|Trade names||Provera, Depo-Provera, Depo-SubQ Provera 104, Curretab, Cycrin, Farlutal, Gestapuran, Perlutex, Veramix, others|
|AHFS/Drugs.com||FDA Professional Drug Information|
|Oral, intramuscular, subcutaneous|
|ATC code||G03AC06 (WHO) G03DA02 (WHO), L02AB02 (WHO)|
|Protein binding||88% (to albumin)|
By mouth: 12–33 hours|
I.M.: ~50 days
S.C.: ~40 days
|Chemical and physical data|
|Molar mass||386.52 g/mol|
|3D model (Jmol)||Interactive image|
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. 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. 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.
MPA is on the World Health Organization's List of Essential Medicines, the most important medication needed in a basic health system.
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. 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.
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.
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. MPA is also prescribed in combination with an estrogen to prevent endometrial hyperplasia in post-menopausal women who are undergoing hormone replacement therapy.
Comparison with progesterone
Proponents of bioidentical hormone replacement therapy believe that progesterone offers fewer side effects and improved quality of life compared to MPA. 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 though it may lead to greater breast tenderness and more sporadic vaginal bleeding. The two compounds do not differentiate in their ability to suppress endometrial hyperplasia, nor does either increase the risk of pulmonary embolism. The two drugs have not been adequately compared in direct tests to clear conclusions about safety and superiority.
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.
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. 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.
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.
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. 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, producing a dramatic decrease in both new and renewal prescriptions for hormone therapy.
MPA increases the risk of breast cancer, dementia and thrombus when used in combination with conjugated equine estrogens to treat the symptoms of menopause. 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. St John's wort may decrease its effectiveness as a contraceptive.
Steroid hormone receptor agonist
MPA acts as an agonist of the progesterone, androgen, and glucocorticoid receptors (PR, AR, and GR, respectively), activating these receptors with EC50 values of approximately 0.01 nM, 1 nM, and 10 nM, respectively. It has negligible affinity for the estrogen receptor. The drug has relatively high affinity for the mineralocorticoid receptor, but in spite of this, it has no mineralocorticoid or antimineralocorticoid activity. 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.
| ||PR (%)||AR (%)||ER (%)||GR (%)||MR (%)|
|PR (promegestone = 100%), AR (metribolone = 100%), ER (E2 = 100%), GR (DEXA = 100%), MR (aldosterone = 100%)|
MPA is a potent agonist of the progesterone receptor with similar affinity and efficacy relative to progesterone. 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. As such, unlike MPA, medroxyprogesterone is not used clinically, though it has seen some use in veterinary medicine.
|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. In accordance, the dosage of MPA used in oral contraceptives in the past was 10 mg per tablet. 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.
| OID = ovulation-inhibiting dosage (without additional estrogen); TFD = endometrial transformation dosage;|
ODP = oral dosage in commercial contraceptive preparations; ECD = estimated comparable dosage
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). 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. 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. 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.
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. However, although MPA does have the capacity to cause androgenic side effects such as acne and hirsutism in some patients (especially women), it seldom actually does so, and when it does, the effects tend to be only mild, regardless of the dosage used. 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. Moreover, MPA rarely causes any androgenic effects in children with precocious puberty, even at very high doses. 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). 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. Thus, this may explain the low propensity of MPA for producing androgenic side effects.
MPA has been found to act as a competitive inhibitor of rat 3α-hydroxysteroid dehydrogenase (3α-HSD). This enzyme is essential for the transformation of progesterone, deoxycorticosterone, and DHT into inhibitory neurosteroids such as allopregnanolone, THDOC, and 3α-androstanediol, respectively. 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. 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. 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. 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.
MPA has been identified as a competitive inhibitor of human 3β-hydroxysteroid dehydrogenase/Δ5-4 isomerase II (3β-HSDII). This enzyme is essential for the biosynthesis of sex steroids and corticosteroids. 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). 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. 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.
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. It has also been found to produce anesthesia via this action in animals when administered at sufficiently high dosages. 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.
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). However, unlike the reduced metabolites of progesterone, DHMPA and THMPA have been found not to modulate the GABAA receptor. 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. 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. 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. 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.
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.
Although MPA and the closely related drug megestrol acetate are effective appetite stimulants at very high dosages, 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.
The oral bioavailability of MPA is 100%. 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. 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. 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. 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.
The terminal half-life of MPA via oral administration has been reported as both 11.6–16.6 hours and 33 hours, whereas the terminal half-lives with intramuscular and subcutaneous injection are 50 and 40 days, respectively. 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. 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%). MPA and/or its metabolites are also metabolized via conjugation.
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. Ovulation resumes when once blood levels of MPA fall below 0.1 ng/mL. 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.
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.
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.
MPA was independently discovered in 1956 by Syntex and the Upjohn Company. 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. 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. 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. 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 were formulations available outside of the U.S. with a different dosage (5 mg MPA and 50 or 75 μg ethinyl estradiol tablets). 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. However, in 1992, the drug was finally approved by the FDA for this indication. 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. 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.
Society and culture
As of November 2016, MPA is available in the United States in the following formulations:
- 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
It is also available in combination with estrogen in the following formulations:
- Oral pills: conjugated estrogens and MPA (Premphase (Premarin, Cycrin 14/14), Premphase 14/14, Prempro, Prempro (Premarin, Cycrin), 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
- Oral pills: ethinyl estradiol and MPA (Provest) – 50 μg / 10 mg
- Aqueous suspension for intramuscular injection: estradiol cypionate and MPA (Lunelle) – 5 mg / 25 mg
- Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 638–. ISBN 978-3-88763-075-1.
- Schindler AE, Campagnoli C, Druckmann R, Huber J, Pasqualini JR, Schweppe KW, Thijssen JH (2008). "Classification and pharmacology of progestins". Maturitas. 61 (1-2): 171–80. doi:10.1016/j.maturitas.2008.11.013. PMID 19434889.
- Kuhl H (2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration". Climacteric. 8 Suppl 1: 3–63. doi:10.1080/13697130500148875. PMID 16112947.
- J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. p. 657. ISBN 978-1-4757-2085-3.
- Hall JA, Morton I (1999). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer. p. 173. ISBN 978-0-7514-0499-9. Retrieved 28 May 2012.
- "MedroxyPROGESTERone: Drug Information Provided by Lexi-Comp". Merck Manual. 2009-12-01. Retrieved 2010-07-08.
- 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 1343717. PMID 1119869.
- "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
- "Medroxyprogesterone". MedlinePlus. 2008-01-09. Retrieved 2010-07-02.
- Panay N, Fenton A (Feb 2010). "Bioidentical hormones: what is all the hype about?". Climacteric. 13 (1): 1–3. doi:10.3109/13697130903550250. PMID 20067429.
- 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 1413960. PMID 16575429.
- Meyler L (2009). Meyler's side effects of endocrine and metabolic drugs. Amsterdam: Elsevier Science. pp. 281–284. ISBN 0-444-53271-4.
- Furness S, Roberts H, Marjoribanks J, Lethaby A, Hickey M, Farquhar C (2009). "Hormone therapy in postmenopausal women and risk of endometrial hyperplasia". The Cochrane Database of Systematic Reviews (2): CD000402. doi:10.1002/14651858.CD000402.pub3. PMID 19370558.
- Holtorf K (Jan 2009). "The bioidentical hormone debate: are bioidentical hormones (estradiol, estriol, and progesterone) safer or more efficacious than commonly used synthetic versions in hormone replacement therapy?" (pdf). Postgraduate Medicine. 121 (1): 73–85. doi:10.3810/pgm.2009.01.1949. PMID 19179815.
- 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.
- 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.
- 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.
- 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 3037166. PMID 21252179.
- 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.
- 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.
- 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 1440328. PMID 15181090.
- Steven R. King (9 November 2012). Neurosteroids and the Nervous System. Springer Science & Business Media. pp. 45–. ISBN 978-1-4614-5559-2.
- Ralph M. Trüeb (26 February 2013). Female Alopecia: Guide to Successful Management. Springer Science & Business Media. pp. 46–. ISBN 978-3-642-35503-5.
- Bentham Science Publishers (September 1999). Current Pharmaceutical Design. Bentham Science Publishers. pp. 717–.
- Amatayakul K, Sivasomboon B, Thanangkul O (1978). "Vitamin and trace mineral metabolism in medroxyprogesterone acetate users". Contraception. 18 (3): 253–69. PMID 720068.
- World Health Organization (2004). Residues of Some Veterinary Drugs in Animals and Food: Monographs Prepared by the Sixty-second Meeting of the Joint FAO/WHO Expert Committee on Food Additives, Rome, 4-12 February 2004. Food & Agriculture Org. p. 49. ISBN 978-92-5-105195-5. Retrieved 28 May 2012.
- Kemppainen JA, Langley E, Wong CI, Bobseine K, Kelce WR, Wilson EM (Mar 1999). "Distinguishing androgen receptor agonists and antagonists: distinct mechanisms of activation by medroxyprogesterone acetate and dihydrotestosterone". Molecular Endocrinology. 13 (3): 440–54. doi:10.1210/mend.13.3.0255. PMID 10077001.
- Bentel JM, Birrell SN, Pickering MA, Holds DJ, Horsfall DJ, Tilley WD (Aug 1999). "Androgen receptor agonist activity of the synthetic progestin, medroxyprogesterone acetate, in human breast cancer cells". Molecular and Cellular Endocrinology. 154 (1-2): 11–20. doi:10.1016/S0303-7207(99)00109-4. PMID 10509795.
- Pullen MA, Laping N, Edwards R, Bray J (Sep 2006). "Determination of conformational changes in the progesterone receptor using ELISA-like assays". Steroids. 71 (9): 792–8. doi:10.1016/j.steroids.2006.05.009. PMID 16784762.
- Index Nominum 2000: International Drug Directory. Taylor & Francis US. 2000. p. 638. ISBN 978-3-88763-075-1. Retrieved 28 May 2012.
- Wikström A, Green B, Johansson ED (1984). "The plasma concentration of medroxyprogesterone acetate and ovarian function during treatment with medroxyprogesterone acetate in 5 and 10 mg doses". Acta Obstet Gynecol Scand. 63 (2): 163–8. PMID 6233840.
- Robert W. Blum (22 October 2013). Adolescent Health Care: Clinical Issues. Elsevier Science. pp. 216–. ISBN 978-1-4832-7738-7.
- Schindler, Adolf E; Campagnoli, Carlo; Druckmann, René; Huber, Johannes; Pasqualini, Jorge R; Schweppe, Karl W; Thijssen, Jos H.H (2003). "Classification and pharmacology of progestins". Maturitas. 46: 7–16. doi:10.1016/j.maturitas.2003.09.014. ISSN 0378-5122.
- Kuhl H (2011). "Pharmacology of Progestogens" (PDF). J Reproduktionsmed Endokrinol. 8 (1): 157–177.
- Marc A. Fritz; Leon Speroff (28 March 2012). Clinical Gynecologic Endocrinology and Infertility. Lippincott Williams & Wilkins. pp. 761–. ISBN 978-1-4511-4847-3.
- Genazzani AR (15 January 1993). Frontiers in Gynecologic and Obstetric Investigation. Taylor & Francis. p. 320. ISBN 978-1-85070-486-7. Retrieved 28 May 2012.
- Poulin R, Baker D, Poirier D, Labrie F (Mar 1989). "Androgen and glucocorticoid receptor-mediated inhibition of cell proliferation by medroxyprogesterone acetate in ZR-75-1 human breast cancer cells". Breast Cancer Research and Treatment. 13 (2): 161–72. doi:10.1007/bf01806528. PMID 2525057.
- 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.
- Saleh FM, Grudzinskas AJ, Bradford JM (11 February 2009). Sex Offenders: Identification, Risk Assessment, Treatment, and Legal Issues. Oxford University Press. p. 44. ISBN 978-0-19-517704-6. Retrieved 28 May 2012.
- Stuart MC, Kouimtzi M, Hill SR (2009). Who Model Formulary 2008. World Health Organization. p. 368. ISBN 978-92-4-154765-9. Retrieved 28 May 2012.
- Birrell SN, Hall RE, Tilley WD (Jan 1998). "Role of the androgen receptor in human breast cancer" (PDF). Journal of Mammary Gland Biology and Neoplasia. 3 (1): 95–103. PMID 10819508.
- Buchanan G, Birrell SN, Peters AA, Bianco-Miotto T, Ramsay K, Cops EJ, Yang M, Harris JM, Simila HA, Moore NL, Bentel JM, Ricciardelli C, Horsfall DJ, Butler LM, Tilley WD (Sep 2005). "Decreased androgen receptor levels and receptor function in breast cancer contribute to the failure of response to medroxyprogesterone acetate". Cancer Research. 65 (18): 8487–96. doi:10.1158/0008-5472.CAN-04-3077. PMID 16166329.
- Rees MC, Hope S, Ravnikar V (12 August 2005). The Abnormal Menstrual Cycle. Taylor & Francis. p. 213. ISBN 978-1-84214-212-7. Retrieved 2 June 2012.
- Aronson JK (20 January 2009). Meyler's Side Effects of Endocrine and Metabolic Drugs. Elsevier. p. 283. ISBN 978-0-444-53271-8. Retrieved 2 June 2012.
- Ettinger B, Golditch IM (Dec 1977). "Medroxyprogesterone acetate for the evaluation of hypertestosteronism in hirsute women". Fertility and Sterility. 28 (12): 1285–8. PMID 590535.
- Correa de Oliveira RF, Novaes LP, Lima MB, Rodrigues J, Franco S, Khenaifes AI, Francalanci CP (Dec 1975). "A new treatment for hirsutism". Annals of Internal Medicine. 83 (6): 817–9. doi:10.7326/0003-4819-83-6-817. PMID 1200527.
- Richman RA, Underwood LE, French FS, Van Wyk JJ (Dec 1971). "Adverse effects of large doses of medroxyprogesterone (MPA) in idiopathic isosexual precocity". The Journal of Pediatrics. 79 (6): 963–71. doi:10.1016/s0022-3476(71)80191-9. PMID 4332067.
- Merrin PK, Alexander WD (Aug 1990). "Cushing's syndrome induced by medroxyprogesterone". BMJ. 301 (6747): 345. doi:10.1136/bmj.301.6747.345-a. PMC 1663616. PMID 2144198.
- Systemic Effects of Oral Glucocorticoids
- 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.
- Penning TM, Sharp RB, Krieger NR (1985). "Purification and properties of 3 alpha-hydroxysteroid dehydrogenase from rat brain cytosol. Inhibition by nonsteroidal anti-inflammatory drugs and progestins". J. Biol. Chem. 260 (28): 15266–72. PMID 2933398.
- Meyer L, Venard C, Schaeffer V, Patte-Mensah C, Mensah-Nyagan AG (Apr 2008). "The biological activity of 3alpha-hydroxysteroid oxido-reductase in the spinal cord regulates thermal and mechanical pain thresholds after sciatic nerve injury". Neurobiology of Disease. 30 (1): 30–41. doi:10.1016/j.nbd.2007.12.001. PMID 18291663.
- Mellon SH, Griffin LD (2002). "Neurosteroids: biochemistry and clinical significance". Trends Endocrinol. Metab. 13 (1): 35–43. PMID 11750861.
- Civic D, Scholes D, Ichikawa L, LaCroix AZ, Yoshida CK, Ott SM, Barlow WE (Jun 2000). "Depressive symptoms in users and non-users of depot medroxyprogesterone acetate". Contraception. 61 (6): 385–90. doi:10.1016/s0010-7824(00)00122-0. PMID 10958882.
- Traish AM, Mulgaonkar A, Giordano N (Jun 2014). "The dark side of 5α-reductase inhibitors' therapy: sexual dysfunction, high Gleason grade prostate cancer and depression". Korean Journal of Urology. 55 (6): 367–79. doi:10.4111/kju.2014.55.6.367. PMC 4064044. PMID 24955220.
- Lee TC, Miller WL, Auchus RJ (1999). "Medroxyprogesterone acetate and dexamethasone are competitive inhibitors of different human steroidogenic enzymes". J. Clin. Endocrinol. Metab. 84 (6): 2104–10. doi:10.1210/jcem.84.6.5646. PMID 10372718.
- Söderpalm AH, Lindsey S, Purdy RH, Hauger R, Wit de H (2004). "Administration of progesterone produces mild sedative-like effects in men and women". Psychoneuroendocrinology. 29 (3): 339–54. PMID 14644065.
- McAuley JW, Kroboth PD, Stiff DD, Reynolds IJ (1993). "Modulation of [3H]flunitrazepam binding by natural and synthetic progestational agents". Pharmacol. Biochem. Behav. 45 (1): 77–83. PMID 8516376.
- Abraham Weizman (1 February 2008). Neuroactive Steroids in Brain Function, Behavior and Neuropsychiatric Disorders: Novel Strategies for Research and Treatment. Springer Science & Business Media. pp. 104,107,112. ISBN 978-1-4020-6854-6.
- Muss HB, Cruz JM (1992). "High-dose progestin therapy for metastatic breast cancer". Ann. Oncol. 3 Suppl 3: 15–20. PMID 1390312.
- Hofbauer KG, Anker SD, Inui A, Nicholson JR (22 December 2005). Pharmacotherapy of Cachexia. CRC Press. pp. 292–. ISBN 978-1-4200-4895-7.
Medroxyprogesterone [acetate] has similarly been shown to increase appetite and food intake with stabilization of body weight at a dose of 1000 mg (500 mg twice daily).13 Although the drug may be used at 500 to 4000 mg daily, side effects increase above oral doses of 1000 mg daily.16
- 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.
- Mishell DR (May 1996). "Pharmacokinetics of depot medroxyprogesterone acetate contraception". The Journal of Reproductive Medicine. 41 (5 Suppl): 381–90. PMID 8725700.
- Ishihara M, Kirdani Y, Osawa Y, Sandberg AA (Jan 1976). "The metabolic fate of medroxyprogesterone acetate in the baboon". Journal of Steroid Biochemistry. 7 (1): 65–70. doi:10.1016/0022-4731(76)90167-9. PMID 1271819.
- Sneader, Walter (2005). "Chapter 18: Hormone analogs". Drug discovery: a history. New York: Wiley. p. 204. ISBN 0-471-89980-1.
- FR 1295307, "Procédé de préparation de dérivés cyclopentano-phénanthréniques", published 1962-06-08, assigned to Syntex SA
- 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
- 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.
- Hartmann KE, Jerome RN, Lindegren ML, Potter SA, Shields TC, Surawicz TS, Andrews JC (2013). Primary Care Management of Abnormal Uterine Bleeding. PMID 23617013.
- Annetine Gelijns (1991). Innovation in Clinical Practice: The Dynamics of Medical Technology Development. National Academies. pp. 167–. NAP:13513.
- William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia. Elsevier. pp. 1501–. ISBN 978-0-8155-1856-3.
- 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.
- 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
- Jeremy I. Levitt (30 April 2015). Black Women and International Law: Deliberate Interactions, Movements and Actions. Cambridge University Press. pp. 230–231. ISBN 978-1-316-29840-4.
- 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, [...]
- Donna Shoupe; Daniel R. Mishell, Jr. (28 September 2015). The Handbook of Contraception: A Guide for Practical Management. Humana Press. pp. 126–. ISBN 978-3-319-20185-6.
- "Drugs@FDA: FDA Approved Drug Products" (HTML). United States Food and Drug Administration. Retrieved 29 November 2016.