FSH levels at ovarian tissue transplantation:

better high or low?

Author: Claus Yding Andersen

Project Proposal: At ovarian tissue transplantation: should FSH by high or low?

Introduction

It is well recognised that in connection with ovarian tissue transplantation (OTT) a high proportion of the surviving follicles from the thawing process is lost due to ischemia and reperfusion injuries during the first week or two. Is it possible to mitigate this follicle loss?
Women undergoing transplantation of frozen/thawed ovarian tissue have often lost ovarian function and are in a postmenopausal state. Consequently, their levels of FSH and LH are significantly elevated—typically exceeding 75 IU/L for FSH and 50 IU/L for LH. Upon transplantation, as the ovarian tissue receives reperfusion and early-stage follicles regain function, they are exposed to these supraphysiological gonadotropin levels, far exceeding those seen during ovarian stimulation in assisted reproductive treatment (ART).

Optimizing Gonadotropin Levels for Follicular Survival and Activation

A key question arises: Do these high gonadotropin levels provide the optimal conditions for activating
transplanted follicles, or would a more physiologically regulated hormonal environment be more  beneficial for early follicular development?
One possibility is that any follicle within the transplanted tissue expressing FSH receptors (FSHR) will be stimulated to grow and may survive. Alternatively, excessively high FSH levels might lead to FSHR
internalization and downregulation, resulting in aberrant follicular growth. It is known that a peak in follicular growth occurs shortly after OTT, leading to a transient rise in AMH levels, which later decline as gonadotropin levels normalize (Silber, 2016). However, the underlying mechanisms driving this first post-transplantation follicular recruitment remain unclear.

Potential Benefits of Lowering Gonadotropins

An alternative approach could involve reducing FSH and LH levels prior to OTT using exogenous oestrogen (e.g., oral contraceptives or oestradiol). This would expose the follicles to more physiological gonadotropin levels, potentially supporting more sustainable follicular development and improving long-term ovarian function.
Additionally, oestradiol plays a crucial role in facilitating vascularization, which could enhance graft survival by reducing ischemia-related follicular loss. Since endogenous oestradiol production from growing follicles occurs only after the initial wave of follicular loss has taken place, administering exogenous oestradiol from one month before to one month after OTT might provide a protective effect.
A few centres already incorporate pre-transplant oestradiol administration (Oktay et al. 2016), though most do not. Notably, our own data suggests that women with residual ovarian activity—indicated by lower FSH levels and some endogenous oestradiol production—more often experience an increase in AMH levels post-transplantation compared to those in full menopause (Hornshøj Greve et al., 2021). However, no conclusive scientific data exist to determine whether lowering FSH and increasing estradiol pre-OTT leads to superior outcomes compared to maintaining high postmenopausal gonadotropin levels.

Scientific Question

Can OTT outcomes be optimized by reducing circulating FSH levels through oral oestradiol administration, leading to improved follicular survival, enhanced ovarian longevity, and better reproductive outcomes?
This study aims to provide evidence on whether modulating gonadotropin levels before OTT can enhance ovarian function and reproductive outcomes in women undergoing fertility preservation.


Study Design

A randomized controlled trial will be conducted in women undergoing OTT who have postmenopausal levels of FSH and LH (>40 IU/L and >20 IU/L, respectively). Participants will be randomized into two groups: one receiving oestradiol treatment and one without hormonal intervention.

Each woman will receive a standardized amount of transplanted ovarian tissue (e.g., half of one ovary). A total of 50 women will be enrolled, requiring a multicentre study design.

Measurements & Endpoints

Hormonal & Ultrasound Monitoring (monthly measurements):

  • FSH, LH, AMH, and oestradiol levels
  • Antral follicle count (AFC) via ultrasound

Menstrual Function:

  • Time to first menstruation post-OTT
  • Number of menstrual cycles during the first year

Ovarian Stimulation Outcomes: If applicable, response to ovarian stimulation within the first year post-OTT

 

If you are interested and would like to have your data included, please get in contact with us info@isfp-fertility.org

Please join this initiative if you wish to have your data included, or have any question regarding the study!

 

References:

  1. Hornshøj Greve V, Dueholm M, Mamsen LS, Kristensen SG, Ernst E, Andersen CY. Hormonal Characteristics of Women Receiving Ovarian Tissue Transplantation with or without Endogenous Ovarian Activity. J Clin Med. 2021;10:5217. PMID: 34830499
    2. Oktay K, Bedoschi G, Pacheco F, Turan V, Emirdar V. First pregnancies, live birth, and in vitro fertilization outcomes after transplantation of frozen-banked ovarian tissue with a human extracellular matrix scaffold using robot-assisted minimally invasive surgery. Am J Obstet Gynecol. 2016;214:94.e1-9. PMID: 26601616
    3. Silber S. How ovarian transplantation works and how resting follicle recruitment occurs: a review of results reported from one center. Womens Health (Lond). 2016;12:217-27. PMID:26900727

 

 

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