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 FDA Professional Drug Information
MedlinePlus a604039
Pregnancy
category
  • US: X (Contraindicated)
Routes of
administration		 Oral, intramuscular, subcutaneous
ATC code G03AC06 (WHO) G03DA02 (WHO), L02AB02 (WHO)
Legal status
Legal status
  • ℞ (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 71-58-9
PubChem (CID) 6279
IUPHAR/BPS 2879
DrugBank DB00603
ChemSpider 6043
UNII C2QI4IOI2G
KEGG C08150 YesY
ChEBI CHEBI:6716
ChEMBL CHEMBL717 YesY
Chemical and physical data
Formula C24H34O4
Molar mass 386.52 g/mol
3D model (Jmol) Interactive image
  (verify)

Medroxyprogesterone acetate (MPA), sold under the brand name Depo-Provera among others, is a steroidal progestin of the 17α-hydroxyprogesterone group and a synthetic derivative of the progestational steroid hormone progesterone.[7][1][8][9] It is used as a hormonal contraceptive, in menopausal hormone replacement therapy, and for the treatment of gynecological disorders, among other indications. MPA is the 17α-acetate ester of medroxyprogesterone, which, in contrast to MPA, was never marketed for clinical use.[7] The term medroxyprogesterone is often inappropriately used as a synonym for MPA, and when it is used, it almost always refers to MPA rather actually than medroxyprogesterone.[10]

MPA is on the World Health Organization's List of Essential Medicines, the most important medication needed in a basic health system.[11]

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.[12] 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.[13]

In males, MPA has been used to control inappropriate sexual behavior to chemically castrate convicted sex offenders.[14]

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.[15]

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.[15] MPA is also prescribed in combination with an estrogen to prevent endometrial hyperplasia in post-menopausal women who are undergoing hormone replacement therapy.[16]

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

Comparison with progesterone

Proponents of bioidentical hormone replacement therapy believe that progesterone offers fewer side effects and improved quality of life compared to MPA.[17] The evidence for this view has been questioned; MPA is better absorbed when taken orally, with a much longer terminal half-life leading to more stable blood levels[18] though it may lead to greater breast tenderness and more sporadic vaginal bleeding.[17] The two compounds do not differentiate in their ability to suppress endometrial hyperplasia,[17] nor does either increase the risk of pulmonary embolism.[19] The two drugs have not been adequately compared in direct tests to clear conclusions about safety and superiority.[13]

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.[12]

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.[20] 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.[21]

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.[15]

Fetuses exposed to progesterones 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.[9] 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,[22] producing a dramatic decrease in both new and renewal prescriptions for hormone therapy.[23]

MPA is known to produce symptoms of depression, anxiety, and irritability in some patients.[24] In addition, unlike progesterone, lowered libido is a reported side effect of MPA in women.[25]

Unlike the related drug cyproterone acetate,[26][27] MPA does not appear to be associated with vitamin B12 deficiency.[28]

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.[9] 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.[15] St John's wort may decrease its effectiveness as a contraceptive.[9]

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.[29] 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.[30][31]

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.[32] 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.[32] As such, unlike MPA, medroxyprogesterone is not used clinically, though it has seen some use in veterinary medicine.[33]

Affinities and efficacies of progesterone, medroxyprogesterone, and MPA at the PR[32]
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.[34] In accordance, the dosage of MPA used in oral contraceptives in the past was 10 mg per tablet.[35] 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.[36]

Progestogenic potencies of MPA and certain other progestogens[36][37][38]
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).[39] 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.[40][41] 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.[42] 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.[43]

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.[40][44][45] However, although MPA does have the capacity to cause androgenic side effects such as acne and hirsutism in some patients (especially women),[46][47] it seldom actually does so, and when it does, the effects tend to be only mild, regardless of the dosage used.[40] 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.[48][49] Moreover, MPA rarely causes any androgenic effects in children with precocious puberty, even at very high doses.[50] 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).[30] 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.[30] 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,[51] steroid diabetes, and adrenal insufficiency at sufficiently high doses.[52]

Steroidogenesis inhibitor

3α-Hydroxysteroid dehydrogenase

MPA has been found to act as a competitive inhibitor of rat 3α-hydroxysteroid dehydrogenase (3α-HSD).[53][54][24][55] This enzyme is essential for the transformation of progesterone, deoxycorticosterone, and DHT into inhibitory neurosteroids such as allopregnanolone, THDOC, and 3α-androstanediol, respectively.[56] 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.[53][54] 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.[24][57] 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.[58] 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).[59] This enzyme is essential for the biosynthesis of sex steroids and corticosteroids.[59] 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).[59] 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.[59] 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.[59]

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.[56][60] It has also been found to produce anesthesia via this action in animals when administered at sufficiently high dosages.[60] 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.[61][62]

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).[61] However, unlike the reduced metabolites of progesterone, DHMPA and THMPA have been found not to modulate the GABAA receptor.[61] 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.[61] 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.[61] 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.[61] 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.[61]

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.[63]

Appetite stimulant

Although MPA and the closely related drug megestrol acetate are effective appetite stimulants at very high dosages,[64] 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.[65]

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.[66] 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.[66]

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%).[67] MPA and/or its metabolites are also metabolized via conjugation.[9]

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.[66] Ovulation resumes when once blood levels of MPA fall below 0.1 ng/mL.[66] 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.[66]

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.[66]

Chemistry

MPA is a pregnane (C21) steroid and a derivative of 17α-hydroxyprogesterone. Specifically, it is the 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[68] by Syntex[69] and the Upjohn Company.[70] 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.[71][72] 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.[73] MPA in combination with ethinyl estradiol was introduced in 1964 by Upjohn in the U.S. under the brand name Provest (10 mg MPA and 50 μg ethinyl estradiol tablets) as an oral contraceptive, but this formulation was discontinued in 1970.[74][75][35] 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[76] were formulations available outside of the U.S. with a different dosage (5 mg MPA and 50 or 75 μg ethinyl estradiol tablets).[77] [78] 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.[79][80] However, in 1992, the drug was finally approved by the FDA for this indication.[79] 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.[81] 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:[82]

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

Discontinued:

See also

References

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  3. 1 2 http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/011839s071lbl.pdf
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  9. 1 2 3 4 5 "MedroxyPROGESTERone: Drug Information Provided by Lexi-Comp". Merck Manual. 2009-12-01. Retrieved 2010-07-08.
  10. ↑ Lenco W, Mcknight M, Macdonald AS (Jan 1975). "Effects of cortisone acetate, methylprednisolone and medroxyprogesterone on wound contracture and epithelization in rabbits". Annals of Surgery. 181 (1): 67–73. doi:10.1097/00000658-197501000-00015. PMC 1343717Freely accessible. PMID 1119869.
  11. ↑ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  12. 1 2 "Medroxyprogesterone". MedlinePlus. 2008-01-09. Retrieved 2010-07-02.
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  14. ↑ Light SA, Holroyd S (Mar 2006). "The use of medroxyprogesterone acetate for the treatment of sexually inappropriate behaviour in patients with dementia" (PDF). Journal of Psychiatry & Neuroscience. 31 (2): 132–4. PMC 1413960Freely accessible. PMID 16575429.
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  18. ↑ Cirigliano M (Jun 2007). "Bioidentical hormone therapy: a review of the evidence" (pdf). Journal of Women's Health. 16 (5): 600–31. doi:10.1089/jwh.2006.0311. PMID 17627398.
  19. ↑ Boothby LA, Doering PL (Aug 2008). "Bioidentical hormone therapy: a panacea that lacks supportive evidence". Current Opinion in Obstetrics & Gynecology. 20 (4): 400–7. doi:10.1097/GCO.0b013e3283081ae9. PMID 18660693.
  20. ↑ Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J (Jul 2002). "Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial". JAMA. 288 (3): 321–33. doi:10.1001/jama.288.3.321. PMID 12117397.
  21. ↑ Bethea CL (Feb 2011). "MPA: Medroxy-Progesterone Acetate Contributes to Much Poor Advice for Women". Endocrinology. 152 (2): 343–345. doi:10.1210/en.2010-1376. PMC 3037166Freely accessible. PMID 21252179.
  22. ↑ Prentice RL, Anderson GL (2008). "The women's health initiative: lessons learned". Annual Review of Public Health. 29: 131–50. doi:10.1146/annurev.publhealth.29.020907.090947. PMID 18348708.
  23. ↑ Buist DS, Newton KM, Miglioretti DL, Beverly K, Connelly MT, Andrade S, Hartsfield CL, Wei F, Chan KA, Kessler L (Nov 2004). "Hormone therapy prescribing patterns in the United States". Obstetrics and Gynecology. 104 (5 Pt 1): 1042–50. doi:10.1097/01.AOG.0000143826.38439.af. PMID 15516400.
  24. 1 2 3 Pazol K, Wilson ME, Wallen K (Jun 2004). "Medroxyprogesterone acetate antagonizes the effects of estrogen treatment on social and sexual behavior in female macaques". The Journal of Clinical Endocrinology and Metabolism. 89 (6): 2998–3006. doi:10.1210/jc.2003-032086. PMC 1440328Freely accessible. PMID 15181090.
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  41. ↑ Brady BM, Anderson RA, Kinniburgh D, Baird DT (Apr 2003). "Demonstration of progesterone receptor-mediated gonadotrophin suppression in the human male". Clinical Endocrinology. 58 (4): 506–12. doi:10.1046/j.1365-2265.2003.01751.x. PMID 12641635.
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  53. 1 2 Sunde A, Rosness PA, Eik-Nes KB (1982). "Effects in vitro of medroxyprogesterone acetate on steroid metabolizing enzymes in the rat: selective inhibition of 3 alpha-hydroxysteroid oxidoreductase activity". J. Steroid Biochem. 17 (2): 197–203. PMID 6213817.
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  65. ↑ Doyle D, Hanks G, Cherny NI (3 February 2005). Oxford Textbook Of Palliative Medicine. Oxford University Press. p. 553. ISBN 978-0-19-856698-4. Retrieved 28 May 2012.
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  69. ↑ FR 1295307, "Procédé de préparation de dérivés cyclopentano-phénanthréniques", published 1962-06-08, assigned to Syntex SA
  70. ↑ US granted 3377364, Spero G, "6-methyl-17alpha-hydroxyprogesterone, the lower fatty acid 17-acylates and methods for producing the same", published 1968-04-09, assigned to Upjohn Company
  71. ↑ William Green (1987). "Odyssey of Depo-Provera: Contraceptives, Carcinogenic Drugs, and Risk-Management Analyses". The. Food Drug Cosm. LJ. Chicago (42): 567–587. Depo-Provera is a drug, manufactured by The Upjohn Co., whose active ingredient is medroxyprogesterone acetate (MPA). FDA first approved the drug in 1959 to treat amenorrhea,5 irregular uterine bleeding, and threatened and habitual abortion.
  72. ↑ Hartmann KE, Jerome RN, Lindegren ML, Potter SA, Shields TC, Surawicz TS, Andrews JC (2013). Primary Care Management of Abnormal Uterine Bleeding. PMID 23617013.
  73. ↑ http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/012541s084lbl.pdf
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  75. ↑ William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia. Elsevier. pp. 1501–. ISBN 978-0-8155-1856-3.
  76. ↑ http://pdf.usaid.gov/pdf_docs/pnaap426.pdf
  77. ↑ Joseph Bolivar De Lee (1966). The ... Year Book of Obstetrics and Gynecology. Year Book Publishers. p. 339. One of these is medroxyprogesterone acetate, which is sold in the United States by Upjohn as Provest, and is obtainable abroad as Provestral, Provestrol, Cyclo-Farlutal, and the more frankly suggestive Nogest.
  78. ↑ Research on Steroids. Pergamon. 1966. pp. 469,542. Medroxyprogesterone acetate 6a-Methyl-D4-pregnene-17a-ol-3,20-dione 17-acetate 1) mg 10+EE (xg 50x20 Provest (Upjohn) Provestral (Upjohn) Provestrol (Upjohn) 2) mg 5 + EE (xg 75x 20 Ciclofarlutal (Farmitalia) 3) mg 5 + EE (xg 50 X
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  80. ↑ name="Women1998"Documentation on Women's Concerns. Library and Documentation Centre, All India Association for Christian Higher Education. January 1998. Upjohn meanwhile, had been repeatedly seeking FDA approval for use of DMPA as a contraceptive, but applications were rejected in 1967, 1978 and yet again in 1983, [...]
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