Combination Of Medroxyprogesterone Acetate Research Articles

The effect of micronized progesterone and medroxyprogesterone acetate in combination with transdermal estradiol on hemostatic biomarkers in postmenopausal women diagnosed with POI and early menopause: a randomized trial.

To compare the impact of micronized progesterone (MP) or medroxyprogesterone acetate (MPA) in combination with transdermal estradiol (t-E2) on traditional coagulation factors and thrombin generation parameters in postmenopausal women diagnosed with premature ovarian insufficiency or early menopause. Randomized prospective trial conducted in women diagnosed with premature ovarian insufficiency or early menopause and an intact uterus, recruited over 28 months. All participants were prescribed t-E2 and randomized to either cyclical MP or MPA using a web-based computer randomization software, Graph Pad. Thrombin generation parameters were measured at baseline and repeated after 3-months. Traditional hemostatic biomarkers were measured at baseline and repeated after 3, 6, and 12-months. Seventy-one participants were screened for the study, of whom 66 met the inclusion criteria. In total, 57 participants were randomized: 44 completed the thrombin generation assessment arm of the study, whilst 32 completed 12-months of the traditional coagulation factor screening component of the trial. Thrombin generation parameters did not significantly change from baseline after 3-months duration for either progestogen component when combined with t-E2, unlike the traditional coagulation factors. Protein C activity, free Protein S, and Antithrombin III levels decreased with time in both treatment arms. Fluctuations in traditional hemostatic biomarkers were not reproduced by parallel changes in thrombin generation parameters that remained neutral in both groups compared with baseline. The absence of statistically significant changes in thrombin generation for the first 3-months of hormone therapy use is reassuring and would suggest a neutral effect of both progestogens on the global coagulation assay.

Impact of micronised progesterone and medroxyprogesterone acetate in combination with transdermal oestradiol on cardiovascular markers in women diagnosed with premature ovarian insufficiency or an early menopause: a randomised pilot trial

To compare the difference between micronised progesterone (MP) and medroxyprogesterone acetate (MPA) in combination with transdermal oestradiol (t-E2) on cardiovascular disease (CVD) risk markers in women diagnosed with an early menopause and premature ovarian insufficiency (EMPOI). The European Society for Cardiology has identified carotid femoral pulse wave velocity (cfPWV) as the gold standard cardiogenic biomarker for risk stratification of arterial disease. Menopause has been shown to augment the age-dependent increase in arterial stiffness, with hormone replacement therapy (HRT) being the mainstay of management of women diagnosed with EMPOI. A pilot randomised prospective open-label trial. Women were randomised to either cyclical MP (Utrogestan® 200mg) or MPA (Provera® 10mg) in conjunction with t-E2 (Evorel® Patches 50mcg/day) for 12 months. Seventy-one subjects were screened, and baseline data are available for 57 subjects. Carotid-femoral pulse wave velocity (cfPWV). PWV did not significantly change from baseline in either treatment arm. MP+t-E2 demonstrated a positive effect on traditional CVD markers, with a significant improvement seen in cardiac output (CO) (0.71±1.01mL/min, 95% CI 0.20 to 1.21) and reduction in diastolic blood pressure (DBP) (-3.43±6.31mmHg, 95% Cl -6.57 to -0.29) and total peripheral resistance (TPR) (-0.15±0.19mmHg⋅min⋅mL-1, 95% CI -0.24 to -0.05) after 12 months. MPA+t-E2, in contrast, did not demonstrate significant changes from baseline in traditional haemodynamic parameters. The positive changes in traditional markers were not reflected in the cardiogenic biomarker, cfPWV, which has demonstrated a higher positive predictive value for cardiovascular events than traditional measurements.

Comparative analysis of the hormone production and gene expression profiles in ovine uterus tissue during oestrus cycle synchronized using medroxyprogesterone acetate plus eCG and prostaglandin analogue

The combination of medroxyprogesterone acetate (MPA) and gonadotropin chorionic (eCG) has been widely used to synchronize oestrus cycle in sheep, but their effects on the gene expression in uterine tissue are yet to be elucidated. To evaluate the effect of MPA + eCG or prostaglandin analogue (PA) treatments on the rate of oestrus cycle synchronization, as well as further hormone production and gene expression profiles in uterine tissue, 14 Santa Inês ewes were randomly selected. The MPA + eCG group (n=7) received intravaginal insertion of MPA-impregnated sponges for 14 days and was administered 350 IU eCG on the day of sponge withdrawal. The PA group (n=7) was administered two doses of 100 μg of PA separated by 12 days. The ewes were assessed for the rate of oestrus cycle synchronization and the serum concentrations of progesterone (P4) and estradiol (E2). Additionally, the expression of estrogen receptor (ERα), progesterone receptor (P4R), and immunolocalization of interferon receptor (IFNAR1) in the uterine tissue samples collected 15th day post-mating were examined. The rate of oestrus cycle synchronization was 100% (n=7/7) and 57.14% (n=4/7) in the MPA + eCG and PA groups, respectively. Moreover, the MPA + eCG group exhibited higher serum concentration of P4 than the PA group (p < 0.05). However, the E2 serum concentration did not differ between the two groups (p > 0.05). The relative expression of P4R and ERα mRNA analyzed using real-time PCR and immunodetection of IFNAR1 were similar between the two groups tested (p > 0.05). Conclusively, MPA + eCG treatment improved the rate of oestrus cycle synchronization and endogenous P4 production; however, it did not affect the expression of sex steroid receptors and IFNAR1 in uterine ovine tissue.

A direct comparison of women's perceptions and acceptability of micronised progesterone and medroxyprogesterone acetate in combination with transdermal oestradiol in the management of young postmenopausal women, under 45 years of age.

To assess the acceptability and perception of postmenopausal women, to two different hormone replacement therapy regimens, in relation to the control of their symptoms and development of adverse effects. Prospectively recruited postmenopausal women, <45 years, were randomised to one of two treatment arms for 12-months: cyclical micronised progesterone or medroxyprogesterone acetate in combination with transdermal oestradiol. A self-reported questionnaire with matrix rating scales was completed and repeated after 3, 6 and 12-months. Symptom control and development of adverse effects. Seventy-one individuals were screened, with baseline data available for 67 subjects. A total of 190 questionnaires were returned. The most commonly reported symptoms were low energy levels, vasomotor symptoms and sexual dysfunction. The prevalence of adverse effects ranged between 57.89 and 87.50%, with a reduction seen in the transdermal oestradiol + micronised progesterone arm (73.91% at 3-months, decreasing to 57.89% at 12-months; p = 0.33), compared to the transdermal oestradiol + medroxyprogesterone acetate arm (76.92% at 3-months, increasing to 87.50% at 12-months; p = 0.69). The main reported adverse effects were bloating, weight change and psychological symptoms. A significant difference was documented between the groups after set intervals, with a greater proportion reporting breast tenderness after 3-months (p = 0.01), lower numbers reporting mood swings at 6-months (p = 0.01) and irritability at 12-months (p = 0.03) in the transdermal oestradiol + micronised progesterone arm compared to the transdermal oestradiol + medroxyprogesterone acetate arm. The acceptability of both regimens was high despite adverse effects, but tolerability of transdermal oestradiol combined with micronised progesterone appeared to be better with fewer women reporting psychological concerns.

New therapeutic approaches for the fertility-sparing treatment of endometrial cancer.

This review seeks to describe new fertility-sparing endometrial cancer (EC) treatment strategies that take into consideration the medical and general health background of patients. We particularly focus on the application of metformin, which is a biguanide widely prescribed for treatment of type 2 diabetes mellitus. Fertility-sparing treatment using progestin is considered a standard treatment option for patients with atypical endometrial hyperplasia (AEH) and EC who desire to conceive. A previous meta-analysis of fertility-sparing treatments revealed a high remission rate; however, high rates of relapse persisted. Most young patients with AEH and EC who are subjected to fertility-sparing treatment have a background of obesity, insulin resistance and abnormal glucose tolerance complicated with polycystic ovary syndrome. Recently, metformin has been attracting more attention in the field of cancer research. Several in vitro and in vivo reports regarding the efficacy of metformin in EC management have accumulated. Thus far, the efficacy of combining metformin with progestin has been revealed in a single phase II study of medroxyprogesterone acetate in combination with metformin as a fertility-sparing treatment for patients with AEH or EC. In addition to improving the metabolic profile of patients with EC having metabolic disorders, metformin supplementation may improve the long-term oncological outcome of these patients. To date, many clinical trials employing progestin and metformin as a fertility-sparing treatment of AEH and EC are ongoing. In the near future, it is expected that the clinical advantage of metformin progestin combination therapy will be clarified.

Clinical prognostic significance and pro-metastatic activity of RANK/RANKL via the AKT pathway in endometrial cancer.

RANK/RANKL plays a key role in metastasis of certain malignant tumors, which makes it a promising target for developing novel therapeutic strategies for cancer. However, the prognostic value and pro-metastatic activity of RANK in endometrial cancer (EC) remain to be determined. Thus, the present study investigated the effect of RANK on the prognosis of EC patients, as well as the pro-metastatic activity of EC cells. The results indicated that those with high expression of RANK showed decreased overall survival and progression-free survival. Statistical analysis revealed the positive correlations between RANK/RANKL expression and metastasis-related factors. Additionally, RANK/RANKL significantly promoted cell migration/invasion via activating AKT/β-catenin/Snail pathway in vitro. However, RANK/RANKL-induced AKT activation could be suppressed after osteoprotegerin (OPG) treatment. Furthermore, the combination of medroxyprogesterone acetate (MPA) and RANKL could in turn attenuate the effect of RANKL alone. Similarly, MPA could partially inhibit the RANK-induced metastasis in an orthotopic mouse model via suppressing AKT/β-catenin/Snail pathway. Therefore, therapeutic inhibition of MPA in RANK/RANKL-induced metastasis was mediated by AKT/β-catenin/Snail pathway both in vitro and in vivo, suggesting a potential target of RANK for gene-based therapy for EC.

Decidualisation of human endometrial stromal cells is associated with increased expression and secretion of prorenin.

BackgroundIn pregnancy, the decidualised endometrium expresses high levels of prorenin and other genes of the renin-angiotensin system (RAS) pathway. In this study we aimed to determined if the RAS was present in endometrial stromal cells and if decidualisation upregulated the expression of prorenin, the prorenin receptor ((P)RR) and associated RAS pathways. Immortalised human endometrial stromal cells (HESCs) can be stimulated to decidualise by combined treatment with medroxyprogesterone acetate (MPA), 17β-estradiol (E2) and cAMP (MPA-mix) or with 5-aza-2’-deoxycytidine (AZA), a global demethylating agent.MethodsHESCs were incubated for 10 days with one of the following treatments: vehicle, MPA-mix, a combination of medroxyprogesterone acetate (MPA) and estradiol-17β alone, or AZA. Messenger RNA abundance and protein levels of prorenin (REN), the (P)RR (ATP6AP2), angiotensinogen (AGT), angiotensin converting enzyme (ACE), angiotensin II type 1 receptor (AGTR1), vascular endothelial growth factor (VEGF), and plasminogen activator inhibitor-1 (PAI-1) were measured by real-time PCR and ELISA’s, respectively. Promyelocytic zinc finger (PLZF) and phospho-inositol-3 kinase (PIK3R1) mRNA abundances were also measured.ResultsHESCs expressed the prorenin receptor (ATP6AP2), REN, AGT, ACE and low levels of AGTR1. MPA-mix and AZA stimulated expression of REN. Prorenin protein secretion was increased in MPA-mix treated HESCs. E2 + MPA had no effect on any RAS genes. MPA-mix treatment was associated with increased VEGF (VEGFA) and PAI-1 (SERPINE1) mRNA and VEGF protein.ConclusionsAn endometrial prorenin receptor/renin angiotensin system is activated by decidualisation. Since (P)RR is abundant, the increase in prorenin secretion could have stimulated VEGF A and SERPINE1 expression via Ang II, as both ACE and AGTR1 are present, or by Ang II independent pathways. Activation of the RAS in human endometrium with decidualisation, through stimulation of VEGF expression and secretion, could be critical in establishing an adequate blood supply to the developing maternal placental vascular bed.

Synthetic gestagens exert differential effects on arterial thrombosis and aortic gene expression in ovariectomized apolipoprotein E-deficient mice.

Combined hormone replacement therapy with oestrogens plus the synthetic progestin medroxyprogesterone acetate (MPA) is associated with an increased risk of thrombosis. However, the mechanisms of this pro-thrombotic effect are largely unknown. The purpose of this study was to: (i) compare the pro-thrombotic effect of MPA with another synthetic progestin, norethisterone acetate (NET-A), (ii) determine if MPA's pro-thrombotic effect can be antagonized by the progesterone and glucocorticoid receptor antagonist mifepristone and (iii) elucidate underlying mechanisms by comparing aortic gene expression after chronic MPA with that after NET-A treatment. Female apolipoprotein E-deficient mice were ovariectomized and treated with placebo, MPA, a combination of MPA + mifepristone or NET-A for 90 days on a Western-type diet. Arterial thrombosis was measured in vivo in a photothrombosis model. Aortic gene expression was analysed using microarrays; GeneOntology and KEGG pathway analyses were conducted. MPA's pro-thrombotic effects were prevented by mifepristone, while NET-A did not affect arterial thrombosis. Aortic gene expression analysis showed, for the first time, that gestagens induce similar effects on a set of genes potentially promoting thrombosis. However, in NET-A-treated mice other genes with potentially anti-thrombotic effects were also affected, which might counterbalance the effects of the pro-thrombotic genes. The pro-thrombotic effects of synthetic progestins appear to be compound-specific, rather than representing a class effect of gestagens. Furthermore, the different thrombotic responses elicited by MPA and NET-A might be attributed to a more balanced, 'homeostatic' gene expression induced in NET-A- as compared with MPA-treated mice.

Reversion of Hormone Treatment Resistance with the Addition of an mTOR Inhibitor in Endometrial Stromal Sarcoma.

Background. Endometrial stromal sarcomas (ESS) are a subtype of gynaecological sarcomas characterized by the overexpression of hormone receptors. Hormone treatment is widely used in ESS but primary or acquired resistance is common. The mammalian target of rapamycin (mTOR) pathway has been suggested to play a key role in the mechanisms of hormone resistance. Recent studies in breast and prostate cancer demonstrate that this resistance can be reversed with the addition of an mTOR inhibitor. This phenomenon has never been reported in ESS. Methods. We report the outcome of one patient with pretreated, progressing low grade metastatic ESS treated with medroxyprogesterone acetate in combination with the mTOR inhibitor sirolimus. Results. Partial response was achieved following the addition of sirolimus to the hormone treatment. Response has been maintained for more than 2 years with minimal toxicity and treatment is ongoing. Conclusion. This case suggests that the resistance to the hormone manipulation in ESS can be reversed by the addition of an mTOR pathway inhibitor. This observation is highly encouraging and deserves further investigation.

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

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

Combined effects of MPA and EBRT in stage Ic endometrial cancer patients

To report the comparative effect of combined medroxyprogesterone acetate (MPA) and external beam pelvic radiotherapy (EBRT) with EBRT alone on local or distant recurrences, overall survival and treatment related toxicities in patients with stage Ic grade 3 endometrial cancer. A retrospective review of 80 International Federation of Gynecology and Obstetrics (FIGO) stage Ic grade 3 endometrial carcinoma patients treated between October 1994 and October 2004 at Renmin Hospital, Wuhan University, China was performed. All patients underwent surgery, of which 40 patients in arm I received combined MPA and EBRT while in arm II 40 patients received only adjuvant EBRT after surgery. The median dose of EBRT in arm I was 50 Gy (range 36–54 Gy) and in arm II was 45.2 Gy (range 43.2–50.4 Gy). Multivariate analysis was performed for the prognostic factors and Kaplan-Meier method was used for overall survival. Of the 80 eligible patients, 40 in each group could be evaluated. The follow-up times ranged from 4–98 months with a median of 45 months. The overall survival rates at five years were 73% among patients treated with combined MPA and EBRT and 28.2% among patients treated with EBRT alone (P < 0.001). The rate of distant metastasis was significantly higher among patients treated with EBRT alone group than combined MPA and EBRT (55% vs 25%, P = 0.006) while no difference in loco regional recurrence rates was observed in both treatment groups. Most of the side effects observed in the combined MPA and EBRT group. Age (P < 0.001) and the presence of progesterone receptors (P = 0.003) were independent significant prognostic factors for overall survival in multiple regression analysis. We has been concluded that the addition of progestagen to external beam pelvic radiotherapy significantly improved survival and reduced distant metastasis among women with stage Ic grade 3 endometrial cancer.

Medroxyprogesterone acetate attenuates long-term effects of 17β-estradiol in coronary arteries from hyperlipidemic rabbits

Objective The progestin component in hormone replacement treatment may oppose the effects of estrogen on vascular function. This study examined the effect of long-term treatment with 17β-estradiol (E 2) alone and in combination with two progestins on K + and Ca 2+-mediated mechanisms in coronary arteries. Methods Watanabe heritable hyperlipidemic rabbits were treated orally with either E 2 (4 mg/day), medroxyprogesterone acetate (MPA) (10 mg/day), norethindrone acetate (NETA) (2 mg/day), E 2 + MPA, E 2 + NETA, or placebo for 16 weeks ( n = 10 in each group). Coronary arteries were used for mRNA and myograph studies. Results E 2 increased vasodilatation induced by sodium nitroprusside and decreased vasocontraction induced by potassium. The first but not the latter response was opposed by MPA. The combination of MPA and E 2, but neither compound alone enhanced nimodipine-induced vasodilatation and increased the expression of L-type voltage-gated Ca 2+ channel mRNA. NETA had no opposing effects. Hormone treatment did not affect large-conductance Ca 2+ activated or ATP-sensitive K + channels or cGMP-dependent protein kinase mRNA expression. Hyperlipidemia had no effect on vascular reactivity. Conclusion When E 2 is administered with MPA, effects of E 2 on nitric oxide and Ca 2+-mediated vascular reactivity in rabbit coronary arteries are modulated. The results suggest that the progestin component in hormone replacement treatment may interfere with the supposed beneficial vascular effects of estrogen.

The effect of mifepristone on estrogen receptors following treatment with medroxyprogesterone acetate in cultured human endometrial explants

Objective: Mifepristone has been recently demonstrated to diminish breakthrough bleeding in users of progestin contraceptives. The purpose of this study was to investigate the use of cultured endometrial explants to study the effects of mifepristone and medroxyprogesterone acetate (MPA) on endometrial sex steroid receptors. Design: Prospective histological, immunocytochemical and molecular analysis. Materials and Methods: Human endometrium was obtained by biopsy during the secretory phase, cut into 1 mm3 pieces, and cultured in D-MEM/F-12 with 5% charcoal-stripped fetal bovine serum on Millicell Organotypic culture inserts for 24 hours. Thereafter, explants were cultured for 48 hours in serum-free media in the absence and presence of 17 beta-estradiol (E2, 1 nm), MPA (100 nm), E2 plus MPA, mifepristone (1 um), and MPA plus mifepristone, respectively. Explants were then frozen for total RNA isolation or fixed in 10% formalin for morphological and immunocytochemical analysis. H & E staining was performed on sections before and after culture. Levels of ER and PR mRNA were determined by RT-PCR while protein levels were evaluated by immunocytochemistry. Results: Explants showed little or no necrosis up to 72 hours of culture on H & E staining. High molecular weight, non-degraded RNA was demonstrated on gel electrophoresis after 72 hours in culture. Using RT-PCR analysis with beta-actin as reference, PR expression was seen to increase after E2, decrease after MPA and slightly increase in the presence of E2 and MPA. These changes were further confirmed by immunocytochemical analysis. It was also demonstrated by immunocytochemistry that MPA decreased PR and ER expression whereas the combination of MPA and mifepristone increased PR and ER expression. Conclusion: Tissue viability of endometrial explants can be maintained in culture up to 72 hours and can be used to directly evaluate the induction or repression of gene products in the endometrium by progestins and anti-progestins. Supported by: NIH HD043189.

Comparison of the reduction of postoperative adhesions by two barriers, one solution, and two pharmacologic agents in the rat uterine model

Objective: To evaluate the effects of two barriers, one solution, and two pharmacologic agents, in single or in combined use, for preventing postsurgical adhesion formation in the rat model. Design: A randomized, prospective study to evaluate the ability of leuprolide acetate, oxidized regenerated cellulose, medroxyprogesterone acetate, sodium hyaluronate, sodium hyaluronate/carboxymethyl cellulose, in single or in combined use, for preventing adhesion formation in a rat model. Animal(s): Wistar female rats. Setting: University animal laboratory. Intervention(s): Intramuscular injection of pharmacologic agents before surgery and intraperitoneal application of barriers and solution at the end of surgery. Main Outcome Measure(s): Two weeks after surgery, a second laparotomy was performed and the extent of adhesion formation was determined. Result(s): All the treatment groups had fewer, less severe adhesions when compared with controls. The combination of medroxyprogesterone acetate and oxidized regenerated cellulose did enhance the adhesion-reducing capacity of oxidized regenerated cellulose. The performance of sodium hyaluronate solution for adhesion prevention was statistically significant, when compared with oxidized regenerated cellulose alone, or sodium hyaluronate used with carboxymethyl cellulose film. Conclusion(s): Pharmacologic agents, barriers, or solutions result in significant reduction of postsurgical adhesions. The sodium hyaluronate solution alone and medroxyprogesterone acetate treatment alone had the least adhesion prevention scores. However, neither monotherapy nor combined therapy proved to be significantly more beneficial.

Comparison of the effects of continuous combined and sequential combined medroxyprogesterone acetate–estradiol treatment on the proliferation of MCF-7 cells

Objective The aim of the study was to examine the effects of two different, clinically relevant, hormone replacement therapy (HRT) regimen types, continuous combined and sequential combined, on breast cancer cells by means of an in vitro model. The study was carried out using the C21-progestin medroxyprogesterone acetate (MPA) in combination with estradiol, and with the proliferation of MCF-7, a human breast cancer cell-line, as end-point.Methods Proliferation of MCF-7 cells was measured by means of a crystal violet staining technique. Growth was triggered using a constant estradiol concentration of 10-10 mol/l, while varying the MPA concentration from 10-11 to 10-6 mol/l.Results The continuous combined model of treatment led to the inhibition of estradiol-induced growth of MCF-7 with MPA concentrations of 10-10 mol/l and upwards, compared with estradiol-alone-induced growth. The sequential combined model showed a greater inhibition at the higher MPA concentrations of 10-8-10-6 mol/l, with reduced sensitivity to inhibition at the lower MPA concentrations tested, of 10-11-10-9 mol/l. The different treatment types resulted in significantly different sensitivities of the MCF-7 cells to inhibition of estradiol-induced proliferation at the higher MPA concentrations of 10-8-10-6 mol/l.Conclusions The results demonstrate the importance of considering in vivo factors in an in vitro model with regard to improving the cell culture techniques used, to obtain a clearer picture of the possible mechanisms involved in the potential breast cancer risk with different HRT regimens.Partly presented at the 2nd Amsterdam Menopause Symposium, Amsterdam, 16–18 April, 2000 and awarded 1st poster prize (abstract BRE 01)

The effect of medroxyprogesterone acetate and heparin in the prevention of postsurgical adhesion formation in the rat uterine model.

To evaluate the effects of depot medroxyprogesterone acetate and heparin in preventing postsurgical adhesion formation in the rat model. A hundred and five female Wistar rats were divided into 7 groups. Groups 1 and 2 were injected with intramuscular 15 mg medroxyprogesterone acetate 3 weeks before surgery and at the end of laparotomy. Groups 3 and 4 were given 15 mg medroxyprogesterone acetate by intramuscular injection, 3 weeks before surgery. An equal volume of intramuscular sterile saline was injected to control groups, 3 weeks before and at the end of surgery. Before abdominal closure, 2 ml of Ringer's lactate was instilled into the peritoneal cavity of all rats, except group 7. Groups 1, 4, and 5 were given 2 ml of intraperitoneal Ringer's lactate containing 500 U heparin/ml. A standardized surgical injury was performed in all rats. Two weeks after surgery, the adhesions were scored on a scale of 0 to 3 according to their thickness-tenacity and vascularity. Kruskall-Wallis and Mann-Whitney U statistical test were used. The preoperative and postoperative administration of medroxyprogesterone acetate resulted in the least number of and the least severe adhesions, when compared with single dose medroxyprogesterone acetate treated rats and controls (p < 0.05). However, the combination of medroxyprogesterone acetate and intraperitoneal heparin did not enhance the adhesion reducing capacity of medroxyprogesterone acetate. Concurrent preoperative and postoperative administration of medroxyprogesterone acetate results in the most significant reduction of postsurgical adhesions. The combination treatment of medroxyprogesterone acetate and heparin does not show any additional effect in the reduction of adhesion formation, when compared with medroxyprogesterone acetate treatment alone.

Estrogens, Progesterone, and Endometrial Cancer

We conducted a case-control study to evaluate the effect of replacement estrogen use alone, and the combined effect of estrogen and progesterone use, on the risk for endometrial cancer. We studied women age 50-64 years at Group Health Cooperative of Puget Sound. We identified 172 incident cases of endometrial cancer diagnosed during the years 1979-1989, and controls of similar age and duration of membership in the plan. Women who had used conjugated estrogens alone for 5 or more years were at increased risk for developing endometrial cancer compared with nonusers [adjusted rate ratio (RR) = 22.0; 95% confidence interval (CI) = 6.5-74.1]. Users of unopposed estrogens of 3-4 years' duration had a relative risk of 1.9 (95% CI = 0.4-8.7). Women who had used medroxyprogesterone acetate in combination with the estrogen therapy for 3 or more years had a risk near that of nonusers (adjusted RR = 1.3; 95% CI = 0.5-3.4) and that of users of unopposed estrogens for less than 5 years. There were insufficient women who used estrogen and progesterone together for 5 or more years to derive a separate risk estimate for these women.

Depo-provera treatment for sex-offending behavior: An evaluation of outcome : Walter J. Meyer, III, Collier Cole, Evangeline Emory University of Texas Medical Branch, Galveston, TX 77555-0429

Forty men, ages 16 to 78 years, with sex-offending behavior, were treated with combined medroxyprogesterone acetate (MPA), group therapy, and individual psychotherapy. Twenty-three are pedophiles; seven, rapists; and 10, exhibitionists. Five had sex-offending behavior that began after head trauma. The duration of MPA therapy, usual intramuscular dose 400 mg/wk, ranged from six months to 12 years, usually more than two years. These men were compared with a control group of 21 men who refused MPA therapy. They had similar types of sex-offending behavior and were treated with psychotherapy alone with follow-up for a period that ranged from two to 12 years. MPA-related side effects included excessive weight gain, malaise, migraine headaches, severe leg cramps, elevation of blood pressure, gastrointestinal complaints, gallbladder stones, and diabetes mellitus. Of the 40 individuals who took MPA, 10 are still on therapy. Eighteen percent reoffended while receiving MPA therapy; 35 percent reoffended after stopping MPA. In contrast, 58 percent of the control patients, who refused and never received MPA, reoffended. Patients defined as regressed were much more likely to reoffend off therapy than the patients defined as fixated. Other risk factors for reoffense include elevated baseline testosterone, previous head injury, never forming a marriage relationship, and alcohol and drug abuse. In spite of significant medical side effects, maintenance MPA offers benefit for the compulsive sex offender by reducing the reoffense rate.

Treatment of Rat Prostatic Adenocarcinoma with Medroxyprogesterone Acetate (mpa): Effects On Growth and Morphology

Rats bearing the Dunning R3327H prostatic carcinoma were castrated and supplemented with testosterone propionate. These rats were then treated with estradiol benzoate or medroxyprogesterone acetate alone or in combination with estradiol During the treatment period of six weeks, the growth rate of the prostatic tumors was measured. At the end of the treatment period the morphology of the tumors was also studied. It was found that medroxyprogesterone acetate is as effective as estradiol in inhibiting the growth of the Dunning prostatic carcinoma and that the combination of medroxyprogesterone acetate and estradiol was more efficient in that respect than estradiol alone.Morphometric evaluation of the tumor epithelium and stroma showed a decrement of epithelial growth in all treatment groups, while the groups treated with medroxyprogesterone acetate, both alone or in combination with estradiol, also showed an inhibited growth of the tumor stroma. It was concluded that medroxyprogesterone acetate probably has direct inhibitory effects on prostatic tumor cells in the Dunning model and that medroxyprogesterone acetate may act in an additive manner with estradiol.

Effects of domperidone and medroxyprogesterone acetate on ventilation in man

If endogenous dopamine acts as an inhibitory neurotransmitter in the carotid bodies in man, domperidone (DP), a selective dopamine D-2 receptor antagonist should stimulate carotid bodies and augment ventilation. Furthermore, the combination of a central ventilatory stimulant, medroxyprogesterone acetate (MPA), with a peripheral ventilatory stimulant, DP, may produce an additive/synergistic ventilatory effect. We conducted a double-blind, placebo-controlled (P), cross-over trial comparing MPA 20 mg three times daily (TID) and DP (20 mg TID) alone and together in 8 healthy male human subjects. Drug effects were measured after 7 days, and a two-week drug washout period was allowed. MPA significantly increased alveolar ventilation (V̇ a), and slopes of hypercapnic and hypoxic ventilatory responses. Domperidone alone significantly increased the slope of the hypoxic response; however, V̇ a and Pa CO 2 did not change significantly. The combination of MPA and DP resulted in ventilatory changes similar to MPA alone. We conclude that in man endogenous dopamine acts as a modulator of chemoreception during hypoxemia, but plays no major role tonically in control of ventilation during normoxemia and normocapnia. Lack of additive effect with combined DP and MPA suggests that these drugs may share the same final common pathway in the process of chemoreception.