Ovarian stimulation in the lutein phase of the menstrual cycle and in the double stimulation mode in patients with lower diminished ovarian reserve values

Krutova V.A., Golovko A.K.

1) Kuban State Medical University Clinic, Ministry of Health of the Russian Federation, Krasnodar, Russia; 2) Kuban State Medical University, Ministry of Health of the Russian Federation, Krasnodar, Russia
In vitro fertilization is still characterized by lower success rates in women who fail to respond adequately to controlled ovarian stimulation, also known as poor responders. To search for an effective treatment for this group of patients is an important problem.
Objective: To provide up-to-date information on the use of protocols for ovarian function stimulation in the luteal phase of the menstrual cycle and in the double stimulation mode in patients with lower ovarian reserve values.
Methods: Publications were sought for in the databases PubMed, eLibrary, Web of Science, Cochrane Library, and CyberLeninka. The search depth was 10 years. The systematic search used the following keywords: ovarian stimulation in the luteal phase, double stimulation, and diminished ovarian reserve; as well as double stimulations, luteal-phase ovarian stimulation, poor ovarian response, controlled ovarian stimulation, and second follicular wave in English-language publications.
Results: The review included 42 of the 89 literature sources analyzed. This review of current studies has shown that ovarian stimulation can be safely and effectively initiated at any point in the menstrual cycle. Double ovarian stimulation is a promising protocol for patients, from whom the largest number of oocytes should be retrieved in the shortest possible time when one superovulation stimulation session is not enough or when the period for assisted reproductive technologies is limited. The literature data indicate that this strategy is a possible option to compensate for the inadequate ovarian response that sometimes occurs in assisted reproductive technology programs, especially in patients with lower ovarian reserve values.
Conclusion: Ovarian function stimulation in the follicular and luteal phases of the menstrual cycle is a new strategy aimed at increasing the numbers of retrieved oocytes and obtained good-quality embryos. Just the same, there is a need for further investigation of the efficiency and safety of double stimulation in patients with diminished ovarian reserve.


in vitro fertilization
diminished ovarian reserve
luteal-phase stimulation
follicular-phase stimulation


  1. Богатырева Х.А., Мишиева Н.Г., Мартазанова Б.А., Лапина В.С., Абубакиров А.Н. Эффективность протоколов стимуляции функции яичников в различные фазы менструального цикла у пациенток со сниженным овариальным резервом. Акушерство и гинекология. 2017; 11: 78-83. [Bogatyreva Kh.A., Mishieva N.G., Martazanova B.A., Lapina V.S., Abubakirov A.N. Efficiency of ovarian stimulation protocols in different phases of menstrual cycle in patients with diminished ovarian reserve. Obstetrics and Gynecology. 2017; 11: 78-83. (in Russian)]. https://dx.doi.org/10.18565/aig.2017.11.78-83.
  2. Ferraretti A.P., La Marca A., Fauser B.C., Tarlatzis B., Nargund G., Gianaroli L.; ESHRE Working Group on Poor Ovarian Response Definition. ESHRE consensus on the definition of 'poor response' to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum. Reprod. 2011; 26(7): 1616-24.
  3. Drakopoulos P., Blockeel C., Stoop D., Camus M., de Vos M., Tournaye H., Polyzos N.P. 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; 31(2): 370-6. https://dx.doi.org/ 10.1093/humrep/dev316.
  4. Polyzos N.P., Nwoye M., Corona R., Blockeel C., Stoop D., Haentjens P. et al. Live birth rates in Bologna poor responders treated with ovarian stimulation for IVF/ICSI. Reprod. Biomed. Online. 2014; 28(4): 469-74. https://dx.doi.org/ 10.1016/j.rbmo.2013.11.010.
  5. La Marca A., Grisendi V., Giulini S., Sighinolfi G., Tirelli A., Argento C. et al. Live birth rates in the different combinations of the Bologna criteria poor ovarian responders: a validation study. J. Assist. Reprod. Genet. 2015; 32(6): 931-7. https://dx.doi.org/10.1007/s10815-015-0476-4.
  6. Rienzi L., Gracia C., Maggiulli R., LaBarbera A.R., Kaser D.J., Ubaldi F.M. et al. Oocyte, embryo and blastocyst cryopreservation in ART: systematic review and meta-analysis comparing slow-freezing versus vitrification to produce evidence for the development of global guidance. Hum. Reprod. Update. 2017; 23(2): 139-55. https://dx.doi.org/10.1093/humupd/dmw038.
  7. Назаренко Т.А., Бурдули А.Г., Мартиросян Я.О., Джанашвили Л.Г. Криоконсервация репродуктивного материала у онкологических больных. Акушерство и гинекология. 2019; 9: 40-9. [Nazarenko T.A., Burduli A.G., Martirosyan Ya.O., Dzhanashvili L.G. Cryopreservation of reproductive material in cancer patients. Obstetrics and Gynecology. 2019; 9: 40-9 (in Russian)]. https://dx.doi.org/10.18565/aig.2019.9.40-49.
  8. Wong K.M., van Wely M., Mol F., Repping S., Mastenbroek S. Fresh versus frozen embryo transfers in assisted reproduction. Cochrane Database Syst. Rev. 2017; (3): CD011184.
  9. Roque M., Valle M., Sampaio M., Geber S. Does freeze-all policy affect IVF outcome in poor ovarian responders? Ultrasound Obstet. Gynecol. 2018; 52(4): 530-4. https://dx.doi.org/10.1002/uog.19000.
  10. Cobo A., Garrido N., Crespo J., Jose R., Pellicer A. Accumulation of oocytes: a new strategy for managing low-responder patients. Reprod. Biomed. Online. 2012; 24(4): 424-32. https://dx.doi.org/10.1016/j.rbmo.2011.12.012.
  11. Alviggi C., Andersen C.Y., Buehler K., Conforti A., De Placido G., Esteves S.C. et al. A new more detailed stratification of low responders to ovarian stimulation: from a poor ovarian response to a low prognosis concept. Poseidon Group (Patient-Oriented Strategies Encompassing Individualize Oocyte Number). Fertil. Steril. 2016; 105(6): 1452-3. https://dx.doi.org/10.1016/j.fertnstert.2016.02.005.
  12. Dahdouh E.M., Balayla J., Garcia-Velasco J.A. Comprehensive chromosome screening improves embryo selection: a meta-analysis. Fertil. Steril. 2015; 104(6): 1503-12. https://dx.doi.org/10.1016/j.fertnstert.2015.08.038.
  13. von Wolff M., Thaler C.J., Frambach T., Zeeb C., Lawrenz B., Popovici R.M. et al. Ovarian stimulation to cryopreserve fertilized oocytes in cancer patients can be started in the luteal phase. Fertil. Steril. 2009; 92(4): 1360-5. https://dx.doi.org/10.1016/j.fertnstert.2008.08.011.
  14. Назаренко Т.А., Мартиросян Я.О., Бирюкова А.М., Джанашвили Л.Г., Иванец Т.Ю., Сухова Ю.В. Опыт стимуляции яичников в режиме «random-start» протоколов для сохранения репродуктивного материала онкологических больных. Акушерство и гинекология. 2020; 4: 52-8. [Nazarenko T.A., Martirosyan Ya.O. Biryukova A.M., Dzhanashvili L.G., Ivanets T.Yu., Sukhova Yu.V., Experience in random-start ovarian stimulation for preserving reproductive material of cancer patients. Obstetrics and Gynecology. 2020; 4: 52-8]. https://dx.doi.org/10.18565/aig.2020.4.52-58.
  15. Hackeloer B.J., Fleming R., Robinson H.P., Adam A.H., Coutts J.R.T. Correlation of ultrasonic and endocrinologic assessment of human follicular development. Am. J. Obstet. Gynecol. 1979; 135(1): 122-8.
  16. Mihm M., Evans A.C. Mechanisms for dominant follicle selection in monovulatory species: a comparison of morphological, endocrine and intraovarian events in cows, mares and women. Reprod. Dom. Anim. 2008; 43(Suppl. 2): 48-56.
  17. Pache T., Wladimiroff J., Dejong F., Hop W., Fauser B. Growth patterns of nondominant ovarian follicles during the normal menstrual cycle. Fertil. Steril. 1990; 54(4): 638-42. https://dx.doi.org/10.1016/s0015-0282(16)53821-7.
  18. McNatty K.P. Cyclic changes in antral fluid hormone concentrations in humans. Clin. Endocrinol. Metab. 1978; 7(3): 577-600. https://dx.doi.org/10.1016/s0300-595x(78)80010-3.
  19. McNatty K.P. Hormonal correlates of follicular development in the human ovary. Aust. J. Biol. Sci. 1981; 34(3): 249-68. https://dx.doi.org/10.1071/bi9810249.
  20. Baerwald A., Adams G., Pierson R. A new model for ovarian follicular development during the human menstrual cycle. Fertil. Steril. 2003; 80(1):116-22. https://dx.doi.org/10.1016/S0015-0282(03)00544-2.
  21. Baerwald A., Adams G., Pierson R. Characteristics of ovarian follicular wave dynamics in women. Biol. Reprod. 2003; 69(3): 1023-31. https://dx.doi.org/10.1095/biolreprod.103.017772.
  22. Rashtian J., Zhang J. Luteal-phase ovarian stimulation increases the number of mature oocytes in older women with severe diminished ovarian reserve. Syst. Biol. Reprod. Med. 2018; 64(3): 216-9. https://dx.doi.org/10.1080/19396368.2018.1448902.
  23. Ubaldi F.M., Capalbo A., Vaiarelli A., Cimadomo D., Colamaria S., Alviggi C. et al. Follicular versus luteal phase ovarian stimulation during the same menstrual cycle (DuoStim) in a reduced ovarian reserve population results in a similar euploid blastocyst formation rate: new insight in ovarian reserve exploitation. Fertil. Steril. 2016;105(6): 1488-95.e1. 1https://dx.doi.org/10.1016/j.fertnstert.2016.03.002.
  24. de Melo Gagliato D., Gonzalez-Angulo A.M., Lei X., Theriault R.L., Giordano S.H., Valero V. et al. Clinical impact of delaying initiation of adjuvant chemotherapy in patients with breast cancer. J. Clin. Oncol. 2014; 32(8): 735-44. https://dx.doi.org/10.1200/JCO.2013.49.7693.
  25. Kuang Y., Chen Q., Hong Q., Lyu Q., Ai A., Fu Y., Shoham Z. Double stimulations during the follicular and luteal phases of poor responders in IVF/ICSI programmes (Shanghai protocol). Reprod. Biomed. Online 2014; 29(6): 684-91. https://dx.doi.org/10.1016/j.rbmo.2014.08.009.
  26. Cimadomo D., Vaiarelli A., Colamaria S., Trabucco E., Alviggi C., Venturella R. et al. Luteal phase anovulatory follicles result in the production of competent oocytes: intra-patient paired case-control study comparing follicular versus luteal phase stimulations in the same ovarian cycle. Hum. Reprod. 2018; 33(8): 1442-8. https://dx.doi.org/10.1093/humrep/dey217.
  27. Vaiarelli A., Cimadomo D., Trabucco E., Vallefuoco R., Buffo L., Dusi L. et al. Double stimulation in the same ovarian cycle (DuoStim) to maximize the number of oocytes retrieved from poor prognosis patients: a multicenter experience and SWOT analysis. Front. Endocrinol. (Lausanne). 2018; 9: 317. https://dx.doi.org/10.3389/fendo.2018.00317.
  28. Boots C.E., Meister M., Cooper A.R., Hardi A., Jungheim E.S. Ovarian stimulation in the luteal phase: systematic review and meta-analysis. J. Assist. Reprod. Genet. 2016; 33(8): 971-80. https://dx.doi.org/10.1007/s10815-016-0721-5.
  29. Lin L.T., Vitale S.G., Chen S.N., Wen Z.H., Tsai H.W., Chern C.U., Tsui K.H. Luteal phase ovarian stimulation May improve oocyte retrieval and oocyte quality in poor ovarian responders undergoing in vitro fertilization: preliminary results from a Single-Center Prospective Pilot Study. Adv. Ther. 2018; 35(6): 847-56. https://dx.doi.org/10.1007/s12325-018-0713-1.
  30. Llácer J., Moliner B., Luque L., Bernabéu A., Lledó B., Castillo J.C. et al. Luteal phase stimulation versus follicular phase stimulation in poor ovarian responders: results of a randomized controlled trial. Reprod. Biol. Endocrinol. 2020; 18(1): 9. https://dx.doi.org/10.1186/s12958-020-00570-7.
  31. Zhang W., Wang M., Wang S., Bao H., Qu Q., Zhang N., Hao C. Luteal phase ovarian stimulation for poor ovarian responders. JBRA Assist. Reprod. 2018; 22(3): 193-8. https://dx.doi.org/10.5935/1518-0557.20180045.
  32. Wu Y., Zhao F.C., Sun Y., Liu P.S. Luteal-phase protocol in poor ovarian response: a comparative study with an antagonist protocol. J. Int. Med. Res. 2017; 45(6): 1731-8. https://dx.doi.org/10.1177/0300060516669898.
  33. Sfakianoudis K., Pantos K., Grigoriadis S., Rapani A., Maziotis E., Tsioulou P. et al. What is the true place of a double stimulation and double oocyte retrieval in the same cycle for patients diagnosed with poor ovarian reserve? A systematic review including a meta-analytical approach. J. Assist. Reprod. Genet. 2020; 37(1): 181-204. https://dx.doi.org/10.1007/s10815-019-01638-z.
  34. Madani T., Hemat M., Arabipoor A., Khodabakhshi S.H., Zolfaghari Z. Double mild stimulation and egg collection in the same cycle for management of poor ovarian responders. J. Gynecol. Obstet. Hum. Reprod. 2019; 48(5): 329-33. https://dx.doi.org/10.1016/j.jogoh.2018.12.004.
  35. Bourdon M., Santulli P., Maignien C., Pocate-Cheriet K., Marcellin L., Chen Y., Chapron C. The ovarian response after follicular versus luteal phase stimulation with a double stimulation strategy. Reprod. Sci. 2020; 27(1): 204-10. https://dx.doi.org/10.1007/s43032-019-00012-9.
  36. Liu C., Jiang H., Zhang W., Yin H. Double ovarian stimulation during the follicular and luteal phase in women ≥38 years: a retrospective case-control study. Reprod. Biomed. Online. 2017; 35(6): 678-84. https://dx.doi.org/10.1016/j.rbmo.2017.08.019.
  37. Luo Y., Sun L., Dong M., Zhan X., Huang L., Zhu X. et al. The best execution of the DuoStim strategy (double stimulation in the follicular and luteal phase of the same ovarian cycle) in patients who are poor ovarian responders. Reprod. Biol. Endocrinol. 2020; 18(1): 102. https://dx.doi.org/10.1186/s12958-020-00655-3.
  38. Kyrou D., Kolibianakis E.M., Venetis C.A., Papanikolaou E.G., Bontis J., Tarlatzis B.C. How to improve the probability of pregnancy in poor responders undergoing in vitro fertilization: a systematic review and meta-analysis. Fertil. Steril. 2009; 91(3): 749-66.
  39. Bedoschi G.M., de Albuquerque F.O., Ferriani R.A., Navarro P.A. Ovarian stimulation during the luteal phase for fertility preservation of cancer patients: case reports and review of the literature. J. Assist. Reprod. Genet. 2010; 27(8): 491-4. https://dx.doi.org/10.1007/s10815-010-9429-0.
  40. Maman E., Meirow D., Brengauz M., Raanani H., Dor J., Hourvitz A. Luteal phase oocyte retrieval and in vitro maturation is an optional procedure for urgent fertility preservation. Fertil. Steril. 2011; 95(1): 64-7. https://dx.doi.org/10.1016/j.fertnstert.2010.06.064.
  41. Cakmak H., Katz A., Cedars M.I., Rosen M.P. Effective method for emergency fertility preservation: random-start controlled ovarian stimulation. Fertil. Steril, 2013; 100(6): 1673-80. https://dx.doi.org/10.1016/j.fertnstert.2013.07.1992.
  42. Kuang Y., Hong Q., Chen Q., Lyu Q., Ai A., Fu Y. et al. Luteal-phase ovarian stimulation is feasible for producing competent oocytes in women undergoing in vitro fertilization/intracytoplasmic sperm injection treatment, with optimal pregnancy outcomes in frozen-thawed embryo transfer cycles. Fertil. Steril. 2014; 101(1): 105-11. https://dx.doi.org/10.1016/j.fertnstert.2013.09.007.

Received 22.07.2021

Accepted 22.11.2021

About the Authors

Viktoriya A. Krutova, Dr. Med. Sci., Professor of the Department of Obstetrics, Gynecology and Perinatology, Kuban State Medical University, Ministry of Healthcare of the Russian Federation; Chief Administrator of the Clinic of Kuban State Medical University, Ministry of Healthcare of the Russian Federation, +7(918)436-69-93,
vik-krutova@yandex.ru, https://orcid.org/0000-0002-9907-7491, 350072, Russia, Krasnodar, Zipovskaya str., 4/1.
Anfisa K. Golovko, Post-graduate student of the Department of Obstetrics, Gynecology and Perinatology, Kuban State Medical University, Ministry of Healthcare of the Russian Federation, +7(964)937-13-04, anfisa.golovko@mail.ru, 350072, Russia, Krasnodar, Zipovskaya str., 4/1.
Corresponding author: Anfisa K. Golovko, anfisa.golovko@mail.ru

Authors’ contributions: Krutova V.A. – concept development – idea formation; conduction of the investigation – analysis and interpretation of the findings; text preparation and editing – critical revision of a draft manuscript with the valuable comment on the intellectual content; development of the design of the investigation; approval of the final version – acceptance of responsibility for all aspects of the investigation, the integrity of all parts of the article and its final version; A.K. Golovko – concept development – formulation or development of key goals and objectives; conduction of the investigation – review of publications on the topic of the article; data collection; text preparation and editing - writing the text of the manuscript; abstract writing; preparation and writing the published work; approval of the final version - acceptance of responsibility for all aspects of the investigation, the integrity of all parts of the article and its final version.
Conflicts of interest: The authors declare that there are no conflicts of interest.
Funding: The authors declare that there is no investigation sponsorship.
For citation:Krutova V.A., Golovko A.K. Ovarian stimulation in the lutein phase of the menstrual cycle and in the double stimulation mode in patients with lower diminished ovarian reserve values.
Akusherstvo i Ginekologiya/ Obstetrics and Gynecology. 2021; 12: 24-30 (in Russian)

Similar Articles

By continuing to use our site, you consent to the processing of cookies that ensure the proper functioning of the site.