Medroxyprogesterone acetate

The most common use of MPA is in the form of DMPA as a long-acting progestogen-only injectable contraceptive to prevent pregnancy in women. It is an extremely effective contraceptive when used with relatively high doses to prevent ovulation. MPA is also used in combination with an estrogen in menopausal hormone therapy in postmenopausal women to treat and prevent menopausal symptoms such as hot flashes, vaginal atrophy, and osteoporosis. In addition to contraception and menopausal hormone therapy, MPA is used in the treatment of gynecological and menstrual disorders such as dysmenorrhea, amenorrhea, and endometriosis. Along with other progestins, MPA was developed to allow for oral progestogen therapy, as progesterone (the progestogen hormone made by the human body) could not be taken orally for many decades before the process of micronization was developed and became feasible in terms of pharmaceutical manufacturing. MPA has also been prescribed in feminizing hormone therapy for transgender women due to its progestogenic and functional antiandrogenic effects. DMPA reduces sex drive in men and is used as a form of chemical castration to control inappropriate or unwanted sexual behavior in those with paraphilias or hypersexuality, including in convicted sex offenders. DMPA has also been used to treat benign prostatic hyperplasia, as a palliative appetite stimulant for cancer patients, and at high doses (800 mg per day) to treat certain hormone-dependent cancers including endometrial cancer, renal cancer, and breast cancer. It has been used to delay puberty in children with precocious puberty but is not satisfactory for this purpose as it is not able to completely suppress puberty (specifically, it does not fully halt skeletal maturation and hence does not sufficiently resolve the reduced height at adulthood). DMPA at high doses has been reported to be definitively effective in the treatment of hirsutism as well. Though not used as a treatment for epilepsy, MPA has been found to reduce the frequency of seizures and does not interact with antiepileptic medications. MPA does not interfere with blood clotting and appears to improve blood parameters for women with sickle cell anemia. Similarly, MPA does not appear to affect liver metabolism, and may improve primary biliary cirrhosis and chronic active hepatitis. Women taking MPA may experience spotting shortly after starting the medication but is not usually serious enough to require medical intervention. With longer use amenorrhea (absence of menstruation) can occur as can irregular menstruation which is a major source of dissatisfaction, though both can result in improvements with iron deficiency and risk of pelvic inflammatory disease and often do not result in discontinuation of the medication. Effectiveness Trussell's estimated perfect use first-year failure rate for DMPA as the average of failure rates in seven clinical trials at 0.3%. It was considered perfect use because the clinical trials measured efficacy during actual use of DMPA defined as being no longer than 14 or 15 weeks after an injection (i.e., no more than 1 or 2 weeks late for a next injection). Prior to 2004, Trussell's typical use failure rate for DMPA was the same as his perfect use failure rate: 0.3%. • DMPA estimated typical use first-year failure rate = 0.3% in: • Contraceptive Technology, 16th revised edition (1994) • Contraceptive Technology, 17th revised edition (1998) • Adopted in 1998 by the FDA for its current Uniform Contraceptive Labeling guidance In 2004, using the 1995 NSFG failure rate, Trussell increased (by 10 times) his typical use failure rate for DMPA from 0.3% to 3%. Trussell did not use 1995 NSFG failure rates as typical use failure rates for the other two then newly available long-acting contraceptives, the Norplant implant (2.3%) and the ParaGard copper T 380A IUD (3.7%), which were (as with DMPA) an order of magnitude higher than in clinical trials. Since Norplant and ParaGard allow no scope for user error, their much higher 1995 NSFG failure rates were attributed by Trussell to contraceptive overreporting at the time of a conception leading to a live birth. • Highly effective at preventing pregnancy. • Injected every 12 weeks. The only continuing action is to book subsequent follow-up injections every twelve weeks, and to monitor side effects to ensure that they do not require medical attention. • No estrogen. No increased risk of deep vein thrombosis, pulmonary embolism, stroke, or myocardial infarction. • Minimal drug interactions (compared to other hormonal contraceptives). • Decreased risk of endometrial cancer. DMPA reduces the risk of endometrial cancer by 80%. The reduced risk of endometrial cancer in DMPA users is thought to be due to both the direct anti-proliferative effect of progestogen on the endometrium and the indirect reduction of estrogen levels by suppression of ovarian follicular development. • Decreased risk of iron deficiency anemia, pelvic inflammatory disease (PID) and ectopic pregnancy. • Decreased symptoms of endometriosis. • Decreased incidence of primary dysmenorrhea, ovulation pain, and functional ovarian cysts. • Decreased incidence of seizures in women with epilepsy. Additionally, unlike most other hormonal contraceptives, DMPA's contraceptive effectiveness is not affected by enzyme-inducing antiepileptic drugs. • Decreased incidence and severity of sickle cell crises in women with sickle-cell disease. following on from the October 2005 National Institute for Health and Clinical Excellence guidelines. Giving advice on these methods of contraception has been included in the 2009 Quality and Outcomes Framework "good practice" for primary care. Comparison Proponents of bioidentical hormone therapy believe that progesterone offers fewer side effects and improved quality of life compared to MPA. The evidence for this view has been questioned; MPA is better absorbed when taken by mouth, with a much longer elimination half-life leading to more stable blood levels though it may lead to greater breast tenderness and more sporadic vaginal bleeding. The two medications have not been adequately compared in direct tests to clear conclusions about safety and superiority. It has also been marketed in the form of 100, 200, 250, 400, and 500 mg oral tablets; 500 and 1,000 mg oral suspensions; and as a 50 mg/mL microcrystalline aqueous suspension for intramuscular injection. A 100 mg/mL microcrystalline aqueous suspension for intramuscular injection was previously available as well. Depo-subQ Provera 104 is a variation of the original intramuscular DMPA that is instead a 104 mg microcrystalline dose in aqueous suspension administered by subcutaneous injection. It contains 69% of the MPA found in the original intramuscular DMPA formulation. It can be injected using a smaller injection needle inserting the medication just below the skin, instead of into the muscle, in either the abdomen or thigh. This subcutaneous injection claims to reduce the side effects of DMPA while still maintaining all the same benefits of the original intramuscular DMPA. ==Contraindications==

MPA is not usually recommended because of unacceptable health risk or because it is not indicated in the following cases: Conditions where the theoretical or proven risks usually outweigh the advantages of using DMPA: • Multiple risk factors for arterial cardiovascular disease • Current deep vein thrombosis or pulmonary embolus • Migraine headache with aura while using DMPA • Before evaluation of unexplained vaginal bleeding suspected of being a serious condition • A history of breast cancer and no evidence of current disease for five years • Active liver disease: (acute viral hepatitis, severe decompensated cirrhosis, benign or malignant liver tumours) • Conditions of concern for estrogen deficiency and reduced HDL levels theoretically increasing cardiovascular risk: • Hypertension with vascular disease • Current and history of ischemic heart disease • History of stroke • Diabetes for over 20 years or with nephropathy/retinopathy/neuropathy or vascular disease Conditions which represent an unacceptable health risk if DMPA is used: • Current or recent breast cancer (a hormonally sensitive tumour) Conditions where use is not indicated and should not be initiated: • Pregnancy MPA is not recommended for use prior to menarche or before or during recovery from surgery. ==Side effects==

In women, the most common adverse effects of MPA are acne, changes in menstrual flow, drowsiness, and can cause birth defects if taken by pregnant women. Other common side effects include breast tenderness, increased facial hair, decreased scalp hair, difficulty falling or remaining asleep, stomach pain, and weight loss or gain. DMPA can affect menstrual bleeding. After a year of use, 55% of women experience amenorrhea (missed periods); after two years, the rate rises to 68%. In the first months of use "irregular or unpredictable bleeding or spotting, or, rarely, heavy or continuous bleeding" was reported. MPA does not appear to be associated with vitamin B12 deficiency. Data on weight gain with DMPA likewise are inconsistent. When used as a form of injected birth control, there is a delayed return of fertility. The average return to fertility is 9 to 10 months after the last injection, taking longer for overweight or obese women. By 18 months after the last injection, fertility is the same as that in former users of other contraceptive methods. There were noticeable adverse effects to the cardiovascular system of those who took the treatment. It was also found that after the user had stopped taking the treatment, bone density changes were observed The formation of meningiomas due to the treatment have been the subject of lawsuits. Blood pressure changes were observed in addition to bone density changes. Mood changes There have been concerns about a possible risk of depression and mood changes with progestins like MPA, and this has led to reluctance of some clinicians and women to use them. However, contrary to widely held beliefs, most research suggests that progestins do not cause adverse psychological effects such as depression or anxiety. According to a 2003 review of DMPA, the majority of published clinical studies indicate that DMPA is not associated with depression, and the overall data support the notion that the medication does not significantly affect mood. In the largest study to have assessed the relationship between MPA and depression to date, in which over 3,900 women were treated with DMPA for up to 7 years, the incidence of depression was infrequent at 1.5% and the discontinuation rate due to depression was 0.5%. This study did not include baseline data on depression, However, some small studies have reported that progestins like MPA might counteract beneficial effects of estrogens against depression. Long-term effects The Women's Health Initiative investigated the use of a combination of oral CEEs and MPA compared to placebo. The study was prematurely terminated when previously unexpected risks were discovered, specifically the finding that though the all-cause mortality was not affected by the hormone therapy, the benefits of menopausal hormone therapy (reduced risk of hip fracture, colorectal and endometrial cancer and all other causes of death) were offset by increased risk of coronary heart disease, breast cancer, strokes and pulmonary embolism. When combined with CEEs, MPA has been associated with an increased risk of breast cancer, dementia, and thrombus in the eye. In combination with estrogens in general, MPA may increase the risk of cardiovascular disease, with a stronger association when used by postmenopausal women also taking CEEs. It was because of these unexpected interactions that the Women's Health Initiative study was ended early due to the extra risks of menopausal hormone therapy, resulting in a dramatic decrease in both new and renewal prescriptions for hormone therapy. Long-term studies of users of DMPA have found slight or no increased overall risk of breast cancer. However, the study population did show a slightly increased risk of breast cancer in recent users (DMPA use in the last four years) under age 35, similar to that seen with the use of combined oral contraceptive pills. The increase in incidence of VTE ranges from 2.2-fold to 3.6-fold. and progestogens by themselves normally do not increase the risk of thrombosis. A 2018 meta-analysis reported that MPA was associated with a 2.8-fold higher risk of VTE than other progestins. While it causes temporary bone loss, most women fully regain their bone density after discontinuing use. The World Health Organization (WHO) recommends that the use not be restricted. The American College of Obstetricians and Gynecologists notes that the potential adverse effects on BMD be balanced against the known negative effects of unintended pregnancy using other birth control methods or no method, particularly among adolescents. Three studies have suggested that bone loss is reversible after the discontinuation of DMPA. Other studies have suggested that the effect of DMPA use on postmenopausal bone density is minimal, perhaps because DMPA users experience less bone loss at menopause. Use after peak bone mass is associated with increased bone turnover but no decrease in bone mineral density. The FDA recommends that DMPA not be used for longer than two years, unless there is no viable alternative method of contraception, due to concerns over bone loss. HIV risk There is uncertainty regarding the risk of HIV acquisition among DMPA users; some observational studies suggest an increased risk of HIV acquisition among women using DMPA, while others do not. The World Health Organization issued statements in February 2012 and July 2014 saying the data did not warrant changing their recommendation of no restriction – Medical Eligibility for Contraception (MEC) category 1 – on the use of DMPA in women at high risk for HIV. Two meta-analyses of observational studies in sub-Saharan Africa were published in January 2015. They found a 1.4- to 1.5-fold increase risk of HIV acquisition for DMPA users relative to no hormonal contraceptive use. In January 2015, the Faculty of Sexual & Reproductive Healthcare of the Royal College of Obstetricians and Gynaecologists issued a statement reaffirming that there is no reason to advise against use of DMPA in the United Kingdom even for women at 'high risk' of HIV infection. A systematic review and meta-analysis of risk of HIV infection in DMPA users published in fall of 2015 stated that "the epidemiological and biological evidence now make a compelling case that DMPA adds significantly to the risk of male-to-female HIV transmission." In 2019, a randomized controlled trial found no significant association between DMPA use and HIV. ==Breastfeeding==

MPA may be used by breastfeeding mothers. Heavy bleeding is possible if given in the immediate postpartum time and is best delayed until six weeks after birth. It may be used within five days if not breast feeding. While a study showed "no significant difference in birth weights or incidence of birth defects" and "no significant alternation of immunity to infectious disease caused by breast milk containing DMPA", a subgroup of babies whose mothers started DMPA at two days postpartum had a 75% higher incidence of doctor visits for infectious diseases during their first year of life. A larger study with longer follow-up concluded that "use of DMPA during pregnancy or breastfeeding does not adversely affect the long-term growth and development of children". This study also noted that "children with DMPA exposure during pregnancy and lactation had an increased risk of suboptimal growth in height," but that "after adjustment for socioeconomic factors by multiple logistic regression, there was no increased risk of impaired growth among the DMPA-exposed children." The study also noted that effects of DMPA exposure on puberty require further study, as so few children over the age of 10 were observed. ==Overdose==

MPA has been studied at "massive" dosages of up to 5,000 mg per day orally and 2,000 mg per day via intramuscular injection, without major tolerability or safety issues described. Overdose is not described in the Food and Drug Administration (FDA) product labels for injected MPA (Depo-Provera or Depo-SubQ Provera 104). In the FDA product label for oral MPA (Provera), it is stated that overdose of an estrogen and progestin may cause nausea and vomiting, breast tenderness, dizziness, abdominal pain, drowsiness, fatigue, and withdrawal bleeding. According to the label, treatment of overdose should consist of discontinuation of MPA therapy and symptomatic care. ==Interactions==

MPA increases the risk of breast cancer, dementia, and thrombus when used in combination with CEEs to treat menopausal symptoms. When used as a contraceptive, MPA does not generally interact with other medications. The combination of MPA with aminoglutethimide to treat metastases from breast cancer has been associated with an increase in depression. St John's wort may decrease the effectiveness of MPA as a contraceptive due to acceleration of its metabolism. ==Pharmacology==

Pharmacodynamics MPA acts as an agonist of the progesterone, androgen, and glucocorticoid receptors (PR, AR, and GR, respectively), It has negligible affinity for the estrogen receptor. Progestogenic activity MPA is a potent agonist of the progesterone receptor with similar affinity and efficacy relative to progesterone. While both MPA and its deacetylated analogue medroxyprogesterone bind to and agonize the PR, MPA has approximately 100-fold higher binding affinity and transactivation potency in comparison. In accordance, the dosage of MPA used in oral contraceptives in the past was 10 mg per tablet. The mechanism of action of progestogen-only contraceptives like DMPA depends on the progestogen activity and dose. High-dose progestogen-only contraceptives, such as DMPA, inhibit follicular development and prevent ovulation as their primary mechanism of action. The progestogen decreases the pulse frequency of gonadotropin-releasing hormone (GnRH) release by the hypothalamus, which decreases the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by the anterior pituitary. Decreased levels of FSH inhibit follicular development, preventing an increase in estradiol levels. Progestogen negative feedback and the lack of estrogen positive feedback on LH release prevent a LH surge. Inhibition of follicular development and the absence of a LH surge prevent ovulation. A secondary mechanism of action of all progestogen-containing contraceptives is inhibition of sperm penetration by changes in the cervical mucus. Inhibition of ovarian function during DMPA use causes the endometrium to become thin and atrophic. These changes in the endometrium could, theoretically, prevent implantation. However, because DMPA is highly effective in inhibiting ovulation and sperm penetration, the possibility of fertilization is negligible. No available data support prevention of implantation as a mechanism of action of DMPA. There is evidence that the suppressive effects of MPA on the HPG axis are mediated by activation of both the PR and the AR in the pituitary gland. Due to its effects on androgen levels, MPA can produce strong functional antiandrogenic effects, and is used in the treatment of androgen-dependent conditions such as precocious puberty in boys and hypersexuality in men. In addition, since the medication suppresses estrogen levels as well, MPA can produce strong functional antiestrogenic effects similarly, and has been used to treat estrogen-dependent conditions such as precocious puberty in girls and endometriosis in women. Due to low estrogen levels, the use of MPA without an estrogen poses a risk of decreased bone mineral density and other symptoms of estrogen deficiency. Oral MPA has been found to suppress testosterone levels in men by about 30% (from 831 ng/dL to 585 ng/dL) at a dosage of 20 mg/day, by about 45–75% (average 60%; to 150–400 ng/dL) at a dosage of 60 mg/day, and by about 70–75% (from 832 to 862 ng/dL to 214 to 251 ng/dL) at a dosage of 100 mg/day. Dosages of oral MPA of 2.5 to 30 mg/day in combination with estrogens have been used to help suppress testosterone levels in transgender women. One study of injectable MPA in men with benign prostatic hyperplasia reported that a single 150 mg dose suppressed testosterone levels into the defined male castrate range (50 of 0.2 μM and a Ki (in rat testicular homogenates) of 0.42 μM. This enzyme is essential for the biosynthesis of sex steroids and corticosteroids. It has also been found to produce anesthesia via this action in animals when administered at sufficiently high dosages. MPA shares some of the same metabolic routes of progesterone and, analogously, can be transformed into metabolites such as 5α-dihydro-MPA (DHMPA) and 3α,5α-tetrahydro-MPA (THMPA). Appetite stimulation Although MPA and the closely related medication megestrol acetate are effective appetite stimulants at very high dosages, the mechanism of action of their beneficial effects on appetite is not entirely clear. However, glucocorticoid, cytokine, and possibly anabolic-related mechanisms are all thought to possibly be involved, and a number of downstream changes have been implicated, including stimulation of the release of neuropeptide Y in the hypothalamus, modulation of calcium channels in the ventromedial hypothalamus, and inhibition of the secretion of proinflammatory cytokines including IL-1α, IL-1β, IL-6, and TNF-α, actions that have all been linked to an increase in appetite. Other activity MPA weakly stimulates the proliferation of MCF-7 breast cancer cells in vitro, an action that is independent of the classical PRs and is instead mediated via the progesterone receptor membrane component-1 (PGRMC1). Certain other progestins are also active in this assay, whereas progesterone acts neutrally. Pharmacokinetics Absorption Surprisingly few studies have been conducted on the pharmacokinetics of MPA at postmenopausal replacement dosages. Following this, levels of MPA decreased to 0.09 to 0.35 ng/mL 12 hours post-administration. Subsequently, MPA levels fell to 0.3 to 0.6 ng/mL 24 hours after administration. Treatment of postmenopausal women with 2.5 or 5 mg/day MPA in combination with estradiol valerate for two weeks has been found to rapidly increase circulating MPA levels, with steady-state concentrations achieved after three days and peak concentrations occurring 1.5 to 2 hours after ingestion. Oral MPA tablets can be administered sublingually instead of orally. Rectal administration of MPA has also been studied. With intramuscular administration of 150 mg microcrystalline MPA in aqueous suspension, the medication is detectable in the circulation within 30 minutes, serum concentrations vary but generally plateau at 1.0 ng/mL (2.6 nmol/L) for 3 months. Following this, there is a gradual decline in MPA levels, and the medication can be detected in the circulation for as long as 6 to 9 months post-injection. Smaller crystals dissolve faster and are absorbed more rapidly, resulting in a shorter duration of action. Distribution The plasma protein binding of MPA is 88%. MPA and/or its metabolites are also metabolized via conjugation. Elimination MPA is eliminated 20 to 50% in urine and 5 to 10% in feces following intravenous administration. Less than 3% of a dose is excreted in unconjugated form. Level–effect relationships With intramuscular administration, the high levels of MPA in the blood inhibit luteinizing hormone and ovulation for several months, with an accompanying decrease in serum progesterone to below 0.4 ng/mL. Ovulation resumes when once blood levels of MPA fall below 0.1 ng/mL. Serum estradiol remains at approximately 50 pg/mL for approximately four months post-injection (with a range of 10–92 pg/mL after several years of use), rising once MPA levels fall below 0.5 ng/mL. Hot flashes are rare while MPA is found at significant blood levels in the body, and the vaginal lining remains moist and creased. The endometrium undergoes atrophy, with small, straight glands and a stroma that is decidualized. Cervical mucus remains viscous. Because of its steady blood levels over the long term and multiple effects that prevent fertilization, MPA is a very effective means of birth control. Time–concentration curves ==Chemistry==

MPA is a synthetic pregnane steroid and a derivative of progesterone and 17α-hydroxyprogesterone. ==History==

MPA was independently discovered in 1956 by Syntex and the Upjohn Company. It was first introduced on 18 June 1959 by Upjohn in the United States under the brand name Provera (2.5, 5, and 10 mg tablets) for the treatment of amenorrhea, metrorrhagia, and recurrent miscarriage. An intramuscular formulation of MPA, now known as DMPA (400 mg/mL MPA), was also introduced, under the brand name brand name Depo-Provera, in 1960 in the U.S. for the treatment of endometrial and renal cancer. MPA in combination with ethinylestradiol was introduced in 1964 by Upjohn in the U.S. under the brand name Provest (10 mg MPA and 50 μg ethinylestradiol tablets) as an oral contraceptive, but this formulation was discontinued in 1970. This formulation was marketed by Upjohn outside of the U.S. under the brand names Provestral and Provestrol, while Cyclo-Farlutal (or Ciclofarlutal) and Nogest-S were formulations available outside of the U.S. with a different dosage (5 mg MPA and 50 or 75 μg ethinylestradiol tablets). Following its development in the late 1950s, DMPA was first assessed in clinical trials for use as an injectable contraceptive in 1963. Upjohn sought approval of intramuscular DMPA as a long-acting contraceptive under the brand name Depo-Provera (150 mg/mL MPA) in 1967, but the application was rejected. However, this formulation was successfully introduced in countries outside of the United States for the first time in 1969, and was available in over 90 countries worldwide by 1992. Upjohn attempted to gain FDA approval of DMPA as a contraceptive again in 1978, and yet again in 1983, but both applications failed similarly to the 1967 application. MPA has also been marketed widely throughout the world under numerous other brand names such as Farlutal, Perlutex, and Gestapuran, among others. Court filings revealed that Pfizer became aware of the meningioma risk in 2023, leading them to request the FDA to add a warning in 2024. However, some lawyers have claimed Pfizer knew of the risks in 2015. The request was denied by the FDA, who claimed the studies didn’t clearly support the warning, but the label was later accepted in June 2025 following a resubmission by Pfizer. The MHRA updated patient guidance in the UK in 2024, in collaboration with Pfizer. In 2025 a class action lawsuit was brought against Pfizer in America on behalf of women who had developed meningiomas after taking the drug for an extended period. Over 1300 women were included when the filing was submitted, expanding to over 3400 women by April 2026. ==Society and culture==

Generic names Medroxyprogesterone acetate is the generic name of the drug and its , , , and , while medrossiprogesterone is the and médroxyprogestérone the of its free alcohol form. It is also known as 6α-methyl-17α-acetoxyprogesterone (MAP) or 6α-methyl-17α-hydroxyprogesterone acetate. • Oral pills: Amen, Curretab, Cycrin, Provera – 2.5 mg, 5 mg, 10 mg • Aqueous suspension for intramuscular injection: Depo-Provera – 150 mg/mL (for contraception), 400 mg/mL (for cancer) • Aqueous suspension for subcutaneous injection: Depo-SubQ Provera 104 – 104 mg/0.65 mL (for contraception) It is also available in combination with an estrogen in the following formulations: • Oral pills: CEEs and MPA (Prempro, Prempro (Premarin, Cycrin), Premphase (Premarin, Cycrin 14/14), Premphase 14/14, Prempro/Premphase) – 0.3 mg / 1.5 mg; 0.45 mg / 1.5 mg; 0.625 mg / 2.5 mg; 0.625 mg / 5 mg While the following formulations have been discontinued: • Oral pills: ethinylestradiol and MPA (Provest) – 50 μg / 10 mg • Aqueous suspension for intramuscular injection: estradiol cypionate and MPA (Lunelle) – 5 mg / 25 mg (for contraception) The state of Louisiana permits sex offenders to be given MPA. Generation Progestins in birth control pills are sometimes grouped by generation. While the 19-nortestosterone progestins are consistently grouped into generations, the pregnane progestins that are or have been used in birth control pills are typically omitted from such classifications or are grouped simply as "miscellaneous" or "pregnanes". Controversy Outside the United States • In 1994, when DMPA was approved in India, India's Economic and Political Weekly reported that "The FDA finally licensed the drug in 1990 in response to concerns about the population explosion in the third world and the reluctance of third world governments to license a drug not licensed in its originating country." Some scientists and women's groups in India continue to oppose DMPA. In 2016, India introduced DMPA depo-medroxyprogesterone IM preparation in the public health system. • The Canadian Coalition on Depo-Provera, a coalition of women's health professional and advocacy groups, opposed the approval of DMPA in Canada. Since the approval of DMPA in Canada in 1997, a $700 million class-action lawsuit has been filed against Pfizer by users of DMPA who developed osteoporosis. In response, Pfizer argued that it had met its obligation to disclose and discuss the risks of DMPA with the Canadian medical community. • Clinical trials for this medication regarding women in Zimbabwe were controversial with regard to human rights abuses and Medical Experimentation in Africa. • A controversy erupted in Israel when the government was accused of giving DMPA to Ethiopian immigrants without their consent. Some women claimed they were told it was a vaccination. The Israeli government denied the accusations but instructed the four health maintenance organizations to stop administering DMPA injections to women "if there is the slightest doubt that they have not understood the implications of the treatment". United States There was a long, controversial history regarding the approval of DMPA by the U.S. Food and Drug Administration. The original manufacturer, Upjohn, applied repeatedly for approval. FDA advisory committees unanimously recommended approval in 1973, 1975 and 1992, as did the FDA's professional medical staff, but the FDA repeatedly denied approval. Ultimately, on 29 October 1992, the FDA approved DMPA for birth control, which had by then been used by over 30 million women since 1969 and was approved and being used by nearly 9 million women in more than 90 countries, including the United Kingdom, France, Germany, Sweden, Thailand, New Zealand and Indonesia. Points in the controversy included: • Animal testing for carcinogenicity – DMPA caused breast cancer tumors in dogs. Critics of the study claimed that dogs are more sensitive to artificial progesterone, and that the doses were too high to extrapolate to humans. The FDA pointed out that all substances carcinogenic to humans are carcinogenic to animals as well, and that if a substance is not carcinogenic it does not register as a carcinogen at high doses. Levels of DMPA which caused malignant mammary tumors in dogs were equivalent to 25 times the amount of the normal luteal phase progesterone level for dogs. This is lower than the pregnancy level of progesterone for dogs, and is species-specific.DMPA caused endometrial cancer in monkeys – 2 of 12 monkeys tested, the first ever recorded cases of endometrial cancer in rhesus monkeys. However, subsequent studies have shown that in humans, DMPA reduces the risk of endometrial cancer by approximately 80%. However, numerous larger subsequent studies have shown that DMPA use does not increase the risk of cervical cancer. • Coercion and lack of informed consent. Testing or use of DMPA was focused almost exclusively on women in developing countries and poor women in the United States, and for mentally disabled people, who in some reported cases were given DMPA long-term for reasons of "menstrual hygiene", although they were not sexually active. • Atlanta/Grady Study – Upjohn studied the effect of DMPA for 11 years in Atlanta, mostly on black women who were receiving public assistance, but did not file any of the required follow-up reports with the FDA. Investigators who eventually visited noted that the studies were disorganized. "They found that data collection was questionable, consent forms and protocol were absent; that those women whose consent had been obtained at all were not told of possible side effects. Women whose known medical conditions indicated that use of DMPA would endanger their health were given the shot. Several of the women in the study died; some of cancer, but some for other reasons, such as suicide due to depression. Over half the 13,000 women in the study were lost to followup due to sloppy record keeping." Consequently, no data from this study was usable. • In 1995, several women's health groups asked the FDA to put a moratorium on DMPA, and to institute standardized informed consent forms. ==Research==

DMPA was studied by Upjohn for use as a progestogen-only injectable contraceptive in women at a dose of 50 mg once a month but produced poor cycle control and was not marketed for this use at this dosage. A combination of DMPA and polyestradiol phosphate, an estrogen and long-lasting prodrug of estradiol, was studied in women as a combined injectable contraceptive for use by intramuscular injection once every three months. High-dose oral and intramuscular MPA monotherapy has been studied in the treatment of prostate cancer but was found to be inferior to monotherapy with cyproterone acetate or diethylstilbestrol. High-dose oral MPA has been studied in combination with diethylstilbestrol and CEEs as an addition to high-dose estrogen therapy for the treatment of prostate cancer in men, but was not found to provide better effectiveness than diethylstilbestrol alone. DMPA has been studied for use as a potential male hormonal contraceptive in combination with the androgens/anabolic steroids testosterone and nandrolone (19-nortestosterone) in men. However, it was never approved for this indication. It was formulated as an oral medication at very high dosages, and was thought to inhibit the signaling of proinflammatory cytokines such as interleukin 6 and tumor necrosis factor alpha, with a mechanism of action that was said to be similar to that of corticosteroids. ==Veterinary use==

MPA has been used to reduce aggression and spraying in male cats. It may be particularly useful for controlling such behaviors in neutered male cats. The medication can be administered in cats as an injection once per month. ==Legal punishment use==

MPA is prescribed as a legal punishment to Chemically Castrate some Sexual Assault offenders under legal Code reference in Louisiana. §43.6. Administration of medroxyprogesterone acetate (MPA) to certain sex offenders. ==See also==