Ethinylestradiol/cyproterone acetate

Ethinylestradiol/cyproterone acetate (EE/CPA), also known as co-cyprindiol and sold under the brand names Diane and Diane-35 among others, is a combination of ethinylestradiol (EE), an estrogen, and cyproterone acetate (CPA), a progestin and antiandrogen, which is used as a birth control pill to prevent pregnancy in women.[2] It is also used to treat androgen-dependent conditions in women such as acne, seborrhea, excessive facial/body hair growth, scalp hair loss, and high androgen levels due to ovaries with cysts.[3][4][5][6][7][8] The medication is taken by mouth once daily for 21 days, followed by a 7-day free interval.[2]

Ethinylestradiol/cyproterone acetate
Combination of
EthinylestradiolEstrogen
Cyproterone acetateProgestogen; Antiandrogen
Clinical data
Trade namesDiane, Diane-35, others
Other namesEE/CPA; Co-cyprindiol; SHB 209 AB; SHB 209 AE; SH-81041
Routes of
administration		By mouth
Drug classEstrogen; Progestogen; Antiandrogen
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID

Medical uses

EE/CPA is used as a combined birth control pill to prevent ovulation and pregnancy in women.[2] It is also approved and used to treat androgen-dependent conditions in women such as acne, seborrhea, hirsutism, female pattern hair loss, and hyperandrogenism due to polycystic ovary syndrome.[2][3][4][5][6][7][8]

Available forms

EE/CPA comes in the form of oral tablets and contains 35 or 50 μg EE and 2 mg CPA per tablet.[2] It is taken once daily for 21 days, followed by a 7-day free interval.[2]

Side effects

Side effects of EE/CPA include dysmenorrhea (10.2%), breast tension or tenderness (6.5%), headache (5.2%), nervousness (4.4%), chloasma (4.2%), depressed mood (3.4%), decreased libido (3.1%), varicosities (2.9%), nausea (1.9%), edema (1.7%), and dizziness (1.1%).[2] The incidence of depression with EE/CPA is the same as that with other birth control pills.[9][10]

Blood clots

The risk of venous thromboembolism with EE/CPA-containing birth control pills is similar to that with EE and gestodene-, desogestrel-, and drospirenone-containing birth control pills and about 50 to 80% higher than with EE and levonorgestrel-containing birth control pills.[11][12][13][14][15] The absolute risk of venous thromboembolism with EE/CPA-containing birth control pills is about 1.2 to 9.9 per 10,000 women-years.[16]

Risk of venous thromboembolism (VTE) with hormone therapy and birth control (QResearch/CPRD)
TypeRouteMedicationsOdds ratio (95% CI)
Menopausal hormone therapyOralEstradiol alone
    ≤1 mg/day
    >1 mg/day		1.27 (1.16–1.39)*
1.22 (1.09–1.37)*
1.35 (1.18–1.55)*
Conjugated estrogens alone
    ≤0.625 mg/day
    >0.625 mg/day		1.49 (1.39–1.60)*
1.40 (1.28–1.53)*
1.71 (1.51–1.93)*
Estradiol/medroxyprogesterone acetate1.44 (1.09–1.89)*
Estradiol/dydrogesterone
    ≤1 mg/day E2
    >1 mg/day E2		1.18 (0.98–1.42)
1.12 (0.90–1.40)
1.34 (0.94–1.90)
Estradiol/norethisterone
    ≤1 mg/day E2
    >1 mg/day E2		1.68 (1.57–1.80)*
1.38 (1.23–1.56)*
1.84 (1.69–2.00)*
Estradiol/norgestrel or estradiol/drospirenone1.42 (1.00–2.03)
Conjugated estrogens/medroxyprogesterone acetate2.10 (1.92–2.31)*
Conjugated estrogens/norgestrel
    ≤0.625 mg/day CEEs
    >0.625 mg/day CEEs		1.73 (1.57–1.91)*
1.53 (1.36–1.72)*
2.38 (1.99–2.85)*
Tibolone alone1.02 (0.90–1.15)
Raloxifene alone1.49 (1.24–1.79)*
TransdermalEstradiol alone
   ≤50 μg/day
   >50 μg/day		0.96 (0.88–1.04)
0.94 (0.85–1.03)
1.05 (0.88–1.24)
Estradiol/progestogen0.88 (0.73–1.01)
VaginalEstradiol alone0.84 (0.73–0.97)
Conjugated estrogens alone1.04 (0.76–1.43)
Combined birth controlOralEthinylestradiol/norethisterone2.56 (2.15–3.06)*
Ethinylestradiol/levonorgestrel2.38 (2.18–2.59)*
Ethinylestradiol/norgestimate2.53 (2.17–2.96)*
Ethinylestradiol/desogestrel4.28 (3.66–5.01)*
Ethinylestradiol/gestodene3.64 (3.00–4.43)*
Ethinylestradiol/drospirenone4.12 (3.43–4.96)*
Ethinylestradiol/cyproterone acetate4.27 (3.57–5.11)*
Notes: (1) Nested case–control studies (2015, 2019) based on data from the QResearch and Clinical Practice Research Datalink (CPRD) databases. (2) Bioidentical progesterone was not included, but is known to be associated with no additional risk relative to estrogen alone. Footnotes: * = Statistically significant (p < 0.01). Sources: See template.

Pharmacology
Main article: Ethinylestradiol § Pharmacology of cyproterone acetate

EE is a synthetic estrogen, or an agonist of the estrogen receptors, the biological target of estrogens like estradiol.[17][4] It also has functional antiandrogenic effects by decreasing the circulating free fractions of androgens.[18] CPA is a progestin (synthetic progestogen), or an agonist of the progesterone receptors, the biological target of progestogens like progesterone.[17][4] It also acts as an antiandrogen, or as an antagonist of the androgen receptor, the biological target of androgens like testosterone and dihydrotestosterone.[17][4] However, it is thought that the antiandrogenic activity of CPA may only be significant at higher doses than are present in birth control pills.[4][19] Both EE and CPA have antigonadotropic effects and act as contraceptives in women by suppressing ovulation.[17] The antigonadotropic effects of EE and CPA also contribute to the antiandrogenic efficacy of the medication by suppressing androgen production by the ovaries.[18]

History

CPA/EE-containing birth control pills were developed by 1975[20][21] and were first introduced for medical use in 1978.[22] They originally contained 50 μg EE (Diane); subsequently, the EE dosage was decreased to 35 μg in a new "low-dose" preparation in 1986 (Diane-35).[4][23][24]

Society and culture

Generic names

Co-cyprindiol, a shortened form of combination of cyproterone acetate and ethinylestradiol, is a generic name of EE/CPA.[25][26][27] It is also known by its former developmental code names SHB 209 AB (Diane)[28][21][29] and SHB 209 AE (Diane-35).[23][24] The developmental code name SH-81041 referred to a combination of high-dose 100 mg CPA and 40–50 μg EE administered in a reverse sequential regimen.[28][20][21]

Brand names

Brand names of EE/CPA include Diane and Diane-35, as well as Adco-Fem, Alisma, Althea, Ancea, Anuar, Avancel, Axira, Bella HEXAL, Bellgyn, Bellune, Brenda-35 ED, Chloe, Clairette, Claudia, Co-Cyprindiol, Cybelle, CyEstra-35, Cypestra-35, Cyprelle, Cyprest, Cypretil, Cypretyl, Cyproderm, Cyprodiol, Cypromix, Dafne-35, Daphne, Dialider, Diane mite, Diane-35 ED, Dianette, Diclin, Dinac, Diva-35, Dixi, Dixi-35, Drina, Elestra, Elisamylan, Elleacnelle, Erika-35, Esdian, Estelle, Estelle-35, Evashine, Evépar, Evilin, Facetix, Femina, Feminac, Feminil mite, Frauline, Giane, Giane-35, Ginet, Ginette, Gynelle, Gyneplen, Gynofen, Holgyeme, Isbela, Jennifer-35, Juliet-35 ED, Juliette, Jene, Lady-Ten, Laila-35 ED, Linface, Lunar, Manoane, Midane, Mileva, Minerva, Morea sanol, Neynna, Nortin, OC-35, Selene, Sucee, Syndi, Tess, Visofid, Vreya, Xylia, Zinnia, and Zyrona.[25]

Availability
Availability of CPA in countries throughout the world (as of March 2018). Turquoise is combined with an estrogen at a low dose, dark blue is alone at a high dose, and light blue is both available.

EE/CPA is available widely throughout the world, including in Europe, North America, South America, East Asia, South Asia, Southeast Asia, and Oceania.[25] It is notably not available in the United States or Japan.[25]

See also

References
  1. https://www.ema.europa.eu/documents/psusa/cyproterone/ethinylestradiol-list-nationally-authorised-medicinal-products-psusa/00000906/202005_en.pdf
  2. https://www.bayer.ca/omr/online/diane-35-pm-en.pdf
  3. Miller JA, Jacobs HS (May 1986). "Treatment of hirsutism and acne with cyproterone acetate". Clin Endocrinol Metab. 15 (2): 373–89. doi:10.1016/S0300-595X(86)80031-7. PMID 2941191.
  4. Hammerstein, J. (1990). "Antiandrogens: Clinical Aspects". Hair and Hair Diseases. pp. 827–886. doi:10.1007/978-3-642-74612-3_35. ISBN 978-3-642-74614-7.
  5. Van der Spuy ZM, le Roux PA (2003). "Cyproterone acetate for hirsutism". Cochrane Database Syst Rev (4): CD001125. doi:10.1002/14651858.CD001125. PMID 14583927.
  6. Jing Z, Liang-Zhi X, Tai-Xiang W, Ying T, Yu-Jian J (October 2008). "The effects of Diane-35 and metformin in treatment of polycystic ovary syndrome: an updated systematic review". Gynecol. Endocrinol. 24 (10): 590–600. doi:10.1080/09513590802288242. PMID 19012104.
  7. Bitzer J, Römer T, Lopes da Silva Filho A (June 2017). "The use of cyproterone acetate/ethinyl estradiol in hyperandrogenic skin symptoms - a review". Eur J Contracept Reprod Health Care. 22 (3): 172–182. doi:10.1080/13625187.2017.1317339. PMID 28447864.
  8. Ruan X, Kubba A, Aguilar A, Mueck AO (June 2017). "Use of cyproterone acetate/ethinylestradiol in polycystic ovary syndrome: rationale and practical aspects". Eur J Contracept Reprod Health Care. 22 (3): 183–190. doi:10.1080/13625187.2017.1317735. PMID 28463030.
  9. Raudrant D, Rabe T (2003). "Progestogens with antiandrogenic properties". Drugs. 63 (5): 463–92. doi:10.2165/00003495-200363050-00003. PMID 12600226.
  10. Seaman HE, Snowball J, de Vries CS (2006). "Cyproterone Acetate + Ethinyloestradiol and the Risk of Depression". Pharmacoepidemiology and Drug Safety. 15 (S1): S25. doi:10.1002/pds.1295. ISSN 1053-8569. PMID 16986216.
  11. Martínez F, Ramírez I, Pérez-Campos E, Latorre K, Lete I (February 2012). "Venous and pulmonary thromboembolism and combined hormonal contraceptives. Systematic review and meta-analysis". Eur J Contracept Reprod Health Care. 17 (1): 7–29. doi:10.3109/13625187.2011.643836. PMID 22239262.
  12. Plu-Bureau G, Maitrot-Mantelet L, Hugon-Rodin J, Canonico M (February 2013). "Hormonal contraceptives and venous thromboembolism: an epidemiological update". Best Pract. Res. Clin. Endocrinol. Metab. 27 (1): 25–34. doi:10.1016/j.beem.2012.11.002. PMID 23384743.
  13. Stegeman BH, de Bastos M, Rosendaal FR, van Hylckama Vlieg A, Helmerhorst FM, Stijnen T, Dekkers OM (September 2013). "Different combined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis". BMJ. 347: f5298. doi:10.1136/bmj.f5298. PMC 3771677. PMID 24030561.
  14. de Bastos M, Stegeman BH, Rosendaal FR, Van Hylckama Vlieg A, Helmerhorst FM, Stijnen T, Dekkers OM (March 2014). "Combined oral contraceptives: venous thrombosis". Cochrane Database Syst Rev (3): CD010813. doi:10.1002/14651858.CD010813.pub2. PMID 24590565.
  15. Dragoman MV, Tepper NK, Fu R, Curtis KM, Chou R, Gaffield ME (June 2018). "A systematic review and meta-analysis of venous thrombosis risk among users of combined oral contraception". Int J Gynaecol Obstet. 141 (3): 287–294. doi:10.1002/ijgo.12455. PMC 5969307. PMID 29388678.
  16. Spitzer WO (December 2003). "Cyproterone acetate with ethinylestradiol as a risk factor for venous thromboembolism: an epidemiological evaluation". J Obstet Gynaecol Can. 25 (12): 1011–8. doi:10.1016/S1701-2163(16)30342-5. PMID 14663535.
  17. Kuhl H (2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration" (PDF). Climacteric. 8 Suppl 1: 3–63. doi:10.1080/13697130500148875. PMID 16112947.
  18. Ekback, Maria Palmetun (2017). "Hirsutism, What to do?" (PDF). International Journal of Endocrinology and Metabolic Disorders. 3 (3). doi:10.16966/2380-548X.140. ISSN 2380-548X.
  19. Pucci E, Petraglia F (December 1997). "Treatment of androgen excess in females: yesterday, today and tomorrow". Gynecol. Endocrinol. 11 (6): 411–33. doi:10.3109/09513599709152569. PMID 9476091.
  20. Grund E, Schmidt-Elmendorff H (November 1975). "Behandlung von Virilisierungs-Erscheinungen: vergleichende Klinische Untersuchung zweier antiandrogenwirksamer Gestagene--Cyproteronazetat, Megestrolazetat" [The treatment of virilizing syndromes. Comparative clinical studies of 2 antiandrogen-active gestagens (cyproterone acetate, megestrol acetate]. Med Welt (in German). 26 (48): 2180–7. PMID 128684.
  21. Hammerstein J, Meckies J, Leo-Rossberg I, Moltz L, Zielske F (June 1975). "Use of cyproterone acetate (CPA) in the treatment of acne, hirsutism and virilism". J. Steroid Biochem. 6 (6): 827–36. doi:10.1016/0022-4731(75)90311-8. PMID 126335.
  22. G. Plewig; A.M. Kligman (6 December 2012). ACNE and ROSACEA. Springer Science & Business Media. pp. 662, 685. ISBN 978-3-642-59715-2.
  23. Fedele L, Cavalli G, Marchini M, Carinelli S, Candiani GB (1986). "Effect of a new oral antiandrogen-estrogen combination on the endometrium: histological and ultrastructural scanning electron microscopy study". Acta Eur. Fertil. 17 (1): 9–13. PMID 3727896.
  24. Fedele L, Marchini M, Cavalli G, Baglioni A, Taccagni GL (May 1987). "Marked deciliation and insufficient secretory modification of endometrial surface during treatment with a new progestogen-estrogen combination". Contraception. 35 (5): 497–505. doi:10.1016/0010-7824(87)90086-2. PMID 3621944.
  25. "Cyproterone". Drugs.com.
  26. NADIR R. FARID; Evanthia Diamanti-Kandarakis (27 February 2009). Diagnosis and Management of Polycystic Ovary Syndrome. Springer Science & Business Media. pp. 237–. ISBN 978-0-387-09718-3.
  27. Adam Balen; Stephen Franks; Roy Homburg; Sean Kehoe (October 2010). Current Management of Polycystic Ovary Syndrome. Cambridge University Press. pp. 131–. ISBN 978-1-906985-41-7.
  28. Hammerstein, J. (1981). "Antiandrogens — Basic Concepts for Treatment". Hair Research. pp. 330–335. doi:10.1007/978-3-642-81650-5_49. ISBN 978-3-642-81652-9.
  29. Lachnitt-Fixson U, Kaufmann J (1977). "Zur bein flussung von androgenisierungsercheinungen-doppelblind. Studium eines cyproteronacetat-haltiges praparats (SHB 209 AB) gegen neogynon". Med. Klin. 72: 1922–1926.
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