Medroxyprogesterone acetate

Source: Wikipedia, the free encyclopedia.
Not to be confused with progesterone, a natural and bioidentical progestogen.

Medroxyprogesterone acetate
Clinical data
Pronunciation/mɛˌdrɒksiproʊˈdʒɛstəroʊn ˈæsɪteɪt/ me-DROKS-ee-proh-JES-tər-ohn ASS-i-tayt[1]
Trade namesDepo-Provera, others
Other namesMPA; DMPA; Methylhydroxyprogesterone acetate; Methylacetoxyprogesterone; MAP; Methypregnone; Metipregnone; 6α-Methyl-17α-hydroxyprogesterone acetate; 6α-Methyl-17α-acetoxyprogesterone; 6α-Methyl-17α-hydroxypregn-4-ene-3,20-dione acetate; NSC-26386
AHFS/Drugs.comMonograph
MedlinePlusa604039
Pregnancy
category
  • AU: D
Progestin; Progestogen ester; Antigonadotropin; Steroidal antiandrogen
ATC code
Legal status
Legal status
conjugates)[6]
Identifiers
  • [(6S,8R,9S,10R,13S,14S,17R)-17-acetyl-6,10,13-trimethyl-3-oxo-2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthren-17-yl] acetate
JSmol)
Melting point207 to 209 °C (405 to 408 °F)
  • C[C@H]1C[C@@H]2[C@H](CC[C@]3([C@H]2CC[C@@]3(C(=O)C)OC(=O)C)C)[C@@]4(C1=CC(=O)CC4)C
  • InChI=InChI=1S/C24H34O4/c1-14-12-18-19(22(4)9-6-17(27)13-21(14)22)7-10-23(5)20(18)8-11-24(23,15(2)25)28-16(3)26/h13-14,18-20H,6-12H2,1-5H3/t14-,18+,19-,20-,22+,23-,24-/m0/s1
  • Key:PSGAAPLEWMOORI-PEINSRQWSA-N
  (verify)

Medroxyprogesterone acetate (MPA), also known as depot medroxyprogesterone acetate (DMPA) in

fat.[10]

Common

artificial progestogen, and as such activates the progesterone receptor, the biological target of progesterone.[4] It also has androgenic activity and weak glucocorticoid activity. Due to its progestogenic activity, MPA decreases the body's release of gonadotropins and can suppress sex hormone levels.[13] It works as a form of birth control by preventing ovulation.[10]

MPA was discovered in 1956 and was introduced for medical use in the United States in 1959.

progestogen-only birth control.[17][18] DMPA is approved for use as a form of long-acting birth control in more than 100 countries.[19][20] In 2021, it was the 238th most commonly prescribed medication in the United States, with more than 1 million prescriptions.[21][22]

Medical uses

The most common use of MPA is in the form of DMPA as a long-acting

gynecological and menstrual disorders such as dysmenorrhea, amenorrhea, and endometriosis.[24] 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.[25]

DMPA reduces

transgender women due to its progestogenic and functional antiandrogenic effects.[33] 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.[34] DMPA at high doses has been reported to be definitively effective in the treatment of hirsutism as well.[35]

Though not used as a treatment for

iron deficiency and risk of pelvic inflammatory disease and often do not result in discontinuation of the medication.[29]

Birth control

Depot medroxyprogesterone acetate (DMPA)
POP
) allowing more reliable return fertility.

DMPA, under brand names such as Depo-Provera and Depo-SubQ Provera 104, is used in

subcutaneous injection and forms a long-lasting depot, 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%.[40]

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%.[40][41] 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%.[42]

  • DMPA estimated typical use first-year failure rate = 0.3% in:
    • Contraceptive Technology, 16th revised edition (1994)[43]
    • Contraceptive Technology, 17th revised edition (1998)[44]
      • Adopted in 1998 by the FDA for its current Uniform Contraceptive Labeling guidance[45]

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%.[40][41]

  • DMPA estimated typical use first-year failure rate = 3% in:
    • Contraceptive Technology, 18th revised edition (2004)[40]
    • Contraceptive Technology, 19th revised edition (2007)[46]

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.[40][47][41]

Advantages

DMPA has a number of advantages and benefits:[48][49][39][50]

The United Kingdom Department of Health has actively promoted

National Institute for Health and Clinical Excellence guidelines.[59] Giving advice on these methods of contraception has been included in the 2009 Quality and Outcomes Framework "good practice" for primary care.[60]

Comparison

Proponents of

sporadic vaginal bleeding.[61] The two compounds do not differentiate in their ability to suppress endometrial hyperplasia,[61] nor does either increase the risk of pulmonary embolism.[63] The two medications have not been adequately compared in direct tests to clear conclusions about safety and superiority.[25]

Available forms

See also: Conjugated estrogens/medroxyprogesterone acetate, Estradiol/medroxyprogesterone acetate, and Estradiol cypionate/medroxyprogesterone acetate

MPA is available alone in the form of 2.5, 5, and 10 mg

combined injectable contraceptive.[11][12][64][19]

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.[68] 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:[69][70]

Conditions where the theoretical or proven risks usually outweigh the advantages of using DMPA:

Conditions which represent an unacceptable health risk if DMPA is used:

Conditions where use is not indicated and should not be initiated:

MPA is not recommended for use prior to menarche or before or during recovery from surgery.[71]

Side effects

In women, the most common

breast tenderness, increased facial hair, decreased scalp hair, difficulty falling or remaining asleep, stomach pain, and weight loss or gain.[24] Lowered libido has been reported as a side effect of MPA in women.[72] 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.[73] MPA does not appear to be associated with vitamin B12 deficiency.[74] Data on weight gain with DMPA likewise are inconsistent.[75][76]

At high doses for the treatment of breast cancer, MPA can cause weight gain and can worsen

diabetes.[29]

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.[48][49] Fetuses exposed to progestogens have demonstrated higher rates of genital abnormalities, low birth weight, and increased ectopic 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.[77]

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.[78][79] However, contrary to widely-held beliefs, most research suggests that progestins do not cause adverse psychological effects such as depression or anxiety.[78] 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.[80] 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.[81]

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%.[80][38][82] This study did not include baseline data on depression,[82] 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.[80] 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%).[82] 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.[76][82][38]

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 of

menopausal hormone therapy, found no change in depressive symptoms.[83][84][85] However, some small studies have reported that progestins like MPA might counteract beneficial effects of estrogens against depression.[78][4][86]

Long-term effects

The

coronary heart disease, breast cancer, strokes and pulmonary embolism.[87]

When combined with CEEs, MPA has been associated with an increased risk of breast cancer,

menopausal hormone therapy,[88] resulting in a dramatic decrease in both new and renewal prescriptions for hormone therapy.[89]

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.[73]

Results of the Women's Health Initiative (WHI) menopausal hormone therapy randomized controlled trials
Clinical outcome Hypothesized
effect on risk 		Estrogen and progestogen
(CEsTooltip conjugated estrogens 0.625 mg/day p.o. + MPATooltip medroxyprogesterone acetate 2.5 mg/day p.o.)
(n = 16,608, with uterus, 5.2–5.6 years follow up) 		Estrogen alone
(CEsTooltip Conjugated estrogens 0.625 mg/day p.o.)
(n = 10,739, no uterus, 6.8–7.1 years follow up)
HRTooltip Hazard ratio 95% CITooltip Confidence interval
AR
Tooltip Attributable risk 		HRTooltip Hazard ratio 95% CITooltip Confidence interval
AR
Tooltip Attributable risk
Coronary heart disease
 Decreased 1.24 1.00–1.54 +6 / 10,000 PYs 0.95 0.79–1.15 −3 / 10,000 PYs
Stroke Decreased 1.31 1.02–1.68 +8 / 10,000 PYs 1.37 1.09–1.73 +12 / 10,000 PYs
Pulmonary embolism Increased 2.13 1.45–3.11 +10 / 10,000 PYs 1.37 0.90–2.07 +4 / 10,000 PYs
Venous thromboembolism
 Increased 2.06 1.57–2.70 +18 / 10,000 PYs 1.32 0.99–1.75 +8 / 10,000 PYs
Breast cancer Increased 1.24 1.02–1.50 +8 / 10,000 PYs 0.80 0.62–1.04 −6 / 10,000 PYs
Colorectal cancer Decreased 0.56 0.38–0.81 −7 / 10,000 PYs 1.08 0.75–1.55 +1 / 10,000 PYs
Endometrial cancer – 0.81 0.48–1.36 −1 / 10,000 PYs – – –
Hip fractures Decreased 0.67 0.47–0.96 −5 / 10,000 PYs 0.65 0.45–0.94 −7 / 10,000 PYs
Total fractures Decreased 0.76 0.69–0.83 −47 / 10,000 PYs 0.71 0.64–0.80 −53 / 10,000 PYs
Total mortality Decreased 0.98 0.82–1.18 −1 / 10,000 PYs 1.04 0.91–1.12 +3 / 10,000 PYs
Global index – 1.15 1.03–1.28 +19 / 10,000 PYs 1.01 1.09–1.12 +2 / 10,000 PYs
Diabetes – 0.79 0.67–0.93 0.88 0.77–1.01
Gallbladder disease Increased 1.59 1.28–1.97 1.67 1.35–2.06
Stress incontinence – 1.87 1.61–2.18 2.15 1.77–2.82
Urge incontinence
 – 1.15 0.99–1.34 1.32 1.10–1.58
Peripheral artery disease – 0.89 0.63–1.25 1.32 0.99–1.77
Probable dementia Decreased 2.05 1.21–3.48 1.49 0.83–2.66
Abbreviations: CEs =
coronary heart disease, stroke, pulmonary embolism, breast cancer, colorectal cancer, endometrial cancer (estrogen plus progestogen group only), hip fractures, and death
from other causes. Sources: See template.

Blood clots

DMPA has been associated in multiple studies with a higher risk of

fibrinolytic factors,[94][95] and progestogens by themselves normally do not increase the risk of thrombosis.[91][92] 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.[91] Alternatively, it is possible that MPA may be an exception among progestins in terms of VTE risk.[96][97][98] A 2018 meta-analysis reported that MPA was associated with a 2.8-fold higher risk of VTE than other progestins.[97] It is possible that the glucocorticoid activity of MPA may increase the risk of VTE.[4][99][98]

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 17 November 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.[100][101] While it causes temporary bone loss, most women fully regain their bone density after discontinuing use.[75] The World Health Organization (WHO) recommends that the use not be restricted.[102][103] 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.[104][105][106] Other studies have suggested that the effect of DMPA use on postmenopausal bone density is minimal,[107] perhaps because DMPA users experience less bone loss at menopause.[108] Use after peak bone mass is associated with increased bone turnover but no decrease in bone mineral density.[109]

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.

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 two years of use.[110]

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.[111] 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.[112][113] Two meta-analyses of observational studies in sub-Saharan Africa were published in January 2015.[114] They found a 1.4- to 1.5-fold increase risk of HIV acquisition for DMPA users relative to no hormonal contraceptive use.[115][116] 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.[117] 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."[118] In 2019, a randomized controlled trial found no significant association between DMPA use and HIV.[119]

Breastfeeding

MPA may be used by

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.[120]

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.[121]

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

withdrawal bleeding.[6] According to the label, treatment of overdose should consist of discontinuation of MPA therapy and symptomatic care.[6]

Interactions

MPA increases the risk of

menopausal symptoms.[71] 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.[29] St John's wort may decrease the effectiveness of MPA as a contraceptive due to acceleration of its metabolism.[71]

Pharmacology

Pharmacodynamics

MPA acts as an

full agonist of these receptors.[126][127]

Relative affinities (%) of MPA and related steroids
Progestogen
 PRTooltip Progesterone receptor ARTooltip Androgen receptor ERTooltip Estrogen receptor GRTooltip Glucocorticoid receptor MRTooltip Mineralocorticoid receptor
Progesterone 50 0 0 10 100
Chlormadinone acetate 67 5 0 8 0
Cyproterone acetate 90 6 0 6 8
Medroxyprogesterone acetate 115 5 0 29 160
Megestrol acetate 65 5 0 30 0
Notes: Values are percentages (%). Reference ligands (100%) were promegestone for the PRTooltip progesterone receptor, metribolone for the ARTooltip androgen receptor, estradiol for the ERTooltip estrogen receptor, dexamethasone for the GRTooltip glucocorticoid receptor, and aldosterone for the MRTooltip mineralocorticoid receptor. Sources: [4]

Progestogenic activity

MPA is a potent

19-nortestosterone derivatives norethisterone and norethisterone acetate is only 0.4 to 0.5 mg/day.[132]

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

cervical mucus.[135] 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.[135]

MPA and related steroids at the progesterone receptor
Compound
Ki
(nM)
EC50
Tooltip Half-maximal effective concentration (nM)a
EC50
Tooltip Half-maximal effective concentration (nM)b
Progesterone 4.3 0.9 25
Medroxyprogesterone 241 47 32
Medroxyprogesterone acetate 1.2 0.6 0.15
Footnotes: a = Coactivator recruitment. b = Reporter cell line. Sources: [128]
Oral potencies of MPA and related steroids
Progestogen OID
(mg/day)		 TFD
(mg/cycle)		 TFD
(mg/day)		 ODP
(mg/day)		 ECD
(mg/day)
Progesterone 300 4200 200–300 – 200
Chlormadinone acetate 1.7 20–30 10 2.0 5–10
Cyproterone acetate 1.0 20 1.0 2.0 1.0
Medroxyprogesterone acetate 10 50 5–10 ? 5.0
Megestrol acetate ? 50 ? ? 5.0
Abbreviations: OID = ovulation-inhibiting dosage (without additional estrogen). TFD = endometrial transformation dosage. ODP = oral dosage in commercial contraceptive preparations. ECD = estimated comparable dosage. Sources: [132][99][136]
Parenteral potencies and durations of progestogens[a][b]
Compound Form Dose for specific uses (mg)[c] DOA[d]
TFD[e] POICD[f] CICD[g]
Algestone acetophenide Oil soln. - – 75–150 14–32 d
Gestonorone caproate Oil soln. 25–50 – – 8–13 d
Hydroxyprogest. acetate[h] Aq. susp. 350 – – 9–16 d
Hydroxyprogest. caproate Oil soln. 250–500[i] – 250–500 5–21 d
Medroxyprog. acetate Aq. susp. 50–100 150 25 14–50+ d
Megestrol acetate Aq. susp. - – 25 >14 d
Norethisterone enanthate Oil soln. 100–200 200 50 11–52 d
Progesterone Oil soln. 200[i] – – 2–6 d
Aq. soln. ? – – 1–2 d
Aq. susp. 50–200 – – 7–14 d
Notes and sources:
  1. ^ Sources: [137][138][139][140][141][142][143][144][145][146][147][148][149][150][151][152][153][154][155]
  2. subcutaneous injection
    .
  3. OID
    Tooltip ovulation-inhibiting dose of OHPC is 250 to 500 mg/month.
  4. ^ Duration of action in days.
  5. ^ Usually given for 14 days.
  6. ^ Usually dosed every two to three months.
  7. ^ Usually dosed once monthly.
  8. ^ Never marketed or approved by this route.
  9. ^ a b In divided doses (2 × 125 or 250 mg for OHPC, 10 × 20 mg for P4).

Antigonadotropic and anticorticotropic effects

MPA suppresses the

estrogen deficiency.[159]

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,[160][161][162] and by about 70–75% (from 832 to 862 ng/dL to 214 to 251 ng/dL) at a dosage of 100 mg/day.[163][164] 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.[165][166][167][168][169][170] 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 (<58 ng/dL) within 7 days and that castration levels of testosterone were maintained for 3 months.[171] 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.[160][172] The typical initial dose of intramuscular MPA for testosterone suppression in men with paraphilias is 400 or 500 mg per week.[160]

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

gene transcription, while at the same time not antagonizing the transcriptional activity of normal androgens like DHT at any concentration.[126] Thus, this may explain the low propensity of MPA for producing androgenic side effects.[126]

MPA shows weak androgenic effects on

HDL cholesterol, DMPA every other week may decrease levels of HDL cholesterol.[4] In addition, MPA has been found to suppress sex hormone-binding globulin (SHBG) production by the liver.[9][180][181] 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 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.[181] 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.[180] In massive-dose studies of oral or injectable MPA (e.g., 500–1,000 mg/day), the medication decreased SHBG levels by about 80%.[182][183][184]

Unlike the related steroids megestrol acetate and cyproterone acetate, MPA is not an antagonist of the AR and does not have direct antiandrogenic activity.[4] As such, although MPA is sometimes described as an antiandrogen, it is not a "true" antiandrogen (i.e., AR antagonist).[161]

Glucocorticoid activity

As an agonist of the GR, MPA has

venous thromboembolism and atherosclerosis.[4] The relative glucocorticoid activity of MPA is among the highest of the clinically used progestins.[4]

Glucocorticoid activity of selected steroids in vitro
Steroid Class TRTooltip Thrombin receptor (↑)a GRTooltip glucocorticoid receptor (%)b
Dexamethasone Corticosteroid ++ 100
Ethinylestradiol Estrogen – 0
Etonogestrel Progestin + 14
Gestodene Progestin + 27
Levonorgestrel Progestin – 1
Medroxyprogesterone acetate Progestin + 29
Norethisterone Progestin – 0
Norgestimate Progestin – 1
Progesterone Progestogen + 10
Footnotes: a =
RBATooltip Relative binding affinity (%) for the glucocorticoid receptor (GR). Strength: – = No effect. + = Pronounced effect. ++ = Strong effect. Sources: [188]

Steroidogenesis inhibition

See also: Steroidogenesis inhibitor and Neurosteroidogenesis inhibitor

MPA has been found to act as a

homogenates) of 0.42 μM.[189][190] 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.[189][190]

MPA has been identified as a competitive inhibitor of human

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.[194]

GABAA receptor allosteric modulation

cognitive/memory impairment, as well as effectiveness as an anticonvulsant in the treatment of catamenial epilepsy.[193][195] It has also been found to produce anesthesia via this action in animals when administered at sufficiently high dosages.[195] 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 GABAA receptor similarly to progesterone.[196][197]

MPA shares some of the same

negative allosteric modulator.[196] Whereas the reduced metabolites of progesterone enhance binding of the benzodiazepine flunitrazepam to the GABAA receptor in vitro, MPA can partially inhibit the binding of flunitrazepam by up to 40% with half-maximal inhibition at 1 μM.[196] 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.[196] 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.[196]

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.[122]

Appetite stimulation

Although MPA and the closely related medication

TNF-α, actions that have all been linked to an increase in appetite.[199]

Other activity

MPA weakly stimulates the

progesterone receptor membrane component-1 (PGRMC1).[200] Certain other progestins are also active in this assay, whereas progesterone acts neutrally.[200] 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.[201]

Pharmacokinetics

Absorption

Surprisingly few studies have been conducted on the pharmacokinetics of MPA at postmenopausal replacement dosages.[202][4] The bioavailability of MPA with oral administration is approximately 100%.[4] 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.[202][203] Following this, levels of MPA decreased to 0.09 to 0.35 ng/mL 12 hours post-administration.[202][203] 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.[202][204] Subsequently, MPA levels fell to 0.3 to 0.6 ng/mL 24 hours after administration.[202][204] 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.[202][205]

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

liquid-chromatography–tandem mass spectrometry (LC–MS/MS), a more accurate method of blood determinations.[206]

Oral MPA tablets can be administered sublingually instead of orally.[207][208][209] Rectal administration of MPA has also been studied.[210]

With

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.[211] 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.[211] 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.[212][213][214] Smaller crystals dissolve faster and are absorbed more rapidly, resulting in a shorter duration of action.[212][213][214] Particle sizes can differ between different formulations of MPA, potentially influencing clinical efficacy and tolerability.[212][213][214][215]

Distribution

The

corticosteroid-binding globulin.[4][9]

Metabolism

The

acetoxy groups of MPA make it more resistant to metabolism and allow for greater bioavailability than oral progesterone.[9]

Elimination

MPA is

unconjugated form.[217]

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.[211] Ovulation resumes when once blood levels of MPA fall below 0.1 ng/mL.[211] 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.[211]

fertilization, MPA is a very effective means of birth control.[211]

Time–concentration curves

Hormone levels with medroxyprogesterone acetate
  • MPA levels with 2.5 or 5 mg/day oral MPA in combination with 1 or 2 mg/day estradiol valerate (Indivina) in postmenopausal women[206]
    MPA levels with 2.5 or 5 mg/day
    Indivina) in postmenopausal women[206]
  • MPA levels after a single 150 mg intramuscular injection of MPA (Depo-Provera) in aqueous suspension in women[218][219]
    MPA levels after a single 150 mg
    aqueous suspension in women[218][219]
  • MPA levels after a single 25 to 150 mg intramuscular injection of MPA (Depo-Provera) in aqueous suspension in women[218][220]
    MPA levels after a single 25 to 150 mg
    aqueous suspension in women[218][220]
  • MPA levels after a single 104 mg subcutaneous injection of MPA (Depo-SubQ Provera) in aqueous suspension in women[8]
    MPA levels after a single 104 mg
    aqueous suspension in women[8]

Chemistry

See also: List of progestogens, Progestogen ester, List of progestogen esters, Steroidal antiandrogen, and List of steroidal antiandrogens

MPA is a

fluoro analogue of MPA and an angiogenesis inhibitor with two orders of magnitude greater potency in comparison to MPA, was investigated for the potential treatment of cancers but was never marketed.[222][223]

History

MPA was independently discovered in 1956 by

oral contraceptive, but this formulation was discontinued in 1970.[228][229][131] 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[230] were formulations available outside of the U.S. with a different dosage (5 mg MPA and 50 or 75 μg ethinylestradiol tablets).[231][232]

Following its development in the late 1950s, DMPA was first assessed in clinical trials for use as an injectable contraceptive in 1963.[233] Upjohn sought FDATooltip 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.[234][235] 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.[36] 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.[234][235] However, in 1992, the medication was finally approved by the FDA, under the brand name Depo-Provera, for use in contraception.[234] 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 of endometriosis-related pelvic pain.[236]

MPA has also been marketed widely throughout the world under numerous other brand names such as Farlutal, Perlutex, and Gestapuran, among others.[129][11]

Society and culture

Generic names

Medroxyprogesterone acetate is the

INNTooltip INN, USANTooltip United States Adopted Name, BANTooltip BANM, and JANTooltip Japanese Accepted Name, while medrossiprogesterone is the DCITTooltip Denominazione Comune Italiana and médroxyprogestérone the DCFTooltip Dénomination Commune Française of its free alcohol form.[221][12][129][237][11] It is also known as 6α-methyl-17α-acetoxyprogesterone (MAP) or 6α-methyl-17α-hydroxyprogesterone acetate.[221][12][129][11]

Brand names

MPA is marketed under a large number of brand names throughout the world.

aqueous suspension for intramuscular injection.[11][12][129] A formulation of MPA as an aqueous suspension for subcutaneous injection is also available in the United States under the brand name Depo-SubQ Provera 104.[11][12] 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.[11][12][129] In addition to single-drug formulations, MPA is marketed in combination with the estrogens CEEs, estradiol, and estradiol valerate.[11][12][129] Brand names of MPA in combination with CEEs as oral tablets in different countries include Prempro, Premphase, Premique, Premia, and Premelle.[11][12][129] Brand names of MPA in combination with estradiol as oral tablets include Indivina and Tridestra.[11][12][129]

Availability

Oral MPA and DMPA are widely available throughout the world.[11] Oral MPA is available both alone and in combination with the estrogens CEEs, estradiol, and estradiol valerate.[11] DMPA is registered for use as a form of birth control in more than 100 countries worldwide.[19][20][11] The combination of injected MPA and estradiol cypionate is approved for use as a form of birth control in 18 countries.[19]

United States

See also: List of progestogens available in the United States

As of November 2016, MPA is available in the United States in the following formulations:[64]

  • 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.[238]

Generation

Progestins in birth control pills are sometimes grouped by generation.

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".[239][240] In any case, based on its date of introduction in such formulations of 1964, MPA could be considered a "first-generation" progestin.[241]

Controversy

Outside the United States

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.[248] Points in the controversy included:

Research

DMPA was studied by

combined injectable contraceptive for use by intramuscular injection once every three months.[263][264][265]

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

high-dose estrogen therapy for the treatment of prostate cancer in men, but was not found to provide better effectiveness than diethylstilbestrol alone.[269]

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.[270] However, it was never approved for this indication.[270]

MPA was investigated by InKine Pharmaceutical, Salix Pharmaceuticals, and the

tumor necrosis factor alpha, with a mechanism of action that was said to be similar to that of corticosteroids.[271][272] The formulation of MPA had the tentative brand names Colirest and Hematrol for these indications.[271]

MPA has been found to be effective in the treatment of manic symptoms in women with bipolar disorder.[273]

Veterinary use

MPA has been used to reduce

spraying in male cats.[274] It may be particularly useful for controlling such behaviors in neutered male cats.[274] The medication can be administered in cats as an injection once per month.[274]

See also

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