Medroxyprogesterone acetate

Medroxyprogesterone acetate
Systematic (IUPAC) name
17α-hydroxy-6α-methylpregn-4-ene-3,20-dione acetate
Clinical data
Trade names Depo-Provera (injection), Provera (oral)
AHFS/Drugs.com FDA Professional Drug Information
MedlinePlus a604039
Pregnancy
category
  • US: X (Contraindicated)
Routes of
administration		 Oral, IM
Legal status
  • ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 99%[1]
Protein binding 88% (to albumin)[1]
Biological half-life 40-60 hours
Identifiers
CAS Number 71-58-9
ATC code G03AC06 (WHO) G03DA02, L02AB02
PubChem CID 6279
IUPHAR/BPS 2879
DrugBank DB00603
ChemSpider 6043
UNII C2QI4IOI2G
KEGG C08150 YesY
ChEBI CHEBI:6716
ChEMBL CHEMBL717 YesY
Chemical data
Formula C24H34O4
Molar mass 386.52 g/mol
  (verify)

Medroxyprogesterone acetate (MPA), also known as 17α-hydroxy-6α-methylprogesterone acetate, is a steroidal progestin, a synthetic variant of the steroid hormone progesterone.[2][3] It is used as a contraceptive, in hormone replacement therapy and for the treatment of endometriosis as well as several other indications.

MPA is a more potent derivative of its parent compound medroxyprogesterone (MP). While medroxyprogesterone is sometimes used as a synonym for medroxyprogesterone acetate,[3] what is almost always being referred to is MPA and not MP.[4] It is on the World Health Organization's List of Essential Medicines, the most important medication needed in a basic health system.[5]

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.[6] 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.[7]

In males, MPA has been used to control inappropriate sexual behavior to chemically castrate convicted sex offenders.[8]

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.[9]

Though not used as a treatment for epilepsy, MPA reduces 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.[9] MPA is also prescribed in combination with an estrogen to prevent endometrial hyperplasia in post-menopausal women who are undergoing hormone replacement therapy.[10]

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

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.[6]

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.[11] 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.[12]

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.[9]

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.[3] 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,[13] producing a dramatic decrease in both new and renewal prescriptions for hormone therapy.[14]

MPA is known to produce symptoms of depression, anxiety, and irritability in some patients.[15] In addition, unlike progesterone, lowered libido is a reported side effect of MPA in women.[16]

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.[3] 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.[9] St John's wort may decrease its effectiveness as a contraceptive.[3]

Pharmacodynamics

Activity profile

MPA acts as an agonist of the progesterone, androgen, and glucocorticoid receptors (PR, AR, and GR, respectively),[1] activating these receptors with EC50 values of approximately 0.01 nM, 1 nM, and 10 nM, respectively.[17] It has very low and likely insignificant affinity for the estrogen and mineralocorticoid receptors (ER and MR, respectively).[1] Although the EC50 values of MPA at the PR and the AR and GR are separated by several orders of magnitude, because it is so potent, and because it is used at relatively high doses in humans, due to binding saturation, it is probable that the overall activation of each of the three receptors is fairly similar. 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.[18][19]

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).[20] 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.[21][22] 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.[23] 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.[24]

As mentioned above, 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.[21][25][26] However, although MPA does have the capacity to cause androgenic side effects such as acne and hirsutism in some patients (especially women),[27][28] it seldom actually does so, and when it does, the effects tend to be only mild, regardless of the dosage used.[21] 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.[29][30] Moreover, MPA rarely causes any androgenic effects in children with precocious puberty, even at very high doses.[31] 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).[18] 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.[18] Thus, this may explain the low propensity of MPA for producing androgenic side effects.

As an agonist of the GR, MPA has glucocorticoid properties, and as a result can cause symptoms of Cushing's syndrome,[32] steroid diabetes, and adrenal insufficiency at sufficiently high doses.[33]

MPA is a known inhibitor of 3α-hydroxysteroid dehydrogenase.[15][34] This enzyme is necessary for the synthesis of the endogenous neurosteroids allopregnanolone, THDOC, and 3α-androstanediol. These neurosteroids have antidepressant and anxiolytic effects, and the blockade of their production could be the cause of the symptoms of depression, anxiety, and irritability that are sometimes seen during treatment with MPA.[15][35] Indeed, other drugs that are known to block the synthesis of these neurosteroids, such as 5α-reductase inhibitors like finasteride, have also been associated with symptoms of depression and anxiety.[36]

Although MPA and the related drug megestrol acetate (which is a close analogue) have been extensively used as appetite stimulants, 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 increased appetite.[37]

Comparison to medroxyprogesterone

Medroxyprogesterone (MP), the parent drug of MPA, is a metabolite of MPA.[38] While both MP and its acylated derivative MPA bind to the PR and both act as agonists, MPA has approximately 100 fold higher binding affinity and transactivation potency compared to MP.[39] As such, MP is not used clinically, though it has seen some use in veterinary medicine.[40]

Ligand PR Ki (nM) Coactivator recruitment EC50 (nM) Reporter cell line EC50 (nM)
Progesterone 4.3 ± 1.0 0.9 ± 0.2 25 ± 11
Medroxyprogesterone acetate 1.2 ± 0.3 0.6 ± 0.08 0.15 ± 0.03
Medroxyprogesterone 241 ± 96 47 ± 14 32 ± 1

Pharmacokinetics

MPA is well-absorbed orally and through intramuscular injection, peaking at 2–4 hours for the former. The half life is 12 to 17 hours for an oral dose, and 40 to 50 days for an intramuscular injection. MPA binds to albumin in the blood, and is metabolized primarily through the liver via hydroxylation and conjugation.[3] Intramuscular MPA is released slowly; a 150 mg dose is first detectable in the blood 30 minutes after injection, plateauing at 1.0 ng/mL for three months, followed by a gradual, tapering decline that lasts up to nine months in some women. The high levels of MPA in the blood inhibits 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.[41]

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.[41]

Comparison with progesterone

Proponents of bioidentical hormone replacement therapy believe progesterone offers fewer side effects and improved quality of life compared to MPA.[42] The evidence for this view has been questioned; MPA is better absorbed when taken orally, with a much longer half life leading to more stable blood levels[43] though it may lead to greater breast tenderness and more sporadic vaginal bleeding.[42] The two compounds do not differentiate in their ability to suppress endometrial hyperplasia,[42] nor does either increase the risk of pulmonary embolism.[44] The two compounds have not been adequately compared in direct tests to clear conclusions about safety and superiority.[7]

History

MPA was independently discovered in 1956[45] by Syntex[46] and the Upjohn Company.[47]

Names

Medroxyprogesterone acetate is the INN, USAN, and BAN.

See also

References

  1. 1 2 3 4 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.
  2. ↑ 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.
  3. 1 2 3 4 5 6 "MedroxyPROGESTERone: Drug Information Provided by Lexi-Comp". Merck Manual. 2009-12-01. Retrieved 2010-07-08.
  4. ↑ 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.
  5. ↑ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  6. 1 2 "Medroxyprogesterone". MedlinePlus. 2008-01-09. Retrieved 2010-07-02.
  7. 1 2 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.
  8. ↑ 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.
  9. 1 2 3 4 Meyler L (2009). Meyler's side effects of endocrine and metabolic drugs. Amsterdam: Elsevier Science. pp. 281–284. ISBN 0-444-53271-4.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ Bethea CL (Feb 2011). "MPA: Medroxy-Progesterone Acetate Contributes to Much Poor Advice for Women". Endocrinology 152 (2): 343–345. doi:10.1210/en.2010-13761. PMC 3037166. PMID 21252179.
  13. ↑ 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.
  14. ↑ 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.
  15. 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 1440328. PMID 15181090.
  16. ↑ Steven R. King (9 November 2012). Neurosteroids and the Nervous System. Springer Science & Business Media. pp. 45–. ISBN 978-1-4614-5559-2.
  17. ↑ 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.
  18. 1 2 3 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.
  19. ↑ 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.
  20. ↑ 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.
  21. 1 2 3 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.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ 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.
  25. ↑ 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.
  26. ↑ 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.
  27. ↑ Rees MCP, 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.
  28. ↑ 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.
  29. ↑ 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.
  30. ↑ 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.
  31. ↑ 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.
  32. ↑ 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.
  33. ↑ Systemic Effects of Oral Glucocorticoids
  34. ↑ 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.
  35. ↑ 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.
  36. ↑ 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.
  37. ↑ 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.
  38. ↑ 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.
  39. ↑ 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.
  40. ↑ Index Nominum 2000: International Drug Directory. Taylor & Francis US. 2000. p. 638. ISBN 978-3-88763-075-1. Retrieved 28 May 2012.
  41. 1 2 Mishell DR (May 1996). "Pharmacokinetics of depot medroxyprogesterone acetate contraception". The Journal of Reproductive Medicine 41 (5 Suppl): 381–90. PMID 8725700.
  42. 1 2 3 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.
  43. ↑ 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.
  44. ↑ 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.
  45. ↑ Sneader, Walter (2005). "Chapter 18: Hormone analogs". Drug discovery: a history. New York: Wiley. p. 204. ISBN 0-471-89980-1.
  46. ↑ FR 1295307, "Procédé de préparation de dérivés cyclopentano-phénanthréniques", published 1962-06-08, assigned to Syntex SA
  47. ↑ 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
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