Dose Of MPA Research Articles

Effect of Citrullus lanatus Seeds Extract on Haematological Parameters After Administration with Medroxyprogesterone Acetate on Female Wistar Rats

This study was carried out to investigate the effect of Citrullus lanatus seeds extract on the haematological parameters after administration with medroxyprogesterone acetate on female Wistar rats. Twenty-five rats weighing 170-230 g were divided into five groups containing five rats each. Group I served as control and received only rat chow and water; Group II received rat chow, water and a high dose of MPA only; Group III received rat chow, water, a high dose of MPA and a high dose of extract; group IV received rat chow, water, high dose of MPA and a low dose of extract, and group V received rat chow, water and high dose of extract only. The administration lasted for twenty-eight days after two weeks of acclimatisation. On the twenty-ninth day, the animals were anaesthetised using chloroform, sacrificed and their blood samples obtained via cardiac puncture for haematology analysis. The results showed that the level of haematological parameters significantly increased (p<0.05) in the rats that received a high dose of MPA and a high dose of Citrullus lanatus seed extract compared to the control group. This suggests that MPA affects bone marrow, which produces blood cells, significantly decreasing platelet count, white blood cell count, red blood cell count, haemoglobin count, packed cell volume, mean corpuscular volume, and mean corpuscular haemoglobin concentration. This study also shows that an aqueous extract of Citrullus lanatus seed is potent in increasing the level of haematological parameters when co-administered with MPA.

Supplementation with mesquite alkaloids extract in diets for lambs fed Bermuda grass improves growth performance

The aim of this study was to evaluate the effects of different concentrations of enriched mesquite piperidine alkaloid extract (MPA levels): 0 (control), 2.3, 4.6 and 9.2 mg/kg; and to compare monensin (MON) 2.1 mg/kg, MPA 0 and MPA 2.3 mg/kg of diet dry matter composed of Tifton 85 (Bermuda grass) hay and concentrate (corn meal, soybean meal, urea and mineral salt). Nutrient intake, digestibility, growth performance, microbial synthesis efficiency, and nitrogen (N) balance were evaluated. Thirty Dorper × Santa Inês lambs, with an initial body weight of 17.50 ± 0.43 kg, were assigned to a completely randomized design. There was no difference (P > 0.10) for the intake of nutrients and metabolizable energy (11 MJ/day) between the diets. The digestibility of DM, OM, CP, EE and, NDFap was lower (P < 0.05) for MPA 2.3 compared to MON and the control diet. Non-fiber carbohydrates (NFC) digestibility tended to be lower (P < 0.10) in comparison with MON and showed quadratic variation (P < 0.05) with MPA levels. MPA 2.3 did not differ (P> 0.10) of the MON and control diets for daily weight gain, but it presented a higher (P < 0.05) efficiency of feeding conversion than MON. There was a linear increase (P < 0.05) for final body weight with MPA levels. There was maximum (P < 0.05) nitrogen excretion in feces and minimum (P < 0.05) digested nitrogen (g/100 g of ingested nitrogen) at the mean dose of MPA 5.7 mg/kg. The results indicate that MPA has potential as a feed additive because it improves growth performance.

Noninvasive transcranial focal stimulation affects the convulsive seizure-induced P-glycoprotein expression and function in rats

Transcranial focal stimulation (TFS) is a noninvasive neuromodulation strategy that reduces seizure activity in different experimental models. Nevertheless, there is no information about the effects of TFS in the drug-resistant phenotype associated with P-glycoprotein (Pgp) overexpression. The present study focused on determining the effects of TFS on Pgp expression after an acute seizure induced by 3-mercaptopropionic acid (MPA). P-glycoprotein expression was analyzed by western blot in the cerebral cortex and hippocampus of rats receiving 5 min of TFS (300 Hz, 50 mA, 200 μs, biphasic charge-balanced squared pulses) using a tripolar concentric ring electrode (TCRE) prior to administration of a single dose of MPA. An acute administration of MPA induced Pgp overexpression in cortex (68 ± 13.4%, p < 0.05 vs the control group) and hippocampus (48.5 ± 14%, p < 0.05, vs the control group). This effect was avoided when TFS was applied prior to MPA. We also investigated if TFS augments the effects of phenytoin in an experimental model of drug-resistant seizures induced by repetitive MPA administration. Animals with MPA-induced drug-resistant seizures received TFS alone or associated with phenytoin (75 mg/kg, i.p.). TFS alone did not modify the expression of the drug-resistant seizures. However, TFS combined with phenytoin reduced seizure intensity, an effect associated with a lower prevalence of major seizures (50%, p = 0.03 vs phenytoin alone). Our experiments demonstrated that TFS avoids the Pgp overexpression induced after an acute convulsive seizure. In addition, TFS augments the phenytoin effects in an experimental model of drug-resistant seizures. According with these results, it is indicated that TFS may represent a new neuromodulatory strategy to revert the drug-resistant phenotype.

Application of immunosuppressants in patients with autosomal dominant polycystic kidney disease after kidney transplantation

To investigate the optimal dose range of immunosuppressants in patients with autosomal dominant polycystic kidney disease (ADPKD) after renal transplantation. A cohort of 68 patients with ADPKD who received their first renal transplantation between March, 2000 and January, 2018 in our institute were retrospectively analyzed, with 68 non-ADPKD renal transplant recipients matched for gender, age and date of transplant as the control group. We analyzed the differences in patient and renal survival rates, postoperative complications and concentrations of immunosuppressive agents between the two groups at different time points within 1 year after kidney transplantation. The concentrations of the immunosuppressants were also compared between the ADPKD patients with urinary tract infections (UTI) and those without UTI after the transplantation. The recipients with ADPKD and the control recipients showed no significantly difference in the overall 1-, 5-, and 10- year patient survival rates (96.6% vs 96.0%, 94.1% vs 93.9%, and 90.6% vs 93.9%, respectively; P &gt; 0.05), 1-, 5-, and 10-year graft survival rates (95.2% vs 96.0%, 90.8% vs 87.2%, and 79.0% vs 82.3%, respectively; P &gt; 0.05), or the incidences of other post- transplant complications including acute rejection, gastrointestinal symptoms, cardiovascular events, pneumonia, and neoplasms (P &gt; 0.05). The plasma concentrations of both tacrolimus and mycophenolate mofetil (MPA) in ADPKD group were significantly lower than those in the control group at 9 months after operation (P &lt; 0.05). The incidence of UTI was significantly higher in ADPKD patients than in the control group (P &lt; 0.05). In patients with ADPKD, those with UTI after transplantation had a significantly higher MPA plasma concentration (P &lt; 0.05). In patients with ADPKD after renal transplant, a higher dose of MPA is associated with a increased risk of UTI, and their plasma concentrations of immunosuppressants for long-term maintenance of immunosuppression regimen can be lower than those in other kidney transplantation recipients.

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.

Regulatory Dendritic Cell (DCreg) Cell Infusion in Living Donor Liver Transplantation

Background Based on strong preclinical data showing that regulatory dendritic cells (DCreg) of donor origin can promote long-term graft survival in rodents and suppress allograft rejection in non-human primates, we have embarked on a first-in-human phase I/II safety and preliminary efficacy trial of donor-derived DCreg in living donor liver transplantation (LTx). Methods In the study protocol, DCreg are generated from elutriated monocytes isolated from the leukapheresed donor,14-28 days (d) before transplant. The donor-derived DCreg are infused iv (target range 2.5-10.106/kg) 7 d before transplant (d −7), while a half dose of MPA is administered from d −7 to d 0. Standard-of-care immunosuppression (steroid, MPA, tacrolimus) is administered post-LTx, and in those patients that meet eligibility criteria for weaning, immunosuppressive therapy is gradually withdrawn, starting with MPA reduction 6 mths post-LTx. Sequential immunological analyses are conducted on recipient blood and tissue samples to track the donor-derived DCreg, evaluate anti-donor reactivity and examine potential mechanisms of immune hyporesponsiveness. In the first LTx recipient (HLA-B12+) to receive donor-derived (HLA-A3+) DCreg, peripheral blood samples were obtained before and after cell infusion; native liver tissue was obtained at the time of graft implantation. Results Donor-derived DCreg generated for infusion were HLA-DR+, CD1c−, CD11c+, CD83−, IRF4lo and expressed a high programed death ligand-1 (PD-L1):CD86 ratio. In parallel small scale in vitro functional analyses, the DCreg failed to respond to LPS, and induced donor-specific hyporesponsiveness of recipient CD4 and CD8 T cells. The donor-derived DCreg (HLA-A3+) displaying a similar phenotype to that exhibited pre-infusion, were detected in whole blood immediately after completion of the cell infusion that comprised 5.106 DCreg/kg (450.106 total DCreg). No infusion reaction or cytokine release response was observed. Three days post-infusion (d −4), HLA-A3+ donor-derived DC could no longer be detected in blood, although a small population of DC co-expressing both recipient (HLA-B12) and donor MHC (HLA-A3), ie cross-dressed DC, were evident in the circulation. At the time of transplant, before graft implantation, cross-dressed (HLA-A3+B12+) DC could also be detected in non-parenchymal cell populations isolated from the diseased native liver. Using a 14-color panel of mAbs, these tissue-resident cross-dressed DC were PD-L1hi, IRF4lo and Foxp3hi Conclusions After safe infusion of donor-derived DCreg into a prospective living donor LTx recipient, cross-dressed DC were detected in the peripheral blood within a few days and in the native diseased liver at the time of graft implantation. These cross-dressed DC, that appear to have acquired donor MHC from the infused DCreg, exhibit low levels of the DC transcription/maturation factor IRF4 and high levels of PD-L1 and Foxp3, suggesting possible in vivo regulatory function.

Medroxyprogesterone acetate, unlike norethisterone, increases HIV-1 replication in human peripheral blood mononuclear cells and an indicator cell line, via mechanisms involving the glucocorticoid receptor, increased CD4/CD8 ratios and CCR5 levels.

High usage of progestin-only injectable contraceptives, which include the intramuscular injectables depo-medroxyprogesterone acetate (DMPA-IM, Depo-Provera) and norethisterone (NET) enanthate (NET-EN or Nur-Isterate), correlates worldwide with areas of high HIV-1 prevalence. Epidemiological data show a significant association between usage of DMPA-IM and increased HIV-1 acquisition but no such association from limited data for NET-EN. Whether MPA and NET have similar effects on HIV-1 acquisition and pathogenesis, and the relationship between these effects and the dose of MPA, are critical issues for women’s health and access to suitable and safe contraceptives. We show for the first time that MPA, unlike NET, significantly increases HIV-1 replication in peripheral blood mononuclear cells (PBMCs) and a cervical cell line model. The results provide novel evidence for a biological mechanism whereby MPA, acting via the glucocorticoid receptor (GR), increases HIV-1 replication by at least in part increasing expression of the CCR5 HIV-1 coreceptor on target T-lymphocytes. MPA, unlike NET, also increases activation of T-cells and increases the CD4/CD8 ratio, suggesting that multiple mechanisms are involved in the MPA response. Our data offer strong support for different biological mechanisms for MPA versus NET, due to their differential GR activity. The dose-dependence of the MPA response suggests that significant effects are observed within the range of peak serum levels of progestins in DMPA-IM but not NET-EN users. Dose-response results further suggest that effects of contraceptives containing MPA on HIV-1 acquisition and disease progression may be critically dependent on dose, time after injection and intrinsic factors that affect serum concentrations in women.

Failure of a single dose of medroxyprogesterone acetate to induce uterine infertility in postnatally treated domestic cats

In mice and sheep, neonatal administration of progesterone or progestins inhibited development of uterine glands. The aims of the present study were (1) to describe uterine gland development on postnatal Days 6 to 8 and (2) to evaluate the effects of a single postnatal administration of a progestin on reproduction and adult uterine glands morphology and function in domestic cats. Necropsy was performed on three 1-week-old female cats which had died unrelated to this study. Ten female kittens were randomly assigned within the first 24 hours of birth to: medroxyprogesterone acetate 10 mg/animal subcutaneously (MPA; n = 6) or placebo (PLC; n = 4) and followed up until puberty when they were mated. Twenty-four days after the end of estrus, ovulation and pregnancy were diagnosed by serum progesterone measurement and ultrasonography, respectively. Then, all the cats were ovariohysterectomized. After necropsy or surgery, the excised organs were histologically evaluated. Seven queens ovulated (4 of 6 MPA and 3 of 4 PLC; P > 0.1) and were pregnant (P > 0.1). Four MPA cats presented endometrial hyperplasia and one of them developed a pyometra. The 1-week-old females presented uterine glands in the stage of budding and incipient penetration of the glandular epithelium into the underlying stroma. The MPA-treated queens revealed that the area occupied by uterine glands per square-micrometer (0.55 ± 0.2 vs. 0.49 ± 0.2; P > 0.1) and the height of the glandular epithelium (μm; 24.5 ± 6.7 vs. 24.4 ± 7.2; P > 0.1) did not differ from those of the PLC group. Neither significant gross nor microscopical differences were also found for ovaries (P > 0.1). It is concluded that 1-week-old kittens had an incipient stage of uterine gland development and that a single postnatal supraphysiological dose of MPA did not alter uterine adenogenesis in this species. Furthermore, this treatment seemed to predispose to uterine disease without prevention of fertility.

Macrophage phenotype modulation to control synovial inflammation

Macrophage phenotype modulation to control synovial inflammation

High-Dose Oral Medroxyprogesterone for Inappropriate Hypersexuality in Elderly Men with Dementia: A Case Series

To retrospectively examine the utility of high-dose oral medroxyprogesterone (MPA) for the treatment of inappropriate hypersexuality (IH) in elderly men with dementia. Ten men aged 65 years or older (median 79.5 years, range 65-93 years) were identified from all admissions at a 170-bed tertiary referral psychiatric hospital between December 2005 and January 2011. Admission records were used to identify subjects who received at least 100 mg daily of oral MPA. The primary outcome of successful treatment was chart documentation of a substantial decline in IH, such that subjects could return to preadmission residence. Data were collected to assess trends in dose, adverse effects, use of other symptom-modifying medications prior to MPA initiation, and successful return to preadmission placement. A trial serotoneric agent was used in 70% of subjects prior to MPA initiation. Sixty percent of subjects failed a trial of an antipsychotic, while 40% did not have response to the use of both a serotonergic agent and an antipsychotic before MPA was initiated. The average daily dose of MPA was 300 mg (range 100-400 mg/day). No adverse effects were documented from physician, nursing, or behavioral health rounding notes; however, adverse effects may not have been systematically assessed at the time of MPA administration. Seventy percent of subjects experienced favorable changes in target behaviors from MPA. Few data exist on effective therapy options for treatment of IH. The minimum concentration of MPA needed to suppress IH in the male body is unknown. MPA was titrated upward, with the efficacy measure being a decrease in inappropriate behaviors. Use of MPA likely contributed to decreased IH; however, other factors involved in hospitalization could have contributed to improved behavior. While requiring further study, high-dose (100-400 mg/day) oral MPA may represent an effective and well-tolerated treatment option for subjects displaying IH.

Differential proteome analysis of human embryonic kidney cell line (HEK-293) following mycophenolic acid treatment

BackgroundMycophenolic acid (MPA) is widely used as a post transplantation medicine to prevent acute organ rejection. In the present study we used proteomics approach to identify proteome alterations in human embryonic kidney cells (HEK-293) after treatment with therapeutic dose of MPA. Following 72 hours MPA treatment, total protein lysates were prepared, resolved by two dimensional gel electrophoresis and differentially expressed proteins were identified by QTOF-MS/MS analysis. Expressional regulations of selected proteins were further validated by real time PCR and Western blotting.ResultsThe proliferation assay demonstrated that therapeutic MPA concentration causes a dose dependent inhibition of HEK-293 cell proliferation. A significant apoptosis was observed after MPA treatment, as revealed by caspase 3 activity. Proteome analysis showed a total of 12 protein spots exhibiting differential expression after incubation with MPA, of which 7 proteins (complement component 1 Q subcomponent-binding protein, electron transfer flavoprotein subunit beta, cytochrome b-c1 complex subunit, peroxiredoxin 1, thioredoxin domain-containing protein 12, myosin regulatory light chain 2, and profilin 1) showed significant increase in their expression. The expression of 5 proteins (protein SET, stathmin, 40S ribosomal protein S12, histone H2B type 1 A, and histone H2B type 1-C/E/F/G/I) were down-regulated. MPA mainly altered the proteins associated with the cytoskeleton (26%), chromatin structure/dynamics (17%) and energy production/conversion (17%). Both real time PCR and Western blotting confirmed the regulation of myosin regulatory light chain 2 and peroxiredoxin 1 by MPA treatment. Furthermore, HT-29 cells treated with MPA and total kidney cell lysate from MMF treated rats showed similar increased expression of myosin regulatory light chain 2.ConclusionThe emerging use of MPA in diverse pathophysiological conditions demands in-depth studies to understand molecular basis of its therapeutic response. The present study identifies the myosin regulatory light chain 2 and peroxiredoxin 1 along with 10 other proteins showing significant regulation by MPA. Further characterization of these proteins may help to understand the diverse cellular effects of MPA in addition to its immunosuppressive activity.

Influence of Intensity of Physical Activity on Adiposity and Cardiorespiratory Fitness in 5–18 Year Olds

Physical activity (PA) is being increasingly promoted in children in an attempt to curb the rising epidemic of childhood obesity and its future consequences of obesity and cardiovascular diseases in adulthood. Although many reviews and guidelines have been published regarding PA in children and adolescents, none have specifically focused on the influence of intensity of activity on the crucial health aspects of fatness and cardiorespiratory fitness. Therefore, we conducted an online search for pertinent literature and reviewed 25 studies for this purpose. We found that there were limited studies that assessed the influence of 'intensity' of PA on health parameters, and there was considerable inconsistency in defining the thresholds for moderate (MPA) and vigorous (VPA) levels of PA. Collectively, we concluded that VPA is a significant predictor of fatness and significantly correlated to fitness. The association between the intensity of PA and cardiorespiratory fitness is more obscure compared with fatness because of limited studies and the varying conclusions made by them. However, decreased adiposity and increased aerobic capacity have been observed with participants who spent more time performing VPA. Further research needs to be undertaken to arrive at uniform thresholds for defining MPA and VPA and to obtain the exact dose of VPA and MPA, individually, to increase aerobic fitness and decrease adiposity.

Quantitative Analysis of Adrenal Cortical Histological Alterations After Application of Medroxyprogesterone Acetate

Results. Gravimetric and variance analysis demonstrated the most remarkable decrease of the adrenal gland weight after the application of 75.0 mg/kg/bw MPA (from 35.66 ± 11.78 to 13.41 ± 8.41 mg (p<0.001). On the other hand, morphometric analysis demonstrated that adrenal cortex volume was the most significantly reduced from 11.30 ± 3.53 in the control group to 2.04 ± 0.90 mm3 in the group treated with 15.0 mg/kg bw MPA (p<0.0001). Adrenal cortex thickness was reduced from 846.06 ± 6.48 to 349.55 ± 4.84 μm after the application of 75.0 mg/kg bw (p < 0.001). After the application of the same dose the glomerular zone thickness was decreased from 48.02 ± 0.44 to 41.40 ± 0.43 μm (p < 0.001), the fascicular zone thickness from 480.72 ± 3.43 to 194.32 ± 2.80 μm (p <0.001) and the reticular zone thicknes reduced from 317.47 ± 4.80 to 113.85 ± 2.28 μm (p < 0.001). The volume of glomerular zone cell nuclei decreased most remarkably from 94.79 ± 0.96 μm3 after the application of 75.0 mg/kg bw to 60.12 ± 0.88 μm3 (p < 0.001). The volume of fascicular zone cell nuceli decreased from 166.30 ± 1.53 to 52.47 ± 0.89 μm3 (p < 0.001), while the volume of reticular zone cell nuceli reduced from 95.61 ± 1.03 to 47.68 ± 0.92 μm3 (p < 0.001). The analysis by means of χ2 test showed that the appearance of tissue necrotic changes in adrenal cortex had a statistical significance only after the application of the highest dose of MPA (p < 0.012).

Evaluation of the Effect of Medroxyprogesterone Acetate on Bone Marrow Progenitor Cells

Various clinical studies have demonstrated that high-dose medroxyprogesterone acetate (HD-MPA) can reduce hematologic toxicity in patients receiving chemotherapy for advanced solid tumors. The underlying mechanism(s) of this action is still unknown. A direct effect of MPA on hemopoietic cells has been postulated, but in vitro studies have given contradictory results. To clarify the biologic activity of MPA on hemopoiesis we have evaluated in vitro growth of pluripotent and committed progenitor cells from bone marrow cells which were preincubated in vitro with various doses of MPA and subsequently treated with or without the S-phase-specific drug arabinoside-cytosine (Ara-C). Four healthy subjects and 8 patients with advanced stage solid tumors with no bone marrow involvement were studied. In our experimental model we did not observe any effect of MPA on Ara-C killing of progenitor cells from either bone marrow mononuclear cells or bone marrow mononuclear cells depleted of T-lymphocytes and adherent cells. These results suggest that MPA does not act directly (or indirectly through the production of cytokines by T-lymphocytes and/or monocytes and macrophages) on bone marrow progenitors. In addition, the supposed mechanism of rendering stem cells less susceptible to the insult of cytotoxic drugs by lowering the number of progenitors in the S-phase has been ruled out by cell kinetic studies.

The antitumor mechanism of progesterone antagonists is a receptor mediated antiproliferative effect by induction of terminal cell death.

The antiprogesterones Onapristone, ZK 112.993 (Schering AG), and Mifepristone (Roussel-Uclaf) proved to possess progesterone receptor-mediated antiproliferative effects in experimental mammary carcinomas. In this study, the potency and mechanism of the antitumor action of Onapristone and ZK 112.993 is characterized by ovariectomized, progestagen and/or estradiol substituted mice bearing hormone-dependent MXT(+) mammary tumours. Medroxyprogesterone acetate (MPA, 0.8 mg/mouse, 3 times weekly, s.c.) could only induce a poor stimulation of tumour growth (% T/C = 40; intact control % T/C = 100), which was only marginally inhibited (% T/C = 21) by Onapristone (0.2 mg/mouse, 6 times weekly, s.c.) during a 6-week therapy. Therefore, the antitumor mechanism of antiprogesterones cannot preferably depend on a classical progesterone antagonism. In contrary, the pronounced stimulation of tumor growth (% T/C = 152) by estradiol benzoate (EB, 0.33 microgram/mouse, 3 times weekly, s.c.) was completely inhibited (% T/C = 7) by the antiprogesterones. An even more stimulated tumour growth was achieved by a combination of EB and MPA (% T/C = 365 using 0.17 mg; % T/C = 225 using 0.8 mg MPA). Onapristone dramatically blocked tumor growth (% T/C = 7) at the lower dose of MPA; no inhibition (% T/C = 203), however, was detected at the higher dose of MPA. These data and a morphological analysis indicate that the potent antitumor activity of the progesterone antagonists depends on the binding to a number of available progesterone receptors high enough to trigger an antiproliferative effect via the induction of terminal differentiation associated with terminal cell death.

The pharmacokinetics of medroxyprogesterone acetate following two different loading dose schedules in advanced carcinoma of the breast.

A loading dose of MPA employing a regimen of 1,000 mg six hourly for 8 doses can achieve plateau levels above 100 ng ml-1 within the first 36 h of treatment, without any untoward toxicity. This raises the possibility of shortening the time to response for this agent. The additional factor of the time required to achieve adequate serum levels may explain the apparent contradictions between reports correlating response rates and dose and those correlating serum level and response.

Medroxyprogesterone acetate in adenomatous hyperplasia of the uterine endometrium. Clinical and morphologic studies on the duration and dosage of gestagen therapy

To learn how effective medroxyprogesterone-acetate is for treating adenomatous hyperplasia of the endometrium, we prescribed a controlled therapy in a randomly selected group of 60 women in whom we had diagnosed adenomatous hyperplasia histologically. The endometria of these women were histologically evaluated before therapy was started and again after three months of therapy. The greatest rate of regression was shown by the 40-59 year old women with adenomatous hyperplasia of grade I (15 of 23 patients). The regression occurred with 50 mg/day within three to eight months. For the women with adenomatous hyperplasia of grade II severity, 100 mg per day were required to obtain a similarly good result. For those with adenomatous hyperplasia of grade III severity, 150 mg per day were needed. The over 60-year old patients required higher doses of MPA over longer time periods for equally good therapeutic results. The patients younger than 40 years of age received lower doses (10-40 mg daily) to maintain or regain their fertility. Their adenomatous hyperplasias regressed with 20-40 mg of MPA daily, whereas with a daily dose of 10 mg their adenomatous hyperplasias recurred. The number of cases here, however, is too small for a statistical analysis. Summarising our results we recommend treating patients with adenomatous hyperplasias of grade I and II severity with MPA until it can be proved histologically that the hyperplasia has regressed. The daily dose needed for grade I hyperplasias is between 50 and 100 mg per day, whereas for grade II between 100 and 150 mg are needed.(ABSTRACT TRUNCATED AT 250 WORDS)

High-dose depot-medroxyprogesterone acetate (DMPA) - effects on lipid and lipoprotein metabolism.

Twenty-one women were given depot-medroxyprogesterone acetate (DMPA) 1000 mg/wk for 6 mth as part of the treatment for endometrial carcinoma in either clinical stage I or II. Total and free cholesterol, triglycerides and phospholipids were analysed in serum and in the ultracentrifugally separated lipoprotein fractions VLDL, LDL and HDL (very low, low and high density lipoproteins). Previous studies have shown little effect on lipoprotein metabolism after lower doses of MPA, unlike progestins of the 19-nor-testosterone series, after which an 'androgenic' lipoprotein pattern is seen, i.e., a decrease in HDL-cholesterol and in triglycerides in serum and VLDL. After this massive DMPA dose, only a slight decrease in HDL-cholesterol was seen, as well as a rise in triglycerides in serum and VLDL. We interpret the latter finding as secondary to an influence on carbohydrate metabolism.

Pharmacokinetics of medroxyprogesterone acetate administered by oral and intramuscular route.

The present study was undertaken to elucidate: 1) The relationship between plasma concentration of medroxyprogesterone-acetate (MPA, ClinovirR, Depo Provera, Upjohn) administered both orally and intramuscularly. 2) The relation between dose and plasma concentration of MPA. Nineteen patients entered the study. In each patient the plasma concentration was monitored after the administration of a single oral and one intramuscular dose of MPA at the following dosage levels: 100 mg (5 patients), 400 mg (5 patients), 800 mg (5 patients) and 1 200 mg (4 patients). The interval between the oral and i.m. administration was 1 week. The results show: 1) A very large interindividual variation in plasma concentration. 2) An increase in plasma concentration after both oral i.m. dose. 3) After the i.m. administration, plasma levels remained steady or increased slightly throughout the test period. 4) After the oral administration the concentration increased rapidly to reach a peak by 2-7 hours, subsequently decreasing. Peak concentrations were 2-10 times higher than after i.m. administration. 5) Over the test period, the plasma concentration x time (0-168 h) is similar in the two modes of administration.

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.