In Vitro Activation of Follicles and Fresh Tissue Auto-transplantation in Primary Ovarian Insufficiency Patients

Jun Zhai, Guidong Yao, Fangli Dong, Zhiqin Bu, Yuan Cheng, Yorino Sato, Linli Hu, Yingying Zhang, Jingyuan Wang, Shanjun Dai, Jing Li, Jing Sun, Aaron J Hsueh, Kazuhiro Kawamura, Yingpu Sun, Jun Zhai, Guidong Yao, Fangli Dong, Zhiqin Bu, Yuan Cheng, Yorino Sato, Linli Hu, Yingying Zhang, Jingyuan Wang, Shanjun Dai, Jing Li, Jing Sun, Aaron J Hsueh, Kazuhiro Kawamura, Yingpu Sun

Abstract

Context: Recently, two patients with primary ovarian insufficiency (POI) delivered healthy babies after in vitro activation (IVA) treatment followed by auto-transplantation of frozen-thawed ovarian tissues.

Objective: This study sought to report the first case of live birth after IVA treatment following fresh ovarian tissue grafting in patients with POI, together with monitoring of follicle development and serum hormonal changes.

Design: This was a prospective observational cohort study.

Setting: We performed IVA treatment in 14 patients with POI with mean age of 29 years, mean duration since last menses of 3.8 years, and average basal FSH level of 94.5 mIU/mL.

Interventions: Prior to IVA treatment, all patients received routine hormonal treatments with no follicle development. We removed one ovary from patients with POI and treated them with Akt stimulators. We improved upon early procedures by grafting back fresh tissues using a simplified protocol.

Main outcome measures: In six of the 14 patients (43%), a total of 15 follicle development waves were detected, and four patients had successful oocyte retrieval to yield six oocytes. For two patients showing no spontaneous follicle growth, human menopausal gonadotropin treatment induced follicle growth at 6-8 months after grafting. After vitro fertilization of oocyte retrieved, four early embryos were derived. Following embryo transfer, one patient became pregnant and delivered a healthy baby boy, with three other embryos under cryopreservation.

Conclusion: IVA technology can effectively activate residual follicles in some patients with POI and allow them to conceive their own genetic offspring. IVA may also be useful for treating patients with ovarian dysfunction including aging women and cancer survivors.

Figures

Figure 1.
Figure 1.
Follicle growth patterns and oocyte retrieval for six POI patients after IVA treatment. Pink ovals with an inner dot indicate spontaneous follicle growth whereas red ovals with an inner dot indicate hormonal induced follicle growth. Right upward arrows indicate follicle growth. Upward arrows pointing to one or two dots indicate successful retrieval of oocyte. A, spontaneous follicle growth with or without E/P. B, GnRH agonist followed by HMG treatment. C, HMG treatment with or without E/P pretreatment. spontaneous; induced; live birth; frozen embryo.
Figure 2.
Figure 2.
Hormonal profiles for six POI patients showing follicle growth after the IVA procedure. Serum levels of estradiol, FSH, and LH (left y-axis) were measured and plotted together with follicle diameters (right y-axis) estimated based on ultrasound monitoring. X-axis represents the number of days after ovarian grafting. Hormonal treatment protocols are also shown. A, spontaneous follicle growth. B, GnRH agonist followed by HMG treatment. C, HMG treatment with or without E/P pretreatment. Abbreviations: E-P, pretreatment with estrogen and progesterone; GnRH-a, GnRH agonist; opu, ovum pickup.
Figure 3.
Figure 3.
Serum AMH levels in five patients with POI showing follicle growth. Serum AMH was measured before and at different times after grafting.

References

    1. Kovanci E, Schutt AK. Premature ovarian failure: Clinical presentation and treatment. Obstet Gynecol Clin North Am. 2015;42:153–161.
    1. Goswami D, Conway GS. Premature ovarian failure. Hum Reprod Update. 2005;11:391–410.
    1. Donnez J, Dolmans MM, Demylle D, et al. Livebirth after orthotopic transplantation of cryopreserved ovarian tissue. Lancet. 2004;364:1405–1410.
    1. Silber SJ, Lenahan KM, Levine DJ, et al. Ovarian transplantation between monozygotic twins discordant for premature ovarian failure. N Engl J Med. 2005;353:58–63.
    1. Meirow D, Levron J, Eldar-Geva T, et al. Pregnancy after transplantation of cryopreserved ovarian tissue in a patient with ovarian failure after chemotherapy. N Engl J Med. 2005;353:318–321.
    1. Silber S, Pineda J, Lenahan K, DeRosa M, Melnick J. Fresh and cryopreserved ovary transplantation and resting follicle recruitment. Reprod Biomed Online. 2015;30:643–650.
    1. Silber SJ. Ovary cryopreservation and transplantation for fertility preservation. Mol Hum Reprod. 2012;18:59–67.
    1. Demeestere I, Simon P, Emiliani S, Delbaere A, Englert Y. Orthotopic and heterotopic ovarian tissue transplantation. Hum Reprod Update. 2009;15:649–665.
    1. Donnez J, Jadoul P, Squifflet J, et al. Ovarian tissue cryopreservation and transplantation in cancer patients. Best Pract Res Clin Obstet Gynaecol. 2010;24:87–100.
    1. Donnez J, Dolmans MM, Diaz C, Pellicer A. Ovarian cortex transplantation: Time to move on from experimental studies to open clinical application. Fertil Steril. 2015;104:1097–1098.
    1. Li J, Kawamura K, Cheng Y, et al. Activation of dormant ovarian follicles to generate mature eggs. Proc Natl Acad Sci U S A. 2010;107:10280–10284.
    1. Kawamura K, Cheng Y, Suzuki N, et al. Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment. Proc Natl Acad Sci U S A. 2013;110:17474–17479.
    1. Suzuki N, Yoshioka N, Takae S, et al. Successful fertility preservation following ovarian tissue vitrification in patients with primary ovarian insufficiency. Hum Reprod. 2015;30:608–615.
    1. Donnez J, Dolmans MM. Transplantation of ovarian tissue. Best Pract Res Clin Obstet Gynaecol. 2014;28:1188–1197.
    1. Dragojević-Dikić S, Rakić S, Nikolić B, Popovac S. Hormone replacement therapy and successful pregnancy in a patient with premature ovarian failure. Gynecol Endocrinol. 2009;25:769–772.
    1. Bidet M, Bachelot A, Bissauge E, et al. Resumption of ovarian function and pregnancies in 358 patients with premature ovarian failure. J Clin Endocrinol Metab. 2011;96:3864–3872.
    1. van Kasteren YM, Schoemaker J. Premature ovarian failure: A systematic review on therapeutic interventions to restore ovarian function and achieve pregnancy. Hum Reprod Update. 1999;5:483–492.
    1. Reddy P, Liu L, Adhikari D, et al. Oocyte-specific deletion of Pten causes premature activation of the primordial follicle pool. Science. 2008;319:611–613.
    1. Gougeon A. Regulation of ovarian follicular development in primates: facts and hypotheses. Endocr Rev. 1996;17:121–155.
    1. Hsueh AJ, Kawamura K, Cheng Y, Fauser BC. Intraovarian control of early folliculogenesis. Endocr Rev. 2015;36:1–24.
    1. Fauser BC, Pache TD, Lamberts SW, Hop WC, de Jong FH, Dahl KD. Serum bioactive and immunoreactive luteinizing hormone and follicle-stimulating hormone levels in women with cycle abnormalities, with or without polycystic ovarian disease. J Clin Endocrinol Metab. 1991;73:811–817.
    1. Tarlatzis BC, Grimbizis G, Pournaropoulos F, et al. The prognostic value of basal luteinizing hormone:follicle-stimulating hormone ratio in the treatment of patients with polycystic ovarian syndrome by assisted reproduction techniques. Hum Reprod. 1995;10:2545–2549.
    1. Visser JA, Themmen AP. Anti-Müllerian hormone and folliculogenesis. Mol Cell Endocrinol. 2005;234:81–86.
    1. Weenen C, Laven JS, Von Bergh AR, et al. Anti-Müllerian hormone expression pattern in the human ovary: Potential implications for initial and cyclic follicle recruitment. Mol Hum Reprod. 2004;10:77–83.
    1. La Marca A, Volpe A. Anti-Müllerian hormone (AMH) in female reproduction: Is measurement of circulating AMH a useful tool? Clin Endocrinol (Oxf). 2006;64:603–610.
    1. Tarlatzis BC, Pados G. Oocyte donation: Clinical and practical aspects. Mol Cell Endocrinol. 2000;161:99–102.
    1. Donnez J, Dolmans MM. Fertility preservation in women. Nat Rev Endocrinol. 2013;9:735–749.
    1. Liu J, Van der Elst J, Van den Broecke R, Dhont M. Early massive follicle loss and apoptosis in heterotopically grafted newborn mouse ovaries. Hum Reprod. 2002;17:605–611.
    1. Cordeiro CN, Christianson MS, Selter JH, Segars JJ. In vitro activation: A possible new frontier for treatment of primary ovarian insufficiency. Reprod Sci. 2016.
    1. Sonmezer M, Oktay K. Fertility preservation in female patients. Hum Reprod Update. 2004;10:251–266.
    1. Kawamura K, Cheng Y, Sun YP, et al. Ovary transplantation: To activate or not to activate. Hum Reprod. 2015;30:2457–2460.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe