Medroxyprogesterone

Sequential conversion of estradiol (E) to 2/4-hydroxyestradiols and 2-/4-methoxyestradiols (MEs) by CYP450s and catechol-O-methyltransferase, respectively, contributes to the inhibitory effects of E on smooth muscle cells (SMCs) via estrogen receptor-independent mechanisms. Because medroxyprogesterone (MPA) is a substrate for CYP450s, /investigators/ hypothesized that MPA may abrogate the inhibitory effects of E by competing for CYP450s and inhibiting the formation of 2/4-hydroxyestradiols and MEs. To test this hypothesis, /the authors/ investigated the effects of E on SMC number, DNA and collagen synthesis, and migration in the presence and absence of MPA. The inhibitory effects of E on cell number, DNA synthesis, collagen synthesis, and SMC migration were significantly abrogated by MPA. For example, E (0.1micromol/L) reduced cell number to 51+/-3.6% of control, and this inhibitory effect was attenuated to 87.5+/-2.9% by MPA (10 nmol/L). Treatment with MPA alone did not alter any SMC parameters, and the abrogatory effects of MPA were not blocked by RU486 (progesterone-receptor antagonist), nor did treatment of SMCs with MPA influence the expression of estrogen receptor-alpha or estrogen receptor-beta. In SMCs and microsomal preparations, MPA inhibited the sequential conversion of E to 2-2/4-hydroxyestradiol and 2-ME. Moreover, as compared with microsomes treated with E alone, 2-ME formation was inhibited when SMCs were incubated with microsomal extracts incubated with E plus MPA. /These/ findings suggest that the inhibitory actions of MPA on the metabolism of E to 2/4-hydroxyestradiols and MEs may negate the cardiovascular protective actions of estradiol in postmenopausal women receiving estradiol therapy combined with administration of MPA.

Medroxyprogesterone acetate (MPA) ... is extensively metabolized in the intestinal mucosa and in the liver. Cytochrome P450s (CYPs) involved in the metabolism of MPA were identified by using human liver microsomes and recombinant human CYPs. In this study, the overall metabolism of MPA was determined as the disappearance of the parent drug from an incubation mixture. The disappearance of MPA in human liver microsomes varied 2.6-fold among the 18 samples studied. The disappearance of MPA in the same panel of 18 human liver microsomes was significantly correlated with triazolam alpha-hydroxylase activity, a marker activity of CYP3A (r = 0.764; P < 0.001). Ketoconazole, an inhibitor of CYP3A4, potently inhibited the disappearance of MPA in 18 human liver microsomes. Anti-CYP3A antibody also inhibited 86% of the disappearance of MPA in human liver microsomes. Although sulfaphenazole (an inhibitor of CYP2C9) and S-mephenytoin (an inhibitor of CYP2C19) partially inhibited the disappearance of MPA, no effect of the anti-CYP2C antibody was observed. The disappearance of MPA did not correlate with either the activity metabolized via CYP2C9 (diclofenac 4'-hydroxylase activity) or the activity metabolized via CYP2C19 (S-mephenytoin 4'-hydroxylase activity). Among the 12 recombinant human CYPs (CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5) studied, only CYP3A4 showed metabolic activity of MPA. These results suggest that CYP3A4 is mainly involved in the overall metabolism of MPA in human liver microsomes.

This report describes a fatal pneumonitis occurring in a breast cancer patient while on adjuvant treatment with radiotherapy and medroxyprogesterone acetate. The clinical and radiologic features, as well as the timing of this pneumonitis, make a radiation pneumonitis more than probable. A radiation pneumonitis was also observed in other patients treated in the same way. Medroxyprogesterone acetate thus seems to act as a radiosensitizer since no such effects were seen in patients treated with radiotherapy alone. The radioenhancing effect is not limited to the lungs, since radioesofagitis was also encountered in similarly treated patients.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1,200(SRC), determined from a structure estimation method(2), indicates that medroxyprogesterone is expected to have low mobility in soil(SRC). Volatilization of medroxyprogesterone from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.3X10-8 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Medroxyprogesterone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.9X10-10 mm Hg at 25 °C(SRC), determined from a fragment constant method(4). Biodegradation data in soil were not available(SRC, 2011).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1,200(SRC), determined from a structure estimation method(2), indicates that medroxyprogesterone is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.3X10-8 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 94(SRC), from an estimated log Kow of 3.50(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). Biodegradation data in water were not available(SRC, 2011).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), medroxyprogesterone, which has an estimated vapor pressure of 1.9X10-10 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase medroxyprogesterone may be removed from the air by wet or dry deposition(SRC). Medroxyprogesterone contains chromophores that absorb at wavelengths >290 nm(3), and therefore may be susceptible to direct photolysis by sunlight(SRC).

Menstrual irregularities and weight gain are the most common adverse effects of medroxyprogesterone. Regarding weight gain, a study reported that medroxyprogesterone use increased by 1.61 in BMI and an average weight gain of 3.23 kg (7.11 lb). Meanwhile, 57.3% of the patients receiving medroxyprogesterone reported irregular menses during the first year. Irregular bleeding decreases to 30% after 24 months and 10% after 24 months. Fifty-five percent of women report amenorrhea after 12 months of therapy, increasing to 68% after 2 years.

Radioimmunoassay methods were used estimating contraceptive levels in breast milk and plasma samples in 7 lactating women after injection of 150 mg medroxyprogesterone acetate. Levels in breast milk were similar to plasma; ratio being almost 1:1 up to 87 days.

Medroxyprogesterone was reported in 14% of 95-144 samples of central California municipal waste water treatment plant effluent with a maximum concentration of 14.9 ng/L(1). It was not detected in a typical dairy waste disposal system for 2000 dairy cows in San Jacinto, CA; samples include fresh manure less than 2 hrs old, piled manure at 2 weeks, and 3 lagoon dams at 3 months(2).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of medroxyprogesterone can be estimated to be 1,200(SRC). According to a classification scheme(2), this estimated Koc value suggests that medroxyprogesterone is expected to have low mobility in soil.

/HUMAN EXPOSURE STUDIES/ When medroxyprogesterone is used as a contraceptive, unintended pregnancies that occur within 1-2 months after IM injection of the drug may be characterized by impaired fetal growth as evidenced by low birthweights, which theoretically could result in an increased risk of neonatal death. However, the attributable risk of this adverse effect is low because such pregnancies are unlikely. The risk of low birthweight was particularly evident when conception was estimated to occur within 4 weeks of medroxyprogesterone injection. ... An increase in polysyndactyly particularly among offspring of women younger than 30 years of age, and chromosomal anomalies also have been observed in neonates born to women who received IM medroxyprogesterone contraception.

/HUMAN EXPOSURE STUDIES/ Milk quality and quantity was studied in 6 breast feeding women admin 150 mg depomedroxyprogesterone acetate im every 3 months. The drug was associated with a decrease in concentration of protein in milk.

/HUMAN EXPOSURE STUDIES/ ...The purpose of this study was to determine the acute effects of MPA when used in combination with estradiol on markers of cardiovascular risk in young women. /The authors/ suppressed endogenous estrogens and progesterone in 10 premenopausal women using a gonadotropin-releasing hormone antagonist (GnRHa) for 10 days. On day 4 of GnRHa subjects received 0.1 mg of estradiol (GnRHa+E(2)), and on day 7 5 mg of MPA was added (GnRHa+E(2)+MPA). Endothelium-dependent vasodilation and endothelium-independent vasodilation of the brachial artery, lipids, homocysteine, high-sensitivity C-reactive protein, and endothelin-1 were assessed during treatment with GnRHa, GnRHa+E(2), and GnRHa+E(2)+MPA. Four additional subjects were tested to validate the efficacy of the GnRHa model and confirm the findings. Endothelium-dependent vasodilation was greater during GnRHa+E(2) than during GnRHa or GnRHa+E(2)+MPA (P = 0.006). Endothelin-1 was lower during GnRHa+E(2) than GnRHa alone (P = 0.039). Endothelin-1 increased with the addition of MPA and was not significantly different from GnRHa alone. There were no differences in the other markers of cardiovascular risk between hormone treatment days. These data suggest that acute MPA administration negates the beneficial effects of estradiol on endothelium-dependent vasodilation in young women. In addition, these data suggest that estradiol decreases endothelin-1 concentrations and the addition of MPA may counteract the effect of estradiol on endothelin-1.

/SIGNS AND SYMPTOMS/ Overdosage of estrogen plus progestin therapy may cause nausea and vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of CE/MPA together with institution of appropriate symptomatic care.

For more Human Toxicity Excerpts (Complete) data for MEDROXYPROGESTERONE (26 total), please visit the HSDB record page.

Medroxyprogesterone's production and use as a progestogen, injectable contraceptive, and hormonal antineoplastic in humans and also as an estrus regulator in veterinary medicine(1) may result in its release to the environment through various waste streams(SRC).

An estimated BCF of 94 was calculated in fish for medroxyprogesterone(SRC), using an estimated log Kow of 3.50(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is moderate(SRC).

The Henry's Law constant for medroxyprogesterone is estimated as 1.3X10-8 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that medroxyprogesterone is expected to be essentially nonvolatile from water surfaces(2). Medroxyprogesterone's Henry's Law constant indicates that volatilization from moist soil surfaces may not occur(SRC). Medroxyprogesterone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.9X10-10 mm Hg(SRC), determined from a fragment constant method(3).

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ A group of virgin female BALB/c mice, eight weeks of age, was divided into three subgroups: 44 received 60 mg progesterone, as 40 mg in a Silastic pellet implanted subcutaneously initially and 20 mg six months later; 45 received 60 mg medroxyprogesterone acetate, as a 40-mg pellet initially and 20 mg six months later; and 47 received 160 mg of the progestogen, 40 mg subcutaneously every three months for one year, representing the protocol used in the development of this model. The incidence of mammary adenocarcinoma and the numbers and latency of the tumours are shown in/the/ table /provided/. The carcinomas induced by medroxyprogesterone acetate were predominantly ductal but included some lobular carcinomas. The incidence of mammary carcinomas in untreated controls was reported previously to be 0/42 at 80-90 weeks of age.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Female BALB/c mice, two months of age, were either left intact or sialoadenectomized. One month after sialoadenectomy, all mice were injected subcutaneously with 40 mg depot medroxyprogesterone acetate, and the same treatment was given every three months for one year. The incidence of ductal and lobular mammary adenocarcinomas in the intact mice was 34/47, and that in the sialoadenectomized group was significantly less (11/48; p < 0.001). The tumor latency was similar: 52.5 +/-3.8 and 50.1 +/- 2.1 weeks, respectively.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Groups of 20 virgin beagle bitches were hysterectomized at four to six months of age and given medroxyprogesterone acetate intramuscularly as an aqueous suspension, at a dose of 0 (control), 30, 180 or 690 mg every three months for 48 months, corresponding to one, six and 23 times the human contraceptive dose. As shown in /the/ table /provided/, the incidence of mammary tumor nodules was increased in treated animals. Histopathological examination of the nodules revealed the presence of hyperplasia, including 13 animals at the high dose with complex lobular hyperplasias. At that dose, the tumor type was predominantly (12/14) complex adenoma. No carcinomas were detected.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Two groups of seven elderly beagle bitches weighing 10-15 kg (median ages, 7 and 6.8 years) that had not previously been treated with progestogens were subjected to surgical ovariohysterectomy to eliminate endogenous progesterone. Four to six weeks later, depot medroxyprogesterone acetate (10 mg/kg bw) or proligestone (50 mg/kg bw) was administered subcutaneously at three-week intervals for a total of eight injections. Four to eight weeks after the last injection, three dogs per group were killed for analysis of tissues, and the remaining four per group were maintained for six months without additional progestogen treatment. After this time, treatment was resumed at the same intervals, for a total of five more injections. The dogs were killed five to eight weeks later. Four dogs served as untreated controls; no abnormalities were found in any organ. The most frequent changes in the progestogen-treated dogs were adrenal atrophy (6/7 receiving medroxyprogesterone acetate and 7/7 receiving proligestone) and benign mammary tumors (5/7 receiving medroxyprogesterone acetate and 5/7 receiving proligestone). Some hepatic and pancreatic toxicity was also observed.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including medroxyprogesterone acetate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Medroxyprogesterone acetate/

THERAPEUTIC CATEGORY (VETERINARY): Progestogen; estrus regulator

MEDICATION

MEDICATION (VET)

Use (kg; approx.) in Germany (2009): >250

Reported impurities include: 6alpha,17a-dimethyl-3,17-dioxo-D-homoandrost-4-en-17aalpha- yl acetate, 6beta-hydroxy-6-methyl-3,20-dioxopregn-4-en-17-yl acetate (6beta-hydroxymedroxyprogesterone acetate), 17-hydroxy-6alpha-methylpregn-4-ene-3,20-dione (medroxyprogesterone), 6-methyl-3,20-dioxopregna-4,6-dien-17-yl acetate, 6alpha-methyl-3,20-dioxo-5beta-pregnan-17-yl acetate (4,5beta-dihydromedroxyprogesterone acetate), 6beta-methyl-3,20-dioxopregn- 4-en-17-yl acetate (6-epimedroxyprogesterone acetate) and 6-methylene-3,20-dioxopregn- 4-en-17-yl acetate. /Medroxyprogesterone acetate/

From 17alpha-hydroxyprogesterone by first forming the 3,21-bisethylene acetal with ethylene glycol, then treating with peracetic acid to give a mixture of the 5alpha,6alpha- and 5beta,6beta-epoxides. With methyl magnesium iodide the alpha-epoxide isomer yields the 5alpha-hydroxy-6beta-methyl derivative, which dehydrates and epimerizes with hydrogen chloride in chloroform to the delta4-6alpha-methyl compound, medroxyprogesterone. Acylation with acetic anhydride and p-toluenesulfonic acid in acetic acid gives medroxyprogesterone acetate.

The bisethylene acetal of 17alpha-hydroxyprogesterone was treated with peracetic acid to give a mixture of 5alpha,6alpha-epoxy-17alpha-hydroxypregnane-3,20-dione bisethylene acetal and the corresponding 5beta,6beta-epoxide. The 5alpha,6alpha-epoxide was refluxed with methylmagnesium bromide in tetrahydrofuran to afford the bisethylene acetal of 5alpha,17alpha- dihydroxy-6beta-methylpregnane-3,20-dione. Dehydration by dilute sodium hydroxide in pyridine produced 6beta-methyl-17alpha-hydroxyprogesterone which was epimerized in chloroform saturated with gaseous hydrogen chloride to 6alpha-methyl-17alpha-hydroxyprogesterone. Alternatively, dehydration and epimerization of 5alpha,17beta-dihydroxy-6beta-methylpregnane- 3,20-dione bisethylene acetal could be effected directly with chloroform or hydrogen chloride. Acylation with acetic anhydride, acetic acid and para-toluenesulfonic acid produced medroxyprogesterone acetate. /Medroxyprogesterone acetate/

...Used in human medicine in US for treatment of endometriosis, habitual abortion and threatened abortion. ...in Oct 1973 US Food & Drug Administration announced plans to withdraw approval for certain strengths and vial sizes ... destined for these applications ... /Medroxyprogesterone acetate/

...In Oct 1973 US Food & Drug Administration proposed to restrict approved uses of medroxyprogesterone acetate tablets to treatment of endometriosis, secondary amenorrhea and abnormal uterine bleeding due to hormonal imbalance, in absence of organ pathology such as submucous fibroids or uterine cancer... /Medroxyprogesterone acetate/

From 1964 until late 1970...product was withdrawn from US market, medroxyprogesterone acetate was used in us as component of oral contraceptives. ... Product was removed...because studies showed that breast nodules developed in beagles given high doses of medroxyprogesterone acetate. /Medroxyprogesterone acetate/