Chemistry:Nomegestrol acetate

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Short description: Chemical compound
Nomegestrol acetate
Nomegestrol acetate.svg
Nomegestrol acetate molecule ball.png
Clinical data
Trade namesAlone: Lutenyl
With E2: Naemis, Zoely
Other namesNOMAC; NOMAc; Nomegesterol acetate; TX-066; TX-525; ORG-10486-0; Uniplant; 19-Normegestrol acetate; 6-Methyl-17α-acetoxy-δ6-19-norprogesterone; 17α-Acetoxy-6-methyl-19-norpregna-4,6-diene-3,20-dione
License data
Routes of
administration		By mouth[1]
Drug classProgestogen; Progestin; Progestogen ester; Steroidal antiandrogen
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability63%[1]
Protein binding97.5–98.0% (to albumin)[1]
MetabolismLiver (by hydroxylation via CYP3A3, CYP3A4, CYP2A6)[1]
MetabolitesSix main metabolites, all essentially inactive[1]
Elimination half-life~50 hours (range 30–80 hours)[1][2]
ExcretionUrine, feces[1]
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC23H30O4
Molar mass370.489 g·mol−1
3D model (JSmol)

Nomegestrol acetate (NOMAC), sold under the brand names Lutenyl and Zoely among others, is a progestin medication which is used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders.[3][1][4][5][6][7] It is available both alone and in combination with an estrogen.[8][9] NOMAC is taken by mouth.[3] A birth control implant for placement under the skin was also developed but ultimately was not marketed.[10][11][12][13]

Side effects of NOMAC include menstrual irregularities, headaches, nausea, breast tenderness, and others.[1][14] NOMAC is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone.[3] It has some antiandrogenic activity and no other important hormonal activity.[3]

Nomegestrol, a related compound, was patented in 1975, and NOMAC was described in 1983.[15][16] NOMAC was first introduced for medical use, for the treatment of gynecological disorders and in menopausal hormone therapy, in Europe in 1986.[1][17][18] It was subsequently approved in Europe in 2011 as a component of birth control pills.[1][17][18] NOMAC is available widely throughout the world.[8][19] It is not available in the United States or Canada .[8][1][17][18]


Medical uses

NOMAC is used alone in the treatment of gynecological disorders including menstrual disturbances (e.g., dysmenorrhea, menorrhagia, oligomenorrhea, polymenorrhea, amenorrhea), vaginal bleeding, breast pain, and premenstrual syndrome and in menopausal hormone therapy.[1][5][14] It is used in combination with estradiol as a birth control pill and in menopausal hormone therapy.[1][17][18] NOMAC-only tablets are also used as a form of progestogen-only birth control, although they are not specifically licensed as such.[20]

Available forms

NOMAC is available both alone and in combination with estrogens.[8][9] The following formulations are available:[8][9]

  • NOMAC 3.75 mg and 5 mg oral tablets (Lutenyl) – indicated for menopausal hormone therapy and gynecological disorders
  • NOMAC 3.75 mg and estradiol 1.5 mg oral tablets (Naemis) – indicated for menopausal hormone therapy
  • NOMAC 2.5 mg and estradiol 1.5 mg oral tablets (Zoely) – indicated for birth control

The availability of these formulations differs by country.[8]

Contraindications

Because NOMAC is metabolized by the liver, hepatic impairment can result in an accumulation of the medication.[21]

Side effects

The side effects of NOMAC are similar to those of other progestogens.[1] It is well tolerated and often produces no side effects.[1] Possible side effects of NOMAC include menstrual irregularities (e.g., abnormal bleeding or spotting), headache, nausea, breast tenderness, and weight gain.[1][17][22][23][14] However, body weight is generally unchanged.[1] Rarely, meningiomas have been reported in association with NOMAC.[24][25][26][27]

Overdose

There have been no reports of serious adverse effects due to overdose of NOMAC.[7] NOMAC has been administered alone at a dosage of up to 40 times the recommended dosage, and the combination of NOMAC and estradiol has been administered in multiple doses of up to 5 times the recommended dosage to women in clinical trials, and no safety concerns or harmful effects were observed in either case.[28][7] Symptoms of NOMAC and estradiol overdose might include nausea, vomiting, and, in young girls, slight vaginal bleeding.[7] There is no antidote for NOMAC overdose and treatment of overdose should be based on symptoms.[7]

Interactions

The metabolism of NOMAC is dependent on CYP3A4, so inhibitors and inducers of this enzyme such as ketoconazole and rifampicin, respectively, as well as some anticonvulsants, may pose a clinically significant drug interaction with NOMAC.[1][2] (For a list of CYP3A4 inhibitors and inducers, see here.)

Pharmacology

Pharmacodynamics

NOMAC has progestogenic activity, antigonadotropic effects, antiandrogenic activity, and no other important hormonal activity.[3]

Relative affinities (%) of nomegestrol acetate and related steroids
Compound PR AR ER GR MR SHBG CBG
Nomegestrol acetate 125 42 0 6 0 0 0
Megestrol acetate 65 5 0 30 0 0 0
Progesterone 50 0 0 10 100 0 36
Notes: Values are percentages (%). Reference ligands (100%) were promegestone for the PR, metribolone for the AR, estradiol for the ER, dexamethasone for the GR, aldosterone for the MR, dihydrotestosterone for SHBG, and cortisol for CBG. Sources: [3]

Progestogenic activity

NOMAC is a potent and pure progestogen, acting as a selective, high-affinity full agonist of the progesterone receptor (PR) (Ki = 3 nM, 67–303% of the relative binding affinity of progesterone),[29] and is said to have higher potency and substantially improved selectivity for the PR relative to medroxyprogesterone acetate (the 6-hydrogenated or non-6-7-double bonded analogue of megestrol acetate and the most widely used progestin).[4][30][31] In accordance, NOMAC is a potent antigonadotropin and exhibits no androgenic, estrogenic,[32] glucocorticoid, or antimineralocorticoid activity,[1] but does possess some antiandrogenic activity.[29][33] Due to its potent antigonadotropic activity, NOMAC has strong functional antiandrogenic and antiestrogenic effects when administered at sufficiently high doses.[1]

Like many other progestogens,[34][35] NOMAC has been assessed and found in vitro to inhibit the conversion of estrone sulfate to estrone (via inhibition of steroid sulfatase) and estrone to estradiol (via inhibition of 17β-HSD) at high concentrations (0.5–50 μM) and to stimulate the conversion of estrone into estrone sulfate (via activation of estrogen sulfotransferase activity) at low concentrations (0.05–0.5 μM), whilst not affecting aromatase activity at any tested concentration (up to 10 μM).[1][5] These activities appear to be PR-dependent, as NOMAC is more potent in producing them in PR-rich cell lines (e.g., T47-D vs. MCF-7) and they can be blocked by the PR antagonist mifepristone (RU-486).[5] Although the clinical implications of these actions are unclear and they have yet to be confirmed in vivo or assessed in clinical studies, it has been suggested that NOMAC and certain other progestins may be useful in the treatment of ER-positive breast cancer by decreasing levels of estrogens in breast tissue.[34][35] In accordance with this notion, in vitro, NOMAC does not have proliferative effects on breast tissue, does not stimulate breast cell proliferation via PGRMC1 (similarly to progesterone), and reduces the breast proliferative effects of estradiol when added to it in medium.[36]

Antigonadotropic effects

The ovulation-inhibiting dosage of NOMAC is 1.5 to 5 mg/day.[1][3][37] Due to its high antigonadotropic activity and its long elimination half-life, the contraceptive effectiveness of NOMAC is maintained even when a dose is missed; clinical studies found no increased incidence of pregnancy with one missed pill of Zoely or even with two missed pills during days 8 to 17 of the menstrual cycle.[2]

Antiandrogenic activity

NOMAC acts as an antagonist of the androgen receptor (AR), with approximately 12 to 31% of the relative binding affinity of testosterone for the AR and 42% of the affinity of metribolone for the AR.[4][31][38][3] Estimates of the antiandrogenic potency of NOMAC are mixed, ranging from 5 to 20%, 20 to 30%, and 90% of that of cyproterone acetate depending on the source.[29][33][3][39][40][41] The antiandrogenic activity of NOMAC may be useful in helping to alleviate acne, seborrhea, and other androgen-dependent symptoms in women.[2][41]

Other activity

Certain progestins have been found to stimulate the proliferation of MCF-7 breast cancer cells in vitro, an action that is independent of the classical PRs and is instead mediated via the progesterone receptor membrane component-1 (PGRMC1).[42] Progesterone and NOMAC, in contrast, act neutrally in this assay.[42] It is unclear if these findings may explain the different risks of breast cancer observed with progesterone and progestins in clinical studies.[43]

Pharmacokinetics

NOMAC is well-absorbed, with an oral bioavailability of 63%.[1] It is 97.5 to 98% protein-bound, to albumin, and does not bind to sex hormone-binding globulin or corticosteroid-binding globulin.[1] The medication is metabolized hepatically via hydroxylation by the enzymes CYP3A3, CYP3A4, and CYP2A6.[1] It has six main metabolites, all of which have no or minimal progestogenic activity.[1] The elimination half-life of NOMAC is approximately 50 hours, with a range of 30 to 80 hours.[1][2] Steady-state concentrations of NOMAC are achieved after five days of repeated administration.[1] As Zoely (2.5 mg/day NOMAC), the average circulating concentrations of NOMAC are 4.5 ng/mL at steady-state, with minimum and maximum concentrations of 3.1 ng/mL and 12.3 ng/mL, respectively.[2] The medication is eliminated via urine and feces.[1]

Chemistry

NOMAC, also known as 17α-acetoxy-6-methyl-δ6-19-norprogesterone or as 17α-acetoxy-6-methyl-19-norpregna-4,6-diene-3,20-dione, is a synthetic norpregnane steroid and a derivative of progesterone belonging to the 19-norprogesterone and 17α-hydroxyprogesterone groups.[15] NOMAC is the C17α acetate ester of nomegestrol and the 19-demethylated (or 19-nor) analogue of megestrol acetate, and can also be referred to as 19-normegestrol acetate.[15][4]

History

Nomegestrol was patented in 1975, and NOMAC, under the developmental code name TX-066, was first described in the literature in 1983.[15][16] It was developed by Theramex Laboratories, a pharmaceutical company in Monaco (a satellite country of France ).[1] The medication was first introduced in Europe alone or in combination with estradiol under the respective brand names Lutenyl and Naemis[5] for the treatment of gynecological disorders and menopausal symptoms in 1986, and was subsequently developed and approved in 2011 in Europe as a birth control pill in combination with estradiol under the brand name Zoely.[1][17][18] As Zoely, NOMAC has been studied in over 4,000 women as a method of birth control.[2]

Society and culture

Generic names

Nomegestrol acetate is the generic name of the drug and its INN, USAN, and BAN.[15][19][8] It is also known by its former developmental code name TX-066.[15][19][8]

Brand names

NOMAC is marketed in combination with estradiol as a birth control pill primarily under the brand name Zoely, in combination with estradiol for use in menopausal hormone therapy primarily under the brand name Naemis, and as a standalone medication for use in menopausal hormone therapy and the treatment of gynecological disorders primarily under the brand name Lutenyl.[8] NOMAC is also marketed alone or in combination with estradiol under a variety of other less common brand names throughout the world.[8]

Availability

Known availability of NOMAC in countries throughout the world (as of August 2018). Alone is NOMAC as a standalone medication. With E2 is in combination with estradiol. Discontinued is no longer available.

NOMAC (either alone (e.g., as Lutenyl) or in combination with estradiol (e.g., as Naemis))[5] is available for the treatment of gynecological disorders and menopausal symptoms in Argentina , Belgium, Brazil , Chile , France ,[44][45] Georgia, Hong Kong, Indonesia, Italy, Lebanon, Lithuania, Malta, Monaco, the Netherlands, Peru, Poland , Portugal, Romania, Slovakia, Taiwan, Tunisia, Turkey, and Vietnam.[8][46][47][19] As a component of birth control pills with estradiol (under the brand name Zoely), NOMAC is available in Argentina , Australia , Austria, Belgium, Chile , Colombia, Croatia, Costa Rica, Denmark , the Dominican Republic, El Salvador, Finland , France , Germany , Guatemala, Honduras, Hungary, Ireland, Israel, Italy, Latvia, Lithuania, Malaysia, Monaco, the Netherlands, New Zealand, Nicaragua, Norway , Panama, Poland , Portugal, Russia , Spain , Slovakia, Sweden, Switzerland , and the United Kingdom .[8][46][47][19] It was expected that Zoely would become available in the United States in 2010,[48] but the FDA rejected the NDA for Zoely in 2011[49] and NOMAC ultimately has not been introduced in any form in this country.[50]

Research

Under the tentative brand name Uniplant, NOMAC was under development by Theramex as a 38 mg or 55 mg 4 cm Silastic (silicone-plastic) subcutaneous birth control implant of one-year duration (75 ug/day or 100 μg/day release rate) in Brazil from the 1990s and was extensively studied for this purpose in clinical trials.[10][11][12][13] The clinical studies included 19,900 women-months of use and demonstrated a one-year failure rate of 0.94%. Uniplant was regarded as showing high effectiveness, and was well tolerated.[13] In spite of this however, "[f]urther plans to make it available have been deferred by decision of the company holding the progestin patent",[51] and, although it continued to be investigated as late as 2006,[52] the implant ultimately never became commercially available.[53][54]

Oral NOMAC was under development for the treatment of breast cancer and for use as a progestogen-only pill for birth control but did not complete development for these indications.[55] An estradiol and NOMAC vaginal ring was under development for use in birth control and to treat dysmenorrhea but did not complete development and was not marketed.[56] A continuous oral formulation of estradiol and NOMAC was under development for the treatment of menopausal symptoms and the treatment or prevention of postmenopausal osteoporosis but did not complete development.[57]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 1.23 1.24 1.25 1.26 1.27 1.28 1.29 1.30 1.31 "Nomegestrol acetate: pharmacology, safety profile and therapeutic efficacy". Drugs 70 (5): 541–559. March 2010. doi:10.2165/11532130-000000000-00000. PMID 20329803. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 "The pharmacology of nomegestrol acetate". Maturitas 71 (4): 345–353. April 2012. doi:10.1016/j.maturitas.2012.01.007. PMID 22364709. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 "Pharmacology of estrogens and progestogens: influence of different routes of administration". Climacteric 8 (Suppl 1): 3–63. August 2005. doi:10.1080/13697130500148875. PMID 16112947. 
  4. ↑ 4.0 4.1 4.2 4.3 Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. 24 January 2012. pp. 1403–. ISBN 978-1-60913-345-0. https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA1403. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 "Effect of nomegestrol acetate on estrogen biosynthesis and transformation in MCF-7 and T47-D breast cancer cells". The Journal of Steroid Biochemistry and Molecular Biology 93 (1): 1–13. January 2005. doi:10.1016/j.jsbmb.2004.11.004. PMID 15748827. 
  6. ↑ "Nomegestrol/estradiol assessment report". European Medicines Agency. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002068/WC500120841.pdf. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 "Australian Public Assessment Report for Nomegestrol acetate/oestradiol". October 2011. https://www.tga.gov.au/sites/default/files/auspar-zoely.pdf. 
  8. ↑ 8.00 8.01 8.02 8.03 8.04 8.05 8.06 8.07 8.08 8.09 8.10 8.11 "Zoely: Uses, Side Effects, Benefits/Risks". https://www.drugs.com/international/nomegestrol.html. 
  9. ↑ 9.0 9.1 9.2 "Zoely Assessment Report". Europeans Medicines Agency. 22 March 2011. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001213/WC500115833.pdf. 
  10. ↑ 10.0 10.1 "Nonmenstrual adverse events during use of implantable contraceptives for women: data from clinical trials". Contraception 65 (1): 63–74. January 2002. doi:10.1016/S0010-7824(01)00289-X. PMID 11861056. 
  11. ↑ 11.0 11.1 "Role of progestins in contraception". Acta Obstetricia et Gynecologica Scandinavica 84 (3): 207–216. March 2005. doi:10.1111/j.0001-6349.2005.00759.x. PMID 15715527. 
  12. ↑ 12.0 12.1 Contraception. John Wiley & Sons. 10 February 2011. pp. 62–. ISBN 978-1-4443-4263-5. https://books.google.com/books?id=ksjJcx1CeKcC&pg=PA62. 
  13. ↑ 13.0 13.1 13.2 "Progestins for contraception: modern delivery systems and novel formulations". Clinical Obstetrics and Gynecology 57 (4): 644–658. December 2014. doi:10.1097/GRF.0000000000000072. PMID 25314087. 
  14. ↑ 14.0 14.1 14.2 "Lutenyl Nomegestrol acetato 5 mg". http://www.teva.com.ar/productos/Documents/SmPC/LUTENYL%2003-15.pdf. 
  15. ↑ 15.0 15.1 15.2 15.3 15.4 15.5 The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. 14 November 2014. p. 883. ISBN 978-1-4757-2085-3. https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PR2. 
  16. ↑ 16.0 16.1 "The pharmacological profile of TX 066 (17 alpha-acetoxy-6-methyl-19-nor-4,6-pregna-diene-3,20-dione), a new oral progestative". Arzneimittel-Forschung 33 (5): 710–715. 1983. PMID 6683550. 
  17. ↑ 17.0 17.1 17.2 17.3 17.4 17.5 "Nomegestrol acetate/estradiol: in oral contraception". Drugs 72 (14): 1917–1928. October 2012. doi:10.2165/11208180-000000000-00000. PMID 22950535. 
  18. ↑ 18.0 18.1 18.2 18.3 18.4 "Nomegestrol acetate-17b-estradiol for oral contraception". Patient Preference and Adherence 7: 607–619. 2013. doi:10.2147/PPA.S39371. PMID 23836965. 
  19. ↑ 19.0 19.1 19.2 19.3 19.4 Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 747–. ISBN 978-3-88763-075-1. https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA747. 
  20. ↑ "Hormonal contraception in women at risk of vascular and metabolic disorders: guidelines of the French Society of Endocrinology". Annales d'Endocrinologie 73 (5): 469–487. November 2012. doi:10.1016/j.ando.2012.09.001. PMID 23078975. 
  21. ↑ "Progestogens in menopausal hormone therapy". Przeglad Menopauzalny = Menopause Review 14 (2): 134–143. June 2015. doi:10.5114/pm.2015.52154. PMID 26327902. 
  22. ↑ "Newer progestogens". The Journal of Family Planning and Reproductive Health Care 29 (1): 13–16. January 2003. doi:10.1783/147118903101197188. PMID 12626173. 
  23. ↑ "Nomegestrol acetate/estradiol: a guide to its use in oral contraception". Drugs & Therapy Perspectives 29 (1): 1–6. 2012. doi:10.1007/s40267-012-0005-9. ISSN 1172-0360. 
  24. ↑ "Spontaneous regression of meningiomas after interruption of nomegestrol acetate: a series of three patients". Acta Neurochirurgica 161 (4): 761–765. April 2019. doi:10.1007/s00701-019-03848-x. PMID 30783806. 
  25. ↑ "Combined hormonal influence of cyproterone acetate and nomegestrol acetate on meningioma: a case report". Acta Neurochirurgica 161 (3): 589–592. March 2019. doi:10.1007/s00701-018-03782-4. PMID 30666456. 
  26. ↑ "Natural history of cavernous sinus meningiomas". Journal of Neurosurgery 130 (2): 435–442. March 2018. doi:10.3171/2017.7.JNS17662. PMID 29600913. 
  27. ↑ "Actualité - Luteran (Acétate de chlormadinone) et Lutényl (Acétate de nomégestrol) et leurs génériques : Des cas de méningiome rapportés - ANSM". https://www.ansm.sante.fr/S-informer/Points-d-information-Points-d-information/Luteran-acetate-de-chlormadinone-et-Lutenyl-acetate-de-nomegestrol-et-leurs-generiques-des-cas-de-meningiome-rapportes-Point-d-information. 
  28. ↑ "NOGEST, 5 mg tablets". http://mri.cts-mrp.eu/download/BE_H_0137_001_FinalSPC.pdf. 
  29. ↑ 29.0 29.1 29.2 "Nomegestrol acetate, a novel progestogen for oral contraception". Steroids 76 (6): 531–539. May 2011. doi:10.1016/j.steroids.2011.02.002. PMID 21335021. 
  30. ↑ Women's Sexual Function and Dysfunction: Study, Diagnosis and Treatment. CRC Press. 17 November 2005. pp. 554–. ISBN 978-1-84214-263-9. https://books.google.com/books?id=3J7TnwpbZQwC&pg=PA554. 
  31. ↑ 31.0 31.1 "Potency of progestogens used in hormonal therapy: toward understanding differential actions". The Journal of Steroid Biochemistry and Molecular Biology 142: 39–47. July 2014. doi:10.1016/j.jsbmb.2013.08.001. PMID 23954501. 
  32. ↑ Breast Cancer: Prognosis, Treatment, and Prevention. CRC Press. 17 July 2002. pp. 224–. ISBN 978-0-203-90924-9. https://books.google.com/books?id=l4XLBQAAQBAJ&pg=PA224. 
  33. ↑ 33.0 33.1 "Progestogens in hormonal replacement therapy: new molecules, risks, and benefits". Menopause 9 (1): 6–15. 2002. doi:10.1097/00042192-200201000-00003. PMID 11791081. 
  34. ↑ 34.0 34.1 "Progestins and breast cancer". Gynecological Endocrinology 23 (sup1): 32–41. October 2007. doi:10.1080/09513590701585003. PMID 17943537. 
  35. ↑ 35.0 35.1 "Breast cancer and steroid metabolizing enzymes: the role of progestogens". Maturitas 65 (Suppl 1): S17–S21. December 2009. doi:10.1016/j.maturitas.2009.11.006. PMID 19962254. 
  36. ↑ "Nomegestrol acetate/estradiol hormonal oral contraceptive and breast cancer risk". Anti-Cancer Drugs 25 (7): 745–750. August 2014. doi:10.1097/CAD.0000000000000050. PMID 24346139. 
  37. ↑ "Pharmacology of Progestogens". J Reproduktionsmed Endokrinol 8 (1): 157–177. 2011. http://www.kup.at/kup/pdf/10168.pdf. 
  38. ↑ Hormone Replacement Therapy and Cardiovascular Disease: The Current Status of Research and Practice. CRC Press. 15 May 2001. pp. 94–. ISBN 978-1-84214-038-3. https://books.google.com/books?id=9vRBX0JqXiAC&pg=PA94. 
  39. ↑ "Metabolic and clinical effects of progestogens". The European Journal of Contraception & Reproductive Health Care 11 (3): 153–161. September 2006. doi:10.1080/13625180600772741. PMID 17056444. 
  40. ↑ "Role of progestins with partial antiandrogenic effects". Climacteric 7 (3): 238–254. September 2004. doi:10.1080/13697130400001307. PMID 15669548. 
  41. ↑ 41.0 41.1 "Comparative pharmacology of newer progestogens". Drugs 51 (2): 188–215. February 1996. doi:10.2165/00003495-199651020-00002. PMID 8808163. 
  42. ↑ 42.0 42.1 "Possible role of PGRMC1 in breast cancer development". Climacteric 16 (5): 509–513. October 2013. doi:10.3109/13697137.2013.800038. PMID 23758160. 
  43. ↑ "Progesterone and Breast Cancer". Endocrine Reviews 41 (2): 320–344. April 2020. doi:10.1210/endrev/bnz001. PMID 31512725. 
  44. ↑ "French hormones: progestins and therapeutic variation in France". Social Science & Medicine 60 (11): 2609–2622. June 2005. doi:10.1016/j.socscimed.2004.10.021. PMID 15814185. 
  45. ↑ "Impact of percutaneous oestradiol gels in postmenopausal hormone replacement therapy on clinical symptoms and endometrium". British Journal of Obstetrics and Gynaecology 104 (3): 305–310. March 1997. doi:10.1111/j.1471-0528.1997.tb11458.x. PMID 9091006. 
  46. ↑ 46.0 46.1 http://www.micromedexsolutions.com/micromedex2/[yes|permanent dead link|dead link}}]
  47. ↑ 47.0 47.1 "Sex hormones and their modulators". Martindale: The Complete Drug Reference (36th ed.). London: Pharmaceutical Press. 2009. p. 2119. ISBN 978-0-85369-840-1. 
  48. ↑ Comprehensive Gynecology. Elsevier Health Sciences. 21 February 2012. pp. 223–. ISBN 978-0-323-09131-2. https://books.google.com/books?id=X5KT_w6Nye8C&pg=PA223. 
  49. ↑ "FDA Turns Down Merck Birth Control Pill, Glaucoma Drug". 10 November 2011. http://www.medpagetoday.com/publichealthpolicy/fdageneral/29571. 
  50. ↑ "Drugs@FDA: FDA Approved Drug Products". United States Food and Drug Administration. http://www.accessdata.fda.gov/scripts/cder/daf/. 
  51. ↑ "Progestin implants". Steroids 65 (10–11): 681–685. 2000. doi:10.1016/S0039-128X(00)00124-0. PMID 11108876. 
  52. ↑ "Effects of a single Silastic contraceptive implant containing nomegestrol acetate (Uniplant) on endometrial morphology and ovarian function for 1 year". Contraception 74 (6): 492–497. December 2006. doi:10.1016/j.contraception.2006.07.013. PMID 17157108. http://www.repositorio.ufba.br/ri/handle/ri/6314. 
  53. ↑ "Progestin implants for female contraception". Contraception 65 (1): 15–19. January 2002. doi:10.1016/S0010-7824(01)00293-1. PMID 11861051. 
  54. ↑ "Contraceptive implants". Seminars in Reproductive Medicine 28 (2): 110–117. March 2010. doi:10.1055/s-0030-1248135. PMID 20352560. 
  55. ↑ "Nomegestrol oral". AdisInsight. Springer Nature Switzerland AG. https://adisinsight.springer.com/drugs/800010246. 
  56. ↑ "Estradiol/Nomegestrol intravaginal ring". AdisInsight. Springer Nature Switzerland AG. https://adisinsight.springer.com/drugs/800036861. 
  57. ↑ "Estradiol/Nomegestrol continuous". AdisInsight. Springer Nature Switzerland AG. https://adisinsight.springer.com/drugs/800010259. 

Further reading

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