An explanation for the true origin of spontaneous pregnancies after subcutaneous ovarian transplantation

28 03 2011

To the Editor:

I read with interest the article by Oktay et al. (1), in which the authors reported spontaneous pregnancies and live births after subcutaneous heterotopic ovarian transplantation to a Hodgkin lymphoma survivor who was rendered menopausal because of preconditioning chemotherapy before hematologic stem cell transplantation (HSCT), and discussed the origin of pregnancies after ovarian transplantation. They have done a good work.

I have great interest in the true origin of the spontaneous pregnancies. Although they mentioned that this patient might get pregnant without heterotopic transplantation, they did believe other explanations need more laboratory and clinical research because the third pregnancy occurred after the patient did not respond to high doses of gonadotropins and her in situ ovary was invisible by ultrasound examination.

On the contrary, we believe that these pregnancies derived from the in situ ovary, in my personal and institutional experience. In addition to clinical evidence, a pilot study about intracytoplasmic sperm injection (ICSI) with autologous oocyte and embryo transfer for infertile patients with premature ovarian failure at our center, found that approximately one thirds of POF patients had developing follicles during estrogen-replacement therapy (ERT).

And Van Kasteren also demonstrated that nearly 50% of young women have intermittent ovarian follicle function and 16% of these cases may exhibit sporadic ovulatory cycles after the diagnosis of POF (2).

The patient’s in situ ovary appeared to be atrophic in some ultrasound examinations and was invisible in others, but the authors had no ultrasound examination evidence of the ovary in the pregnancy cycles. In our research we also found that both ovaries of most of the POF patients were obviously small, even invisible, and had no response to high doses of gonadotropins. However, close inspection of these patients surprisingly revealed some intermittent ovarian function.

Our 14 POF patients were observed for 38 cycles with estrogen-replacement therapy. In 23 cycles, growing follicles were observed and oocytes were collected in 7 cycles. The clinical situation implied some intermittent and unpredictable ovarian function, which may continue for decades (3).

Inspiringly, Oktay et al. performed subcutaneous ovarian transplantation for the cancer survivor and restored her hormonal function, which resulted in her menstrual bleeding. The graft had hormonal function, which contributes to improved ovulation of the in situ ‘‘menopausal’’ ovary. This is similar to hormone replacement treatment used in the study of Tartagni et al. (4) and our clinical research (unpublished data).

Xin Chen, M.D., M.Sc.
Center for Reproductive Medicine, Department of Obstetrics and Gynecology
Nanfang Hospital
Southern Medical University
Guangzhou, People’s Republic of China

References
1. Oktay K, Türkçüoğlu I, Rodriguez-Wallberg KA et al. Four spontaneous pregnancies and three live births following subcutaneous transplantation of frozen banked ovarian tissue: What is the explanation?. Fertil Steril 2011;95:804.e7-e10.

2. 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;5:483-92.

3. Nelson LM, Bakalov VK. Mechanisms of follicular dysfunction in 46, XX spontaneous premature ovarian failure. Endocrinol Metal Clin North Am 2003;32:613–7.

4. Tartagni M, Cicinelli E, Pergola GD et al. Effects of pretreatment with estrogens on ovarian sitmulation with gonadotropins in women with premature ovarian failure: a randomized, placebo-controlled trial. Fertil Steril 2007;87:858-61.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.03.090

The Authors Respond:

It is correct that, as we already discussed in our manuscript, pregnancies do happen after HSCT but rare. While it is still possible that the pregnancies reported in our manuscript could have happened with or without the ovarian transplantation, this is highly unlikely because of the following:

1) The patient was menopausal for two and a half years as confirmed by high FSH levels.

2) The patient was sexually active during that period leading to the ovarian transplant and never conceived.

3) The patient conceived shortly after ovarian transplantation, 4 consecutive pregnancies resulted in 3 livebirths in a span of 5 years and 8 months.

4) There is accumulating evidence on ovarian niche and its impact on regeneration of putative germ stem cells (1, 2).

Furthermore, previous studies do not show a benefit of hormone replacement therapy on spontaneous pregnancy rates in women with premature ovarian failure or primary ovarian insufficiency (3) and for that reason we do not think that the resuming ovarian function, albeit intermittent, had a role in the establishment of these pregnancies.

The work ongoing in others and our research laboratories will soon shed light onto the mechanism of our clinical observations reported in this manuscript (4).

Kutluk Oktay, M.D.
Ilgın Türkçüoğlu, M.D.
Kenny Rodriguez-Wallberg, M.D., Ph.D.
Institute for Fertility Preservation and Reproductive Medicine Department of Obstetrics & Gynecology
New York Medical College
Valhalla, New York

References
1. Oktay K, Goswami S, Darzynkiewicz Z. Manipulating ovarian aging: a new frontier in fertility preservation. Aging (Albany NY). 2011;3:19-21.

2. Niikura Y, Niikura T, Tilly JL. Aged mouse ovaries possess rare premeiotic germ cells that can generate oocytes following transplantation into a young host environment. Aging (Albany NY). 2009;1:971-8.

3. van Kasteren YM, Schoemaker J. Premature ovarian failure: a systematic review on therapeutic interventions to restore ovarian function and achieve pregnancy. Human Reprod Update. 1999;5:483–492.

4. Oktay K, Türkçüoğlu I, Rodriguez-Wallberg KA. Four spontaneous pregnancies and three live births following subcutaneous transplantation of frozen banked ovarian tissue: what is the explanation? Fertil Steril. 2011;95:804.e7-10.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.03.089

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