Chemistry:High-dose estrogen

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Short description: Type of hormone therapy
High-dose estrogen
Drug class
Estradiol valerate.svg
Estradiol valerate, an estrogen which has been used as a means of HDE.
Class identifiers
SynonymsPseudopregnancy (when used in combination with a progestogen)
ATC codeG03C
Biological targetEstrogen receptors (ERα, ERβ, mERs (e.g., GPER, others))
Chemical classSteroidal; Nonsteroidal

High-dose estrogen (HDE) is a type of hormone therapy in which high doses of estrogens are given.[1] When given in combination with a high dose of a progestogen, it has been referred to as pseudopregnancy.[2][3][4][5] It is called this because the estrogen and progestogen levels achieved are in the range of the very high levels of these hormones that occur during pregnancy.[6] HDE and pseudopregnancy have been used in medicine for a number of hormone-dependent indications, such as breast cancer, prostate cancer, and endometriosis, among others.[1][7][2] Both natural or bioidentical estrogens and synthetic estrogens have been used and both oral and parenteral routes may be used.[8][9]

Medical uses

HDE and/or pseudopregnancy have been used in clinical medicine for the following indications:

The nonsteroidal estrogen diethylstilbestrol as well as other stilbestrols were previously to support pregnancy and reduce the risk of miscarriage, but subsequent research found that diethylstilbestrol was both ineffective and teratogenic.[24]

HDE should be combined with a progestogen in women with an intact uterus as unopposed estrogen, particularly at high dosages, increases the risk of endometrial hyperplasia and endometrial cancer.[25] The majority of women with an intact uterus will develop endometrial hyperplasia within a few years of estrogen treatment even with mere replacement dosages of estrogen if a progestogen is not taken concomitantly.[25] The addition of a progestogen to estrogen abolishes the increase in risk.[26]

Available forms

The following steroidal estrogens have been used in HDE therapy:[1][27][28]

As well as the following nonsteroidal estrogens (which are now little or not at all used):[27]

Progestogens that have been used in pseudopregnancy regimens include hydroxyprogesterone caproate, medroxyprogesterone acetate, and cyproterone acetate, among others.[2] Progesterone has been little-used for such purposes likely due to its poor pharmacokinetics (e.g., low oral bioavailability and short elimination half-life).[29]

Side effects

General adverse effects of HDE may include breast enlargement, breast pain and tenderness, nipple enlargement and hyperpigmentation, nausea and vomiting, headache, fluid retention, edema, melasma, hyperprolactinemia, galactorrhea, amenorrhea, reversible infertility, and others.[30] More uncommon but serious side effects may include thrombus and thrombosis (e.g., venous thromboembolism), other cardiovascular events (e.g., myocardial infarction, stroke), prolactinoma, cholestatic jaundice, gallbladder disease, and gallstones.[30] In women, HDE may cause amenorrhea and rarely endometrial hyperplasia or endometrial cancer, but the risk of adverse endometrial changes is minimized or offset with pseudopregnancy regimens due to the progestogen component. The tolerability profile of HDE is worse in men compared to women. Side effects of HDE specific to men may include gynecomastia (breast development), feminization and demasculinization in general (e.g., reduced body hair, decreased muscle mass and strength, feminine changes in fat mass and distribution, and reduced penile and testicular size), and sexual dysfunction (e.g., reduced libido and erectile dysfunction).[30]

The use of HDE in men has been associated with cellulite, which has been attributed to androgen deficiency.[31]

Pharmacology

Estrogens are agonists of the estrogen receptors (ERs), the biological target of endogenous estrogens such as estradiol. When used in high doses, estrogens are powerful antigonadotropins, strongly inhibiting secretion of the gonadotropins luteinizing hormone and follicle-stimulating hormone from the pituitary gland, and in men are able to completely suppress gonadal androgen production and reduce testosterone levels into the castrate range.[32] This is most of the basis of their use in prostate cancer and benign prostatic hyperplasia.[32][28] When estradiol or an estradiol ester is used for HDE in men, levels of estradiol of at least approximately 200 pg/mL are necessary to suppress testosterone levels into the castrate range.[33]

Synthetic and nonsteroidal estrogens like ethinylestradiol and diethylstilbestrol are resistant to hepatic metabolism and for this reason have dramatically increased local potency in the liver.[34][9][35] As a result, they have disproportionate effects on hepatic protein production and a greatly increased risk of blood clots relative to endogenous and bioidentical forms of estrogen like estradiol and estradiol esters.[36] Unlike synthetic estrogens, bioidentical estrogens are efficiently inactivated in the liver even at high dosages or high circulating levels, as in pregnancy, although changes in hepatic protein production can still occur.[34][9][35]

A study that used high- to very-high-dose oral estradiol to treat postmenopausal women with estrogen receptor-positive breast cancer found that mean steady-state estradiol levels in the 6 mg/day group were about 300 pg/mL and in the 30 mg/day group were about 2,400 pg/mL.[37] An example pseudopregnancy regimen in women which has been used in clinical studies is intramuscular injections of 40 mg/week estradiol valerate and 250 mg/week hydroxyprogesterone caproate.[3] It has been found to result in estradiol levels of about 3,100 pg/mL at 3 months of therapy and 2,500 pg/mL at 6 months of therapy.[3]

Levels of estrogen and progesterone in normal human pregnancy are very high.[6] Estradiol levels are 1,000 to 5,000 pg/mL during the first trimester, 5,000 to 15,000 pg/mL during the second trimester, and 10,000 to 40,000 pg/mL during the third trimester,[38] with a mean of 25,000 pg/mL at term and levels as high as 75,000 pg/mL measurable in some women.[39] Levels of progesterone are 10 to 50 ng/mL in the first trimester and rise to 50 to 280 ng/mL in the third trimester,[40] with a mean of around 150 ng/mL at term.[41] Although only a small fraction of estradiol and progesterone are unbound in circulation, the amounts of free and thus biologically active estradiol and progesterone increase to similarly large extents as total levels during pregnancy.[41] As such, pregnancy is a markedly hyperestrogenic and hyperprogestogenic state.[42][43] Levels of estradiol and progesterone are both up to 100-fold higher during pregnancy than during normal menstrual cycling.[44]

Pseudopregnancy simulates the hormonal profile of the first trimester of pregnancy.[45]

History

HDE has been used since the discovery and introduction of estrogens in the 1930s.[44] It was first found to be effective in the treatment of prostate cancer in 1941[46] and in the treatment of breast cancer in 1944.[1][47] HDE was the first medical therapy for prostate cancer and breast cancer.[48] Pseudopregnancy was developed in the 1950s following the introduction of progestins with improved potency and pharmacokinetics, at which time it was used to treat hypoplasia of the uterus and breasts and endometriosis.[3][4][49] In modern times, pseudopregnancy is rarely used.[4] However, studies in the mid-1990s were conducted and found it to be rapidly effective for increasing bone mineral density in women with osteopenia due to hypoestrogenism.[3][4] HDE has also commonly been used in transgender women since the 1960s.[50][51][52]

Oral HDE for prostate cancer with diethylstilbestrol was used widely in men with prostate cancer until the mid-1960s, when it was compared directly to orchiectomy and was associated with improved cancer-related mortality but worse overall survival, mainly due to previously unrecognized cardiovascular side effects.[46][53] As a result of this study, HDE for prostate cancer fell out of favor.[46] However, in recent times there has been a resurgence in interest of HDE for prostate cancer with safer, bioidentical and parenteral forms of estrogen that don't share the same risks like polyestradiol phosphate and transdermal estradiol.[54] Modern HDE for prostate cancer has a variety of advantages and benefits over conventional androgen deprivation therapy with castration, including fewer side effects like osteoporosis, hot flashes, and impairment in cognitive, emotional, and sexual domains, potentially superior quality of life, and considerable cost savings.[54] The main drawback of modern HDE for prostate cancer is a high incidence of gynecomastia of about 40 to 77%, although it is generally only mildly or modestly discomforting.[54] In addition, prophylactic irradiation of the breasts can be used to prevent it and has minimal side effects, mostly consisting of temporary skin discoloration.[54]

Following continued clinical research after the discovery of the effectiveness of HDE for breast cancer in 1944, HDE, most commonly with diethylstilbestrol and to a lesser extent ethinylestradiol, became the standard of care for the treatment of breast cancer in postmenopausal women from the early 1960s onwards.[1] In the 1970s, the antiestrogen tamoxifen was found to be effective for the treatment of breast cancer and was introduced for medical use.[1] Comparative studies found that the two therapies showed equivalent effectiveness, but that tamoxifen had reduced toxicity.[1] As a result, antiestrogen therapy became the first-line treatment for breast cancer and almost completely replaced HDE.[1] However, in the 1990s, HDE was revisited for breast cancer and was found to be effective in the treatment of women with acquired resistance to antiestrogen therapy.[1] Since then, research on HDE for breast cancer has continued, and safer, bioidentical forms of estrogen like estradiol and estradiol valerate have also been studied and found to be effective.[1] A major review was published in 2017 summarizing the literature to date.[1]

Research

Pseudopregnancy has been suggested for use in decreasing the risk of breast cancer in women, though this has not been assessed in clinical studies.[55] Natural pregnancy before the age of 20 has been associated with a 50% lifetime reduction in the risk of breast cancer.[56] Pseudopregnancy has been found to produce decreases in risk of mammary gland tumors in rodents similar to those of natural pregnancy, implicating high levels of estrogen and progesterone in this effect.[56]

See also

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 "The use of high-dose estrogens for the treatment of breast cancer". Maturitas 95: 11–23. January 2017. doi:10.1016/j.maturitas.2016.10.010. PMID 27889048. 
  2. ↑ 2.0 2.1 2.2 Victor Gomel; Andrew Brill (27 September 2010). Reconstructive and Reproductive Surgery in Gynecology. CRC Press. pp. 90–. ISBN 978-1-84184-757-3. https://books.google.com/books?id=C4TOBQAAQBAJ&pg=PA90. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 "Rapid increase in lumbar spine bone density in osteopenic women by high-dose intramuscular estrogen-progestogen injections. A preliminary report". Hormone and Metabolic Research 26 (9): 428–31. September 1994. doi:10.1055/s-2007-1001723. PMID 7835827. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 "High-dose estrogen-progestogen injections in gonadal dysgenesis, ovarian hypoplasia, and androgen insensitivity syndrome: Impact on bone density". Adolescent and Pediatric Gynecology 8 (1): 20–23. 1995. doi:10.1016/S0932-8610(12)80156-3. ISSN 0932-8610. 
  5. ↑ "The Treatment of Endometriosis by Inducing Pseudopregnancy with Ovarian Hormones". Fertility and Sterility 10 (6): 539–556. 1959. doi:10.1016/S0015-0282(16)33602-0. ISSN 0015-0282. 
  6. ↑ 6.0 6.1 Kenneth L. Becker (2001). Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. pp. 1059–1060. ISBN 978-0-7817-1750-2. https://books.google.com/books?id=FVfzRvaucq8C&pg=PA1059. 
  7. ↑ 7.0 7.1 "The evolving role of estrogen therapy in prostate cancer". Clinical Prostate Cancer 1 (2): 81–9. September 2002. doi:10.3816/cgc.2002.n.009. PMID 15046698. 
  8. ↑ 8.0 8.1 "Parenteral estrogens for prostate cancer: can a new route of administration overcome old toxicities?". Clinical Genitourinary Cancer 5 (3): 198–205. December 2006. doi:10.3816/CGC.2006.n.037. PMID 17239273. 
  9. ↑ 9.0 9.1 9.2 "Estrogen therapy and liver function--metabolic effects of oral and parenteral administration". The Prostate 14 (4): 389–95. 1989. doi:10.1002/pros.2990140410. PMID 2664738. 
  10. ↑ "Diethylstilboestrol for the treatment of prostate cancer: past, present and future". Scandinavian Journal of Urology 48 (1): 4–14. February 2014. doi:10.3109/21681805.2013.861508. PMID 24256023. 
  11. ↑ Berkowitz RS, Barbieri RL, Kistner RW, Ryan KJ (1995). Kistner's Gynecology: Principles and Practice. Mosby. p. 263. ISBN 978-0-8151-7479-0. https://books.google.com/books?id=WAdtAAAAMAAJ. "Hormonal therapy. During the past 40 years, the medical management of endometriosis has become significantly more sophisticated. In the early 1950s the high-dose estrogen regimen of Karnaky was the only available hormonal treatment for endometriosis. In the 1960s and 1970s, Kistner's "pseudopregnancy" and "progestin-only" regimens dominated the medical management of endometriosis.69 During the 1980s, danazol became the primary hormonal agent used in the treatment of endometriosis. In the 1990s the GnRH agonists have become the most frequently used drugs for the treatment of endometriosis. These advances have significantly expanded the hormonal armamentarium of the gynecologist when treating endometriosis." 
  12. ↑ "The history of DES, lessons to be learned". Pharmacy World & Science 27 (3): 139–43. June 2005. doi:10.1007/s11096-005-3663-z. PMID 16096877. 
  13. ↑ "Early-life factors, in-utero exposures and endometriosis risk: a meta-analysis". Reproductive Biomedicine Online 41 (2): 279–289. August 2020. doi:10.1016/j.rbmo.2020.04.005. PMID 32532666. 
  14. ↑ "Management of Endocrine Disease: Diagnostic and therapeutic approach of tall stature". European Journal of Endocrinology 176 (6): R339–R353. June 2017. doi:10.1530/EJE-16-1054. PMID 28274950. 
  15. ↑ "Estrogens and selective estrogen receptor modulators in acromegaly". Endocrine 54 (2): 306–314. November 2016. doi:10.1007/s12020-016-1118-z. PMID 27704479. 
  16. ↑ "Gonadal suppressive and cross-sex hormone therapy for gender dysphoria in adolescents and adults". Pharmacotherapy 34 (12): 1282–97. December 2014. doi:10.1002/phar.1487. PMID 25220381. 
  17. ↑ "High dose estrogen treatment increases bone mineral density in male-to-female transsexuals receiving gonadotropin-releasing hormone agonist in the absence of testosterone". European Journal of Endocrinology 153 (1): 107–13. July 2005. doi:10.1530/eje.1.01943. PMID 15994752. 
  18. ↑ Gunther Göretzlehner; Christian Lauritzen; Thomas Römer; Winfried Rossmanith (1 January 2012). Praktische Hormontherapie in der Gynäkologie. Walter de Gruyter. pp. 385–. ISBN 978-3-11-024568-4. https://books.google.com/books?id=TIs2WhfYzZ4C&pg=PA385. 
  19. ↑ "Hormonal breast augmentation: prognostic relevance of insulin-like growth factor-I". Gynecological Endocrinology 12 (2): 123–7. April 1998. doi:10.3109/09513599809024960. PMID 9610425. 
  20. ↑ "[Therapeutic pseudopregnancy]" (in de). Geburtshilfe und Frauenheilkunde 19: 593–604. July 1959. PMID 13853204. 
  21. ↑ "Premenstrual syndrome and premenstrual dysphoric disorder". Primary Care 29 (1): 1–12, v. March 2002. doi:10.1016/s0095-4543(03)00070-8. PMID 11856655. 
  22. ↑ "The role of estrogen therapy in postpartum psychiatric disorders: an update". CNS Spectrums 10 (12): 944–52. December 2005. doi:10.1017/s1092852900010518. PMID 16344831. 
  23. ↑ "Pharmacotherapy of postpartum psychosis". Expert Opinion on Pharmacotherapy 4 (10): 1651–8. October 2003. doi:10.1517/14656566.4.10.1651. PMID 14521476. 
  24. ↑ "Current perspective of diethylstilbestrol (DES) exposure in mothers and offspring". Reproductive Toxicology 71: 71–77. August 2017. doi:10.1016/j.reprotox.2017.04.009. PMID 28461243. 
  25. ↑ 25.0 25.1 Alfred E. Chang; Patricia A Ganz; Daniel F. Hayes; Timothy Kinsella, Harvey I. Pass, Joan H. Schiller, Richard M. Stone, Victor Strecher (8 December 2007). Oncology: An Evidence-Based Approach. Springer Science & Business Media. pp. 928–. ISBN 978-0-387-31056-5. https://books.google.com/books?id=vxh6u1-ETk0C&pg=PA928. 
  26. ↑ Rodolfo Paoletti; P.G. Crosignani; P. Kenemans; N.K. Wenger, Ann S. Jackson (11 July 2007). Women's Health and Menopause: Risk Reduction Strategies — Improved Quality of Health. Springer Science & Business Media. pp. 67–. ISBN 978-0-585-37973-9. https://books.google.com/books?id=tnnpYy_EaiEC&pg=PA67. 
  27. ↑ 27.0 27.1 Christoffel Jos van Boxtel; Budiono Santoso; I. Ralph Edwards (2008). Drug Benefits and Risks: International Textbook of Clinical Pharmacology. IOS Press. pp. 458–. ISBN 978-1-58603-880-9. https://books.google.com/books?id=xQqVbRqA2N8C&pg=PA458. 
  28. ↑ 28.0 28.1 Michael Oettel; Ekkehard Schillinger (6 December 2012). Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen. Springer Science & Business Media. pp. 540–. ISBN 978-3-642-60107-1. https://books.google.com/books?id=wBvyCAAAQBAJ&pg=PA540. 
  29. ↑ Roy G. Farquharson; Mary D. Stephenson (2 February 2017). Early Pregnancy. Cambridge University Press. pp. 259–. ISBN 978-1-107-08201-4. https://books.google.com/books?id=novcDQAAQBAJ&pg=PA259. 
  30. ↑ 30.0 30.1 30.2 Aurel Lupulescu (24 October 1990). Hormones and Vitamins in Cancer Treatment. CRC Press. pp. 40–. ISBN 978-0-8493-5973-6. https://books.google.com/books?id=VddUa-2cp-YC&pg=PA40. 
  31. ↑ "Cellulite: Etiology, Classification, Pathology, and Treatment". Aesthetic Medicine. 2012. pp. 265–272. doi:10.1007/978-3-642-20113-4_25. ISBN 978-3-642-20112-7. https://archive.org/details/aestheticmedicin00pren. 
  32. ↑ 32.0 32.1 Waun Ki Hong; American Association for Cancer Research (2010). Holland-Frei Cancer Medicine 8. PMPH-USA. pp. 753–. ISBN 978-1-60795-014-1. https://books.google.com/books?id=R0FbhLsWHBEC&pg=PA753. 
  33. ↑ "Single drug polyestradiol phosphate therapy in prostatic cancer". American Journal of Clinical Oncology 11 Suppl 2: S101-3. 1988. doi:10.1097/00000421-198801102-00024. PMID 3242384. 
  34. ↑ 34.0 34.1 "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. 
  35. ↑ 35.0 35.1 "Are all estrogens the same?". Maturitas 47 (4): 269–75. April 2004. doi:10.1016/j.maturitas.2003.11.009. PMID 15063479. 
  36. ↑ Donna Shoupe (10 February 2011). Contraception. John Wiley & Sons. pp. 79–. ISBN 978-1-4443-4263-5. https://books.google.com/books?id=ksjJcx1CeKcC&pg=PA79. 
  37. ↑ "Lower-dose vs high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: a phase 2 randomized study". JAMA 302 (7): 774–80. August 2009. doi:10.1001/jama.2009.1204. PMID 19690310. 
  38. ↑ http://www.ilexmedical.com/files/PDF/Estradiol_ARC.pdf [bare URL PDF]
  39. ↑ "Correlation of serum hormone concentrations in maternal and umbilical cord samples". Cancer Epidemiology, Biomarkers & Prevention 12 (5): 452–6. May 2003. PMID 12750241. 
  40. ↑ http://www.ilexmedical.com/files/PDF/Progesterone_ARC.pdf [bare URL PDF]
  41. ↑ 41.0 41.1 Hormones, Brain and Behavior, Five-Volume Set. Academic Press. 18 June 2002. pp. 54–. ISBN 978-0-08-053415-2. https://books.google.com/books?id=6GgHpQdk8vYC&pg=PA54. 
  42. ↑ Arthur J. Atkinson (2012). Principles of Clinical Pharmacology. Academic Press. pp. 399–. ISBN 978-0-12-385471-1. https://books.google.com/books?id=ei_TnqM5z24C&pg=PA399. 
  43. ↑ Gérard Chaouat, Olivier Sandra and Nathalie Lédée (8 November 2013). Immunology of Pregnancy 2013. Bentham Science Publishers. pp. 10–. ISBN 978-1-60805-733-7. https://books.google.com/books?id=ie4YDgAAQBAJ&pg=PA10. 
  44. ↑ 44.0 44.1 Knobil and Neill's Physiology of Reproduction. Academic Press. 15 November 2014. pp. 2289, 2386. ISBN 978-0-12-397769-4. https://books.google.com/books?id=I1ACBAAAQBAJ&pg=PA2386. 
  45. ↑ "Sterility and Infertility". Ovarian Function and its Disorders. 1981. pp. 333–345. doi:10.1007/978-94-009-8195-9_12. ISBN 978-94-009-8197-3. 
  46. ↑ 46.0 46.1 46.2 Donald Tindall; James Mohler (20 April 2009). Androgen Action in Prostate Cancer. Springer Science & Business Media. pp. 56–. ISBN 978-0-387-69179-4. https://books.google.com/books?id=L6NMZizNLMoC&pg=PA56. 
  47. ↑ Philipp Y. Maximov; Russell E. McDaniel; V. Craig Jordan (23 July 2013). Tamoxifen: Pioneering Medicine in Breast Cancer. Springer Science & Business Media. pp. 4–. ISBN 978-3-0348-0664-0. https://books.google.com/books?id=p-W5BAAAQBAJ&pg=PA4. 
  48. ↑ Bruce Chabner; Dan Louis Longo (1996). Cancer Chemotherapy and Biotherapy: Principles and Practice. Lippincott-Raven Publishers. p. 186. ISBN 978-0-397-51418-2. https://books.google.com/books?id=TZNrAAAAMAAJ. "High-dose estrogen therapy was the first medical treatment for metastatic prostate and breast carcinoma." 
  49. ↑ Eric J. Thomas; J. Rock (6 December 2012). Modern Approaches to Endometriosis. Springer Science & Business Media. pp. 221–222. ISBN 978-94-011-3864-2. https://books.google.com/books?id=AFP1CAAAQBAJ&pg=PA222. 
  50. ↑ Harry Benjamin (1966). The Transsexual Phenomenon. Julian Press. ISBN 978-0-446-82426-2. https://books.google.com/books?id=S1iHGwAACAAJ. 
  51. ↑ Dallas Denny (13 May 2013). Current Concepts in Transgender Identity. Routledge. pp. 293–. ISBN 978-1-134-82110-5. https://books.google.com/books?id=jiJMyBGmEkQC&pg=PA293. 
  52. ↑ Legato MJ (15 May 2017). Principles of Gender-Specific Medicine: Gender in the Genomic Era. Elsevier Science. pp. 96–. ISBN 978-0-12-803542-9. https://books.google.com/books?id=khATDgAAQBAJ&pg=PA96. "Oral estradiol doses are often double to quadruple that needed for postmenopausal women (i.e., 1-2mg) and higher doses may be needed for individuals with testes present (up to 4 or 8mg/day)." 
  53. ↑ "The use of estrogen therapy in men". Current Opinion in Pharmacology 3 (6): 650–4. December 2003. doi:10.1016/j.coph.2003.07.004. PMID 14644018. 
  54. ↑ 54.0 54.1 54.2 54.3 "Therapy Insight: parenteral estrogen treatment for prostate cancer--a new dawn for an old therapy". Nature Clinical Practice. Oncology 3 (10): 552–63. October 2006. doi:10.1038/ncponc0602. PMID 17019433. 
  55. ↑ "Prevention of breast cancer in premenopausal women". Journal of the National Cancer Institute. Monographs (16): 61–5. 1994. PMID 7999471. 
  56. ↑ 56.0 56.1 "Potential Mechanisms underlying the Protective Effect of Pregnancy against Breast Cancer: A Focus on the IGF Pathway". Frontiers in Oncology 6: 228. 2016. doi:10.3389/fonc.2016.00228. PMID 27833901. 




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