O-002 Expanding the ovary’s reproductive lifespan: Preservation and Rejuvenation
Authors: Pellicer A 
Published: August 2021

Abstract

Study question
The ovary has short lifespan. Genetic and pathologic alterations make it shorter. Moreover, many women delay fertility requiring expanded ovarian function. Can be realistically achieved?

Summary answer
The reproductive lifespan of the ovary can be expanded to a certain extent in physiologic and pathologic (premature ovarian insufficiency (POI)) conditions.

What is known already
In ovaries functioning in physiologic conditions, oocyte cryopreservation (OC) is an established method to expand the reproductive lifespan allowing women to postpone fertility without compromising oocyte’s performance. In oncology, ovarian tissue cryopreservation/ ovarian tissue transplantation (OTC/OTT) and OC are widely employed. In POI patients, there are resting follicles in 1/3 of patients. Different techniques have been developed to “awake” these follicles. Some surgical procedures disrupt Hippo signaling to induce primordial follicle growth; , others intend to employ the growth factors contained in blood; some others use bone marrow-derived stem cells to reach similar goals.

Study design, size, duration
A literature search was done to identify the most recent and informative studies on the different techniques applied to increase the reproductive lifespan of the ovaries, including those clinically available, such as OC, and others still considered experimental, such as OCT/OTT, injection of platelets-enriched plasma (PRP), culture-free in vitro activation(CF-IVA), and autologous stem cell ovarian transplantation (ASCOT).

Participants/materials, setting, methods
Outcome of 641 healthy women performing OC and ART cycles. In oncology, OC in 80 women and OTC/OTT in 285 patients willing to conceive was analyzed. Both techniques were compared in the same setting in oncology : 1024 undergoing OC and 800 performing OCT. In POI, we analyzed the outcome of 304 women after PRP; 11 undergoing CF-IVA; and 28 ASCOT patients. The most relevant experimental techniques were also analyzed to understand future directions.

Main results and the role of chance
When it comes to expanding the reproductive function in physiologic conditions, mostly due to delay in childbearing, the follow-up of 641 women out of 1073 who underwent OC and subsequent embryo transfer (ET) has shown 68.8% cumulative live birth rates (C-LBR). Age matters because C-LBR decreased &gt;50% after age 35 yrs. If only the endocrine function of the ovary is considered, OCT/OTT has consistently shown almost 86% efficacy.
In Oncology, OC provided 42.1% C-LBR in 80 individuals after cure, while the follow-up of 285 women from 5 different centers after OCT/OTT yield 26% LBR. Both OC and OTT were compared in the same setting and OC proved to be slightly better, with 32.6% LBR as compared to 22.8% in OCT/OTT.
Regarding POI, the use of intraovarian PRP injection in 304 women displayed 8% LBR; CF-IVA 36.3% LBR in 11 women; and ASCOT 10% LBR in 10 POI patients and 27.8% in 18 poor responders (PR).
Experimental data suggest that a combination of ASCOT and PRP must be the best alternative to activate dormant follicles in POI women.
Limitations, reasons for caution: None of the studies was a RCT, and many had not controls, most are descriptive. Regarding oncology patients OC is save and reassuring. The experience shows that OCT/OTT is also safe, although some Scientific Societies label OCT/OTT still as experimental. All the techniques employed in POI are ­experimental yet.

Wider implications of the findings
Expanding the reproductive lifespan of the ovary in health and disease (oncology and others) employing OC is a routine; OCT/OTT can be also applied to expand the endocrine function of the ovaries. The best and less invasive method to activate follicles in POI and PR still needs to be defined.

Trial registration number
NCT02240342; NCT03535480; NCT04475744; NCT02354963