Андростендион как потенциальный предиктор овариального ответа в программах вспомогательных репродуктивных технологий
Андростендион как потенциальный предиктор овариального ответа в программах вспомогательных репродуктивных технологий
Бурдули А.Г., Кициловская Н.А., Сухова Ю.В. и др. Андростендион как потенциальный предиктор овариального ответа в программах вспомогательных репродуктивных технологий. Гинекология. 2020; 22 (1): e. 38. DOI: 10.26442/20795696.2020.1.200010
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Burduli A.G., Kitsilovskaya N.A., Sukhova Yu.V. et al. Androstenedione as a potential predictor of ovarian response in assisted reproductive technology programs. Gynecology. 2020; 22 (1): e. 38.
DOI: 10.26442/20795696.2020.1.200010
Андростендион как потенциальный предиктор овариального ответа в программах вспомогательных репродуктивных технологий
Бурдули А.Г., Кициловская Н.А., Сухова Ю.В. и др. Андростендион как потенциальный предиктор овариального ответа в программах вспомогательных репродуктивных технологий. Гинекология. 2020; 22 (1): e. 38. DOI: 10.26442/20795696.2020.1.200010
________________________________________________
Burduli A.G., Kitsilovskaya N.A., Sukhova Yu.V. et al. Androstenedione as a potential predictor of ovarian response in assisted reproductive technology programs. Gynecology. 2020; 22 (1): e. 38.
DOI: 10.26442/20795696.2020.1.200010
Цель. Оценить возможность использования уровня андростендиона в сыворотке крови и фолликулярной жидкости для прогнозирования овариального ответа
в программах вспомогательных репродуктивных технологий и провести сравнительный анализ результатов, полученных 2 методами – иммунохемилюминесцентного анализа (ИХЛА) и высокоэффективной жидкостной хроматографии с масс-спектрометрией (ВЭЖХ-МС/МС). Материалы и методы. В проспективное исследование были включены 55 супружеских пар, проходивших лечение в рамках программы экстракорпорального оплодотворения/интрацитоплазматической инъекции сперматозоида и переноса эмбрионов. Пациенток разделили на 3 группы в зависимости от ответа яичников на овариальную стимуляцию: 1-я – 1–3 ооцита (n=4), 2-я – 4–9 ооцитов (n=27), 3-я – свыше 10 ооцитов (n=24). Определение уровня андростендиона осуществляли в сыворотке крови, полученной в день проведения трансвагинальной пункции яичников, и в образцах фолликулярной жидкости на базе лабораторий ФГБУ «НМИЦ АГП им. акад. В.И. Кулакова» с использованием ИХЛА и метода ВЭЖХ-МС/МС. Результаты. Уровень андростендиона в сыворотке крови в день проведения трансвагинальной пункции яичников, определенный методом ВЭЖХ-МС/МС, повышался по мере увеличения числа полученных ооцитов. Метод ИХЛА позволил выявить разницу в концентрации андростендиона между группами с полученным числом ооцитов менее 3 и более 10. При этом уровень андростендиона, определенный с помощью ИХЛА, достоверно различался между группами пациенток (р<0,05). Сравнение уровня андростендиона в сыворотке крови, определенного ИХЛА и ВЭЖХ-МС/МС, показало высокие корреляции между значениями [ρ=0,73 (р<0,001)], что позволяет равноценно применять оба метода с учетом имеющейся оснащенности клинической базы. Заключение. Предикция ответа яичников на овариальную стимуляцию является важным этапом программ вспомогательных репродуктивных технологий. Определение концентрации андростендиона в сыворотке крови в день проведения трансвагинальной пункции яичников на основе высокоспецифичных методов (ИХЛА и ВЭЖХ-МС/МС) может быть использовано в прогнозировании степени овариального ответа наряду с традиционной оценкой овариального резерва на основании определения уровня антимюллерова гормона в раннюю фолликулярную фазу менструального цикла.
Ключевые слова: овариальный ответ, программа вспомогательных репродуктивных технологий, фолликулярная жидкость, стероидные гормоны, андростендион, высокоэффективная жидкостная хроматография с масс-спектрометрией, иммунохемилюминесцентный анализ.
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Aim. To assess the possibility of using androstenedione levels in blood serum and follicular fluid to predict ovarian response in assisted reproductive technology programs and to conduct a comparative analysis of the results obtained by 2 methods – chemiluminescent immunoassay (CLIA) and high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS). Materials and methods. A prospective study included 55 couples who received in vitro fertilization/intracytoplasmic sperm injection and embryo transfer program therapy. The patients were divided into 3 groups depending on the ovarian response to stimulation: 1st (1–3 oocytes, n=4), 2nd (4–9 oocytes, n=27), 3rd (over 10 oocytes, n=24). Androstenedione levels were measured in blood serum obtained on the day of transvaginal ovarian puncture and in follicular fluid samples with CLIA and HPLC-MS/ MS methods at the laboratories of Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology. Results. On the day of transvaginal ovarian puncture, the serum androstenedione levels, which were measured by HPLC-MS/MS, were increasing with an increase of the number of oocytes obtained. The CLIA method revealed a difference in the androstenedione levels between the groups with the number of oocytes obtained of less than
3 and more than 10. Moreover, the androstenedione levels measured by CLIA were significantly different between the patient groups (p<0.05).
Comparison of serum androstenedione levels measured by CLIA and HPLC-MS/MS, showed high correlations between the values [ρ= 0.73 (p<0.001)], which makes it possible to use both methods equally, given the existing equipment of the clinical base. Conclusion. Prediction of ovarian response to stimulation is an important step in assisted reproductive technology programs. Measuring androstenedione concentration in blood serum on the day of transvaginal ovarian puncture with highly specific methods (CLIA and HPLC-MS/MS) can be used to predict the degree of ovarian response along with the traditional assessment of the ovarian reserve based on determining anti-Mullerian hormone levels in the early follicular phase of the menstrual cycle. Key words: ovarian response, assisted reproductive technology program, follicular fluid, steroid hormones, androstenedione, high-performance liquid chromatography-mass spectrometry, chemiluminescent immunoassay.
1. Van Loendersloot LL, van Wely M, Limpens J et al. Predictive factors in in vitro fertilization (IVF): a systematic review and meta-analysis. Hum Reprod Update 2010; 16 (Issue 6): 577–89.
2. Conforti A, Cariati F, Vallone R et al. Individualization of treatment in controlled ovarian stimulation: myth or reality? Biochim Clin 2017; 41: 294–305.
3. Sunkara SK, Rittenberg V, Raine-Fenning N et al. Association between the number of eggs and live birth in IVF treatment: an analysis of 400 135 treatment cycles. Hum Reprod 2011; 26: 1768–74.
4. Alviggi C, Andersen CY, Buehler K et al. Poseidon Group (Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number). A new more detailed stratification of low responders to ovarian stimulation: from a poor ovarian response to a low prognosis concept. Fertil Steril 2016; 105: 1452–3.
5. Conforti, A, Esteves SC, Picarelli S et al. Novel approaches for diagnosis and management of low prognosis patients in assisted reproductive technology: the POSEIDON concept. Panminerva Medica 2019; 61 (1). DOI: 10.23736/s0031-0808.18.03511-5
6. Baker VL, Brown MB, Luke B, Conrad KP. Association of number of retrieved oocytes with live birth rate and birth weight: an analysis of 231,815 cycles of in vitro fertilization. Fertil Steril 2015; 103: 931–938e932.
7. Drakopoulos P, Blockeel C, Stoop D et al. Conventional ovarian stimulation and single embryo transfer for IVF/ICSI. How many oocytes do we need to maximize cumulative live birth rates after utilization of all fresh and frozen embryos? Hum Reprod 2016, dev316. DOI: 10.1093/humrep/dev316
8. Riccetti L, De Pascali F, Gilioli L et al. Genetics of gonadotropins and their receptors as markers of ovarian reserve and response in controlled ovarian stimulation. Best Pract Res Clin Obstet Gynaecol 2017; 44: 15–25. DOI: 10.1016/j.bpobgyn.2017.04.002
9. Conforti A, Alfano S, De Rosa P et al. The role of gonadotropin polymorphisms and their receptors in assisted reproductive technologies and controlled ovarian stimulation: A prospective observational study. Ital J Gynaecol Obstet 2017; 29: 15–21.
10. Alviggi C, Guadagni R, Conforti A et al. Association between intrafollicular concentration of benzene and outcome of controlled ovarian stimulation in IVF/ICSI cycles: a pilot study. J Ovarian Res 2014; 7: 67.
11. Alviggi C, Conforti A, Esteves SC et al. International Collaborative Group for the Study of r-hLH (iCOSLH). Recombinant luteinizing hormone supplementation in assisted reproductive technology: a systematic review. Fertil Steril 2018; 109: 644–64.
12. Мамедова Н.Р. Роль экзогенного ЛГ в фолликуло- и оогенезе при проведении программ вспомогательной репродукции. Автореф. … дис. канд. мед. наук. 2012 г.
[Mamedova N.R. Rol' ekzogennogo LG v follikulo- i oogeneze pri provedenii programm vspomogatel'noi reproduktsii. Avtoref. … dis. kand. med. nauk. Moscow, 2012 (in Russian).]
13. Ferraretti AP, Gianaroli L, Magli MC et al. Exogenous luteinizing hormone in controlled ovarian hyperstimulation for assisted reproduction techniques. Fertil Steril 2004; 82: 1521–6.
14. De Placido G, Alviggi C, Perino A et al. Recombinant human LH supplementation versus recombinant human FSH (rFSH) step-up protocol during controlled ovarian stimulation in normogonadotrophic women with initial inadequate ovarian response to rFSH. A multicentre, prospective, randomized controlled trial. Hum Reprod 2005; 20: 390–6.
15. Falck B. Site of production of oestrogen in rat ovary as studied in micro-transplants. Acta Physiol Scand (Suppl.) 1959; 47: 1–101.
16. Bosch E, Labarta E, Crespo J et al. Impact of luteinizing hormone administration on gonadotropin-releasing hormone antagonist cycles: an age-adjusted analysis. Fertil Steril 2011; 95: 1031–6.
17. Davison SL, Bell R, Donath S et al. Androgen levels in adult females: changes with age, menopause, and oophorectomy. J Clin Endocrinol Metab 2005; 90: 3847–53.
18. Welt CK, Jimenez Y, Sluss PM et al. Control of estradiol secretion in reproductive aging. Hum Reprod 2006; 21: 2189–93.
19. Venetis CA, Kolibianakis EM, Tarlatzi TB, Tarlatzis BC. Evidence-based management of poor ovarian response. Ann N Y Acad Sci 2010; 1205: 199–206.
20. Lebbe M, Woodruff TK. Involvement of androgens in ovarian health and disease. Mol Hum Reprod 2013; 19: 828–83.
21. Maninger N, Wolkowitz OM, Reus VI et al. Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). Front Neuroendocrinol 2009; 30 (1): 65–91. DOI: 10.1016/j.yfrne.2008.11.002
22. Longcope C, Franz C, Morello C et al. Steroid and gonadotropin levels in women during the peri-menopausal years. Maturitas 1986; 8: 189–96.
23. Goswami M, Nikolaou D. Is AMH Level, Independent of Age, a Predictor of Live Birth in IVF? J Hum Reprod Sci 2017; 10 (1): 24–30.
24. Kedem-Dickman A, Maman E, Yung Y et al. Anti-Mullerian hormone is highly expressed and secreted from cumulus granulosa cells of stimulated preovulatory immature and atretic oocytes. Reprod BioMed Online 2012; 24 (5): 540–6.
25. Frattarelli JL, Gerber MD. Basal and cycle androgen levels correlate with in vitro fertilization stimulation parameters but do not predict pregnancy outcome. Fertil Steril 2006; 86: 51–7.
26. Ferrario M, Secomandi R, Cappato M et al. Ovarian and adrenal androgens may be useful markers to predict oocyte competence and embryo development in older women. Gynecol Endocrinol 2015; 31 (2): 125–30. DOI: 10.3109/09513590.2014.964639
27. Taketsuru H, Hirao Y, Takenouchi N et al. Effect of androstenedione on the growth and meiotic competence of bovine oocytes from early antral follicles. Zygote 2012; 20: 407–15.
28. Kushnir M, Naessen T, Wanggren K et al. Exploratory study of the association of steroid profiles in stimulated ovarian follicular fluid with outcomes of IVF treatment. J Steroid Biochem Mol Biol 2016; 162: 126–33.
29. Walters K, Eid S, Edwards M et al. Steroid profiles by liquid chromatography-mass spectrometry of matched serum and single dominant ovarian follicular fluid from women undergoing IVF. Reprod BioMed Online 2018. DOI: 10.1016/j.rbmo.2018.10.006
30. Малышева Н.М., Колесникова Г.С., Иоутси В.А. и др. Сравнительный анализ результатов определения тестостерона в сыворотке крови на анализаторах Architect и Vitros и методом высокоэффективной жидкостной хроматографии – тандемной масс-спектрометрии. Клин. лабораторная диагностика. 2017; 10.
[Malysheva N.M., Kolesnikova G.S., Ioutsi V.A. et al. Sravnitel'nyi analiz rezul'tatov opredeleniia testosterona v syvorotke krovi na analizatorakh Architect i Vitros i metodom vysokoeffektivnoi zhidkostnoi khromatografii – tandemnoi mass-spektrometrii. Klin. laboratornaia diagnostika. 2017; 10 (in Russian).]
31. Handelsman D. Mass spectrometry, immunoassay and valid steroid measurements in reproductive medicine and science. Hum Reprod 2017; 32: 1147–50.
32. McCartney CR, Burt Solorzano CM, Patrie JT et al. Estimating testosterone concentrations in adolescent girls: Comparison of two direct immunoassays to liquid chromatography-tandem mass spectrometry. Steroids. 2018. 140. 10.1016/j.steroids.2018.09.001.
33. Abide Yayla, C, Ozkaya E, Kayatas Eser S et al. Association of basal serum androgen levels with ovarian response and ICSI cycle outcome.
Ir J Med Sci 2018; 187: 409.
34. De los Santos MJ, García-Laez V, Beltrán D et al. The follicular hormonal profile in low-responder patients undergoing unstimulated cycles: is it hypoandrogenic? Hum Reprod 2013; 28 (Issue 1): 224–9.
35. Zhang M, Niu W, Wang Y et al. Dehydroepiandrosterone treatment in women with poor ovarian response undergoing IVF or ICSI: a systematic review and meta-analysis. J Assist Reprod Genet 2016 33: 981–91.
________________________________________________
1. Van Loendersloot LL, van Wely M, Limpens J et al. Predictive factors in in vitro fertilization (IVF): a systematic review and meta-analysis. Hum Reprod Update 2010; 16 (Issue 6): 577–89.
2. Conforti A, Cariati F, Vallone R et al. Individualization of treatment in controlled ovarian stimulation: myth or reality? Biochim Clin 2017; 41: 294–305.
3. Sunkara SK, Rittenberg V, Raine-Fenning N et al. Association between the number of eggs and live birth in IVF treatment: an analysis of 400 135 treatment cycles. Hum Reprod 2011; 26: 1768–74.
4. Alviggi C, Andersen CY, Buehler K et al. Poseidon Group (Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number). A new more detailed stratification of low responders to ovarian stimulation: from a poor ovarian response to a low prognosis concept. Fertil Steril 2016; 105: 1452–3.
5. Conforti, A, Esteves SC, Picarelli S et al. Novel approaches for diagnosis and management of low prognosis patients in assisted reproductive technology: the POSEIDON concept. Panminerva Medica 2019; 61 (1). DOI: 10.23736/s0031-0808.18.03511-5
6. Baker VL, Brown MB, Luke B, Conrad KP. Association of number of retrieved oocytes with live birth rate and birth weight: an analysis of 231,815 cycles of in vitro fertilization. Fertil Steril 2015; 103: 931–938e932.
7. Drakopoulos P, Blockeel C, Stoop D et al. Conventional ovarian stimulation and single embryo transfer for IVF/ICSI. How many oocytes do we need to maximize cumulative live birth rates after utilization of all fresh and frozen embryos? Hum Reprod 2016, dev316. DOI: 10.1093/humrep/dev316
8. Riccetti L, De Pascali F, Gilioli L et al. Genetics of gonadotropins and their receptors as markers of ovarian reserve and response in controlled ovarian stimulation. Best Pract Res Clin Obstet Gynaecol 2017; 44: 15–25. DOI: 10.1016/j.bpobgyn.2017.04.002
9. Conforti A, Alfano S, De Rosa P et al. The role of gonadotropin polymorphisms and their receptors in assisted reproductive technologies and controlled ovarian stimulation: A prospective observational study. Ital J Gynaecol Obstet 2017; 29: 15–21.
10. Alviggi C, Guadagni R, Conforti A et al. Association between intrafollicular concentration of benzene and outcome of controlled ovarian stimulation in IVF/ICSI cycles: a pilot study. J Ovarian Res 2014; 7: 67.
11. Alviggi C, Conforti A, Esteves SC et al. International Collaborative Group for the Study of r-hLH (iCOSLH). Recombinant luteinizing hormone supplementation in assisted reproductive technology: a systematic review. Fertil Steril 2018; 109: 644–64.
12. Mamedova N.R. Rol' ekzogennogo LG v follikulo- i oogeneze pri provedenii programm vspomogatel'noi reproduktsii. Avtoref. … dis. kand. med. nauk. Moscow, 2012 (in Russian).
13. Ferraretti AP, Gianaroli L, Magli MC et al. Exogenous luteinizing hormone in controlled ovarian hyperstimulation for assisted reproduction techniques. Fertil Steril 2004; 82: 1521–6.
14. De Placido G, Alviggi C, Perino A et al. Recombinant human LH supplementation versus recombinant human FSH (rFSH) step-up protocol during controlled ovarian stimulation in normogonadotrophic women with initial inadequate ovarian response to rFSH. A multicentre, prospective, randomized controlled trial. Hum Reprod 2005; 20: 390–6.
15. Falck B. Site of production of oestrogen in rat ovary as studied in micro-transplants. Acta Physiol Scand (Suppl.) 1959; 47: 1–101.
16. Bosch E, Labarta E, Crespo J et al. Impact of luteinizing hormone administration on gonadotropin-releasing hormone antagonist cycles: an age-adjusted analysis. Fertil Steril 2011; 95: 1031–6.
17. Davison SL, Bell R, Donath S et al. Androgen levels in adult females: changes with age, menopause, and oophorectomy. J Clin Endocrinol Metab 2005; 90: 3847–53.
18. Welt CK, Jimenez Y, Sluss PM et al. Control of estradiol secretion in reproductive aging. Hum Reprod 2006; 21: 2189–93.
19. Venetis CA, Kolibianakis EM, Tarlatzi TB, Tarlatzis BC. Evidence-based management of poor ovarian response. Ann N Y Acad Sci 2010; 1205: 199–206.
20. Lebbe M, Woodruff TK. Involvement of androgens in ovarian health and disease. Mol Hum Reprod 2013; 19: 828–83.
21. Maninger N, Wolkowitz OM, Reus VI et al. Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). Front Neuroendocrinol 2009; 30 (1): 65–91. DOI: 10.1016/j.yfrne.2008.11.002
22. Longcope C, Franz C, Morello C et al. Steroid and gonadotropin levels in women during the peri-menopausal years. Maturitas 1986; 8: 189–96.
23. Goswami M, Nikolaou D. Is AMH Level, Independent of Age, a Predictor of Live Birth in IVF? J Hum Reprod Sci 2017; 10 (1): 24–30.
24. Kedem-Dickman A, Maman E, Yung Y et al. Anti-Mullerian hormone is highly expressed and secreted from cumulus granulosa cells of stimulated preovulatory immature and atretic oocytes. Reprod BioMed Online 2012; 24 (5): 540–6.
25. Frattarelli JL, Gerber MD. Basal and cycle androgen levels correlate with in vitro fertilization stimulation parameters but do not predict pregnancy outcome. Fertil Steril 2006; 86: 51–7.
26. Ferrario M, Secomandi R, Cappato M et al. Ovarian and adrenal androgens may be useful markers to predict oocyte competence and embryo development in older women. Gynecol Endocrinol 2015; 31 (2): 125–30. DOI: 10.3109/09513590.2014.964639
27. Taketsuru H, Hirao Y, Takenouchi N et al. Effect of androstenedione on the growth and meiotic competence of bovine oocytes from early antral follicles. Zygote 2012; 20: 407–15.
28. Kushnir M, Naessen T, Wanggren K et al. Exploratory study of the association of steroid profiles in stimulated ovarian follicular fluid with outcomes of IVF treatment. J Steroid Biochem Mol Biol 2016; 162: 126–33.
29. Walters K, Eid S, Edwards M et al. Steroid profiles by liquid chromatography-mass spectrometry of matched serum and single dominant ovarian follicular fluid from women undergoing IVF. Reprod BioMed Online 2018. DOI: 10.1016/j.rbmo.2018.10.006
30. Malysheva N.M., Kolesnikova G.S., Ioutsi V.A. et al. Sravnitel'nyi analiz rezul'tatov opredeleniia testosterona v syvorotke krovi na analizatorakh Architect i Vitros i metodom vysokoeffektivnoi zhidkostnoi khromatografii – tandemnoi mass-spektrometrii. Klin. laboratornaia diagnostika. 2017; 10 (in Russian).
31. Handelsman D. Mass spectrometry, immunoassay and valid steroid measurements in reproductive medicine and science. Hum Reprod 2017; 32: 1147–50.
32. McCartney CR, Burt Solorzano CM, Patrie JT et al. Estimating testosterone concentrations in adolescent girls: Comparison of two direct immunoassays to liquid chromatography-tandem mass spectrometry. Steroids. 2018. 140. 10.1016/j.steroids.2018.09.001.
33. Abide Yayla, C, Ozkaya E, Kayatas Eser S et al. Association of basal serum androgen levels with ovarian response and ICSI cycle outcome.
Ir J Med Sci 2018; 187: 409.
34. De los Santos MJ, García-Laez V, Beltrán D et al. The follicular hormonal profile in low-responder patients undergoing unstimulated cycles: is it hypoandrogenic? Hum Reprod 2013; 28 (Issue 1): 224–9.
35. Zhang M, Niu W, Wang Y et al. Dehydroepiandrosterone treatment in women with poor ovarian response undergoing IVF or ICSI: a systematic review and meta-analysis. J Assist Reprod Genet 2016 33: 981–91.
ФГБУ «Национальный медицинский исследовательский центр акушерства, гинекологии и перинатологии
им. академика В.И. Кулакова» Минздрава России, Москва, Россия
*burdulianna@gmail.com
________________________________________________
Anna G. Burduli, Natalia A. Kitsilovskaya, Yuliya V. Sukhova, Irina A. Vedikhina, Tatiana Yu. Ivanets, Vitaliy V. Chagovets, Nataliia L. Starodubtseva, Vladimir E. Frankevich
Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russia
*burdulianna@gmail.com