Background: Preservation before treatment and ovarian protection during treatment

Anti-Müllerian hormone (AMH) is being studied as a candidate for reducing ovarian follicle loss during chemotherapy. A narrative review published in the Journal of Assisted Reproduction and Genetics summarized preclinical evidence for the protective effects of recombinant AMH (rAMH) and the challenges of clinical translation. Potential benefits were observed in studies involving mice and human ovarian tissue, but no human clinical trials had administered rAMH before or after chemotherapy by the time the review was written.

Chemotherapy damages oocyte DNA and triggers cell death. When granulosa cells in growing follicles are damaged and AMH levels fall, the signal that suppresses activation of dormant primordial follicles may also weaken. In the “burnout through overactivation” model, many follicles enter the growth phase at once and are then lost. Direct cell death, as well as damage to ovarian stroma and microvasculature, also contributes; which pathway predominates in humans remains debated.

Oocyte, embryo, and ovarian tissue cryopreservation secure reproductive cells or tissue before treatment. These methods are distinct from approaches intended to reduce ovarian damage during treatment. Gonadotropin-releasing hormone (GnRH) agonists are also used as an adjunct, but the review noted limitations in their protective effects and the need to develop candidates that regulate follicle activation.

Key findings: Signals that maintain dormancy and preclinical protective effects

AMH is secreted by granulosa cells in growing follicles and suppresses activation of early-stage follicles. When AMH binds to the type II AMH receptor (AMHR2), a complex including a type I receptor forms, leading to phosphorylation of the intracellular signaling proteins SMAD1/5/8. The review describes this signaling, along with regulation of the PI3K/AKT/FOXO3a and mTOR pathways, as mechanisms that maintain primordial follicle dormancy. FOXO3a remains in the cell nucleus and suppresses expression of growth-related genes, while inhibition of mTOR activity limits metabolic activation.

Mouse studies included in the review reported preservation of primordial follicles and maintenance of fertility when rAMH was administered alongside cyclophosphamide. In doxorubicin-exposed mice, reduced DNA damage and cell-death responses, as well as improved reproductive outcomes over six months, were also observed. Some mouse studies found no impairment of anticancer activity, but these findings do not establish oncologic safety in humans.

Studies using in vitro culture and xenografting of human ovarian tissue also support the possibility of suppressing follicle activation. However, treatment did not prevent follicle loss caused by hypoxia immediately after xenografting. Responses were not consistent: in sheep, suppression of primordial follicle entry into growth was not observed, and in some human tissue cultures, high-dose rAMH instead promoted early follicle growth. These findings show why species, dose, developmental stage, and hormonal environment must be considered.

Implications and outlook: Sustained exposure and functional recovery are development challenges

Development of rAMH requires confirmation that the exposure needed for protection can be maintained and that normal ovarian function recovers after administration ends. In one mouse study, labeled rAMH administered intraperitoneally was detected in ovarian granulosa cells up to 7 hours after administration, but not at 17 hours. This was a tissue-detection result from that experiment; it does not indicate a human half-life or dosing interval. It illustrates why repeated dosing or sustained delivery is being considered.

Large-scale production of biologically active protein remains another challenge. Complex structure and glycosylation requirements, together with low production yields, present manufacturing barriers. Gene delivery could provide long-term exposure, but stopping expression and managing reversibility are difficult. AMHR2 is also present in tissues outside the ovary, making evaluation of systemic effects and long-term safety essential.

The authors proposed prioritizing safety, reversibility, pharmacokinetics, and pharmacodynamics in future early-stage clinical studies. Whether preservation of follicle counts or blood hormone markers leads to better reproductive outcomes will require long-term follow-up. This paper is a review of preclinical findings and outstanding challenges, rather than an experiment demonstrating clinical efficacy of a new treatment. Further evidence and discussion are available in the full paper.