serum PK measurements on 23 separate days. Trough levels of estradiol and MPA were obtained on Days 1, 29 and 57, prior to each of the three injections. Steady-state concentrations of MPA and estradiol were assessed during the third treatment month on Days 58, 60, 62, 64, 67, 69, 71, 75, 78 and 85. MPA and serum progesterone levels were measured during the follow-up phase to assess MPA clearance (Days 92, 99, 106, 113, 120, 127, 134 and 141) and return of ovulation (Days 103, 106, 131 and 134). ResultsIn the steady state, mean serum MPA concentrations peaked at 1.31 ng/mL at 4.1 days. Mean estradiol levels peaked at 254 pg/mL by 3.3 days. Ovulation was suppressed for at least 77 days post third injection in all but one woman. ConclusionsOnce monthly injections of Cyclofem resulted in contraceptive levels of MPA without accumulation of hormones, consistent with a previous US study.

Cognitive-impairing effects of medroxyprogesterone acetate in the rat: independent and interactive effects across time.

The synthetic progestin medroxyprogesterone acetate (MPA), widely used in hormone therapy (HT) and as the contraceptive Depo Provera, is implicated in detrimental cognitive effects in women. Recent evidence in aged ovariectomized (Ovx) rodents shows that short-term MPA treatment impairs cognition and alters the GABAergic system. Using rats, we evaluated the long-lasting cognitive and GABAergic effects of MPA administered in young adulthood (Early-MPA), modeling contraception, and how this early exposure interacts with later MPA treatment (Late-MPA), modeling HT. Early-MPA treatment involved weekly anti-ovulatory MPA injections (3.5 mg) from 4 to 8 months of age in ovary-intact rats. At 10 months old, rats were Ovx and weekly MPA injections were re-initiated and continued throughout testing for Late-MPA treatment. On the water radial-arm maze, all MPA-treated groups showed working memory impairment compared to Controls (p < 0.05); Early + Late-MPA rats were impaired on multiple dimensions of working memory (p < 0.05). On the Morris maze, Late-MPA rats showed greater overnight forgetting compared to Controls (p < 0.05). At study conclusion, MPA was detected in serum in all MPA-treated groups except Early-MPA, confirming treatment and clearance from serum in Early-MPA rats. In animals with detectable serum MPA, higher MPA levels were associated with less dorsal-hippocampal glutamic acid decarboxylase, the synthesizing enzyme for GABA (p = 0.0059). Findings suggest that MPA treatment leads to long-lasting cognitive impairments in the rodent, even in the absence of circulating MPA in animals given prior MPA treatment, which may relate to the GABAergic system. Further research defining the parameters of the negative impact of this widely used progestin on brain and cognition is warranted.

Progesterone Receptors in the Developing Genital Tubercle: Implications for the Endocrine Disruptor Hypothesis as the Etiology of Hypospadias

In fetal mice genital tubercles the ontogenetic expression of progesterone receptors and the effect of in utero estrogen and testosterone exposure were investigated. To evaluate ontogenetic progesterone receptor expression genital tubercles from untreated fetuses at gestational days 12, 14, 16 and 18, and newborn pups were prepared for real-time reverse transcriptase-polymerase chain reaction or immunohistochemistry. To evaluate estrogen and testosterone effects pregnant dams were gavaged once daily with corn oil (vehicle), ethinyl estradiol or testosterone propionate from gestational days 12 through 17. At gestational day 19 the genital tubercles of delivered fetuses were harvested for morphological examination and then pooled for real-time reverse transcriptase-polymerase chain reaction. Progesterone receptor protein was first detected at gestational day 12 in the urethral plate and mesenchyma. At later stages staining intensity increased with a greater progesterone receptor signal, especially in the urethra. Progesterone receptor mRNA expression showed different increasing patterns in each sex until birth. However, no difference was noted between male and female genital tubercles in terms of the distribution and quantity of progesterone receptor expression. In utero ethinyl estradiol led to 8.2, 9.7 and 5.2-fold increases in progesterone receptor mRNA in females and in males with and without hypospadias, respectively. Testosterone propionate significantly decreased progesterone receptor mRNA levels in females and males. Progesterone receptors are expressed in developing genital tubercles, suggesting a direct role of progesterone in normal genital tubercle patterning. Their increasing expression until birth also implies increasing sensitivity of the genital tubercles to the effects of estrogenic and progestogenic endocrine disruptors during fetal life. Ethinyl estradiol and testosterone propionate lead to opposing effects on progesterone receptor expression, in addition to their opposing morphological effects on the genital tubercles. These findings expand our knowledge of genital tubercle morphogenesis and provide important information for understanding the effects of endocrine disruptors.

Serum medroxyprogesterone acetate levels in new and repeat users of depot medroxyprogesterone acetate at the end of the dosing interval

In the absence of published data on serum medroxyprogesterone acetate (MPA) levels in South African users, this study examines such levels in new and repeat users of depot medroxyprogesterone acetate at the end of the dosing interval. The study was undertaken at three family-planning clinics in Durban, South Africa. Serum MPA levels were measured in 94 Black African, Indian and White women returning between 11 and 14 weeks after their last injection. The median serum MPA level was 0.88 (range, <0.04–1.77) ng/mL and wide interindividual variability was observed. Levels in all but one woman were higher than 0.1 ng/mL, the level at which ovulation is reported to resume. MPA levels were not found to vary according to weight, body mass index or ethnicity. Although there was a slight tendency towards higher MPA levels with longer duration of use (r = 0.13), the wide interindividual variability precluded the possibility of determining whether this was a real trend. A prospective study, using standardized assay techniques and following individual women, is required to further clarify this issue.

Pharmacokinetics of estradiol valerate and medroxyprogesterone acetate in different age groups of postmenopausal women

Objectives: To study whether ageing affects the pharmacokinetics of estradiol valerate (E 2V) or medroxyprogesterone acetate (MPA) in postmenopausal women. Methods: Forty-six postmenopausal women from two essentially similar pharmacokinetic studies were divided into three age categories: under 60 years ( n=15), between 60 and 65 years ( n=18) and over 65 years ( n=13). They all were treated for 12 days or 14 days with four galenically identical tablets containing combinations of 1 mg or 2 mg E 2V and 2.5 mg or 5 mg MPA. The studies followed an open, randomised cross-over design with no washout between the periods. Serum estradiol and MPA concentrations were measured at steady state on study day 12 or 14 of each period. Results: No statistically significant differences were observed in the peak concentration ( C max), time to peak ( t max), AUC or elimination half-life for estradiol or MPA between the different age groups. In spite of the lack of statistical significance the AUC was on an average 1.6-fold and C max 1.40-fold higher in the oldest group of women than in the youngest group and age was found significant as a continuous variable for AUC and C max for MPA but not for estradiol. Conclusions: The results suggest that there would be no significant changes in the pharmacokinetics of estradiol between women under 60 and over 65 years of age. However, a significant trend towards higher MPA concentrations and bioavailability was observed with increasing age. The results suggest that from the pharmacokinetic point of view the relationship between estradiol and MPA dose to be used in elderly could be different from that in younger postmenopausal women, while no pharmacokinetic reasons to use lower estradiol doses in the elderly were observed.

Rapid and sensitive analysis of medroxyprogesterone acetate in human serum by gas chromatography-mass spectrometry

Medroxyprogesterone acetate (MPA) is one of the major drugs used in endocrine therapy for advanced or recurrent breast cancer. The present study describes an accurate and reproductible gas chromatographic-mass spectrometric(GC-MS) method to measure MPA in serum.

An Analysis of Serum Interleukin-6 Levels to Predict Benefits of Medroxyprogesterone Acetate in Advanced or Recurrent Breast Cancer

Treatment of advanced or recurrent breast cancer with medroxyprogesterone acetate (MPA) shows high response rates and the accessory effects of appetite stimulation, improvement in performance status (PS) and bone marrow protection. In recent years, interleukin-6 (IL-6) has been reported to cause cachexia. In this study, to clarify the significance of IL-6 in advanced or recurrent breast cancer, the relationship between the IL-6 level and clinical findings or effect of MPA was investigated. Sixty-five patients with recurrent or advanced breast cancer participated in a prospective study. The age of patients ranged from 28 to 79 years with an average age of 51.3 years. IL-6 level was investigated in these patients dosed with 800 mg/day of MPA and in 17 postoperative nonrecurrent patients. Serum MPA level was measured by high-performance liquid chromatography and IL-6 level was measured prior to MPA administration, 4 weeks (in 59 cases) and 12 weeks (in 32 patients) after MPA administration by ELISA. Serum IL-6 level was significantly higher in recurrent cases, especially in those with visceral metastasis. Further, in patients for whom MPA therapy was effective, the IL-6 level prior to the treatment was clearly low. The IL-6 level was significantly increased after 4 weeks. However, response to MPA was significantly higher and PS was improved in those cases demonstrating less increased IL-6 levels after 4 weeks. In addition, the effect of MPA was significantly related to a higher serum concentration of MPA-positive ER, and longer disease-free interval, although there was no significant predictive factor for the clinical effect of MPA therapy in multivariate analysis. In conclusion, MPA therapy was effective in cases demonstrating a low IL-6 level and less increased IL-6 levels after 4 weeks. PS was improved in those cases in which the degree of IL-6 increase was suppressed by MPA, and many such cases showed low IL-6 levels prior to MPA therapy. Furthermore, PS was improved even in nonresponders to MPA. Therefore, it is suggested that MPA therapy might be useful in treating recurrent breast cancer, and its benefits might be mediated by IL-6.

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 (E 2C) (MPA/E 2C) (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 ≥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/E 2C, 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 ≥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 ≥4.7 ng/mL, was observed as early as 63 days after the third and final monthly intramuscular injection of MPA/E 2C, suggesting that consistent suppression of the hypothalamic-pituitary-ovarian axis is reversible after discontinuation of dosing.

Lunelle™ monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension): steady-state pharmacokinetics of MPA and E 2 in surgically sterile women

The steady-state pharmacokinetics and pharmacodynamics of medroxyprogesterone acetate (MPA) and estradiol (E 2, released from E 2C by esterase enzymes) were characterized after administration to surgically sterile women. This report describes the pharmacokinetics of this multiple-dose and open-labeled study (pharmacodynamics are reported in a subsequent article in this issue). Women with regular menstrual cycles were studied for one control cycle, 3 consecutive treatment months, and 3–5 months of follow-up. Blood samples were drawn before each monthly dose and at specified time points after the third monthly injection. A total of 16 women were enrolled, 14 of whom completed the study. These 14 women (13 white, one black) ranged in age from 28 to 43.4 years, in body weight from 47.6 to 68.9 kg, and in height from 150 to 175 cm. Mean serum MPA concentrations peaked in the first week after administration of MPA/E 2C (Lunelle™ Monthly Contraceptive Injection). The mean MPA C max and AUC 0−t(last) were 1.25 ng/mL and 32.13 ng · day/mL, respectively. Serum MPA concentrations declined with a mean terminal half-life of 14.7 days, indicating that absorption from the injection site is prolonged after administration of MPA/E 2C. The time for MPA concentrations to fall below the lower limit of quantitation (i.e., <10 pg/mL) after the third injection ranged from 63 to 84 days. The average MPA trough (C min, day 28) concentrations for the three consecutive monthly injections ranged from 0.44 to 0.47 pg/mL, indicating that steady-state conditions were achieved after the first injection. The MPA C min values were well above threshold levels required to suppress ovulation throughout the injection interval. Absorption of E 2 from the injection site was also prolonged after injection of MPA/E 2C. Mean concentrations of E 2 peaked at approximately 2 days after the third injection, and the average C max was 247 pg/mL. Serum E 2 levels declined with a terminal half-life of approximately 8 days; E 2 levels returned to baseline (typically, approximately 100 pg/mL) by 14 days after each injection. The average trough (C min, day 28) levels for E 2 ranged from 40 to 55 pg/mL. The results of this study demonstrate that steady-state conditions are achieved after the first injection of MPA/E 2C; no further MPA or E 2 accumulation occurs beyond the first injection. Furthermore, the E 2 peak observed after injection of MPA/E 2C is similar to the nontreated preovulatory E 2 range and returns to baseline levels by approximately 14 days after injection.

A Randomized Controlled Comparative Study of Oral Medroxyprogesterone Acetate 1,200 and 600 mg in Patients with Advanced or Recurrent Breast Cancer

A randomized controlled comparative study of oral medroxyprogesterone acetate (MPA) 1,200 mg (arm I) and 600 mg (arm II) was conducted in 80 patients with advanced or recurrent breast cancer. There were no significant differences between arm I and arm II in terms of response rate, duration of response and survival, or in terms of incidence and severity of adverse reactions. The lowest serum MPA concentration in responders tended to be higher than that in nonresponders. In the cohort of this study, the lowest concentration in partial response was 17.4 ng/ml, suggesting that this level may be the required minimum serum concentration.

Pharmacokinetic study of low- versus high-dose medroxyprogesterone acetate (MPA) in women.

The present study was conducted to compare the pharmacokinetics (PK) of low-dose versus high-dose medroxyprogesterone (MPA) as a once-daily oral administration. Of 32 patients, all women, enrolled in this PK study, 18 received 600 mg MPA daily and 14 received 1200 mg daily. Detailed PK data were obtained on day 1 and after more than 4 weeks of MPA treatment. In addition, multiple data for the minimum steady-state concentration (Css min) were analyzed. The MPA serum concentrations were measured by high-performance liquid chromatography. Wide interpatient variability was found in the PK parameters obtained both on day 1 and after more than 4 weeks. There were no clear relationships between the oral dose and the MPA peak concentration (Cmax), area under the time versus concentration curve (AUC), or mean Css min. Weight gains of 10% or more were demonstrated more frequently in the high-dose group (P < 0.01). Liver dysfunction (n = 5) did not influence the PK of MPA. Five patients demonstrated extremely low AUC and Cmax (< 10 ng/ml) values on day 1. Phenobarbital, dexamethasone and betamethasone were being taken concomitantly with the MPA each by one patient. The serum MPA concentrations were markedly increased after the discontinuation of phenobarbital in that patient, suggesting a drug interaction. At present we cannot recommend the high dose of MPA, except in clinical studies, from a PK or a pharmacodynamic points of view.

Pharmacodynamic effects of depot-medroxyprogesterone acetate (DMPA) administered to lactating women on their male infants

Normal postpartum women, who had a spontaneous vaginal delivery of one full-term male infant, free of congenital abnormalities and other diseases, were recruited for this study. Thirteen women received 150 mg depot-medroxyprogesterone acetate (DMPA), intramuscularly on days 42 + 1 and 126 + 1 postpartum. Infants of nine mothers, who did not receive DMPA, served as controls. Blood samples were collected from treated mothers on days 44, 47, 74, 124, 128, and 130 postpartum for medroxyprogesterone acetate (MPA) measurements. Four-hour urine coltections were obtained from all 22 infants in the morning on days 38, 40, 42, 44, 46, 53, 60, 67, 74, 88, 102, 116, 122, 124, 126, 128, 130, and 137. Urinary follicle stimulating hormone (FSH), luteinizing hormone (LH), unconjugated testosterone, and unconjugated cortisol were measured by tadioimmunoassay, and serum MPA and urinary MPA metabolites were measured by gas chromatography-mass spectrometry (GC-MS). No MPA metabolites could be detected in the urine of the infants from the DMPA-receiving mothers. Hormonal profiles in the urine samples were not suppressed in comparison with those of the control infants. The present study demonstrates that DMPA, administered to the mother, does not influence the hormonal regulation of the breast-fed normal male infant.

Benefits of Medroxyprogesterone Acetate (MPA) in Advanced or Recurrent Breast Cancer with Higher Serum Concertration.

The efficacy of medroxyprogesterone acetate (MPA) therapy in controlling progressive measurable metastatic breast cancer was assessed in 61 patients. In addition serum MPA concentrations were measured by high performance liquid chromatography (HPLC) and subjective effects of treatment were monitored. Overall 24 patients (39.3%) achieved an objective response(2 complete responses [ CR ] and 22 partial responses [ PR ]). There was no significant relationships between response to therapy and menopausal status, metastatic sites, previous therapy, histological type, or disease-free interval. Patients with estrogen (ER) and progesterone (PgR) receptor-positive tumors responded more frequently. Significant differences in serum MPA concentrations were seen between responders and non-responders, objective tumor shrinkage being seen in patients with serum levels in excess of 55 ng/ml. There were few cases responding to the therapy with serum MPA concentrations lower than 25 ng/ml. The serum MPA levels significantly correlated with an improvement in the performance status and survival. Patients with serum MPA concentrations lower than 25 ng/ml had significantly poorer survival. There was a significant relationship between MPA level and dose per area of boby surface (mg/ m(2)) in cases with CR or PR or no change (NC). However, the serum levels of patients with progressive disease despite therapy were lower than the expected levels based on the body surface area. This study demonstrated that serum MPA concentration is a determining factor for therapeutic benefit in advanced or recurrent breast cancer.