New hope for infertility patients with premature ovarian insufficiency: IVA treatment using fresh ovarian tissue grafting.

courtesy: www.ivf-worldwide.com 

Premature ovarian insufficiency (POI) affects 1 in 100 women below the age of 40 years.  It causes amenorrhea, elevated FSH and hypoestrogenism. Diagnosed with POI is a life changing situation for many women, especially those who have still not completed their family. [1] POI is due to early exhaustion of ovarian follicles due to genetic, autoimmune, iatrogenic or other causes.[2]

Autologous ovarian transplantation is used in patients with malignancy to preserve fertility while radiotherapy and chemotherapy treatments. But, traditional transplantation is not useful in patients with POI because the endocrine and reproductive functions of the ovaries have already ceased. Until now, women with POI does conceive by In-Vitro fertilization by donor’s egg or go for surrogacy or adoption. By undergoing IVA, she has a chance to have her own biological child.

IVA or In Vitro Activation, is a new procedure to obtain mature eggs for women with POI, it involves a twostep procedure consisting of in vitro activation of follicles followed by fragmentation into smaller ovarian cubes and incubation with drugs before grafting.  The second step consists of oocyte retrieval followed by IVF and embryo transfer before pregnancy.

Phosphatase and tensin homolog (PTEN) enzyme inhibitors and phosphatidylinositol-3 kinase activators were used to activate the AKT pathway in dormant follicles leading to follicular growth. Ovarian fragmentation also interferes with the Hippo signaling leading to ovarian follicular development.[3]

A study results published in The Journal of clinical endocrinology and metabolism have translated this lab based IVA results into actual clinical practice resulting in birth of two healthy babies without cryopreservation of the ovarian tissue.

In this groundbreaking prospective observational cohort study, 14 patients with POI underwent IVA. The women were average 4 years past LMP, around 29 years of age and mean FSH level of 94.5 mIU/mL.

All the patients have received prior gonadotrophins treatment with no results before entering the study. The larger of the two ovaries was removed by laparoscopy, cut into strips and the strips were further cubed. The ovarian cubes were incubated to activate the AKT pathway. The cubes were cultured for two days and after 2 days of In Vitro activation they were transplanted back beneath the serosa of both fallopian tubes. A part of the ovarian tissue was cryopreserved for use at later date and 10-20% of the tissue was examined microscopically for residual follicles.

The patients underwent routine follicle stimulating protocols. Six (43%) of the fourteen patients showed follicular development. Four patients had successful oocyte retrieval, resulting in four embryos. Two women successfully delivered healthy infants following embryo transfer while 3 embryos were cryopreserved for future use.

An earlier study by Suzuki N et al published in Journal of Human Reproduction also reported two successful live birth following ovarian tissue vitrification in patients with primary ovarian insufficiency.[4]

"Although I believed, based on our previous research, that this IVA approach would work, I monitored the pregnancy closely and, when the baby was in a breech presentation, I performed the caesarean section myself," said Dr. Kazuhiro Kawamura, an associate professor of obstetrics and gynecology who led the team at St. Marianna.

"I could not sleep the night before the operation, but when I saw the healthy baby, my anxiety turned to delight. The couple and I hugged each other in tears. I hope that IVA will be able to help patients with primary ovarian insufficiency throughout the world."

Future randomized studies are needed before IVA can become a part of routine clinical practice for infertility patients. The researchers are considering several aspects like new drugs to target the Hippo and PTEN pathways to stimulate the ovaries without surgery.

It is too early to say that it can be used for wider application, but a new option has certainly been added to the ART armamentarium.

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[1] http://www.uptodate.com/contents/early-menopause-primary-ovarian-insufficiency-beyond-the-basics

[2] http://humrep.oxfordjournals.org/content/early/2015/01/06/humrep.deu353.full.pdf

[3] Kawamura K, Cheng Y, Suzukia N, et al. Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment. PNAS. 2013. 

[4] Suzuki N, Yoshioka N, Takae S, Sugishita Y, Tamura M, Hashimoto S, Morimoto Y, Kawamura K.

Hum Reprod. 2015 Mar;30(3):608-15