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PubMed1981

Effects of different progestogens on lipoproteins during postmenopausal replacement therapy.

To study the effects of different types of progestogens on lipoprotein metabolism, we treated three groups of postmenopausal women (six subjects each) for three weeks with estradiol valerate, 2 mg per day, and continued the treatment with different sequential estradiol-progestogen regimens as follows: Group A received norethindrone acetate, 10 mg per day, from Day 15 to Day 24 of the cycle; Group B, medroxyprogesterone acetate, 10 mg per day; and Group C, norgestrel, 0.5 mg per day. These regimens were followed by two consecutive cycles. Total cholesterol decreased in all groups by 10 to 18 per cent from the base-line values (P < 0.05). High-density-lipoprotein (HDL) cholesterol decreased by 20 per cent from the base-line level during treatment with both the estradiol-norethindrone acetate (P < 0.05) and estradiol-norgestrel (P < 0.01) regimens, whereas estradiol with medroxyprogesterone acetate was not associated with a significant change in HDL cholesterol. Our results suggest that the androgenic progestogens of the 19-nortestosterone series reverse the beneficial effect of postmenopausal estrogen treatment on HDL cholesterol, whereas the hydroxyprogesterone derivative medroxyprogesterone acetate has no such effect.

Cholesterol↗
PubMed1979

The effect of an injectable progestogen contraceptive on blood coagulation and fibrinolysis.

In 26 women receiving either medroxyprogesterone acetate (Depo-Provera) injections or combined oestrogen-progestogen pills for contraception, tests of coagulation and fibrinolysis were performed before treatment, and after 8, 16 and 24 weeks of therapy. In the medroxyprogesterone group no significant changes were induced in fibrinogen, the vitamin K-dependent factors, or antithrombin III. Plasminogen levels fell during therapy, and were significantly lower than pre-treatment values after 16 and 24 weeks. By contrast, the 13 women receiving oral contraceptives showed raised levels of fibrinogen and plasminogen after 8 weeks of treatment, and of factors VII and X after 24 weeks. These data suggest that medroxyprogesterone acetate injections induce fewer changes in the blood coagulation system than oral contraceptives.

Adult↗
PubMed1985

[Changes in serum lipoproteins under hormonal therapy of breast carcinoma and other endocrine-dependent tumors].

The higher the low-density-lipoprotein cholesterol (beta lipoprotein) level, the greater the risk that coronary heart disease will develop, alpha-lipoprotein fractions (high-density-lipoproteins) are considered to be protective factors. Medroxyprogesterone acetate is responsible for characteristic changes of the lipoprotein patterns indicating enhanced coronary risks. Medroxyprogesterone acetate is applied in the therapy of breast, uterus and ovarian cancer. A statistically significant decrease was observed in alpha-lipoproteins whereas beta-lipoproteins increased without statistical significance. A similar reaction can be observed under the combination therapy of aminoglutethimide and medroxyprogesterone acetate, whereas the combination of cortisone and aminoglutethimide has a distinct influence on beta-lipoproteins but the alpha-lipoprotein level remains uninfluenced. According to these data the effect of an adjuvant application of these drugs must be carefully evaluated due to an increase of coronary risks.

Aminoglutethimide↗
PubMed1990

Aromatase activity of human adipose tissue stromal cells: effects of thyroid hormones and progestogens.

In order to determine the direct effects of thyroid hormones and progestogens on extraglandular aromatization, human adipose stromal cells in monolayer culture were used as a model system for this study on the regulation of aromatase enzyme activity. It was found that 1-thyroxine at 2- and 4-fold normal concentrations (220 and 440 nM, respectively) and triiodothyronine at 4-fold normal concentration (7.4 nM) had no effect on basal, dibutyryl cyclic AMP ((Bu)2 cAMP)-induced, or dexamethasone-induced aromatization. Medroxyprogesterone acetate at a concentration of 25.9 nM, but not progesterone, 47.7 nM, stimulated basal aromatization slightly but not significantly. In contrast, both medroxyprogesterone acetate and progesterone potentiated the effect of (Bu)2 cAMP on aromatase activity (P less than 0.05 and P less than 0.01, respectively) but had no effect on dexamethasone-stimulated aromatase activity. We concluded that (i) the increased peripheral aromatization associated with hyperthyroidism is not due to the direct effect of thyroid hormones on aromatase activity, and (ii) neither progesterone nor medroxyprogesterone acetate inhibit aromatase activity of adipose tissue stromal cells, but may stimulate this activity under certain conditions.

Adipose Tissue↗
PubMed1992

Progestin and estrogen control of cathepsin D expression and processing in rat uterine luminal epithelium and stroma-myometrium.

Progestins increase the activity and rate of synthesis of cathepsin D, a lysosomal aspartyl protease, in the uterine luminal epithelium in ovariectomized rats. Western blot analysis of luminal epithelial proteins determined that the progestin, medroxyprogesterone acetate (MPA) increased the 43-kDa form of cathepsin D by 7-fold in 24 hr, whereas estradiol increased the amount of the same form by only 2-fold. To examine the precursor-product relationship between cathepsin D proteins in the luminal epithelium and stroma-myometrium after progestin or estradiol treatment, uterine proteins were prelabeled by incubation with [35S]methionine in vitro, cathepsin D was isolated by immunoprecipitation, and equal amounts of labeled cathepsin D were subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis. After each hormonal treatment in each uterine tissue, a 48-kDa precursor was processed into a 44-kDa cathepsin D product. Endoglycosidase H digestion of [35S]methionine-labeled cathepsin D from the luminal epithelium and stroma-myometrium of medroxyprogesterone-treated rats shifted the molecular masses of the cathepsin D proteins by approximately 5.7 kDa. To examine the contribution of increased mRNA to increased rates of cathepsin D synthesis, we measured levels of cathepsin D mRNA in uterine tissues after progestin and estrogen treatment. Total RNA was isolated from the uterine luminal epithelium and from the stroma-myometrium. Northern blot analysis identified a single 2.2-kb RNA band corresponding to the size expected for cathepsin D mRNA. Medroxyprogesterone increased levels of cathepsin D mRNA in the luminal epithelium (greater than 17-fold) and in the stroma myometrium (3-fold), with maximum increases at 9 hr after treatment. Estradiol also increased cathepsin D mRNA levels in both uterine tissues, but by only 2-fold. No hormonal effects on liver cathepsin D mRNA were observed. Increases in cathepsin D synthesis and activity in uterine tissues in response to progestin and estrogen appear to depend in part upon increased levels of mRNA.

Animals↗
PubMed1991

Effects of sex steroids on skin 5 alpha-reductase activity in vitro.

Skin 5 alpha-reductase activity is the major factor influencing the manifestation of androgen excess. Although oral contraceptives have been useful for the treatment of androgen excess, little is known of the independent effects of the various progestins and estrogens on inhibition of skin 5 alpha-reductase activity. We incubated minces of normal genital and pubic skin with physiologic concentrations of 3H-testosterone to assess 5 alpha-reductase activity by its conversion to 3H-dihydrotestosterone. In separate experiments, 5 alpha-reductase activity was assessed before and after the addition of progesterone, medroxyprogesterone acetate, levonorgestrel, norethindrone, 17 beta-estradiol, and ethinyl estradiol. Progesterone, levonorgestrel, and norethindrone demonstrated 97 +/- 5.3%, 47.9 +/- 6.3%, and 59 +/- 4.6% inhibition, respectively, of genital skin 5 alpha-reductase activity at 10(-4) mol/L (P less than .01). Medroxyprogesterone acetate, however, failed to affect 5 alpha-reductase activity at similar doses. Estradiol exhibited 40.8 +/- 14.2% inhibition at 10(-4) mol/L (P less than .01), whereas ethinyl estradiol at concentrations from 10(-8) to 10(-4) mol/L failed to inhibit 5 alpha-reductase activity. We conclude that progesterone and the 19-nor-derivatives inhibit 5 alpha-reductase activity at high doses, whereas medroxyprogesterone acetate does not. Therefore, the 19-nor-progestin component may expand the usefulness of oral contraceptives in the treatment of hirsutism by an inhibitory action on skin 5 alpha-reductase activity.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1986

Experimental combined hormone therapy on human breast carcinomas serially transplanted into nude mice.

Experimental combined hormone therapy with tamoxifen, aminoglutethimide and medroxyprogesterone acetate was investigated using three hormone-dependent human breast carcinomas serially transplanted into nude mice. The antitumor effect of combined tamoxifen and aminoglutethimide was better than that of either tamoxifen or aminoglutethimide alone. Since aminoglutethimide significantly reduced the level of estrogen and the uterine weight in normal female mice, the antitumor effect of combined tamoxifen and aminoglutethimide was assumed to be a result of the low estrogen level produced by aminoglutethimide, favoring the competition of tamoxifen with estrogen receptors. There was no additive antitumor effect of the combination of tamoxifen and medroxyprogesterone acetate, although serum medroxyprogesterone acetate levels in nude mice were almost equivalent to those of humans. These results indicate that combination hormone therapy, especially with and aminoglutethimide, might be a promising method for clinical application.

Adult↗
PubMed1986

Is Provera the ideal progestogen for addition to postmenopausal estrogen therapy?

In a dose-ranging study, medroxyprogesterone acetate, 2.5, 5, or 10 mg daily, was given for 12 days of each calendar month to postmenopausal women also receiving conjugated estrogens, 0.625 mg daily, continuously. Endometrial biopsy specimens were taken on the sixth day of combined therapy for histologic, ultrastructural and biochemical evaluation. Medroxyprogesterone acetate induced secretory and ultrastructural changes within the endometrium, but the responses were variable and inconsistent. Suppression of epithelial deoxyribonucleic acid synthesis appeared dose-dependent. The levels of nuclear estradiol receptor, although reduced to within the secretory phase range, were not significantly lower than the values observed during the estrogen-only phase of treatment. Induction of both estradiol and isocitrate dehydrogenase activities was to within the secretory phase ranges, but the magnitude of these responses appeared less than those observed previously with other progestogens. Both morphologically and biochemically, medroxyprogesterone acetate, even at high dosage, produced suboptimal responses. Further studies are required to establish whether this is a dose-related effect.

Biopsy↗
PubMed1982

Abnormalities of fuel metabolism in the polycystic ovary syndrome.

To investigate the metabolic effects of medroxyprogesterone acetate, carbohydrate and lipid metabolism in women with polycystic ovary syndrome was evaluated before and after long-term therapy with this drug. The effects of suppression of pituitary gonadotropins and ovarian sex steroids were correlated with the response to an oral glucose load and with a serum lipid profile. Twenty of 25 women with polycystic ovary syndrome weighted more than 150% of their ideal body weight. None of the patients had fasting hyperglycemia. Fasting and peak serum insulin responses to glucose were abnormally high in most patients with polycystic ovary syndrome. Fasting serum insulin had a significant positive correlation with percent ideal body weight (r = .7, P less than .01). High density lipoprotein cholesterol was low in all patients studied, whereas total cholesterol and serum triglyceride levels were normal. Therapy with medroxyprogesterone acetate did not affect body weight, glucose tolerance, or serum lipids. The correlations between serum testosterone and high-density lipoprotein cholesterol or insulin levels were not significant (P greater than .1). The authors conclude that medroxyprogesterone acetate does not affect the metabolic syndrome of obesity, hyperinsulinemia, and decreased high-density lipoprotein cholesterol that is commonly seen in patients with polycystic ovary syndrome.

Adult↗
PubMed1995

A potential single insertion protocol for quinacrine pellet non-surgical female sterilization.

Two preliminary single-insertion clinical trials of the quinacrine pellet method of non-surgical female sterilization were compared. Both trials used transcervical application of quinacrine, 252 mg, and diclofenac, 75 mg, as pellets. In the first trial (21 April 1992 to 17 February 1993), 58 women received oral contraceptives for three months. In the second trial (19 February 1993 to 25 May 1994), 229 women received medroxyprogesterone acetate, 150 mg IM, at the time of quinacrine insertion. At 18 months, the life-table pregnancy failure rate per 100 women of the first trial was 8.6 (SE 3.7), whereas the failure rate for the medroxyprogesterone acetate group was 0.5 (SE 0.5), p<0.05. There were no serious complications or side-effects in either group. Larger confirming trials with random allocation and long-term systematic follow-up are needed to determine whether a single injection of medroxyprogesterone improves the efficacy of quinacrine.

Cervix Uteri↗
PubMed1989

The biologic significance of cytologic atypia in progestogen-treated endometrial hyperplasia.

Eighty-five menopausal women (mean age 56 years) with endometrial hyperplasia without (65 patients, group 1) and with cytologic atypia (20 patients, group 2) were followed up prospectively from 2 to 12 years (mean 7 years) to shed insight into their respective response to oral medroxyprogesterone acetate therapy. In group 1 9 of 65 patients (14%) had persistence, 4 (6%) had recurrence, and none developed carcinoma. In group 2 10 of 20 patients (50%) had persistence and 5 had recurrence with cytologically atypical disease. Five of 20 patients (25%) developed adenocarcinoma at 2 to 7 years (mean 5.5 years) after starting medroxyprogesterone acetate therapy. The data suggest that most women with hyperplasia respond to progestogenic therapy and are not at increased risk of developing cancer. The patients with an unfavorable response to medroxyprogesterone acetate and a significant elevation in cancer risk can be identified on the basis of cytologic atypia.

Adenocarcinoma↗
PubMed1989

Comparison of in vivo bioavailability of progestational agents into the rat uterus and liver and the effect of plasma protein binding.

The in vivo bioavailabilities of three clinically available progestational agents were evaluated with a previously described rat model. With this model a single-injection, double-isotope technique was performed to calculate and compare the unidirectional extractions of progesterone, 19-nortestosterone, and medroxyprogesterone acetate into the rat uterus and liver. To assess the role of plasma protein binding in the extraction of these agents, steroids were presented in four different vehicles: (1) Ringer's solution, 0.1% bovine serum albumin; (2) Ringer's solution, 4% bovine serum albumin; (3) Ringer's solution, 0.8 mg/ml, alpha 1-acid glycoprotein; (4) human pregnancy serum. The results revealed that liver extraction always exceeded uterine extraction for each progestin, regardless of the vehicle, and that liver extraction was approximately 100% for all steroids. With regard to the uterus, when binding proteins were not present in the injectate, the extraction of the three steroids was similar; the uterine vasculature was relatively permeable to these progestins, and bovine serum albumin and alpha 1-acid glycoprotein had no major effect on the uptake into the uterus. However, when human pregnancy serum was in the injectate, the extractions of progesterone and 19-nortestosterone into the rat uterus were significantly diminished. In contrast, pregnancy serum had no effect on the uptake of medroxyprogesterone acetate into the uterus, with the extraction equal to that of Ringer's solution alone. This suggests that, regardless of potential binding proteins, medroxyprogesterone acetate displays greater bioavailability than that of the other progestogens studied.

Albumins↗
PubMed1982

Lipid metabolic studies in oophorectomised women: effects on serum lipids and lipoproteins of three synthetic progestogens.

Norethisterone acetate, medroxyprogesterone acetate and levonorgestrel were administered to oophorectomised women to evaluate the effects they have on lipid metabolism. Blood samples were drawn after a 3 wk period without hormone therapy and after 3 wk on each progestogen. Serum and lipoprotein lipids were followed and an oral glucose tolerance test with blood glucose and plasma insulin determinations were performed. The nortestosterone derivatives, norethisterone acetate and levonorgestrel, decreased high density lipoprotein cholesterol as well as alpha-lipoproteincholesterol, while the 17-hydroxyprogesterone derivative medroxyprogesterone acetate did not. Norethisterone acetate and medroxyprogesterone acetate impaired glucose tolerance. A difference between nortestosterone derivatives and 17-hydroxyprogesterone derivatives having an effect on high density lipoproteins is suggested.

Adult↗
PubMed2006

The use of progestational agents for preterm birth: lessons from a mouse model.

OBJECTIVE: On the basis of the recent Maternal Fetal Medicine Unit Networks clinical trial, the American College of Obstetricians and Gynecologists supports the administration of 17-alpha hydroxyprogesterone caproate to high-risk patients. Because inflammation/infection is believed to be a contributing factor in many cases of preterm birth, it is imperative to understand the effect of 17-alpha hydroxyprogesterone caproate treatment in this clinical situation. STUDY DESIGN: Using a mouse model of localized intrauterine inflammation, we investigated the ability of progestational agents to prevent preterm birth. On gestational day 15 (E15), dams were assigned randomly to treatment with 17-alpha hydroxyprogesterone caproate, medroxyprogesterone acetate, or vehicle before intrauterine infusion of lipopolysaccharide. All dams were monitored for morbidity and preterm birth. Three separate sets of experiments were performed to assess different outcomes at 6, 24, and 96 hours. At 6 and 24 hours, C-reactive protein, interleukin-6, and interleukin-10 levels were measured in maternal serum by enzyme-linked immunosorbent assay. RESULTS: Pretreatment with 17-alpha hydroxyprogesterone caproate or medroxyprogesterone acetate before intrauterine lipopolysaccharide treatment significantly decreased the preterm birth rate, compared with lipopolysaccharide treatment alone. Medroxyprogesterone acetate treatment was more effective than 17-alpha hydroxyprogesterone caproate treatment in the prevention of preterm birth and resulted in live pups at term. Treatment with 17-alpha hydroxyprogesterone caproate was associated with significant maternal morbidity. CONCLUSION: In the setting of intrauterine inflammation, progestational agents decrease the preterm birth rate but can result in maternal morbidity. 17-Alpha hydroxyprogesterone caproate should not be used in patients who are suspected of having subclinical infection and/or acute preterm labor. The mechanisms by which progestational agents inhibit preterm birth warrants further investigations so that the use of this drug to appropriate populations could be pursued without undue fetal or maternal harm.

17 alpha-Hydroxyprogesterone Caproate↗
PubMed2004

Lack of efficacy of estradiol for depression in postmenopausal women: a randomized, controlled trial.

BACKGROUND: Estrogen has been considered as a potential antidepressant in postmenopausal women. Our goal was to study whether estrogen therapy is effective in treating depressive disorders in older postmenopausal women and to determine whether progestins are associated with a deterioration of mood. METHODS: After 2 weeks of single-blind placebo treatment in 87 patients, 57 were randomly assigned to receive 8 weeks of treatment with estradiol (.1 mg/day; n = 31) or placebo (n = 26). All patients were then treated with medroxyprogesterone 10 mg/day for 2 weeks combined with the study patch. Depressive symptoms were rated with the 21-item Hamilton Depression and Center for Epidemiologic Studies Depression scales. RESULTS: A clinically significant antidepressant effect of estradiol was excluded after 8 weeks of estradiol treatment. The estradiol group and placebo group improved in depressive symptoms at a similar rate based on the Hamilton Depression Scale (40% decreases in depression for estradiol vs. 44% for placebo). No significant increase in depressive symptoms was demonstrated with the use of progestins; however, positive affect decreased slightly with the use of combined estradiol-medroxyprogesterone compared with medroxyprogesterone alone (5.8%, p =.027). CONCLUSIONS: Estradiol cannot be considered as an effective treatment in postmenopausal women with mild to moderate depression.

Adult↗
PubMed1998

Effects of adding C-19 versus C-21 progestin to conjugated estrogen in moderately hypercholesterolemic postmenopausal women.

OBJECTIVE: Our purpose was to compare the effects on fasting plasma lipoprotein lipids of adding low dosage C-19 continuous progestin (dl-norgestrel) versus conventional low-dosage continuous C-21 progestin (medroxyprogesterone acetate) to cyclic conjugated estrogen therapy. STUDY DESIGN: Nine hypercholesterolemic postmenopausal women with intact uteri were randomly assigned in a prospective, double-blind, two-period crossover study of conjugated estrogen plus either (1) dl-norgestrel (0.05 mg/day) or (2) medroxyprogesterone acetate (2.5 mg/day) for 1 year and after an appropriate washout period were switched to the alternative regimen for another year. Four subjects received conjugated estrogen only. RESULTS: Compared with baselines, each of the C-19 and C-21 progestin regimens significantly increased plasma high-density lipoprotein cholesterol (15% vs 12%) and reduced the ratio of total cholesterol/high-density lipoprotein cholesterol (20% vs 15%, respectively), but only the former significantly reduced plasma triglycerides (24% vs 0.3%, p < 0.05). CONCLUSIONS: Low dosages of either dl-norgestrel (C-19) or medroxyprogesterone acetate (C-21) when combined with conjugated estrogen significantly improve plasma lipoprotein lipids of postmenopausal women.

Cholesterol↗
PubMed2002

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.

Animals↗
PubMed1999

Effect of menopause and different combined estradiol-progestin regimens on basal and growth hormone-releasing hormone-stimulated serum growth hormone, insulin-like growth factor-1, insulin-like growth factor binding protein (IGFBP)-1, and IGFBP-3 levels.

OBJECTIVE: To determine the effects of menopause and three different formulations of E2 plus medroxyprogesterone acetate on serum concentrations of basal and growth hormone-releasing hormone (GHRH)-stimulated growth hormone (GH), insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein (IGFBP)-1, IGFBP-3, insulin, and C peptide. DESIGN: Prospective, controlled trial. SETTING: Menopausal outpatient clinic at an academic tertiary care hospital. PATIENT(S): Nineteen postmenopausal women with different menopausal ages. Seventeen premenopausal women were included as controls. INTERVENTION(S): Oral estrogen (E2 valerate, 2 mg/d) or transdermal estrogen (50-microg or 100-microg E2 patch) was administered for 8 weeks. Medroxyprogesterone acetate (5 mg/d) was administered during weeks 3, 4, 7, and 8 of each protocol. Blood samples were collected before treatment and after the completion of each protocol from postmenopausal women, and on cycle days 6-8 from premenopausal women. MAIN OUTCOME MEASURE(S): Levels of GH, IGF-1, IGFBP-1, IGFBP-3, insulin, and C peptide. RESULT(S): Basal GH levels were negatively correlated with age in premenopausal women but not in postmenopausal women. The area under the GHRH-induced GH curve decreased in older postmenopausal women after the oral estrogen protocol. Levels of IGF-1 diminished after the oral E2 protocol in postmenopausal women. CONCLUSION(S): The administration of oral, but not transdermal, E2 plus medroxyprogesterone acetate at the usual clinical doses used in postmenopausal women decreased IGF-1 levels and the response of GH to GHRH in older women. No substantial changes were detected in IGFBP-1, IGFBP-3, insulin, or C peptide levels.

Adult↗