Medroxyprogesterone acetate

Medroxyprogesterone acetate
Clinical data
Trade names Provera, Depo-Provera, Depo-SubQ Provera 104, Curretab, Cycrin, Farlutal, Gestapuran, Perlutex, Veramix, others[1]
AHFS/Drugs.com Monograph
MedlinePlus a604039
Pregnancy
category
  • US: X (Contraindicated)
Routes of
administration		 by mouth, intramuscular, subcutaneous
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 99%[2]
Protein binding 88% (to albumin)[2]
Biological half-life By mouth: 12–33 hours[3][4]
I.M.: ~50 days[5]
S.C.: ~40 days[6]
Identifiers
Synonyms NSC-26386[7]
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.000.689
Chemical and physical data
Formula C24H34O4
Molar mass 386.52 g/mol
3D model (JSmol)
  (verify)

Medroxyprogesterone acetate (MPA), sold under the brand name Depo-Provera among others, is a hormonal medication of the progestin type.[8] It is used as birth control and as part of hormone replacement therapy for menopausal symptoms.[8] It is also used to treat endometriosis, abnormal uterine bleeding, abnormal sexuality in males, and certain types of cancer.[8] It is used by mouth or injection into a muscle or under the skin[8]

Common side effects include no periods, abdominal pain, headaches, and anxiety.[8] Other serious side effects include bone loss, blood clots, allergic reactions, depression, and liver problems.[8] Use is not recommended during pregnancy as it may harm the baby.[8] It works by decreasing the body's release of gonadotropins.[8]

Medroxyprogesterone acetate was patented and came into medical use in 1958.[9] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[10] The wholesale cost in the developing world is about 0.59 to 1.57 USD per vial.[11] In the United Kingdom this dose costs the NHS about 6.01 pounds.[12] In the United States it costs less than 25 USD a dose as of 2015.[13]

Medical uses

In females, the most common use of MPA is as an oral or depot-injected contraceptive and also as the progestin component of menopausal hormone replacement therapy to prevent endometrial hyperplasia and cancer. MPA is also used as a treatment for endometriosis, dysmenorrhea, and amenorrhea.[14] MPA, along with other progestins were developed to allow the hormones to be taken orally, as progesterone (the hormone made by the human body) could not be taken orally before the process of micronization was developed.[15]

In males, MPA has been used to control inappropriate sexual behavior to chemically castrate convicted sex offenders.[16]

MPA is an extremely effective contraceptive when used with relatively high doses to prevent ovulation. It has also been used to treat benign prostatic hyperplasia, as a palliative appetite stimulant for cancer patients, and at high doses (800 mg per day) to treat hormone-dependent cancers of primarily the breast, but also other types.[17]

Though not used as a treatment for epilepsy, MPA has been found to reduce the frequency of seizures and does not interact with anti-epileptic medications. MPA does not interfere with blood clotting and appears to improve blood parameters for women with sickle cell anemia. Similarly, MPA does not appear to affect liver metabolism, and may improve primary biliary cirrhosis and chronic active hepatitis. Women taking MPA may experience spotting shortly after starting the medication but is not usually serious enough to require medical intervention. With longer use amenorrhoea can occur as can irregular menstruation which is a major source of dissatisfaction, though both can result in improvements with iron deficiency and risk of pelvic inflammatory disease and often do not result in discontinuing the medication.[17] MPA is also prescribed in combination with an estrogen to prevent endometrial hyperplasia in post-menopausal women who are undergoing hormone replacement therapy.[18]

MPA has also been prescribed in hormone replacement therapy for male-to-female transgender individuals due to its progestogenic and antigonadotropic effects.

Birth control

Medroxyprogesterone acetate by injection
Background
Type Hormonal
First use ?
Failure rates (first year)
Perfect use 0.2%[19]
Typical use 6%[19]
Usage
Duration effect 3 months
(12–14 weeks)
Reversibility 3–18 months
User reminders Maximum interval is just under 3 months
Advantages and disadvantages
STI protection No
Period disadvantages 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.

Estimates of first-year failure rates are about 0.3%.[20]

Perfect use

Trussell's estimated perfect use first-year failure rate for medroxyprogesterone acetate by injection as the average of failure rates in seven clinical trials at 0.3%.[20][21] It was considered perfect use because the clinical trials measured efficacy during actual use of medroxyprogesterone acetate 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).

Typical use

Prior to 2004, Trussell's typical use failure rate for medroxyprogesterone acetate by injection was the same as his perfect use failure rate: 0.3%.[22]

In 2004, using the 1995 NSFG failure rate, Trussell increased (by 10 times) his typical use failure rate for medroxyprogesterone acetate by injection from 0.3% to 3%.[20][21]

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 medroxyprogesterone acetate by injection) 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.[20][27][21]

Benefits

medroxyprogesterone acetate by injection has several advantages:[28][29][30][31]

The United Kingdom Department of Health has actively promoted Long Acting Reversible Contraceptive use since 2008, particularly for young people;[39] following on from the October 2005 National Institute for Health and Clinical Excellence guidelines.[40] Giving advice on these methods of contraception has been included in the 2009 Quality and Outcomes Framework "good practice" for primary care.[41]

Other uses

Depo-Provera is also used with male sex offenders as a form of chemical castration as it has the effect of reducing sex drive in males.[42]

Comparison with progesterone

Proponents of bioidentical hormone replacement therapy believe that progesterone offers fewer side effects and improved quality of life compared to MPA.[43] The evidence for this view has been questioned; MPA is better absorbed when taken by mouth, with a much longer terminal half-life leading to more stable blood levels[44] though it may lead to greater breast tenderness and more sporadic vaginal bleeding.[43] The two compounds do not differentiate in their ability to suppress endometrial hyperplasia,[43] nor does either increase the risk of pulmonary embolism.[45] The two drugs have not been adequately compared in direct tests to clear conclusions about safety and superiority.[15]

Contraindications

It is not usually recommended because of unacceptable health risk or because it is not indicated in the following cases:[46][47]

Conditions where the theoretical or proven risks usually outweigh the advantages of using Depo-Provera:

Conditions which represent an unacceptable health risk if Depo-Provera is used:

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

Side effects

In females, the most common adverse effects are acne, changes in menstrual flow, drowsiness, and can cause birth defects if taken by pregnant women. Other common side effects include breast tenderness, increased facial hair, decreased scalp hair, difficulty falling or remaining asleep, stomach pain, and weight loss or gain.[14]

The Women's Health Initiative investigated the use of MPA and conjugated equine estrogens 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 the hormone replacement therapy (reduced risk of hip fracture, colorectal and endometrial cancer and all other causes of death) were offset by increased risk of coronary heart disease, breast cancer, strokes and pulmonary embolism.[48] However, the study focused on MPA only and extrapolated the benefits versus risks to all synthetic progesterones—a conclusion that has been challenged by several researchers as unjustified and leading to unnecessary avoidance of HRT for many women as synthetic progesterones are not alike.[49]

At high doses for the treatment of breast cancer, MPA can cause weight gain, worsen diabetes mellitus and edema (particularly of the face). Adverse effects peak at five weeks, and are reduced with lower doses. Less frequent effects may include thrombosis (though it is not clear if this is truly a risk, it cannot be ruled out), painful urination, anxiety, headache, nausea and vomiting. When used to treat benign prostatic hyperplasia, more frequent complaints include reduced libido, impotence, reduced ejaculate volume, and within three days, chemical castration. MPA may cause reduced bone density though this appears to be reversible to a normal level even after years of use. At extremely high doses (used to treat cancer, not for contraception) MPA may cause adrenal suppression and interfere with carbohydrate metabolism but does not cause diabetes.[17]

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. When used as a form of injected birth control, MPA can reduce fertility for as long as 10 months, taking longer for overweight or obese women. When combined with conjugated equine estrogens (Premarin), MPA has been associated with an increased risk of breast cancer, dementia and thrombus in the eye. In combination with estrogens in general, MPA may increase the risk of cardiovascular disease, with a stronger association when used by post-menopausal women also taking CEE. MPA is not recommended for use prior to menarche or before or during recovery from surgery.[50] It was because of these unexpected interactions that the Women's Health Initiative study was ended early due the extra risks of hormone replacement therapy,[51] producing a dramatic decrease in both new and renewal prescriptions for hormone therapy.[52]

MPA is known to produce symptoms of depression, anxiety, and irritability in some patients.[53] In addition, unlike progesterone, lowered libido is a reported side effect of MPA in women.[54]

Unlike the related drug cyproterone acetate,[55][56] MPA does not appear to be associated with vitamin B12 deficiency.[57]

Black box warning

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.[60][61] While it causes temporary bone loss, most women regain their bone density after discontinuing use. The World Health Organization (WHO) recommends that the use not be restricted.[62][63] 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 Depo-Provera.[64][65][66] Other studies have suggested that the effect of medroxyprogesterone acetate by injection use on post-menopausal bone density is minimal,[67] perhaps because Depo users experience less bone loss at menopause.[68] Use after peak bone mass is associated with increased bone turnover but no decrease in bone mineral density.[69]

The FDA recommends that medroxyprogesterone acetate by injection not be used for longer than 2 years, unless there is no viable alternative method of contraception, due to concerns over bone loss.[61] 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 medroxyprogesterone acetate by injection beyond 2 years of use.[70]

HIV risk

There is uncertainty regarding the risk of HIV acquisition among DMPA users; some observational studies suggest an increased risk, others do not.[71] 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.[72][73]

Two meta-analyses of observational studies in sub-Saharan Africa were published in January 2015.[74] They found a 1.4 to 1.5 fold increase risk of HIV acquisition for DMPA users relative to no hormonal contraceptive use.[75][76] 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.[77]

A large, four-year randomized controlled trial of hormonal contraception and HIV in sub-Saharan Africa (to provide better evidence than currently available observational studies) that is planned to begin in 2015[78] has been controversial.[79][80][81][82][83]

Breastfeeding

Depo-Provera may be used by breast-feeding mothers. Heavy bleeding is possible if given in the immediate postpartum time and is best delayed until six weeks after birth. It may be used within five days if not breast feeding. While a study showed "no significant difference in birth weights or incidence of birth defects" and "no significant alternation of immunity to infectious disease caused by breast milk containing DMPA", a subgroup of babies whose mothers started Depo-Provera at 2 days postpartum had a 75% higher incidence of doctor visits for infectious diseases during their first year of life.[84]

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.[85]

Interactions

MPA increases the risk of breast cancer, dementia and thrombus when used in combination with conjugated equine estrogens to treat the symptoms of menopause.[50] When used as a contraceptive, MPA does not generally interact with other drugs. When combined with aminoglutethimide to treat metastases from breast cancer, MPA is associated with an increase in depression.[17] St John's wort may decrease its effectiveness as a contraceptive.[50]

Mechanism of action

The mechanism of action of progestogen-only contraceptives depends on the progestogen activity and dose. High-dose progestogen-only contraceptives, such as injectable DMPA, inhibit follicular development and prevent ovulation as their primary mechanism of action.[86][87] 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.[28][29]

A secondary mechanism of action of all progestogen-containing contraceptives is inhibition of sperm penetration by changes in the cervical mucus.[88]

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.[88]

Pharmacodynamics

Steroid hormone receptor agonist

MPA acts as an agonist of the progesterone, androgen, and glucocorticoid receptors (PR, AR, and GR, respectively),[2] activating these receptors with EC50 values of approximately 0.01 nM, 1 nM, and 10 nM, respectively.[89] It has negligible affinity for the estrogen receptor.[2] The drug has relatively high affinity for the mineralocorticoid receptor, but in spite of this, it has no mineralocorticoid or antimineralocorticoid activity.[4] The intrinsic activities of MPA in activating the PR and the AR have been reported to be at least equivalent to those of progesterone and dihydrotestosterone (DHT), respectively, indicating that it is a full agonist of these receptors.[90][91]

Relative binding affinities of progesterone and 17α-hydroxyprogesterone derivatives[4]
Progestogen
 PR (%) AR (%) ER (%) GR (%) MR (%)
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
PR (promegestone = 100%), AR (metribolone = 100%), ER (E2 = 100%), GR (DEXA = 100%), MR (aldosterone = 100%)

Progestogenic activity

MPA is a potent agonist of the progesterone receptor with similar affinity and efficacy relative to progesterone.[92] 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.[92] As such, unlike MPA, medroxyprogesterone is not used clinically, though it has seen some use in veterinary medicine.[93]

Affinities and efficacies of progesterone, medroxyprogesterone, and MPA at the PR[92]
Ligand PR Ki Coactivator recruitment EC50 Reporter cell line EC50
Progesterone 4.3 ± 1.0 nM 0.9 ± 0.2 nM 25 ± 11 nM
Medroxyprogesterone 241 ± 96 nM 47 ± 14 nM 32 ± 1 nM
Medroxyprogesterone acetate 1.2 ± 0.3 nM 0.6 ± 0.08 nM 0.15 ± 0.03 nM

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.[94] In accordance, the dosage of MPA used in oral contraceptives in the past was 10 mg per tablet.[95] 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 0.4–0.5 mg/day.[96]

Progestogenic potencies of MPA and certain other progestogens[96][97][98]
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
Medrogestone 10 60 10 – 10
Norethisterone 0.4 120 ? 0.5 0.7–1.0
Norethisterone acetate 0.5 50 ? 0.6 1.0
Levonorgestrel 0.05 6.0 0.15 0.1–0.15 0.075
OID = ovulation-inhibiting dosage (without additional estrogen); TFD = endometrial transformation dosage;
ODP = oral dosage in commercial contraceptive preparations; ECD = estimated comparable dosage

Antigonadotropic activity

In addition to its direct effects on steroid receptors, MPA, at sufficient doses, inhibits the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes, resulting in a marked suppression of gonadotropin, androgen, estrogen, adrenocorticotropic hormone (ACTH), and cortisol levels as well as concentrations of sex hormone-binding globulin (SHBG).[99] There is evidence that the downregulatory effects of MPA on the HPG axis are mediated by activation of both PRs and ARs in the pituitary gland.[100][101] Due to its effects on androgen levels, MPA has strong functional antiandrogen properties, and it is used in androgen-sensitive conditions such as precocious puberty in prepubescent boys and hypersexuality in men.[102] In addition, since it affects estrogen levels similarly, unlike many other antiandrogens such as spironolactone and cyproterone acetate which have a high propensity for causing gynecomastia via indirect stimulation of estrogen, MPA is not thought to possess any estrogenic effects. Indeed, due to its inhibitory effects on estrogen levels, it has potent antiestrogenic effects, and has been used to treat precocious puberty in prepubescent girls. Accordingly, MPA should not be used in high doses without an estrogen in women due to the risk of osteoporosis and other symptoms associated with hypoestrogenism.[103]

Androgenic activity

MPA is a potent full agonist of the AR. Its activation of the AR has been shown to play an important and major role in its antigonadotropic effects and in its beneficial effects against breast cancer.[100][104][105] However, although MPA does have the capacity to cause androgenic side effects such as acne and hirsutism in some patients (especially women),[106][107] it seldom actually does so, and when it does, the effects tend to be only mild, regardless of the dosage used.[100] 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.[108][109] Moreover, MPA rarely causes any androgenic effects in children with precocious puberty, even at very high doses.[110] The reason for the general lack of virilizing effects with MPA, despite it binding to and activating the AR with a high affinity and this action 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 in a fundamentally different way than other agonists of the receptor such as dihydrotestosterone (DHT).[90] 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.[90] Thus, this may explain the low propensity of MPA for producing androgenic side effects.

Glucocorticoid activity

As an agonist of the GR, MPA has glucocorticoid activity, and as a result can cause symptoms of Cushing's syndrome,[111] steroid diabetes, and adrenal insufficiency at sufficiently high doses.[112]

Steroidogenesis inhibitor

3α-Hydroxysteroid dehydrogenase

MPA has been found to act as a competitive inhibitor of rat 3α-hydroxysteroid dehydrogenase (3α-HSD).[113][114][53][115] This enzyme is essential for the transformation of progesterone, deoxycorticosterone, and DHT into inhibitory neurosteroids such as allopregnanolone, THDOC, and 3α-androstanediol, respectively.[116] MPA is described as extremely potent in its inhibition of rat 3α-HSD, with an IC50 of 0.2 μM and a Ki (in rat testicular homogenates) of 0.42 μM.[113][114] Inhibitory neurosteroids have antidepressant and anxiolytic effects, and the blockade of their production could be causative of the symptoms of depression, anxiety, and irritability that have been associated with MPA treatment.[53][117] Indeed, other drugs that are known to block the synthesis of these neurosteroids, such as 5α-reductase inhibitors like finasteride and dutasteride, have also been associated with symptoms of depression and anxiety.[118] However, it should be noted that inhibition of 3α-HSD by MPA does not appear to have been confirmed yet using human proteins, and the concentrations required with rat proteins are far above typical human therapeutic concentrations.

3β-Hydroxysteroid dehydrogenase

MPA has been identified as a competitive inhibitor of human 3β-hydroxysteroid dehydrogenase/Δ5-4 isomerase II (3β-HSDII).[119] This enzyme is essential for the biosynthesis of sex steroids and corticosteroids.[119] The Ki of MPA for inhibition of 3β-HSDII is 3.0 μM, and this concentration is reportedly near the circulating levels of the drug 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).[119] Aside from 3β-HSDII, 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.[119] 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-HSDII could be responsible for its effectiveness in these conditions.[119]

GABAA receptor allosteric modulator

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 GABAA 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.[116][120] It has also been found to produce anesthesia via this action in animals when administered at sufficiently high dosages.[120] 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 may modulate the GABAA receptor similarly to progesterone.[121][122]

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).[121] However, unlike the reduced metabolites of progesterone, DHMPA and THMPA have been found not to modulate the GABAA receptor.[121] Conversely, unlike progesterone, MPA itself actually modulates the GABAA receptor, although notably not at the neurosteroid binding site, but rather than act as a potentiator of the receptor, MPA appears to act as a negative allosteric modulator.[121] 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.[121] 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.[121] 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.[121]

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.[123]

Appetite stimulant

Although MPA and the closely related drug megestrol acetate are effective appetite stimulants at very high dosages,[124] 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.[125]

Pharmacokinetics

Absorption

The oral bioavailability of MPA is 100%.[4] Treatment of postmenopausal women with 2.5 or 5 mg/day MPA in combination with estradiol valerate for two weeks has been found to rapidly increase circulating MPA levels, with steady-state concentrations achieved after three days and peak concentrations occurring 1.5 to 2 hours after ingestion.[4] With 2.5 mg/day MPA, levels of the drug 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 60 years of age or over, and with 5 mg/day MPA, levels were 0.6 ng/mL (1.6 nmol/L) and 0.9 ng/mL (2.3 nmol/L), respectively.[4] With intramuscular administration of a 150 mg dose of MPA, the drug 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.[126] Following this, there is a gradual decline in MPA levels, and the drug can be detected in the circulation for as long as nine months post-injection.[126]

Distribution

In the circulation, 88% of MPA is bound to albumin, with no binding to sex hormone-binding globulin or corticosteroid-binding globulin.[4]

Metabolism

The terminal half-life of MPA via oral administration has been reported as both 11.6–16.6 hours[3] and 33 hours,[4] whereas the terminal half-lives with intramuscular and subcutaneous injection are 50 and 40 days, respectively.[5][6] The metabolism of MPA is mainly via hydroxylation, such as of positions C6β and C21, but 3- and 5-dihydro and 3,5-tetrahydro metabolites of MPA are also formed.[4] 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%).[127] MPA and/or its metabolites are also metabolized via conjugation.[50]

Relation to clinical effects

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.[126] Ovulation resumes when once blood levels of MPA fall below 0.1 ng/mL.[126] 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.[126]

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 fertilisation, MPA is a very effective means of birth control.[126]

Chemistry

MPA is a synthetic pregnane (C21) steroid and a derivative of 17α-hydroxyprogesterone. Specifically, it is the 17α-acetate ester of medroxyprogesterone or the 6α-methylated analogue of hydroxyprogesterone acetate. MPA is known chemically as 6α-methyl-17α-acetoxyprogesterone or as 6α-methyl-17α-acetoxypregn-4-en-3,20-dione, and its generic name is a contraction of 6α-methyl-17α-hydroxyprogesterone acetate. MPA is closely related to other 17α-hydroxyprogesterone derivatives such as chlormadinone acetate, cyproterone acetate, and megestrol acetate, as well as to medrogestone and nomegestrol acetate.

History

MPA was independently discovered in 1956[128] by Syntex[129] and the Upjohn Company.[130] It was first introduced on 18 June 1959 by Upjohn in the United States under the brand name Provera (2.5, 5, and 10 mg tablets) for the treatment of amenorrhea, metrorrhagia, and recurrent miscarriage.[131][132] An intramuscular formulation, Depo-Provera (400 mg/mL MPA), was also introduced in 1960 in the U.S. for the treatment of endometrial and renal cancer.[133] MPA in combination with ethinylestradiol was introduced in 1964 by Upjohn in the U.S. under the brand name Provest (10 mg MPA and 50 μg ethinylestradiol tablets) as an oral contraceptive, but this formulation was discontinued in 1970.[134][135][95] 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[136] were formulations available outside of the U.S. with a different dosage (5 mg MPA and 50 or 75 μg ethinylestradiol tablets).[137][138]

Upjohn also sought FDA approval of intramuscular MPA as a long-acting contraceptive under the brand name Depo-Provera (150 mg/mL MPA) but the applications were rejected in 1967, 1978, and yet again in 1983.[139][140] However, in 1992, the drug was finally approved by the FDA for this indication.[139] A subcutaneous formulation was introduced in the U.S. under the brand name Depo-SubQ Provera 104 (104 mg/0.65 mL MPA) in December 2004 as a contraceptive, and subsequently was also approved for the treatment of endometriosis-related pelvic pain.[141] MPA has also been marketed widely throughout the rest of the world as Provera and Depo-Provera as well as Farlutal, Perlutex, and Gestapuran, among many other brand names.[1]

Society and culture

Generic name

The generic name of MPA is medroxyprogesterone acetate, and this is also its INN, USAN, BAN, and JAN.

Availability

United States

As of November 2016, MPA is available in the United States in the following formulations:[142]

It is also available in combination with estrogen in the following formulations:

Discontinued:

Commercial products

Depo-Provera is the brand name for a 150 mg aqueous injection of DMPA depot medroxyprogesterone acetate. It is applied in the form of an intramuscular injection. The shot must be injected into the thigh or buttocks or deltoid four times a year (every 11 to 13 weeks) and provides pregnancy protection instantaneously after the first injection.[143] It was approved in the United States by the FDA for contraceptive use on 29 October 1992,[144] and for management of endometriosis-related pain on 25 March 2005. Depo-subQ Provera 104, also manufactured by Pfizer, is a variation of the original Depo Shot that is instead a 104 mg subcutaneous injection. It contains 69 percent of progestin found in the original Depo-Provera shot. This can be injected using a smaller injection needle inserting the hormone 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 the progestin while still maintaining all the same benefits of the original Depo shot.

Controversy

Outside the United States

United States

There was a long, controversial history regarding the approval of Depo-Provera 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 Depo-Provera, 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.[144] Points in the controversy included:

See also

References

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