Medroxyprogesterone

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%.^[45][46] 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%.^[47]

• DMPA estimated typical use first-year failure rate = 0.3% in:
  • Contraceptive Technology, 16th revised edition (1994)^[48]
  • Contraceptive Technology, 17th revised edition (1998)^[49]
    • Adopted in 1998 by the FDA for its current Uniform Contraceptive Labeling guidance^[50]

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%.^[45][46]

• DMPA estimated typical use first-year failure rate = 3% in:
  • Contraceptive Technology, 18th revised edition (2004)^[45]
  • Contraceptive Technology, 19th revised edition (2007)^[51]

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.^[45][52][46]

Advantages

DMPA has a number of advantages and benefits:^{[53][54][44][55]}

• 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%.^[56][57][58] 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.^[59]
• Decreased risk of iron deficiency anemia, pelvic inflammatory disease (PID), ectopic pregnancy,^[60][61] and uterine fibroids.
• 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.^[62]
• Decreased incidence and severity of sickle cell crises in women with sickle-cell disease.^[44]

The United Kingdom Department of Health has actively promoted Long Acting Reversible Contraceptive use since 2008, particularly for young people;^[63] following on from the October 2005 National Institute for Health and Clinical Excellence guidelines.^[64] Giving advice on these methods of contraception has been included in the 2009 Quality and Outcomes Framework "good practice" for primary care.^[65]

Blood clots

DMPA has been associated in multiple studies with a higher risk of venous thromboembolism (VTE) when used as a form of progestogen-only birth control in premenopausal women.^{[96][97][98][99]} The increase in incidence of VTE ranges from 2.2-fold to 3.6-fold.^{[96][97][98][99]} Elevated risk of VTE with DMPA is unexpected, as DMPA has little or no effect on coagulation and fibrinolytic factors,^[100][101] and progestogens by themselves normally do not increase the risk of thrombosis.^[97][98] It has been argued that the higher incidence with DMPA has reflected preferential prescription of DMPA to women considered to be at an increased risk of VTE.^[97] Alternatively, it is possible that MPA may be an exception among progestins in terms of VTE risk.^{[102][103][104]} A 2018 meta-analysis reported that MPA was associated with a 2.8-fold higher risk of VTE than other progestins.^[103] It is possible that the glucocorticoid activity of MPA may increase the risk of VTE.^{[6][105][104]}

Bone density

DMPA may cause reduced bone density in premenopausal women and in men when used without an estrogen, particularly at high doses, though this appears to be reversible to a normal level even after years of use.

On November 17, 2004, the United States Food and Drug Administration put a black box warning on the label, indicating that there were potential adverse effects of loss of bone mineral density.^[106][107] While it causes temporary bone loss, most women fully regain their bone density after discontinuing use.^[80] The World Health Organization (WHO) recommends that the use not be restricted.^[108][109] 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.^{[110][111][112]} Other studies have suggested that the effect of DMPA use on postmenopausal bone density is minimal,^[113] perhaps because DMPA users experience less bone loss at menopause.^[114] Use after peak bone mass is associated with increased bone turnover but no decrease in bone mineral density.^[115]

The FDA recommends that DMPA not be used for longer than 2 years, unless there is no viable alternative method of contraception, due to concerns over bone loss.^[107] However, a 2008 Committee Opinion from the American Congress of Obstetricians and Gynecologists (ACOG) advises healthcare providers that concerns about bone mineral density loss should neither prevent the prescription of or continuation of DMPA beyond 2 years of use.^[116]

Progestogenic activity

MPA is a potent agonist of the progesterone receptor with similar affinity and efficacy relative to progesterone.^[133] 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.^[133] As such, unlike MPA, medroxyprogesterone is not used clinically, though it has seen some use in veterinary medicine.^[2] The oral dosage of MPA required to inhibit ovulation (i.e., the effective contraceptive dosage) is 10 mg/day, whereas 5 mg/day was not sufficient to inhibit ovulation in all women.^[134] In accordance, the dosage of MPA used in oral contraceptives in the past was 10 mg per tablet.^[135] For comparison to MPA, the dosage of progesterone required to inhibit ovulation is 300 mg/day, whereas that of the 19-nortestosterone derivatives norethisterone and norethisterone acetate is only 0.4 to 0.5 mg/day.^[136]

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.^[137][138] 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.^[53][54] A secondary mechanism of action of all progestogen-containing contraceptives is inhibition of sperm penetration by changes in the cervical mucus.^[139] 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.^[139]

Antigonadotropic and anticorticotropic effects

MPA suppresses the hypothalamic–pituitary–adrenal (HPA) and hypothalamic–pituitary–gonadal (HPG) axes at sufficient dosages, resulting decreased levels of gonadotropins, androgens, estrogens, adrenocorticotropic hormone (ACTH), and cortisol, as well as levels of sex hormone-binding globulin (SHBG).^[15] 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.^[141][142] 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.^[143] 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.^[144]

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 to 75% (average 60%; to 150–400 ng/dL) at a dosage of 60 mg/day,^{[145][146][147]} and by about 70 to 75% (from 832–862 ng/dL to 214–251 ng/dL) at a dosage of 100 mg/day.^[148][149] 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.^{[150][151][152][153][154][155]} Very high dosages of intramuscular MPA of 150 to 500 mg per week (but up to 900 mg per week) can suppress testosterone levels to less than 100 ng/dL.^[145][156] The typical initial dose of intramuscular MPA for testosterone suppression in men with paraphilias is 400 or 500 mg per week.^[145]

Androgenic activity

MPA is a potent full agonist of the AR. Its activation of the AR may play an important and major role in its antigonadotropic effects and in its beneficial effects against breast cancer.^{[141][157][158]} However, although MPA may produce androgenic side effects such as acne and hirsutism in some women,^[159][160] it rarely does so, and when such symptoms occur, they tend to be mild, regardless of the dosage used.^[141] In fact, likely due to its suppressive actions on androgen levels, it has been reported that MPA is generally highly effective in improving pre-existing symptoms of hirsutism in women with the condition.^[161][162] Moreover, MPA rarely causes any androgenic effects in children with precocious puberty, even at very high doses.^[163] The reason for the general lack of virilizing effects with MPA, despite it binding to and activating the AR with high affinity and this action potentially playing an important role in many of its physiological and therapeutic effects, is not entirely clear. However, MPA has been found to interact with the AR differently compared to other agonists of the receptor such as dihydrotestosterone (DHT).^[14] The result of this difference appears to be that MPA binds to the AR with a similar affinity and intrinsic activity to that of DHT, but requires about 100-fold higher concentrations for a comparable induction of gene transcription, while at the same time not antagonizing the transcriptional activity of normal androgens like DHT at any concentration.^[14] Thus, this may explain the low propensity of MPA for producing androgenic side effects.^[14]

MPA shows weak androgenic effects on liver protein synthesis, similarly to other weakly androgenic progestins like megestrol acetate and 19-nortestosterone derivatives.^[6][9] While it does not antagonize estrogen-induced increases in levels of triglycerides and HDL cholesterol, DMPA every other week may decrease levels of HDL cholesterol.^[6] In addition, MPA has been found to suppress sex hormone-binding globulin (SHBG) production by the liver.^{[9][164][165]} At a dosage of 10 mg/day oral MPA, it has been found to decrease circulating SHBG levels by 14 to 18% in women taking 4 mg/day oral estradiol valerate.^[9] Conversely, in a study that combined 2.5 mg/day oral MPA with various oral estrogens, no influence of MPA on estrogen-induced increases in SHBG levels was discerned.^[165] In another, higher-dose study, SHBG levels were lower by 59% in a group of women treated with 50 mg/day oral MPA alone relative to an untreated control group of women.^[164]

Unlike the related steroids megestrol acetate and cyproterone acetate, MPA is not an antagonist of the AR and does not have direct antiandrogenic activity.^[6] As such, although MPA is sometimes described as an antiandrogen, it is not a "true" antiandrogen (i.e., AR antagonist).^[146]

Glucocorticoid activity

As an agonist of the GR, MPA has glucocorticoid activity, and as a result can cause symptoms of Cushing's syndrome,^[166] steroid diabetes, and adrenal insufficiency at sufficiently high doses.^[167] It has been suggested that the glucocorticoid activity of MPA may contribute to bone loss.^[168] The glucocorticoid activity of MPA may also result in an upregulation of the thrombin receptor in blood vessel walls, which may contribute to procoagulant effects of MPA and risk of venous thromboembolism and atherosclerosis.^[6] The relative glucocorticoid activity of MPA is among the highest of the clinically used progestins.^[6]

Steroidogenesis inhibition

MPA has been found to act as a competitive inhibitor of rat 3α-hydroxysteroid dehydrogenase (3α-HSD).^{[169][170][171][172]} This enzyme is essential for the transformation of progesterone, deoxycorticosterone, and DHT into inhibitory neurosteroids such as allopregnanolone, THDOC, and 3α-androstanediol, respectively.^[173] MPA has been described as very potent in its inhibition of rat 3α-HSD, with an IC₅₀ of 0.2 μM and a K_i (in rat testicular homogenates) of 0.42 μM.^[169][170] However, inhibition of 3α-HSD by MPA does not appear to have been confirmed using human proteins yet, and the concentrations required with rat proteins are far above typical human therapeutic concentrations.^[169][170]

MPA has been identified as a competitive inhibitor of human 3β-hydroxysteroid dehydrogenase/Δ^5-4 isomerase II (3β-HSD II).^[174] This enzyme is essential for the biosynthesis of sex steroids and corticosteroids.^[174] The K_i of MPA for inhibition of 3β-HSD II is 3.0 μM, and this concentration is reportedly near the circulating levels of the medication that are achieved by very high therapeutic dosages of MPA of 5 to 20 mg/kg/day (dosages of 300 to 1,200 mg/day for a 60 kg (132 lb) person).^[174] Aside from 3β-HSD II, other human steroidogenic enzymes, including cholesterol side-chain cleavage enzyme (P450scc/CYP11A1) and 17α-hydroxylase/17,20-lyase (CYP17A1), were not found to be inhibited by MPA.^[174] MPA has been found to be effective in the treatment of gonadotropin-independent precocious puberty and in breast cancer in postmenopausal women at high dosages, and inhibition of 3β-HSD II could be responsible for its effectiveness in these conditions.^[174]

GABA_A receptor allosteric modulation

Progesterone, via transformation into neurosteroids such as 5α-dihydroprogesterone, 5β-dihydroprogesterone, allopregnanolone, and pregnanolone (catalyzed by the enzymes 5α- and 5β-reductase and 3α- and 3β-HSD), is a positive allosteric modulator of the GABA_A receptor, and is associated with a variety of effects mediated by this property including dizziness, sedation, hypnotic states, mood changes, anxiolysis, and cognitive/memory impairment, as well as effectiveness as an anticonvulsant in the treatment of catamenial epilepsy.^[173][175] It has also been found to produce anesthesia via this action in animals when administered at sufficiently high dosages.^[175] MPA was found to significantly reduce seizure incidence when added to existing anticonvulsant regimens in 11 of 14 women with uncontrolled epilepsy, and has also been reported to induce anesthesia in animals, raising the possibility that it might modulate the GABA_A receptor similarly to progesterone.^[176][177]

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).^[176] However, unlike the reduced metabolites of progesterone, DHMPA and THMPA have been found not to modulate the GABA_A receptor.^[176] Conversely, unlike progesterone, MPA itself actually modulates the GABA_A receptor, although notably not at the neurosteroid binding site.^[176] However, rather than act as a potentiator of the receptor, MPA appears to act as a negative allosteric modulator.^[176] Whereas the reduced metabolites of progesterone enhance binding of the benzodiazepine flunitrazepam to the GABA_A receptor in vitro, MPA can partially inhibit the binding of flunitrazepam by up to 40% with half-maximal inhibition at 1 μM.^[176] However, the concentrations of MPA required for inhibition are high relative to therapeutic concentrations, and hence, this action is probably of little or no clinical relevance.^[176] The lack of potentiation of the GABA_A receptor by MPA or its metabolites is surprising in consideration of the apparent anticonvulsant and anesthetic effects of MPA described above, and they remain unexplained.^[176]

Clinical studies using massive dosages of up to 5,000 mg/day oral MPA and 2,000 mg/day intramuscular MPA for 30 days in women with advanced breast cancer have reported "no relevant side effects", which suggests that MPA has no meaningful direct action on the GABA_A receptor in humans even at extremely high dosages.^[128]

Appetite stimulation

Although MPA and the closely related medication megestrol acetate are effective appetite stimulants at very high dosages,^[178] 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.^[179]

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).^[180] Certain other progestins are also active in this assay, whereas progesterone acts neutrally.^[180] It is unclear if these findings may explain the different risks of breast cancer observed with progesterone, dydrogesterone, and other progestins such as medroxyprogesterone acetate and norethisterone in clinical studies.^[181]

Absorption

Surprisingly few studies have been conducted on the pharmacokinetics of MPA at postmenopausal replacement dosages.^[182][6] The bioavailability of MPA with oral administration is approximately 100%.^[6] A single oral dose of 10 mg MPA has been found to result in peak MPA levels of 1.2 to 5.2 ng/mL within 2 hours of administration using radioimmunoassay.^[182][183] Following this, levels of MPA decreased to 0.09 to 0.35 ng/mL 12 hours post-administration.^[182][183] In another study, peak levels of MPA were 3.4 to 4.4 ng/mL within 1 to 4 hours of administration of 10 mg oral MPA using radioimmunoassay.^[182][184] Subsequently, MPA levels fell to 0.3 to 0.6 ng/mL 24 hours after administration.^[182][184] In a third study, MPA levels were 4.2 to 4.4 ng/mL after an oral dose of 5 mg MPA and 6.0 ng/mL after an oral dose of 10 mg MPA, both using radioimmunoassay as well.^[182][185]

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 3 days and peak concentrations occurring 1.5 to 2 hours after ingestion.^[6][186] With 2.5 mg/day MPA, levels of the medication were 0.3 ng/mL (0.8 nmol/L) in women under 60 years of age and 0.45 ng/mL (1.2 nmol/L) in women 65 years of age or over, and with 5 mg/day MPA, levels were 0.6 ng/mL (1.6 nmol/L) in women under 60 years of age and in women 65 years of age or over.^[6][186] Hence, area-under-curve levels of the medication were 1.6 to 1.8 times higher in those who were 65 years of age or older relative to those who were 60 years of age or younger.^[9][186] As such, levels of MPA have been found to vary with age, and MPA may have an increased risk of side effects in elderly postmenopausal women.^[9][6][186] This study assessed MPA levels using liquid-chromatography–tandem mass spectrometry (LC–MS/MS), a more accurate method of blood determinations.^[186]

Oral MPA tablets can be administered sublingually instead of orally.^{[187][188][189]} Rectal administration of MPA has also been studied.^[190]

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.^[191] 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.^[191] The particle size of MPA crystals significantly influences its rate of absorption into the body from the local tissue depot when used as a microcrystalline aqueous suspension via intramuscular injection.^{[192][193][194]} Smaller crystals dissolve faster and are absorbed more rapidly, resulting in a shorter duration of action.^{[192][193][194]} Particle sizes can differ between different formulations of MPA, potentially influencing clinical efficacy and tolerability.^{[192][193][194][195]}

Distribution

The plasma protein binding of MPA is 88%.^[6][9] It is weakly bound to albumin and is not bound to sex hormone-binding globulin or corticosteroid-binding globulin.^[6][9]

Metabolism

The elimination half-life of MPA via oral administration has been reported as both 11.6 to 16.6 hours^[8] and 33 hours,^[6] whereas the elimination half-lives with intramuscular and subcutaneous injection of microcrystalline MPA in aqueous suspension are 50 and 40 days, respectively.^[10][11] The metabolism of MPA is mainly via hydroxylation, including at positions C6β, C21, C2β, and C1β, mediated primarily via CYP3A4, but 3- and 5-dihydro and 3,5-tetrahydro metabolites of MPA are also formed.^[6][9] Deacetylation of MPA and its metabolites (into, e.g., medroxyprogesterone) has been observed to occur in non-human primate research to a substantial extent as well (30 to 70%).^[196] MPA and/or its metabolites are also metabolized via conjugation.^[76] The C6α methyl and C17α acetoxy groups of MPA make it more resistant to metabolism and allow for greater bioavailability than oral progesterone.^[9]

Elimination

MPA is eliminated 20 to 50% in urine and 5 to 10% in feces following intravenous administration.^[197] Less than 3% of a dose is excreted in unconjugated form.^[197]

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.^[191] Ovulation resumes when once blood levels of MPA fall below 0.1 ng/mL.^[191] 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.^[191]

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.^[191]

Time–concentration curves

United States

As of November 2016, MPA is available in the United States in the following formulations:^[69]

• 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.^[219]

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." ^[223] Some scientists and women's groups in India continue to oppose DMPA.^[224] In 2016, India introduced DMPA depo-medroxyprogesterone IM preparation in the public health system.^[225]
• The Canadian Coalition on Depo-Provera, a coalition of women's health professional and advocacy groups, opposed the approval of DMPA in Canada.^[226] 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.^[227]
• 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".^[228]

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 October 29, 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.^[229] 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.^[230]
  DMPA caused endometrial cancer in monkeys – 2 of 12 monkeys tested, the first ever recorded cases of endometrial cancer in rhesus monkeys.^[231] However, subsequent studies have shown that in humans, DMPA reduces the risk of endometrial cancer by approximately 80%.^[56][57][58]
  Speaking in comparative terms regarding animal studies of carcinogenicity for medications, a member of the FDA's Bureau of Drugs testified at an agency DMPA hearing, "...Animal data for this drug is more worrisome than any other drug we know of that is to be given to well people."
• Cervical cancer in Upjohn/NCI studies. Cervical cancer was found to be increased as high as 9-fold in the first human studies recorded by the manufacturer and the National Cancer Institute.^[232] However, numerous larger subsequent studies have shown that DMPA use does not increase the risk of cervical cancer.^{[233][234][235][236][237]}
• 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,^[238] raising serious questions about coercion and lack of informed consent, particularly for the illiterate^[239] and for the mentally challenged, who in some reported cases were given DMPA long-term for reasons of "menstrual hygiene", although they were not sexually active.^[240]
• 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.^[238]
• WHO Review – In 1992, the WHO presented a review of DMPA in four developing countries to the FDA. The National Women's Health Network and other women's organizations testified at the hearing that the WHO was not objective, as the WHO had already distributed DMPA in developing countries. DMPA was approved for use in United States on the basis of the WHO review of previously submitted evidence from countries such as Thailand, evidence which the FDA had deemed insufficient and too poorly designed for assessment of cancer risk at a prior hearing.
• The Alan Guttmacher Institute has speculated that United States approval of DMPA may increase its availability and acceptability in developing countries.^[238][241]
• In 1995, several women's health groups asked the FDA to put a moratorium on DMPA, and to institute standardized informed consent forms.^[242]