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PubMed1975

Responsivity of pituitary gonadotropes to luteinizing hormone-releasing factor in idiopathic precocious puberty, precocious thelarche, precocious adrenarche, and in patients treated with medroxyprogesterone acetate.

One hundred micrograms synthetic luteinizing hormone-releasing factor (LRF) were administered to 13 girls and 2 boys with idiopathic precocious puberty, 3 girls with precocious thelarche, 2 girls with precocious adrenarche, and 5 children treated with medroxyprogesterone acetate (MPA). Luteinizing hormone (LH), follicle-stimulating hormone (FSH), and sex steroid responses were assessed. The mean readily releasable LH rose to a peak of 8.4 plus or minus 1. 8 ng/ml (LER 960) in the children with idiopathic precocious puberty and was significantly greater than in normal prepubertal (1.8 plus or minus 0.14) or pubertal children (4.9 ng/ml) (LER 869) was higher in precocious puberty but not significantly greater than in normal prepubertal (5.3 plus or minus 1.9) or pubertal girls (6.0 plus or minus 1.2). The mean concentration of plasma estradiol rose significantly above resting levels after LRF in the girls with idiopathic precocious puberty. The LH response in girls with precocious the larche was in the prepubertal range. In 4 of 5 children with sexual precocity treated with MPA, the LH release evoked by LRF was diminished.

Child↗
PubMed2004

Effects of medroxyprogesterone and estradiol on the recovery of spermatogenesis in irradiated rats.

Suppression of intratesticular testosterone (ITT) levels is required for spermatogenic recovery in rats after irradiation, but maintenance of peripheral testosterone (T) levels is important for many male functions. Considering the preservation of peripheral T while suppressing ITT, we tested the effects of a combination of a progestin, medroxyprogesterone acetate (MPA), plus T on spermatogenic recovery after irradiation, and compared its effects to those of T alone or T combined with estradiol (E2). Rats were given testicular irradiation (6 Gy) and treated during wk 3-7 after irradiation with MPA + T, or the individual steroids with or without GnRH antagonist (GnRH-ant), or GnRH-ant alone, or T + E2. Whereas GnRH-ant alone stimulated differentiation in 55% of tubules 13 wk after irradiation compared with 0% in irradiated-only rats, the addition of MPA reduced the percentage of tubules showing differentiation to 18%. However, T or MPA alone or the combination of the two induced germ cell differentiation in only 2-4% of tubules. In contrast, E2 stimulated differentiation in 88% of tubules, and T combined with E2 still resulted in differentiation in 30% of tubules. Although both MPA and E2 suppressed ITT levels to approximately 2% of control (2 ng/g testis), MPA was a less effective stimulator of spermatogenic recovery than E2 or GnRH-ant alone. MPA's function as a weak androgen was likely responsible for inhibiting spermatogenic recovery, as was the case for all other tested androgens. Thus, for clinical protection or restoration of spermatogenesis after radiation or chemotherapy by suppressing T production, MPA, at least in the doses used in the present study, is suboptimal. The combination of an estrogen with T appears to be most effective for stimulating such recovery.

Animals↗
PubMed2004

Differential signal transduction of progesterone and medroxyprogesterone acetate in human endothelial cells.

The conjugated equine estrogens-only arm of the Women's Health Initiative trial, showing a trend toward protection from heart disease as opposed to women receiving also medroxyprogesterone acetate (MPA), strengthens the debate on the cardiovascular effects of progestins. We compared the effects of progesterone (P) or MPA on the synthesis of nitric oxide and on the expression of leukocyte adhesion molecules, characterizing the signaling events recruited by these compounds. Although P significantly increases nitric oxide synthesis via transcriptional and nontranscriptional mechanisms, MPA is devoid of such effects. Moreover, when used together with physiological estradiol (E2) concentrations, P potentiates E2 effects, whereas MPA impairs E2 signaling. These findings are observed both in isolated human endothelial cells as well as in vivo, in ovariectomized rat aortas. A marked difference in the recruitment of MAPK and phosphatidylinositol-3 kinase explains the divergent effects of the two gestagens. In addition, both P and MPA decrease the adhesiveness of endothelial cells for leukocytes when given alone or with estrogen. MPA is more potent than P in inhibiting the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1. However, when administered together with physiological amounts of glucocorticoids, MPA (which also binds glucocorticoid receptor) markedly interferes with the hydrocortisone-dependent stabilization of the transcription factor nuclear factor kappaB and with the expression of adhesion molecules, acting as a partial glucocorticoid receptor antagonist. Our findings show significant differences in the signal transduction pathways recruited by P and MPA in endothelial cells, which may have relevant clinical implications.

Cell Communication↗
PubMed2005

Medroxyprogesterone acetate induces cell proliferation through up-regulation of cyclin D1 expression via phosphatidylinositol 3-kinase/Akt/nuclear factor-kappaB cascade in human breast cancer cells.

The mechanism of medroxyprogesterone acetate (MPA)-induced cell proliferation in human breast cancer cells remains elusive. We examined the mechanism by which MPA affects the cyclin D1 expression in progesterone receptor (PR)-positive T47D human breast cancer cells. MPA (10 nM) treatment for 48 h induced proliferation of the cells (1.6-fold induction). MPA induced cyclin D1 expression (3.3-fold induction), and RU486, a selective PR antagonist, blocked the MPA-induced cell proliferation and cyclin D1 expression (23% inhibition). MPA increased both the protein level (2.2-fold induction) and promoter activity (2.7-fold induction) of cyclin D1 in MCF-7 cells transfected with PRB but not with PRA. Although MPA transcriptionally activated cyclin D1 expression, cyclin D1 promoter does not have progesterone-responsive element-related sequence. We further examined the mechanism for the regulation of the cyclin D1 expression. Because the cyclin D1 promoter contains three putative nuclear factor-kappaB (NFkappaB)-binding motifs and NFkappaB is a substrate of Akt, we investigated the effect of the phosphatidylinositol 3-kinase (PI3K)/Akt/NFkappaB cascade on the responses of cyclin D1 to MPA. MPA induced the transient phosphorylation of Akt (2.7-fold induction at 5 min), and treatment with PI3K inhibitor (wortmannin) attenuated the MPA-induced up-regulation of cyclin D1 expression (40% inhibition) and cell proliferation (40% inhibition). MPA also induced phosphorylation of inhibitor of NFkappaBalpha (IkappaBalpha) (2.3-fold induction), and treatment with wortmannin attenuated the MPA-induced IkappaBalpha phosphorylation (60% inhibition). Treatment with an IkappaBalpha phosphorylation inhibitor (BAY 11-7085) or a specific NFkappaB nuclear translocation inhibitor (SN-50) attenuated the MPA-induced up-regulation of both cyclin D1 expression (80 and 50% inhibition, respectively) and cell proliferation (55 and 34% inhibition, respectively). Because MPA induced a transient phosphorylation of Akt and the cyclin D1 promoter contains no progesterone-responsive element-related sequence, the MPA-induced cell proliferation through PRB by up-regulation of cyclin D1 expression via the PI3K/Akt/NFkappaB cascade may be a nongenomic mechanism.

Antineoplastic Agents, Hormonal↗
PubMed1978

A direct effect of medroxyprogesterone acetate on 17 beta-hydroxysteroid dehydrogenase in adult rat testis.

Sixty-day-old rats were divided into four groups and treated for 30 days with either medroxyprogesterone acetate (Provera), gonadotropins (bovine LH and ovine FSH), Provera plus gonadotropins, or saline. The progestin treatment resulted in a lowering of plasma levels of testosterone, androstenedione, and LH, as well as in a reduction of epididymal sperm counts and accessory sex organ weights. The progestin-treated groups showed markedly lower levels of testicular 17 beta-hydroxysteroid dehydrogenase activity (35% of controls) and delta 5,3 beta-hydroxysteroid dehydrogenase activity (70% of controls). Rats treated with only gonadotropins exhibited reduced 17 beta-hydroxysteroid dehydrogenase but increased delta 5,3 beta-hydroxysteroid dehydrogenase activities. It was concluded from these results that progestins may affect testicular steroidogenesis and spermatogenesis not only by reducing LH secretion but also by a direct effect on the testis, as LH suppression could not account for the inhibition of 17 beta-hydroxysteroid dehydrogenase activity. Long term progestin treatment did not alter the steroidogenic response of the testis to acute administration of LH, although the testosterone to androstenedione ratio in plasma was decreased.

17-Hydroxysteroid Dehydrogenases↗
PubMed1980

The in vivo glucocorticoid and antiglucocorticoid actions of medroxyprogesterone acetate.

The in vivo glucocorticoid actions of medroxyprogesterone acetate [6 alpha-methyl-17-acetoxy-pregn-4-ene-3,20-dione (MPA)] were assessed in intact prepubertal female Wistar rats using five simultaneous assays: plasma glucose, plasma corticosterone, hepatic glycogen content, hepatic tyrosine aminotransferase activity, and croton oil-induced ear inflammation. Antiglucocorticoid acitivity was measured through interference by MPA with the glucocorticoid effect of a standard 5-microgram dose of dexamethasone in these same assays. The glucocorticoid activity of MPA was evident from suppression of corticosterone and ear inflammation and stimulation of tyrosine aminotransferase activity. The antiglucocorticoid activity of MPA was detected through inhibition of basal and dexamethasone-stimulated hepatic glycogen and partial reversal of the suppression of ear inflammation by dexamethasone. The progestational steroid MPA was thus found to have assay-specific glucocorticoid and antiglucocorticoid actions and may have a potential use in the treatment of some states of glucocorticoid excess.

Animals↗
PubMed1976

Medroxyprogesterone acetate: a steroid with potent progestational activity but low receptor affinity in the guinea pig uterus.

The guinea pig progestin receptor appears to be unique among mammalian receptors studied to date in that it displays a low binding affinity for some biologically potent 17 alpha-substituted progestinss. [3H]Medroxyprogesterone acetate (MPA) was synthesized and used to investigate this dichotomy between binding affinity and biological activity. The comparison of cytoplasmic and nuclear receptor binding characteristics suggested that progesterone and MPA were bound to the same receptor but with different affinities. Following an intravenous injection of 3H-steroids, the plasma level of progesterone was lower than that of MPA at all time points. Correspondingly, for up to 6 hours following steroid administration, progesterone levels were lower in uterine cytoplasm and higher in nuclei than those of MPA. However, by 24 hours, MPA nuclear levels were higher than those of progesterone, in accordance with plasma levels. We conclude that the potent biological activity of MPA relative to progesterone is due in part to its slower rate of metabolism and longer nuclear retention.

Animals↗
PubMed1976

The in vivo metabolism of progestins. I. The metabolic clearance rates of progesterone and medroxyprogesterone acetate in the dog.

[3H]Medroxyprogesterone acetate (MPA) was synthesized by selective catalytic tritiation of the delta1-olefinic bond of 6alpha-methyl-17alpha-hydroxy-pregn-1,4-diene-3,20 dione acetate. [14C]MPA was synthesized by acetylation of 6alpha-methyl-17alpha-hydroxy-pregn-4-ene-3,20-dione with [14C]acetic anhydride. These radioactive materials were used to determine the MPA metabolic clearance rates (MCRMPA)and volumes of distribution (VoMPA) in dogs by the single injection technique. The metabolism of progesterone was also studied in the same animals. The MCRMPA (696 +/- 51 l/day) was only one-half that of progesterone (1332 +/- 59). By contrast, the volumes of distribution for the two steroids were similar. The metabolic clearance rates and the volumes of distribution for MPA and progesterone did not change during treatment with amino-glutethimide, a drug which is known to alter steroid metabolism in man.

Aminoglutethimide↗
PubMed1995

The effect of medroxyprogesterone acetate on bone metabolism in the oophorectomized, tamoxifen-treated rat.

Tamoxifen (TAM) is used primarily in the management of breast cancer, and it also has bone-sparing effects similar to estrogen. In breast cancer patients TAM may have a potential role in the prevention and management of osteoporosis. TAM therapy is associated with uterine hyperplasia, and medroxyprogesterone acetate (MPA) added to the regimen provides protection against this. Due to the potential combined use of MPA and TAM in the clinical setting, this study was conducted to assess whether MPA acted synergistically, dampened, or enhanced the TAM effect on bone. Seventy-five female rats (60 oophorectomized; Ox), were randomized into five groups and received either TAM (0.1 mg/kg.day) and/or MPA (0.3 mg/kg.day) therapy over 28 days as follows: 1) sham; 2) Ox; 3) Ox plus TAM; 4) Ox plus MPA; and 5) Ox plus TAM plus MPA. Blood was sampled on days 0, 14, and 28 for measurement of ionized calcium, PTH, 1,25-dihydroxyvitamin D, osteocalcin, and insulin-like growth factor 1. TAM-treated rats showed a reduction in body weight serum osteocalcin, PTH, and insulin-like growth factor 1. Histomorphometric analysis of the proximal tibia showed less cancellous bone volume in Ox rats, and the effect was attenuated by TAM. MPA alone had no significant effect on cancellous bone volume. All the bone formation parameters evaluated (bone formation rate, mineral apposition rate, percent calcein-labeled surface, and number of osteoblasts) were higher in Ox rats compared with sham-operated rats and were lower in TAM-treated rats compared with Ox rats. These parameters were not changed by MPA, alone or in combination with TAM. The number of osteoclasts was higher in Ox rats compared with sham-operated rats and was reduced by TAM. MPA therapy alone or in combination with TAM did not affect number of osteoclasts. These results suggest that MPA neither dampened nor enhanced the effect of TAM on bone.

Animals↗
PubMed2002

Impact of progestins on estrogen-induced neuroprotection: synergy by progesterone and 19-norprogesterone and antagonism by medroxyprogesterone acetate.

Estrogen replacement therapy is associated with improvement of cognitive deficits and reduced incidence of Alzheimer's disease. To compare the impact of therapeutically relevant progestins on estrogen-induced neuroprotection, we treated primary hippocampal neuron cultures with 17beta-E2 and progestin, alone and in combination, 48 h before glutamate insult. Estrogen, progesterone, and 19-norprogesterone, alone or in combination, protected against glutamate toxicity. In contrast, medroxyprogesterone acetate (MPA) failed to protect against glutamate toxicity. Not only was MPA an ineffective neuroprotectant but it attenuated the estrogen- induced neuroprotection when coadministered. We addressed the role of MAPK activation in neuroprotection by ovarian steroids. Estrogen and all three progestins tested, alone or in combination, activated MAPK, indicating another mechanism of protection. Bcl-2 expression has been shown to prevent cell death and is up-regulated by 17beta-E2. Progesterone and 19-norprogesterone, alone or in combination with estrogen, increased Bcl-2 expression. In contrast, MPA blocked estrogen-induced Bcl-2 expression when coadministered. These results may have important implications for the effective use of hormone replacement therapy in the maintenance of neuronal function during menopause and aging and for protection against neurodegenerative diseases such as Alzheimer's disease.

Animals↗
PubMed2002

The effects of short-term medroxyprogesterone acetate and micronized progesterone on glucose metabolism and lipid profiles in patients with polycystic ovary syndrome: a prospective randomized study.

In this prospective, randomized study we determined 10-d effects of medroxyprogesterone acetate (MPA) and micronized progesterone (MP) either orally or per vaginally on hormonal parameters, glucose metabolism and lipid profiles in patients with polycystic ovary syndrome (PCOS). Twenty-eight consecutive women with PCOS were randomized to receive 10-d MPA, oral MP, or vaginal MP. Hormonal parameters, insulin levels, oral glucose tolerance test, lipid profiles, and homeostasis model assessment and quantitative insulin sensitivity check indexes were assessed in all groups before and after treatment. Oral MPA and oral MP decreased LH (15.64 +/- 13.17 to 7.27 +/- 4.35 IU/liter, P = 0.028, and 18.85 +/- 11.86 to 10.49 +/- 6.48 IU/liter, P = 0.009, respectively) and total testosterone (5.85 +/- 2.80 to 3.40 +/- 1.72 nmol/liter, P = 0.013, and 5.29 +/- 2.98 to 3.43 +/- 2.10 nmol/liter, P = 0.037, respectively) levels. Hormonal parameters did not change with vaginal MP. Basal insulin (123.42 +/- 97.50 to 87.38 +/- 48.68 pmol/liter; P = 0.021) and homeostasis model assessment levels decreased, and quantitative insulin sensitivity check index increased significantly in the oral MPA group. Low density lipoprotein cholesterol and lipoprotein (a) levels decreased only in the MPA group. In conclusion, short-term oral MP and especially oral MPA might ameliorate insulin sensitivity in patients with PCOS. Vaginal MP has no effect on glucose metabolism and lipid profiles. LH, total testosterone, and insulin levels may be affected from the short-term progesterone treatment.

Administration, Intravaginal↗
PubMed2003

A randomized controlled trial of estrogen replacement therapy in long-term users of depot medroxyprogesterone acetate.

Long-term use of the injectable contraceptive depot medroxyprogesterone acetate (DMPA, Depo-Provera) is associated with a reduction in bone mineral density (BMD), particularly in the lumbar spine. The cause of DMPA-associated bone loss is not known, but the relative estrogen deficiency induced by DMPA use could be responsible. We have undertaken a randomized, double-blind controlled trial of oral estrogen replacement therapy in 38 premenopausal women (mean age 37) with a minimum 2 yr DMPA use who had a below average baseline lumbar spine BMD (T score < or = 0). Nineteen women were allocated to receive conjugated estrogens (0.625 mg/d orally) and 19 to receive a matching placebo. All continued with regular DMPA injections throughout the study. Areal bone density was measured by dual energy x-ray absorptiometry at the lumbar spine, femoral neck, and total body sites every 6 months for 2 yr; the main outcome measure being the change in areal BMD at the lumbar spine. At baseline, the two groups were well matched for demographic, anthropometric, and biochemical variables, and for BMD. Twenty-seven subjects completed at least 18 months in the study, and 26 the full 2 yr, with similar numbers dropping out from each group (mainly for personal reasons). In the estrogen-treated group, mean lumbar spine BMD increased 1%, whereas in the placebo group it fell 2.6%, over 2 yr. The between group differences were 2.0% at 12 months (P = 0.058), 3.2% at 18 months (P < 0.01), and 3.5% at 24 months (P < 0.002). Differences of lesser statistical magnitude were seen at the femoral neck (between group differences at 2 yr: 2.7%, P = 0.24), Ward's triangle (5.0%, P = 0.055), greater trochanter (3.6%, P = 0.056), total body (1.3%, P = 0.046), legs (1.3%, P = 0.065), and trunk (2.0%, P = 0.029). There were no major adverse events. These data support the view that the likely cause of DMPA-associated bone loss is estrogen deficiency and demonstrate that it can be arrested by estrogen replacement therapy.

Absorptiometry, Photon↗
PubMed2004

Male hormonal contraception: effects of injections of testosterone undecanoate and depot medroxyprogesterone acetate at eight-week intervals in chinese men.

Surveys indicate that one form of acceptable male hormonal contraception would consist of injections given at 2- to 3-month intervals. This report describes a study of depot medroxyprogesterone acetate (DMPA) and testosterone undecanoate (TU) injected at 8-wk intervals for suppression of spermatogenesis in healthy Chinese men. After screening, 30 healthy volunteers were enrolled and randomly assigned to one of three dose groups (n = 10/group): 1000 mg TU (group A); 1000 mg TU plus 150 mg DMPA (group B); 1000 mg TU plus 300 mg DMPA (group C). All doses were given as im injections at 8-wk intervals. The study consisted of an 8-wk control (baseline) period, a 24-wk treatment period, and a 24-wk recovery period. Consistent azoospermia or severe oligozoospermia was achieved and maintained in all volunteers during the treatment period, except for two men in the TU-alone group who experienced a rebound in sperm concentrations. An 8-wk regimen of TU plus DMPA at both tested combination doses effectively suppressed spermatogenesis to azoospermia in Chinese men. All volunteers tolerated the injections; no serious adverse effects were reported. The lower-dose combination is recommended for further testing in an expanded clinical trial or contraceptive efficacy study.

Adult↗
PubMed2004

Medroxyprogesterone acetate antagonizes the effects of estrogen treatment on social and sexual behavior in female macaques.

Medroxyprogesterone acetate (MPA) commonly is used in contraception and hormone replacement therapy. However, little is known about its effects within the central nervous system. Using ovariectomized pigtail macaques (Macaca nemestrina), we evaluated the potential for MPA to antagonize estradiol (E2) effects on female sociosexual behavior. Subjects (n = 6) were treated sequentially with placebo, E2 alone, E2 + progesterone (P4), and E2 + MPA. The order of treatments was balanced among subjects, and equimolar quantities of P4 and MPA were administered. During each treatment period, female sexual initiation rates, anxiety-related behavior, and aggression were recorded. Treatment with E2 alone induced a substantial rise in female sexual initiation rates. Although concurrent P4 treatment failed to significantly inhibit sexual behavior, MPA treatment markedly antagonized E2's effects. Neither the E2-only nor the E2 + P4 treatment had an impact on aggression rates, but the E2 + MPA treatment induced a significant rise in this behavior. Both MPA and P4 counteracted the effect of E2 on measures of anxiety. These findings suggest that MPA antagonizes certain behavioral effects of E2 that may be beneficial to women, and that it does so more profoundly or in ways that endogenous P4 does not. The marked increase in aggression seen during MPA treatment suggests that production of negative affect may be a particularly serious side effect of MPA.

Aggression↗
PubMed2005

Medroxyprogesterone acetate and dihydrotestosterone induce coronary hyperreactivity in intact male rhesus monkeys.

Coronary hyperreactivity (CH), characterized by persistent severe vasoconstrictions in response to vasoconstrictor challenge, is oppositely influenced by progesterone (P) and medroxyprogesterone acetate (MPA) treatment in surgically menopausal primates. In this study we tested whether multiweek MPA or dihydrotestosterone (DHT) exposure induced CH in intact male rhesus monkeys. Coronary angiographic experiments with intracoronary serotonin and the thromboxane A(2) analog U46619 stimulated brief vasoconstriction (for 1-3 min) in large epicardial coronaries in untreated male monkeys. In contrast, MPA- and DHT-treated monkeys displayed long-duration constrictions (>5 min), with significantly greater reductions in the minimal diameters of epicardial coronaries. Immunocytochemistry demonstrated androgen receptors (AR) and P receptors in aorta and coronary arteries, and immunocytochemistry and Western blotting showed AR and P receptors in rhesus coronary vascular muscle cells. In vivo, MPA or DHT increased thromboxane prostanoid (TP) receptor expression in the aorta. In vitro, MPA or DHT increased, whereas P did not change, TP receptor expression in primary coronary vascular muscle cell. This MPA- or DHT-mediated increase in TP receptor expression was attenuated by the AR antagonist flutamide. MPA or DHT induction of CH in intact adult male primates, hypothesized to occur via androgenic up-regulation of vascular muscle TP receptor expression, could predispose to CH-mediated myocardial ischemia.

Animals↗
PubMed1979

In vivo metabolism of progestins. V. The effect of protocol design on the estimated metabolic clearance rate and volume of distribution of medroxyprogesterone acetate in women.

The metabolism of the synthetic progestin, [3H]medroxyprogesterone acetate (MPA), was studied in women using a single injection technique. Computer-implemented analysis was used to calculate the MCR (MCRMPA) and volume of distribution (VoMPA) from the steroid disappearance curve. The value of an objective curve-fitting technique was demonstrated. The effect of protocol design (number and frequency of samples) on these metabolic parameters was evaluated. The estimation of VoMPA was most sensitive to alterations of experimental design and biological variability, while MCR was less easily effected. The MCRMPA of 1668 +/- 146 (SEM) liters/day was lower than that for progesterone but higher than that of another synthetic steroid, dexamethasone. Treatment of women with MPA or aminoglutethimide, two drugs known to increase the rates of testosterone and dexamethasone metabolism, respectively, did not alter MCRMPA. From these observations we conclude 1) with the single injection technique it is difficult to estimate Vo of compounds such as MPA which are rapidly metabolized and 2) the MCRMPA was higher than expected and less susceptible to drug-induced changes than the clearance of other steroids.

Aminoglutethimide↗
PubMed1993

An evaluation of the effect of gonadotropin-releasing hormone analogs and medroxyprogesterone acetate on uterine leiomyomata volume by magnetic resonance imaging: a prospective, randomized, double blind, placebo-controlled, crossover trial.

The purpose of this study was to prospectively compare the effectiveness of administering medroxyprogesterone acetate (MPA; 20 mg/day) in either the first (protocol A) or last (protocol B) 12-week period along with a 6-month course of the GnRH analog (GnRH-a; leuprolide acetate; 1 mg/day, sc) on uterine and leiomyomata volumes and hormone (estradiol, LH, and FSH) and serum lipid (total cholesterol, triglycerides, and high and low density lipoprotein) levels. Sixteen women were randomized into protocol A or B, received either MPA or placebo along with GnRH-a, respectively, and were then crossed over at 12 weeks to placebo or MPA, respectively, for the final 12-week interval of GnRH-a therapy. Total, myoma, and nonmyoma uterine volumes were determined by magnetic resonance imaging, and serum studies were performed at the beginning of the study and at 12 and 24 weeks. In both protocols, LH and estradiol levels declined by 80-90% (P < 0.03) and 55-72% (P < 0.02) of the baseline, respectively, at 12 weeks and remained at this level at 24 weeks. There were no significant changes in the other laboratory tests between protocols or longitudinally over time. Total uterine volume decreased to 73% of the baseline at 12 weeks in protocol B (P < 0.04), but did not change in protocol A. After crossover at 12 weeks, the total uterine volume of women in protocol A decreased to 74% of the baseline (P < 0.02) at 24 weeks. Between-protocol comparisons demonstrated a greater decline in total uterine volume in protocol B than A at 12 weeks, but after cross-over, MPA addition was associated with a significant increase in total uterine volume (protocol B) compared to a decrease in protocol A at 24 weeks (P < 0.005). In contrast, although myoma volume declined in both protocols, no significant changes in myoma volume were detected within or between groups over the treatment period. Nonmyoma volume changes in protocols A and B roughly paralleled total uterine volume changes, with MPA coadministration showing a correlation with a reversal in the GnRH-a-associated decrease in nonmyomatous tissue volume.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1996

Short-term effects of high dose oral medroxyprogesterone acetate on bone density in premenopausal women.

Despite the widespread use of the C21 progestin medroxyprogesterone acetate (MPA) in hormone replacement therapy and gynecological practice, its effects on bone density are uncertain, with contradictory reports in the literature. We have examined the short term changes in bone density at the lumbar spine (a predominantly trabecular site) and the femoral neck (a predominantly cortical site) in 13 premanopausal women prescribed high dose MPA (50 mg/day) for gynecological disorders and in 12 control subjects. Compared to basal values, lumbar spine bone mineral density (measured by dual energy x-ray absorptiometry) fell progressively by a mean 2.4% at 6 months and 4.1% at 12 months (both P < 0.01); in five subjects who continued the drug, it had fallen by a mean 5.9% at 20 months (P < 0.002). The spinal bone loss in the MPA users was significantly greater than that in controls (P < 0.005 at 6 months; P < 0.01 at 12 months) and occurred despite a significant gain in body weight in the women using MPA (median, 3.5 kg at 6 months; P < 0.01). In four subjects in whom bone density was measured 6 months after cessation of MPA, spinal bone density showed significant recovery (mean increment, 2.8%; P < 0.025). Femoral neck bone density measurements did not differ between the groups. MPA induced amenorrhea in all subjects who continued with it beyond 6 months, and the amenorrheic subjects were estrogen deficient (median plasma estradiol, 70 pmol/L). We conclude that, when given in doses sufficient to induce hypogonadism, MPA use is associated with significant early loss of trabecular bone, which is probably the consequence of estrogen deficiency.

Administration, Oral↗