Depo-Provera Mechanism of Action

Pharmacology: Pharmacodynamics: Medroxyprogesterone acetate (17a-hydroxy-6a-methylprogesterone acetate) is a derivative of progesterone.
Mechanism of Action: MPA is a synthetic progestin (structurally related to the endogenous hormone progesterone) which has been demonstrated to possess several pharmacologic actions on the endocrine system: Inhibition of pituitary gonadotropins (FSH and LH); Decrease of ACTH and hydrocortisone blood levels; Decrease of circulating testosterone; Decrease of circulating estrogen levels (as the result of both FSH inhibition and enzymatic induction of hepatic reductase, resulting in increased clearance of testosterone and consequent decreased conversion of androgens to estrogens).
All of these actions result in a number of pharmacological effects, as described as follows.
Contraception: DMPA, when administered parenterally at the recommended dose to women, inhibits the secretion of gonadotropins which, in turn, prevents follicular maturation and ovulation and causes thickening of cervical mucus which inhibits sperm entry into the uterus.
Gynecology: Medroxyprogesterone acetate (MPA), administered parenterally in the recommended doses to women with adequate endogenous estrogen, transforms proliferative into secretory endometrium. Androgenic and anabolic effects have been noted, but the drug is apparently devoid of significant estrogenic activity. Parenterally administered DMPA inhibits gonadotropin production, which in turn prevents follicular maturation and ovulation.
Endometriosis: Suppression of serum estradiol concentrations are likely to be responsible for the therapeutic effect on endometriosis-associated pain.
Oncology: MPA demonstrates antitumor activity. When MPA is given to patients at high doses it is effective in the palliative treatment of hormone-responsive malignant neoplasms.
Clinical Studies: BMD Studies: BMD Changes in Adult Women: In a non-randomized controlled clinical study comparing adult women using DMPA contraceptive injection (150 mg IM) for up to 5 years to women who elected to use no hormonal contraception, 42 DMPA users completed 5 years of treatment and provided at least 1 follow-up BMD measurement after stopping DMPA. Among DMPA users, BMD declined during the first 2 years of use, with little declines in subsequent years. Mean changes in lumbar spine BMD of -2.86%, -4.11%, -4.89%, -4.93% and -5.38% after 1, 2, 3, 4 and 5 years, respectively, were observed. Mean decreases in BMD of the total hip and femoral neck were similar. There were no significant changes in BMD in the control women over the same period of time.
BMD Recovery Post-treatment in Adult Women: In the same study population, there was partial recovery of BMD toward baseline values during the 2-year period after stopping use of DMPA injection (150 mg IM).
After 5 years of treatment with DMPA injection (150 mg IM), the mean % change in BMD from baseline was -5.4%, -5.2% and -6.1% at the spine, total hip and femoral neck, respectively, while untreated control women, over the same time interval, showed mean changes from baseline of +/- 0.5% or less at the same skeletal sites. Two years after stopping DMPA injections, mean BMD had increased at all 3 skeletal sites but deficits remained: -3.1%, -1.3% and -5.4% at the spine, total hip and femoral neck, respectively. At the same time point, women in the control group showed mean changes from baseline BMD of 0.5%, 0.9% and -0.1% at the spine, total hip and femoral neck, respectively.
BMD Changes in Adolescent Females (12-18 years): The effect of DMPA injectable (150 mg IM) use on BMD for up to 240 weeks (4.6 years) was evaluated in an open-label non-comparative clinical study of 159 adolescent females (12-18 years) who elected to begin treatment with DMPA; 114 of the 159 participants used DMPA continuously (4 injections during each 60-week period) and had BMD measured at Week 60. BMD declined during the first 2 years of use with little change in subsequent years. After 60 weeks of DMPA use, mean % BMD changes from baseline were -2.5%, -2.8% and -3.0% at the spine, total hip and femoral neck, respectively. A total of 73 subjects continued to use DMPA through 120 weeks; mean % BMD changes from baseline were -2.7%, -5.4% and -5.3% at the spine, total hip and femoral neck, respectively. A total of 28 subjects continued to use DMPA through 240 weeks; mean % BMD changes from baseline were -2.1%, -6.4% and -5.4% at the spine, total hip and femoral neck, respectively.
BMD Recovery Post-treatment in Adolescents: In the same study, 98 adolescent participants received at least 1 DMPA injection and provided at least 1 follow-up BMD measurement after stopping DMPA use, with DMPA treatment for up to 240 weeks (equivalent to 20 DMPA injections) and post-treatment follow-up extending for up to 240 weeks after the final DMPA injection. The median number of injections received during the treatment phase was 9. At the time of the final DMPA injection, BMD % changes from baseline were -2.7%, -4.1% and -3.9% at the spine, total hip and femoral neck, respectively. Over time these mean BMD deficits fully recovered after DMPA was discontinued. Full recovery required 1.2 years at the lumbar spine, 4.6 years at the total hip and 4.6 years at the femoral neck. Longer duration of treatment and smoking were associated with slower recovery. See Additional Warnings and Precautions for Specific Use: Contraception/Endometriosis - Injectable Formulations: Loss of Bone Mineral Density (BMD) under Precautions.
Relationship of fracture incidence to use of DMPA injectable (150 mg IM) or non-use by women of reproductive age.
A retrospective cohort study to assess the association between DMPA injection and the incidence of bone fractures was conducted in 312,395 female contraceptive users in the UK. The incidence rates of fracture were compared before and after DMPA use started and also between DMPA users and women who used other contraceptives but had no recorded use of DMPA. Among women using DMPA, use of DMPA was not associated with an increase in fracture risk (incident rate ratio=1.01, 95% CI 0.92-1.11, comparing the study follow-up period with up to 2 years of observation prior to DMPA use). However, DMPA users did have more fractures than non-users not only after first contraceptive use (IRR=1.23, 95% CI 1.16-1.30), but also before first contraceptive use (IRR=1.28, 95% CI 1.07-1.53).
In addition, fractures at the specific bone sites characteristic of osteoporotic fragility fractures (spine, hip, pelvis) were not more frequent among DMPA users compared to non-users (IRR=0.95, 95% CI 0.74-1.23), nor was there any evidence that longer use of DMPA (2 years or more) confers greater risk for fracture compared to less than 2 years of use.
These data demonstrate that DMPA users have an inherently different fracture risk profile to non-users for reasons not related to DMPA use.
Maximum follow-up in this study was 15 years, therefore, possible effects of DMPA that might extend beyond 15 years of follow-up cannot be determined.
Women's Health Initiative Study: The WHI CEE (0.625 mg)/MPA (2.5 mg) trial enrolled 16,608 post-menopausal women aged 50-79 years with intact uteri at baseline, to assess the risks and benefits of the combined therapy compared with placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (non-fatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. The study was stopped early after an average follow-up of 5.2 years (planned duration 8.5 years) because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the "global index" (see Breast Cancer under Precautions).
The combination CEE/MPA therapy reported a significant decrease in osteoporotic (23%) and total (24%) fractures.
Million Women Study: The MWS was a prospective cohort study enrolling 1,084,110 women in the UK aged 50-64 years of whom 828,923 with defined time since menopause were included in the main analyses of risk of breast cancer in relation to MHT. Overall, 50% of the study population had used MHT at some point. Most current users of MHT at baseline reported using preparations containing estrogen-alone (41%) or estrogen-progestin combinations (50%). The average duration of follow-up was 2.6 years for analyses of cancer incidence and 4.1 years for analyses of mortality (see Breast Cancer under Precautions).
Observational Studies of Breast Cancer Risk: A large meta-analysis of observational studies generated evidence for the type and timing of MHT on breast cancer risk. After ceasing MHT, some excess risk persisted for more than 10 years; its magnitude depended on the duration of previous use.
It was reported that, when estrogen plus progestin therapy was taken for more than 5 years, the increased risk may persist for 10 years or more after discontinuation of treatment: See Table 1.

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The reported risk at 10 years or more after discontinuation of treatment was not increased when therapy was taken for less than 5 years: See Table 2.

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In current users, the increased risk of breast cancer in women taking combined estrogen-progestin MHT becomes apparent after about 1-4 years: See Table 3.

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Heart and Estrogen-progestin Replacement Studies: HERS and HERS II studies were two randomized, prospective secondary prevention trials on the long-term effects of oral continuous combined CEE/MPA (0.625 mg CEE plus 2.5 mg MPA) regimen in post-menopausal women with CHD (see Cardiovascular Disorders under Precautions). 2,763 post-menopausal women with a mean age of 66.7 years and with intact uteri were enrolled in this study. The average duration of follow-up was 4.1 years for HERS and 2.7 additional years (for a total of 6.8 years) for HERS II (see Cardiovascular Disorders under Precautions).
Women's Health Initiative Memory Study: The WHIMS, a substudy of WHI, enrolled 4,532 predominantly healthy post-menopausal women aged 65 to 79 years to evaluate the effects of CEE/MPA (0.625 mg CEE plus 2.5 mg MPA) or CEE-alone (0.625 mg) on the incidence of probable dementia compared with placebo. The average duration of follow-up was 4.05 years for the CEE/MPA (see Dementia under Precautions).
Pharmacokinetics: Absorption: Following intramuscular administration, MPA is slowly released, resulting in low, but persistent levels in the circulation. Immediately after intramuscular injection of 150 mg/mL MPA, plasma levels were 1.7±0.3 nmol/L. Two weeks later, levels were 6.8±0.8 nmol/L. Mean time to peak is approximately 4 to 20 days following an intramuscular dose. Serum medroxyprogesterone acetate levels gradually decline and remain relatively constant at about 1 ng/mL for 2-3 months. Circulating levels can be detected for as long as 7 to 9 months following an intramuscular injection.
Distribution: MPA is approximately 90% to 95% protein bound. Volume of distribution is reported as 20±3 liters. Medroxyprogesterone acetate crosses the blood-brain-barrier, and the placental barrier (see Use in Pregnancy & Lactation). Low levels of medroxyprogesterone acetate have been detected in breast milk of lactating women (see Use in Pregnancy & Lactation) administered 150 mg of medroxyprogesterone acetate by the IM route.
Metabolism: MPA is metabolized in the liver.
Elimination: The elimination half-life following single intramuscular injection is about 6 weeks. Medroxyprogesterone acetate is primarily excreted in the feces, via biliary secretion. Approximately 30% of an intramuscular dose is secreted in the urine after 4 days.
Toxicology: Preclinical Safety Data: Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term intramuscular administration of medroxyprogesterone acetate (DMPA) has been shown to produce mammary tumors in beagle dogs. There was no evidence of a carcinogenic effect associated with the oral administration of oral MPA to rats and mice. Medroxyprogesterone acetate was not mutagenic in a battery of in vitro or in vivo genetic toxicity assays. Medroxyprogesterone acetate at high doses is an antifertility drug and high doses would be expected to impair fertility until the cessation of treatment.