MPA was discovered in 1956 and was introduced for medical use in the United States in 1959.[13][14][9] It is on theWorld Health Organization's List of Essential Medicines.[15] MPA is the most widely used progestin in menopausal hormone therapy and inprogestogen-only birth control.[16][17] DMPA is approved for use as a form of long-acting birth control in more than 100 countries.[18][19] In 2022, it was the 276th most commonly prescribed medication in the United States, with more than 800,000 prescriptions.[20][21]
Especially in first injection may be frequent spotting
Period advantages
Usually no periods from 2nd injection
Benefits
Especially good if poor pill compliance. Reduced endometrial cancer risk.
Risks
Reduced bone density, which may reverse after discontinuation
Medical notes
For those intending to start family, suggest switch 6 months prior to alternative method (e.g.POP) allowing more reliable return fertility.
DMPA, under brand names such as Depo-Provera and Depo-SubQ Provera 104, is used inhormonal birth control as a long-lasting progestogen-only injectable contraceptive to prevent pregnancy in women.[37][38] It is given byintramuscular orsubcutaneous injection and forms a long-lastingdepot, from which it is slowly released over a period of several months. It takes one week to take effect if given after the first five days of the period cycle, and is effective immediately if given during the first five days of the period cycle. Estimates of first-year failure rates are about 0.3%.[39]
Trussell's estimatedperfect use first-year failure rate for DMPA as the average of failure rates in seven clinical trials at 0.3%.[39][40] It was consideredperfect 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'stypical use failure rate for DMPA was the same as hisperfect use failure rate: 0.3%.[41]
DMPA estimatedtypical use first-year failure rate = 0.3% in:
Trussell did not use 1995 NSFG failure rates astypical use failure rates for the other two then newly available long-acting contraceptives, theNorplant implant (2.3%) and the ParaGard copper T 380AIUD (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.[39][46][40]
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.[citation needed]
Decreased risk ofendometrial cancer. DMPA reduces the risk of endometrial cancer by 80%.[50][51][52] 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.[53]
Proponents ofbioidentical hormone therapy believe that progesterone offers fewer side effects and improved quality of life compared to MPA.[60] The evidence for this view has been questioned; MPA is better absorbed when taken by mouth, with a much longerelimination half-life leading to more stable blood levels[61] though it may lead to greater breast tenderness and moresporadic vaginal bleeding.[60] The two compounds do not differentiate in their ability to suppressendometrial hyperplasia,[60] nor does either increase the risk ofpulmonary embolism.[62] The two medications have not been adequately compared in direct tests to clear conclusions about safety and superiority.[24]
MPA is available alone in the form of 2.5, 5, and 10 mgoraltablets, as a 150 mg/mL (1 mL) or 400 mg/mL (2.5 mL)microcrystallineaqueous suspension forintramuscular injection, and as a 104 mg (0.65 mL of 160 mg/mL) microcrystalline aqueous suspension forsubcutaneous injection.[63][64] 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.[65][66] A 100 mg/mL microcrystalline aqueous suspension for intramuscular injection was previously available as well.[63] In addition to single-drug formulations, MPA is available in the form of oral tablets in combination withconjugated estrogens (CEEs),estradiol, andestradiol valerate for use in menopausal hormone therapy, and is available in combination withestradiol cypionate in a microcrystalline aqueous suspension as acombined injectable contraceptive.[10][11][63][18]
Depo-Provera is the brand name for a 150 mg microcrystalline aqueous suspension of DMPA that is administered by intramuscular injection. The shot must be injected into thigh, buttock, or deltoid muscle four times a year (every 11 to 13 weeks), and provides pregnancy protection instantaneously after the first injection.[67] 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.
In women, the most commonadverse effects of MPA are acne, changes in menstrual flow, drowsiness, and can causebirth defects if taken by pregnant women. Other common side effects includebreast tenderness, increased facial hair, decreased scalp hair, difficulty falling or remaining asleep, stomach pain, and weight loss or gain.[23] Loweredlibido has been reported as a side effect of MPA in women.[71] DMPA can affect menstrual bleeding. After a year of use, 55% of women experienceamenorrhea (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.[72] MPA does not appear to be associated withvitamin B12 deficiency.[73] Data on weight gain with DMPA likewise are inconsistent.[74][75]
At high doses for the treatment of breast cancer, MPA can cause weight gain and can worsendiabetes mellitus andedema (particularly of the face). Adverse effects peak at five weeks, and are reduced with lower doses. Less frequent effects may includethrombosis (though it is not clear if this is truly a risk, it cannot be ruled out),painful urination,headache,nausea, andvomiting. When used as a form ofandrogen deprivation therapy in men, more frequent complaints include reducedlibido,impotence, reducedejaculate volume, and within three days,chemical castration. At extremely high doses (used to treat cancer, not for contraception) MPA may causeadrenal suppression and may interfere with carbohydrate metabolism, but does not causediabetes.[28]
When used as a form of injected birth control, there is a delayed return offertility. 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.[47][48]Fetuses exposed to progestogens have demonstrated higher rates of genital abnormalities, low birth weight, and increasedectopic pregnancy particularly when MPA is used as an injected form of long-term birth control. A study of accidental pregnancies among poor women in Thailand found that infants who had been exposed to DMPA during pregnancy had a higher risk of low birth weight and an 80% greater-than-usual chance of dying in the first year of life.[76] There were noticeable adverse effects to the cardiovascular system of those who took the treatment.[77] It was also found that after the user had stopped taking the treatment, bone density changes were observed[78] The formation of meningiomas due to the treatment have been the subject of lawsuits.[79] Blood pressure changes were observed in addition to bone density changes.[80]
There have been concerns about a possible risk ofdepression andmood changes with progestins like MPA, and this has led to reluctance of some clinicians and women to use them.[81][82] However, contrary to widely-held beliefs, most research suggests that progestins do not cause adverse psychological effects such as depression oranxiety.[81] A 2018 systematic review of the relationship between progestin-based contraception and depression included three large studies of DMPA and reported no association between DMPA and depression.[83] 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.[84]
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%.[83][37][85] This study did not include baseline data on depression,[85] and due to the incidence of depression in the study, the FDA required package labeling for DMPA stating that women with depression should be observed carefully and that DMPA should be discontinued if depression recurs.[83] A subsequent study of 495 women treated with DMPA over the course of 1 year found that the mean depression score slightly decreased in the whole group of continuing users from 7.4 to 6.7 (by 9.5%) and decreased in the quintile of that group with the highest depression scores at baseline from 15.4 to 9.5 (by 38%).[85] Based on the results of this study and others, a consensus began emerging that DMPA does not in fact increase the risk of depression nor worsen the severity of pre-existing depression.[75][85][37]
Similarly to the case of DMPA for hormonal contraception, the Heart and Estrogen/Progestin Replacement Study (HERS), a study of 2,763 postmenopausal women treated with 0.625 mg/day oral CEEs plus 2.5 mg/day oral MPA or placebo for 36 months as a method ofmenopausal hormone therapy, found no change in depressive symptoms.[86][87][88] However, some small studies have reported that progestins like MPA might counteract beneficial effects of estrogens against depression.[81][3][89]
TheWomen'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 ofhip fracture,colorectal andendometrial cancer and all other causes of death) were offset by increased risk ofcoronary heart disease,breast cancer,strokes andpulmonary embolism.[90]
When combined with CEEs, MPA has been associated with an increased risk of breast cancer,dementia, andthrombus in the eye. In combination with estrogens in general, MPA may increase the risk ofcardiovascular disease, with a stronger association when used bypostmenopausal women also taking CEEs. It was because of these unexpected interactions that theWomen's Health Initiative study was ended early due to the extra risks ofmenopausal hormone therapy,[91] resulting in a dramatic decrease in both new and renewal prescriptions for hormone therapy.[92]
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 ofcombined oral contraceptive pills.[72]
DMPA has been associated in multiple studies with a higher risk ofvenous thromboembolism (VTE) when used as a form of progestogen-only birth control in premenopausal women.[93][94][95][96] The increase in incidence of VTE ranges from 2.2-fold to 3.6-fold.[93][94][95][96] Elevated risk of VTE with DMPA is unexpected, as DMPA has little or no effect oncoagulation andfibrinolytic factors,[97][98] and progestogens by themselves normally do not increase the risk of thrombosis.[94][95] 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.[94] Alternatively, it is possible that MPA may be an exception among progestins in terms of VTE risk.[99][100][101] A 2018meta-analysis reported that MPA was associated with a 2.8-fold higher risk of VTE than other progestins.[100] It is possible that theglucocorticoid activity of MPA may increase the risk of VTE.[3][102][101]
DMPA may cause reducedbone 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 17 November 2004, the United StatesFood and Drug Administration put ablack box warning on the label, indicating that there were potential adverse effects of loss of bone mineral density.[103][104] While it causes temporarybone loss, most women fully regain their bone density after discontinuing use.[74] TheWorld Health Organization (WHO) recommends that the use not be restricted.[105][106] 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.[107][108][109] Other studies have suggested that the effect of DMPA use on postmenopausal bone density is minimal,[110] perhaps because DMPA users experience less bone loss at menopause.[111] Use after peak bone mass is associated with increased bone turnover but no decrease in bone mineral density.[112]
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.[104] However, a 2008 Committee Opinion from theAmerican 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 two years of use.[113]
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.[114] 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.[115][116] Two meta-analyses of observational studies in sub-Saharan Africa were published in January 2015.[117] They found a 1.4- to 1.5-fold increase risk of HIV acquisition for DMPA users relative to no hormonal contraceptive use.[118][119] 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.[120] 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."[121] In 2019, a randomized controlled trial found no significant association between DMPA use and HIV.[122]
MPA may be used bybreastfeeding mothers. Heavy bleeding is possible if given in the immediatepostpartum 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.[123]
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.[124]
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 majortolerability orsafety issues described.[125][126][127] Overdose is not described in theFood and Drug Administration (FDA) product labels for injected MPA (Depo-Provera or Depo-SubQ Provera 104).[6][7] In the FDA product label for oral MPA (Provera), it is stated that overdose of an estrogen and progestin may causenausea andvomiting,breast tenderness,dizziness,abdominal pain,drowsiness,fatigue, andwithdrawal bleeding.[5] According to the label, treatment of overdose should consist of discontinuation of MPA therapy and symptomatic care.[5]
Notes: Values are percentages (%). Referenceligands (100%) werepromegestone for thePRTooltip progesterone receptor,metribolone for theARTooltip androgen receptor,estradiol for theERTooltip estrogen receptor,dexamethasone for theGRTooltip glucocorticoid receptor, andaldosterone for theMRTooltip mineralocorticoid receptor.Sources:[3]
MPA is a potentagonist of theprogesterone receptor with similaraffinity andefficacy relative toprogesterone.[131] While both MPA and its deacetylated analoguemedroxyprogesterone bind to and agonize the PR, MPA has approximately 100-fold higherbinding affinity andtransactivation potency in comparison.[131] As such, unlike MPA, medroxyprogesterone is not used clinically, though it has seen some use inveterinary medicine.[132] The oral dosage of MPA required to inhibitovulation (i.e., the effective contraceptive dosage) is 10 mg/day, whereas 5 mg/day was not sufficient to inhibit ovulation in all women.[133] In accordance, the dosage of MPA used in oral contraceptives in the past was 10 mg per tablet.[134] For comparison to MPA, the dosage ofprogesterone required to inhibit ovulation is 300 mg/day, whereas that of the19-nortestosterone derivativesnorethisterone andnorethisterone acetate is only 0.4 to 0.5 mg/day.[135]
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, inhibitfollicular development and preventovulation as their primary mechanism of action.[136][137] The progestogen decreases the pulse frequency ofgonadotropin-releasing hormone (GnRH) release by thehypothalamus, which decreases the release offollicle-stimulating hormone (FSH) andluteinizing hormone (LH) by theanterior pituitary. Decreased levels of FSH inhibit follicular development, preventing an increase inestradiol levels. Progestogennegative feedback and the lack ofestrogenpositive feedback on LH release prevent a LH surge. Inhibition of follicular development and the absence of a LH surge prevent ovulation.[47][48] A secondary mechanism of action of all progestogen-containing contraceptives is inhibition ofsperm penetration by changes in thecervical mucus.[138] Inhibition of ovarian function during DMPA use causes theendometrium 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 offertilization is negligible. No available data support prevention of implantation as a mechanism of action of DMPA.[138]
MPA and related steroids at the progesterone receptor
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,[163][164][165] and by about 70–75% (from 832 to 862 ng/dL to 214 to 251 ng/dL) at a dosage of 100 mg/day.[166][167] 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.[168][169][170][171][172][173] One study of injectable MPA in men withbenign prostatic hyperplasia reported that a single 150 mg dose suppressed testosterone levels into the defined male castrate range (<58 ng/dL) within 7 days and that castration levels of testosterone were maintained for 3 months.[174] Very high doses of intramuscular MPA of 150 to 500 mg per week (but up to 900 mg per week) have similarly been reported to suppress testosterone levels to less than 100 ng/dL.[163][175] The typical initial dose of intramuscular MPA for testosterone suppression in men with paraphilias is 400 or 500 mg per week.[163]
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 againstbreast cancer.[159][176][177] However, although MPA may produce androgenic side effects such asacne andhirsutism in some women,.[178][179] 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.[180][181] However, MPA has been seen to cause androgenic effects in children with precocious puberty.[182] The reason for the general lack ofvirilizing 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 asdihydrotestosterone (DHT).[129] 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 ofgene transcription, while at the same time not antagonizing the transcriptional activity of normal androgens like DHT at any concentration.[129] Thus, this may explain the low propensity of MPA for producing androgenic side effects.[129]
MPA shows weak androgenic effects onliver protein synthesis, similarly to other weakly androgenic progestins likemegestrol acetate and19-nortestosteronederivatives.[3][8] While it does not antagonize estrogen-induced increases in levels oftriglycerides andHDL cholesterol, DMPA every other week may decrease levels of HDL cholesterol.[3] In addition, MPA has been found to suppresssex hormone-binding globulin (SHBG) production by theliver.[8][183][184] At a dosage of 10 mg/day oral MPA, it has been found to decrease circulating SHBG levels by 14–18% in women taking 4 mg/day oralestradiol valerate.[8] 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.[184] 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.[183] In massive-dose studies of oral or injectable MPA (e.g., 500–1,000 mg/day), the medication decreased SHBG levels by about 80%.[185][186][187]
MPA shares some of the samemetabolic routes of progesterone and, analogously, can be transformed into metabolites such as 5α-dihydro-MPA (DHMPA) and 3α,5α-tetrahydro-MPA (THMPA).[199] However, unlike the reduced metabolites of progesterone, DHMPA and THMPA have been found not to modulate the GABAA receptor.[199] Conversely, unlike progesterone, MPA itself actually modulates the GABAA receptor, although notably not at the neurosteroid binding site.[199] However, rather than act as a potentiator of the receptor, MPA appears to act as anegative allosteric modulator.[199] Whereas the reduced metabolites of progesterone enhance binding of thebenzodiazepineflunitrazepam to the GABAA receptorin vitro, MPA can partially inhibit the binding of flunitrazepam by up to 40% with half-maximal inhibition at 1 μM.[199] 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.[199] The lack of potentiation of the GABAA 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.[199]
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 GABAA receptor in humans even at extremely high dosages.[125]
Surprisingly few studies have been conducted on thepharmacokinetics of MPA at postmenopausal replacement dosages.[205][3] Thebioavailability of MPA withoral administration is approximately 100%.[3] 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 usingradioimmunoassay.[205][206] Following this, levels of MPA decreased to 0.09 to 0.35 ng/mL 12 hours post-administration.[205][206] 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.[205][207] Subsequently, MPA levels fell to 0.3 to 0.6 ng/mL 24 hours after administration.[205][207] 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.[205][208]
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, withsteady-state concentrations achieved after three days and peak concentrations occurring 1.5 to 2 hours after ingestion.[3][209] 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.[3][209] 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.[8][209] 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.[8][3][209] This study assessed MPA levels usingliquid-chromatography–tandem mass spectrometry (LC–MS/MS), a more accurate method of blood determinations.[209]
Withintramuscular administration of 150 mgmicrocrystalline MPA inaqueous 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.[214] 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.[214] Theparticle size of MPA crystals significantly influences its rate of absorption into the body from the local tissuedepot when used as a microcrystalline aqueous suspension via intramuscular injection.[215][216][217] Smaller crystals dissolve faster and are absorbed more rapidly, resulting in a shorter duration of action.[215][216][217] Particle sizes can differ between different formulations of MPA, potentially influencing clinical efficacy and tolerability.[215][216][217][218]
Theelimination half-life of MPA via oral administration has been reported as both 11.6 to 16.6 hours[5] and 33 hours,[3] whereas the elimination half-lives withintramuscular andsubcutaneous injection of microcrystalline MPA in aqueous suspension are 50 and 40 days, respectively.[6][7] Themetabolism of MPA is mainly viahydroxylation, including at positions C6β, C21, C2β, and C1β, mediated primarily viaCYP3A4, but 3- and 5-dihydro and 3,5-tetrahydrometabolites of MPA are also formed.[3][8] 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%).[219] MPA and/or its metabolites are also metabolized viaconjugation.[70] The C6αmethyl and C17αacetoxygroups of MPA make it more resistant to metabolism and allow for greater bioavailability than oralprogesterone.[8]
With intramuscular administration, the high levels of MPA in the blood inhibitluteinizing hormone andovulation for several months, with an accompanying decrease in serum progesterone to below 0.4 ng/mL.[214] Ovulation resumes when once blood levels of MPA fall below 0.1 ng/mL.[214] 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.[214]
MPA was independently discovered in 1956 bySyntex and theUpjohn Company.[13][14][227][228] It was first introduced on 18 June 1959 by Upjohn in theUnited States under the brand name Provera (2.5, 5, and 10 mg tablets) for the treatment ofamenorrhea,metrorrhagia, andrecurrent miscarriage.[229][230] 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 ofendometrial andrenal cancer.[27] MPA in combination withethinylestradiol was introduced in 1964 by Upjohn in the U.S. under the brand name Provest (10 mg MPA and 50 μg ethinylestradiol tablets) as anoral contraceptive, but this formulation was discontinued in 1970.[231][232][134] 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[233] were formulations available outside of the U.S. with a different dosage (5 mg MPA and 50 or 75 μg ethinylestradiol tablets).[234][235]
Following its development in the late 1950s, DMPA was first assessed in clinical trials for use as an injectable contraceptive in 1963.[236] Upjohn soughtFDATooltip Food and Drug Administration 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.[237][238] 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.[35] 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.[237][238] However, in 1992, the medication was finally approved by the FDA, under the brand name Depo-Provera, for use in contraception.[237] A subcutaneous formulation of DMPA was introduced in the United States as a contraceptive under the brand name Depo-SubQ Provera 104 (104 mg/0.65 mL MPA) in December 2004, and subsequently was also approved for the treatment ofendometriosis-related pelvic pain.[239]
MPA has also been marketed widely throughout the world under numerous other brand names such as Farlutal, Perlutex, and Gestapuran, among others.[132][10]
Medroxyprogesterone acetate is thegeneric name of the drug and itsINNTooltip INN,USANTooltip United States Adopted Name,BANTooltip BANM, andJANTooltip Japanese Accepted Name, whilemedrossiprogesterone is theDCITTooltip Denominazione Comune Italiana andmédroxyprogestérone theDCFTooltip Dénomination Commune Française of its free alcohol form.[224][11][132][240][10] It is also known as6α-methyl-17α-acetoxyprogesterone (MAP) or6α-methyl-17α-hydroxyprogesterone acetate.[224][11][132][10]
MPA is marketed under a large number of brand names throughout the world.[10][11][132] Its most major brand names are Provera as oral tablets and Depo-Provera as anaqueous suspension for intramuscular injection.[10][11][132] A formulation of MPA as an aqueous suspension for subcutaneous injection is also available in theUnited States under the brand name Depo-SubQ Provera 104.[10][11] Other brand names of MPA formulated alone include Farlutal and Sayana for clinical use and Depo-Promone, Perlutex, Promone-E, and Veramix for veterinary use.[10][11][132] In addition to single-drug formulations, MPA is marketed in combination with the estrogens CEEs, estradiol, and estradiol valerate.[10][11][132] Brand names of MPA in combination with CEEs as oral tablets in different countries include Prempro, Premphase, Premique, Premia, and Premelle.[10][11][132] Brand names of MPA in combination with estradiol as oral tablets include Indivina and Tridestra.[10][11][132]
Oral MPA and DMPA are widely available throughout the world.[10] Oral MPA is available both alone and in combination with the estrogens CEEs, estradiol, and estradiol valerate.[10] DMPA is registered for use as a form of birth control in more than 100 countries worldwide.[18][19][10] The combination of injected MPA and estradiol cypionate is approved for use as a form of birth control in 18 countries.[18]
Progestins in birth control pills are sometimes grouped by generation.[242][243] While the19-nortestosterone progestins are consistently grouped into generations, thepregnane 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".[242][243] In any case, based on its date of introduction in such formulations of 1964, MPA could be considered a "first-generation" progestin.[244]
In 1994, when DMPA was approved in India, India'sEconomic 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."[245] Some scientists and women's groups in India continue to oppose DMPA.[246] In 2016, India introduced DMPA depo-medroxyprogesterone IM preparation in the public health system.[247]
The Canadian Coalition on Depo-Provera, a coalition of women's health professional and advocacy groups, opposed the approval of DMPA in Canada.[248] Since the approval of DMPA in Canada in 1997, a $700 millionclass-action lawsuit has been filed against Pfizer by users of DMPA who developedosteoporosis. In response, Pfizer argued that it had met its obligation to disclose and discuss the risks of DMPA with the Canadian medical community.[249]
A controversy erupted inIsrael 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".[250]
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 theUnited Kingdom,France,Germany,Sweden,Thailand,New Zealand andIndonesia.[251] Points in the controversy included:
Animal testing forcarcinogenicity – 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 normalluteal phase progesterone level for dogs. This is lower than the pregnancy level of progesterone for dogs, and is species-specific.[252] DMPA caused endometrial cancer in monkeys – 2 of 12 monkeys tested, the first ever recorded cases of endometrial cancer inrhesus monkeys.[253] However, subsequent studies have shown that in humans, DMPAreduces the risk of endometrial cancer by approximately 80%.[50][51][52] 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 theNational Cancer Institute.[254] However, numerous larger subsequent studies have shown that DMPA use does not increase the risk of cervical cancer.[255][256][257][258][259]
Coercion and lack of informed consent. Testing or use of DMPA was focused almost exclusively on women indeveloping countries and poor women in the United States,[260] raising serious questions about coercion and lack of informed consent, particularly for the illiterate[261] 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.[262]
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 werelost to followup due to sloppy record keeping." Consequently, no data from this study was usable.[260]
WHO Review – In 1992, the WHO presented a review of DMPA in four developing countries to the FDA. TheNational 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.[260][263]
In 1995, several women's health groups asked the FDA to put a moratorium on DMPA, and to institute standardized informed consent forms.[264]
High-dose oral and intramuscular MPA monotherapy has been studied in the treatment of prostate cancer but was found to be inferior to monotherapy withcyproterone acetate ordiethylstilbestrol.[269][270][271] High-dose oral MPA has been studied in combination with diethylstilbestrol and CEEs as an addition tohigh-dose estrogen therapy for the treatment ofprostate cancer in men, but was not found to provide better effectiveness than diethylstilbestrol alone.[272]
MPA has been used to reduceaggression andspraying in male cats.[277] It may be particularly useful for controlling such behaviors inneutered male cats.[277] The medication can be administered in cats as an injection once per month.[277]
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^Vanderstappen D, Bonte J (1992). "New trends in the use of medroxyprogesterone acetate as a chemotherapeutic agent in gynecologic malignancies".European Journal of Gynaecological Oncology.13 (2):113–123.PMID1534051.
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^Trussell J (2007)."Contraceptive Efficacy". In Hatcher RA, Trussell J, Nelson AL, Cates W, Stewart FH, Kowal D (eds.).Contraceptive Technology (19th rev. ed.). New York: Ardent Media. Archived fromthe original on 31 May 2008. Retrieved21 June 2007.
^abcHatcher RA (2004). "Depo-Provera Injections, Implants, and Progestin-Only Pills (Minipills)". In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Guest F, Kowal D (eds.).Contraceptive Technology (18th rev. ed.). New York: Ardent Media. pp. 461–494.ISBN978-0-9664902-5-1.
^abcSperoff L, Darney PD (2005). "Injectable Contraception".A Clinical Guide for Contraception (4th ed.). Philadelphia: Lippincott Williams & Wilkins. pp. 201–220.ISBN978-0-7817-6488-9.
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^abKaunitz AM (December 2001). "Current options for injectable contraception in the United States".Seminars in Reproductive Medicine.19 (4):331–337.doi:10.1055/s-2001-18641.PMID11727175.S2CID39556669.
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^ab"Depot-medroxyprogesterone acetate (DMPA) and risk of endometrial cancer. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives".International Journal of Cancer.49 (2):186–190. September 1991.doi:10.1002/ijc.2910490207.PMID1831802.S2CID221776781.
^Santen RJ (2004). "Endocrinology of Breast and Endometrial Cancer". In Strauss III JF, Barbieri RL (eds.).Yen and Jaffe's Reproductive Endocrinology (5th ed.). Philadelphia: Elsevier Saunders. pp. 787–809.ISBN978-0-7216-9546-4.
^Bartz D, Goldberg AB (2011). "Injectable contraceptives". In Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Kowal D, Policar MS (eds.).Contraceptive technology (20th revised ed.). New York: Ardent Media. pp. 212–213.ISBN978-1-59708-004-0.OCLC781956734.Advantages of DMPA Injectables. 5. Reduced risk of ectopic pregnancy. Compared with women who use no contraceptive at all, women who use DMPA have a reduced risk for having an ectopic pregnancy. Although the overall risk of pregnancy and thus ectopic pregnancy is lowered by DMPA, the possibility of an ectopic pregnancy should be excluded if a woman using DMPA becomes pregnant. One study showed that 1.5% of women who got pregnant on DMPA had an ectopic pregnancy, the same ectopic rate as women who conceived while not using contraception.27
^Borgatta L, Murthy A, Chuang C, Beardsley L, Burnhill MS (September 2002). "Pregnancies diagnosed during Depo-Provera use".Contraception.66 (3):169–172.doi:10.1016/S0010-7824(02)00340-2.PMID12384205.
^"Sexual Health Ruleset"(PDF).New GMS Contract Quality and Outcome Framework - Implementation Dataset and Business Rules. Primary Care Commissioning. 1 May 2009.Archived(PDF) from the original on 10 August 2011. Retrieved19 June 2009. Summarized at *"Contraception - Management QOF indicators".NHS Clinical Knowledge Summaries. NHS Institute for Innovation and Improvement. Retrieved19 June 2009.[permanent dead link]
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^abNelson AL (2014). "DMPA: battered and bruised but still needed and used in the USA".Expert Review of Obstetrics & Gynecology.5 (6):673–686.doi:10.1586/eog.10.60.ISSN1747-4108.
^Kaunitz AM (1999). "Long-acting hormonal contraception: assessing impact on bone density, weight, and mood".International Journal of Fertility and Women's Medicine.44 (2):110–117.PMID10338269.Despite the efficacy and increasing acceptability of these long-term methods, some clinicians and women are reluctant to use them because of concerns regarding reduction in bone density with DMPA, and depressive symptoms and body weight issues with both injectables and implants. Recent multicenter experience showed no increase in depressive symptoms after 1 year's DMPA use and 2 years' Norplant use, even among users with the highest mean depressive symptom scores pre-therapy.
^Westhoff C (August 2003). "Depot-medroxyprogesterone acetate injection (Depo-Provera): a highly effective contraceptive option with proven long-term safety".Contraception.68 (2):75–87.doi:10.1016/s0010-7824(03)00136-7.PMID12954518.Another common patient tolerability concern reported with hormonal contraception is the effect on mood [95]. The majority of published reports indicate that DMPA does not cause depressive symptoms. In a large, 1-year, clinical trial of DMPA in 3857 US women, fewer than 2% of users reported depression [15]. Other reports in various settings, including a private practice [96], adolescent clinics [97,98], a psychiatric hospital [99] and inner-city family-planning clinics [100,101], have not found an adverse effect of DMPA on depression. [...] Using a variety of objective indices for depressive symptoms, the overall data for both OCs and DMPA are supportive that these agents have no significant effect on mood. Although history of mood symptoms prior to OC use may predispose a subgroup of women to negative mood changes, the data for DMPA suggest that even women who have depressive symptoms prior to treatment can tolerate therapy with no exacerbation of these symptoms.
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^Hofbauer KG, Anker SD, Inui A, Nicholson JR (22 December 2005).Pharmacotherapy of Cachexia. CRC Press. pp. 292–.ISBN978-1-4200-4895-7.Medroxyprogesterone [acetate] has similarly been shown to increase appetite and food intake with stabilization of body weight at a dose of 1000 mg (500 mg twice daily).13 Although the drug may be used at 500 to 4000 mg daily, side effects increase above oral doses of 1000 mg daily.16
^abcdefStanczyk FZ, Bhavnani BR (July 2014). "Use of medroxyprogesterone acetate for hormone therapy in postmenopausal women: is it safe?".The Journal of Steroid Biochemistry and Molecular Biology.142:30–38.doi:10.1016/j.jsbmb.2013.11.011.PMID24291402.S2CID22731802.
^abVictor A, Johansson ED (September 1976). "Pharmacokinetic observations on medroxyprogesterone acetate administered orally and intravaginally".Contraception.14 (3):319–329.doi:10.1016/0010-7824(76)90099-8.PMID975821.
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