HEALTH OF WOMAN. 2017.10(126):122–127

Шурпяк С. А., Пирогова В. И.
Львовский национальный медицинский университет имени Данила Галицкого

В современном мире проблема как спорадического, так и привычного невынашивания беременности не теряет актуальности. Несмотря на многочисленные исследования этиологии и патогенеза потерь беременностей, все еще остается много вопросов, на которые еще нужно найти ответы.
Целью этого системного обзора является предоставление клиницистам короткого документа, основанного на современных научных доказательствах, данных доказательной медицины и мировых клинических протоколах, в котором подытожены фактические знания о роли прогестерона в физиологии имплантации, а также сориентировано потенциальное и правильное использование прогестерона и прогестагенов для лечения недостаточности лютеиновой фазы (НЛФ) и угрозы прерывания беременности в различных клинических условиях. Поскольку в настоящее время роль прогестерона как одного из важнейших гормонов, обеспечивающих раннюю поддержку беременности, не вызывает сомнений.
Проанализированные современные данные мировых исследований свидетельствуют, что именно природный микронизированный прогестерон должен быть препаратом выбора при лечении привычного невынашивания, связанного с НЛФ.
Ключевые слова: микронизированный натуральный прогестерон, невынашивание беременности, недостаточность лютеиновой фазы, вагинальный путь введения, сублингвальный путь введения, прогестерон.

Литература

1. Nybo Anderson AM, Wohlfahrt J, Christens P, Olsen J, Melbye M. Maternal age and fetal loss: population based register linkage study. BMJ 2000;320:1708–12. https://doi.org/10.1136/bmj.320.7251.1708

2. Regan L, Braude PR, Trembath PL. Influence of past reproductive performance on risk of spontaneous abortion. BMJ 1989;299:541–5. https://doi.org/10.1136/bmj.299.6698.541; PMid:2507063 PMCid:PMC1837397

3. Nybo Anderson AM, Wohlfahrt J, Christens P, Olsen J, Melbye M. Maternal age and fetal loss: population based register linkage study. BMJ 2000;320:1708–12. https://doi.org/10.1136/bmj.320.7251.1708

4. de la Rochebrochard E, Thonneau P. Paternal age and maternal age are risk factors for miscarriage; results of amulticentre European study. Hum Reprod 2002;17:1649–56. https://doi.org/10.1093/humrep/17.6.1649; PMid:12042293

5. Clifford K, Rai R, Regan L. Future pregnancy outcome in unexplained recurrent first trimester miscarriage. HumReprod 1997;12:387–9. https://doi.org/10.1093/humrep/12.2.387

6. Wilson WA, Gharavi AE, Koike T, Lockshin MD, Branch DW, Piette JC, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum 1999;42:1309–11. https://doi.org/10.1002/1529-0131(199907)42:7<1309::AID-ANR1>3.0.CO;2-F

7. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4:295–306. https://doi.org/10.1111/j.1538-7836.2006.01753.x; PMid:16420554

8. Lyden TW, Vogt E, Ng AK, Johnson PM, Rote NS. Monoclonal antiphospholipid antibody reactivity against human placental trophoblast. J Reprod Immunol 1992;22:1–14. https://doi.org/10.1016/0165-0378(92)90002-L

9. Di Simon N, De Carolis S, Lanzone A, Ronsisvalle E, Giannice R, Caruso A. In vitro effect of antiphospholipid antibody-containing sera on basal and gona-dotrophin releasing hormone-dependent human chorionic gonadotrophin release by cultured trophoblast cells. Placenta 1995;16:75–83. https://doi.org/10.1016/0143-4004(95)90083-7

10. Sthoeger ZM, Mozes E, Tartakovsky B. Anti-cardiolipin antibodies induce pregnancy failure by impairing embryonic implantation. Proc Natl Acad Sci U S A 1993;90:6464–7. https://doi.org/10.1073/pnas.90.14.6464; PMid:8341656 PMCid:PMC46952

11. Katsuragawa H, Kanzaki H, Inoue T, Hirano T, Mori T, Rote NS. Monoclonal antibody against phosphatidylserine inhibits in vitro human trophoblastic hormone production and invasion. Biol Reprod 1997;56:50–8. https://doi.org/10.1095/biolreprod56.1.50; PMid:9002632

12. Bose P, Black S, Kadyrov M, Weissenborn U, Neulen J, Regan L, et al. Heparin and aspirin attenuate placental apoptosis in vitro: implications for early pregnancy failure. Am J Obstet Gynecol 2005;192:23–30. https://doi.org/10.1016/j.ajog.2004.09.029; PMid:15671997

13. Salmon JE, Girardi G, Holers VM. Activation of complement mediates antiphospholipid antibody-induced pregnancy loss. Lupus 2003;12:535–8. https://doi.org/10.1191/0961203303lu397oa; PMid:12892394

14. De Wolf F, Carreras LO, Moerman P, Vermylen J, Van Assche A, Renaer M. Decidual vasculopathy and extensive placental infarction in a patient with repeated thromboembolic accidents, recurrent fetal loss, and a lupus anticoagulant. Am J Obstet Gynecol 1982; 142: 829–34. https://doi.org/10.1016/S0002-9378(16)32527-3

15. Out HJ, Kooijman CD, Bruinse HW, Derksen RH. Histopathological findings in placentae from patients with intra-uterine fetal death and anti-phospholipid antibodies. Eur J Obstet Gynecol Reprod Biol 1991;41:179–86. https://doi.org/10.1016/0028-2243(91)90021-C

16. Peaceman AM, Rehnberg KA. The effect of immunoglobulin G fractions from patients with lupus anticoagulant on placental prostacyclin and thromboxane production. Am J Obstet Gynecol 1993;169:1403–6. https://doi.org/10.1016/0002-9378(93)90408-B

17. Lockwood CJ, Romero R, Feinberg RF, Clyne LP, Coster B, Hobbins JC. The prevalence and biologic significance of lupus anticoagulant and anticardiolipin antibodies in a general obstetric population. Am J Obstet Gynecol 1989;161:369–73. https://doi.org/10.1016/0002-9378(89)90522-X

18. Pattison NS, Chamley LW, McKay EJ, Liggins GC, Butler WS. Antiphospholipid antibodies in pregnancy: prevalence and clinical association. Br J Obstet Gynaecol 1993; 100: 909–13. https://doi.org/10.1111/j.1471-0528.1993.tb15105.x; PMid:8217972

19. Rai RS, Clifford K, Cohen H, Regan L. High prospective fetalloss rate in untreated pregnancies of women with recurrentmiscarriage and antiphospholipid antibodies. Hum Reprod 1995; 10: 3301–4. https://doi.org/10.1093/oxfordjournals.humrep.a135907; PMid:8822463

20. Carp H, Toder V, Aviram A, Daniely M, Mashiach S, Barkai G. Karyotype of the abortus in recurrent miscarriage. Fertil Steril 2001;75:678–82. https://doi.org/10.1016/S0015-0282(00)01801-X

21. Stephenson MD, Awartani KA, Robinson WP. Cytogenetic analysis of miscarriages from couples with recurrent miscarriage: a case–control study. Hum Reprod 2002;17:446–51. https://doi.org/10.1093/humrep/17.2.446; PMid:11821293

22. Stephenson MD, Awartani KA, Robinson WP. Cytogenetic analysis of miscarriages from couples with recurrent miscarriage: a case–control study. Hum Reprod 2002;17:446–51. https://doi.org/10.1093/humrep/17.2.446; PMid:11821293

23. Ogasawara M, Aoki K, Okada S, Suzumori K. Embryonic karyotype of abortuses in relation to the number of previous miscarriages. Fertil Steril 2000;73:300–4. https://doi.org/10.1016/S0015-0282(99)00495-1

24. Grimbizis GF, Camus M, Tarlatzis BC, Bontis JN, Devroey P. Clinical implications of uterine malformations and hysteroscopic treatment results. Hum Reprod Update 2001;7:161–74. https://doi.org/10.1093/humupd/7.2.161; PMid:11284660

25. Hanson U, Persson B, Thunell S. Relationship between haemoglobin A1C in early type 1 (insulin-dependent) diabetic pregnancy and the occurrence of spontaneousabortion and fetal malformation in Sweden. Diabetologia 1990; 33: 100–4. https://doi.org/10.1007/BF00401047; PMid:2328844

26. Mills JL, Simpson JL, Driscoll SG, Jovanovic-Peterson L, Van Allen M, Aarons JH, et al. Incidence of spontaneous abortion among normal women and insulin-dependent diabetic women whose pregnancies were identified within 21 days of conception. N Engl J Med 1988;319:1617–23. https://doi.org/10.1056/NEJM198812223192501; PMid:3200277

27. Abalovich M, Gutierrez S, Alcaraz G, Maccallini G, Garcia A, Levalle O. Overt and subclinical hypothyroidism complicating pregnancy. Thyroid 2002; 12: 63–8. https://doi.org/10.1089/105072502753451986; PMid:11838732

28. Mills JL, Simpson JL, Driscoll SG, Jovanovic-Peterson L, Van Allen M, Aarons JH, et al. Incidence of spontaneous abortion among normal women and insulin-dependent diabetic women whose pregnancies were identified within 21 days of conception. N Engl J Med 1988;319:1617–23. https://doi.org/10.1056/NEJM198812223192501; PMid:3200277

29. Abalovich M, Gutierrez S, Alcaraz G, Maccallini G, Garcia A, Levalle O. Overt and subclinical hypothyroidism complicating pregnancy. Thyroid 2002; 12: 63–8.

30. Rai R, Backos M, Rushworth F, Regan L. Polycystic ovaries and recurrent miscarriage – a reappraisal. Hum Reprod 2000;15:612–5. https://doi.org/10.1089/105072502753451986; PMid:11838732

31. Craig LB, Ke RW, Kutteh WH. Increased prevalence of insulin resistance in women with a history of recurrent pregnancy loss. Fertil Steril 2002;78:487–90. https://doi.org/10.1016/S0015-0282(02)03247-8

32. Cocksedge KA, Saravelos SH, Wang Q, Tuckerman E, Laird SM, Li TC. Does free androgen index predict subsequent pregnancy outcome in women with recurrent miscarriage? Hum Reprod 2008;23:797–802. https://doi.org/10.1093/humrep/den022; PMid:18263637

33. Regan L, Jivraj S. Infection and pregnancy loss. In: MacLean AB, Regan L, Carrington D, editors. Infection and pregnancy. London: RCOG Press; 2001. p. 291–304.

34. Practice Committee of the American Society for Reproductive Medicine. Current clinical irrelevance of luteal phase deficiency: a committee opinion. Fertil Steril. 2015;103:e27–32. https://doi.org/10.1016/j.fertnstert.2014.12.128; PMid:25681857

35. Cakmak H, Taylor HS. Implantation failure: molecular mechanisms and clinical treatment. Hum Reprod Update. 2011;17:242–53. https://doi.org/10.1093/humupd/dmq037; PMid:20729534 PMCid:PMC3039220

36. Simon C, Martin JC, Pellicer A. Paracrine regulators of implantation. Baillieres Best Pract Res Clin Obstet Gynaecol. 2000;14:815–26. https://doi.org/10.1053/beog.2000.0121; PMid:11023802

37. Strowitzki T, Germeyer A, Popovici R, von Wolff M. The human endometrium as a fertility-determining factor. Hum Reprod Update. 2006;12:617–30. https://doi.org/10.1093/humupd/dml033; PMid:16832043

38. Wang H, Dey SK. Roadmap to embryo implantation: clues from mouse models. Nat Rev Genet. 2006; 7: 185–99. https://doi.org/10.1038/nrg1808; PMid:16485018

39. Dey SK, Lim H, Das SK, Reese J, Paria BC, Daikoku T, et al. Molecular cues to implantation. Endocr Rev. 2004;25:341–73. https://doi.org/10.1210/er.2003-0020; PMid:15180948

40. Zapantis G, Szmyga MJ, Rybak EA, Meier UT. Premature formation of nucleolar channel systems indicates advanced endometrial maturation following controlled ovarian hyperstimulation. Hum Reprod. 2013;28:3292–300. https://doi.org/10.1093/humrep/det358; PMid:24052503 PMCid:PMC3895983

41. Druckmann R, Druckmann MA. Progesterone and the immunology of pregnancy. J Steroid Biochem Mol Biol. 2005;97:389–96. https://doi.org/10.1016/j.jsbmb.2005.08.010; PMid:16198558

42. Szekeres-Bartho J, Wilczynski JR, Basta P, Kalinka J. Role of progesterone and progestin therapy in threatened abortion and preterm labour. Front Biosci. 2008;13:1981–90. https://doi.org/10.2741/2817; PMid:17981685

43. Simoncini T, Caruso A, Garibaldi S, Fu XD, Giretti MS, Baldacci C, et al. Activation of nitric oxide synthesis in human endothelial cells using nomegestrol acetate. Obstet Gynecol. 2006;108:969–78. https://doi.org/10.1097/01.AOG.0000233184.64531.84; PMid:17012461

44. Hill MJ, Whitcomb BW, Lewis TD, Wu M, Terry N, DeCherney AH, et al. Progesterone luteal support after ovulation induction and intrauterine insemination: a systematic review and meta-analysis. Fertil Steril. 2013; 100: 1373–80. https://doi.org/10.1016/j.fertnstert.2013.07.1028; https://doi.org/10.1016/j.fertnstert.2013.06.034; PMid:23876537

45. Csapo AI, Pulkkinen MO, Wiest WG. Effects of luteectomy and progesterone replacement therapy in early pregnant patients. Am J Obstet Gynecol. 1973;115:759–65. https://doi.org/10.1016/0002-9378(73)90517-6

46. Filicori M, Flamigni C, Meriggiola MC, Ferrari P, Michelacci L, Campaniello E, et al. Endocrine response determines the clinical outcome of pulsatile gonadotropin-releasing hormone ovulation induction in different ovulatory disorders. J Clin Endocrinol Metab. 1991;72:965–72. https://doi.org/10.1210/jcem-72-5-965; PMid:1902487

47. Homer HA, Li TC, Cooke ID. The septate uterus: a review of management and reproductive outcome. Fertil Steril. 2000;73:1–14. https://doi.org/10.1016/S0015-0282(99)00480-X

48. Afifi K, Anand S, Nallapeta S, Gelbaya TA. Management of endometrial polyps in subfertile women: a systematic review. Eur J Obstet Gynecol Reprod Biol. 2010;151:117–21. https://doi.org/10.1016/j.ejogrb.2010.04.005; PMid:20430512

49. Pritts EA, Parker WH, Olive DL. Fibroids and infertility: an updated systematic review of the evidence. Fertil Steril. 2009;91:1215–23. https://doi.org/10.1016/j.fertnstert.2008.01.051; PMid:18339376

50. Johnson N, van Voorst S, Sowter MC, Strandell A, Mol BW. Surgical treatment for tubal disease in women due to undergo in vitro fertilisation. Cochrane Database Syst Rev. 2010; doi: 10.1002/14651858. https://doi.org/10.1002/14651858

51. Duffy JM, Arambage K, Correa FJ, Olive D, Farquhar C, Garry R, et al. Laparoscopic surgery for endometriosis. Cochrane Database Syst Rev. 2014; https://doi.org/10.1002/14651858..

52. Noyes RW, Haman JO. Accuracy of endometrial dating; correlation of endometrial dating with basal body temperature and menses. Fertil Steril. 1953;4:504–17. https://doi.org/10.1016/S0015-0282(16)31446-7

53. Nikas G. Pinopodes as markers of endometrial receptivity in clinical practice. Hum Reprod. 1999;14:99–106. https://doi.org/10.1093/humrep/14.suppl_2.99; PMid:10690805

54. Sharkey AM, Smith SK. The endometrium as a cause of implantation failure. Best Pract Res Clin Obstet Gynaecol. 2003;17:289–307. https://doi.org/10.1016/S1521-6934(02)00130-X

55. Lessey BA, Killam AP, Metzger DA, Haney AF, Greene GL, McCarty Jr KS. Immunohistochemical analysis of human uterine estrogen and progesterone receptors throughout the menstrual cycle. J Clin Endocrinol Metab. 1988;67:334–40. https://doi.org/10.1210/jcem-67-2-334; PMid:2455728

56. Shoupe D, Mishell Jr DR, Lacarra M, Lobo RA, Horenstein J, D’Ablaing G, et al. Correlation of endometrial maturation with four methods of estimating day of ovulation. Obstet Gynecol. 1989;73:88–92. https://doi.org/10.1097/00006254-198910000-00018; https://doi.org/10.1097/00006250-198906000-00036

57. Lindhard A, Ravn V, Bentin-Ley U, Horn T, Bangsboell S, Rex S, et al. Ultrasound characteristics and histological dating of the endometrium in a natural cycle in infertile women compared with fertile controls. Fertil Steril. 2006;86:1344–55. https://doi.org/10.1016/j.fertnstert.2006.03.052; PMid:16978615

58. Ng EH, Chan CC, Tang OS, Yeung WS, Ho PC. Changes in endometrial and subendometrial blood flow in IVF. Reprod Biomed Online. 2009; 18: 269–75. https://doi.org/10.1016/S1472-6483(10)60265-9

59. Talbi S, Hamilton AE, Vo KC, Tulac S, Overgaard MT, Dosiou C, et al. Molecular phenotyping of human endometrium distinguishes menstrual cycle phases and underlying biological processes in normo-ovulatory women. Endocrinol. 2006;147:1097–121. https://doi.org/10.1210/en.2005-1076; PMid:16306079

60. Jordan J, Craig K, Clifton DK, Soules MR. Luteal phase defect: the sensitivity and specificity of diagnostic methods in common clinical use. Fertil Steril. 1994;62:54–62. https://doi.org/10.1016/S0015-0282(16)56815-0

61. Filicori M, Butler JP, Crowley Jr WF. Neuroendocrine regulation of the corpus luteum in the human. Evidence for pulsatile progesterone secretion. J Clin Invest. 1984;73:1638–47. https://doi.org/10.1172/JCI111370; PMid:6427277 PMCid:PMC437074

62. McGovern PG, Myers ER, Silva S, Coutifaris C, Carson SA, Legro RS, et al. Absence of secretory endometrium after false-positive home urine luteinizing hormone testing. Fertil Steril. 2004;82:1273–7. https://doi.org/10.1016/j.fertnstert.2004.03.070; PMid:15533341

63. Lessey BA. Assessment of endometrial receptivity. Fertil Steril. 2011; 96: 522–9. https://doi.org/10.1016/j.fertnstert.2011.07.1095; PMid:21880273

64. Haouzi D, Assou S, Mahmoud K, Tondeur S, Rиme T, Hedon B, et al. Gene expression profile of human endometrial receptivity: comparison between natural and stimulated cycles for the same patients. Hum Reprod. 2009;24:1436–45. https://doi.org/10.1093/humrep/dep039 PMid:19246470 PMCid:PMC2871799

65. Tapia-Pizarro A, Figueroa P, Brito J, Marнn JC, Munroe DJ, Croxatto HB. Endometrial gene expression reveals compromised progesterone signaling in women refractory to embryo implantation. Reprod Biol Endocrinol. 2014;12:92. https://doi.org/10.1186/1477-7827-12-92; PMid:25248672 PMCid:PMC4181418

66. Anteby EY, Natanson-Yaron S, Hamani Y, Sciaki Y, Goldman-Wohl D, Greenfield C, et al. Fibroblast growth factor-10 and fibroblast growth factor receptors 1–4: expression and peptide localization in human decidua and placenta. Eur J Obstet Gynecol Reprod Biol. 2005;119:27–35. https://doi.org/10.1016/j.ejogrb.2004.05.014; PMid:15734081

67. Sak ME, Gul T, Evsen MS, Soydinc HE, Sak S, Ozler A, et al. Fibroblast growth factor-1 expression in the endometrium of patients with repeated implantation failure after in vitro fertilization. Eur Rev Med Pharmacol Sci. 2013;17:398–402. PMid:23426545

68. National Collaborating Centre for Women’s and Children’s Health (UK). Fertility: Assessment and Treatment for People with Fertility Problems. London (UK): RCOG Press; 2004. National Institute for Health and Clinical Excellence: Guidance.

69. Guzick DS, Zeleznik A. Efficacy of clomiphene citrate in the treatment of luteal phase deficiency: quantity versus quality of preovulatory follicles. Fertil Steril. 1990; 54(2):206–10. PubMed: 2379621. https://doi.org/10.1016/S0015-0282(16)53690-5

70. Katz Z, Lancet M, Skornik J, et al. Teratogenicity of progestogens given during the first trimester of pregnancy. Obstet Gynecol Surv. 1985; 40(11): 697–8. https://doi.org/10.1097/00006254-198511000-00016

71. Murray DL, Reich L, Adashi EY. Oral clomiphene citrate and vaginal progesterone suppositories in the treatment of luteal phase dysfunction: a comparative study. Fertil Steril. 1989; 51(1):35–41. [PubMed: 2910717]. https://doi.org/10.1016/S0015-0282(16)60424-7

72. Daya S. Efficacy of progesterone support for pregnancy in women with recurrent miscarriage. A meta-analysis of controlled trials. Br J Obstet Gynaecol. 1989; 96(3):275–80. [PubMed: 2653415]. https://doi.org/10.1111/j.1471-0528.1989.tb02386.x; PMid:2653415.

73. Vaisbuch E, de Ziegler D, Leong M, et al. Luteal-phase support in assisted reproduction treatment: real-life practices reported worldwide by an updated website-based survey. Reprod Biomed Online. 2014; 28(3):330–5. https://doi.org/10.1016/j.rbmo.2013.10.022; PMid:24447959.

74. Miles RA, Paulson RJ, Lobo RA, et al. Pharmacokinetics and endometrial tissue levels of progesterone after administration by intramuscular and vaginal routes: a comparative study. Fertil Steril. 1994; 62(3):485–90. [PubMed: 8062942]. https://doi.org/10.1016/S0015-0282(16)56935-0

75. Doody KJ, Schnell VL, Foulk RA, et al. Endometrin for luteal phase support in a randomized, controlled, open-label, prospective in-vitro fertilization trial using a combination of Menopur and Bravelle for controlled ovarian hyperstimulation. Fertil Steril. 2009; 91(4):1012–7. https://doi.org/10.1016/j.fertnstert.2008.01.069; PMid:18371963.

76. Mary D. Stephenson, M.D.,Dana McQueen, M.D., M.A.S.Michelle Winter, M.D., Harvey J. Kliman, M.D., Ph.D. “Luteal start vaginal micronized progesterone improves pregnancy success in women with recurrent pregnancy loss” Fertility and Sterility, March 2017 Volume 107, Issue 3, Pages 684–690.e2. https://doi.org/10.1016/j.fertnstert.2016.11.029; PMid:28081870