Restoration of ovarian endocrine function with encapsulated immune-isolated human ovarian xenograft in ovariectomized mice

Sep 28, 2026

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Anticancer therapy can exhaust the nonrenewable ovarian follicle reserve, causing premature ovarian insufficiency and broad endocrine, musculoskeletal, and neurological complications. Hormone replacement therapy is the only approved option but does not adequately reproduce ovarian physiology or cyclic hormonal feedback. This study tests whether human ovarian tissue delivered via an immune-isolating hydrogel capsule restores ovarian endocrine function in ovariectomized immunodeficient mice, assessing integration, hormone output, estrous cycling, and histological follicle development.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages10

Reading Time25 min

AccessFree to download

Introduction

Rationale: cancer treatment effects on ovarian reserve

Limitations of hormone replacement therapy

Alternative strategy: ovarian tissue transplantation

HEALTH AND MEDICINE Restoration of ovarian endocrine function with encapsulated immune-isolated human ovarian xenograft in ovariectomized mice Margaret A. Brunette1,2, Monica A. Rionda1, Delaney Sinko1, Jordan H. Machlin3, Gabrielle M. Blevins1, Marisa Leo1, AnsenTan1, Bipasha Ray4, Marilia Cascalho5,6, Vasantha Padmanabhan7,8, Ariella Shikanov1,3,8* Anticancer treatments may cause depletion of the nonrenewable ovarian reserve of follicles, the source of key hormones, leading to premature ovarian insufficiency (POI) and substantial endocrine, musculoskeletal, and neurological complications. Hormone replacement therapy, the only approved treatment for POI, poorly mimics ovarian physiology. Here, we examined whether human ovarian tissue implanted in an immune-isolating hydrogel-based capsule restored ovarian endocrine function in ovariectomized immunodeficient mice. Daily vaginal cytology, hormone measurements, and histological analysis demonstrated that the encapsulated xenografts integrated into themurine hypothalamic-pituitary-gonad axis and responded to circulating gonadotropins. Without exogenous stimulation, regular estrous cyclicity resumed 12 weeks postimplantation, and mice experienced three to eight estrous cycles in 20 weeks. Large antral follicles, ~3 millimeters in diameter, were present in the grafts, consistent with regular cyclicity and increasing levels of estradiol that reached 50 picograms per milliliter, demonstrating integration with the host physiology and restoration of ovarian endocrine function, similar to the nonencapsulated controls. copyright © 2026 the Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. no claim to original U.S. Government Works. distributed under a creative commons Attribution noncommercial license 4.0 (cc BY-nc) . INTRODUCTION The population of pediatric cancer survivors continues to grow, with an estimated 9000 new diagnoses in 2024 for children aged 0 to 14 (1, 2). This results in more children and teenagers being diagnosed with and surviving cancer, as well as living into adolescence and adulthood (1, 2). While having cancer in remission is a major milestone, it is important to consider the patient’s quality of life after treatment. Chemotherapy and radiation are particularly harmful to the nonrenewable follicular reserve in the ovaries (3) . Damage to the ovaries may prevent or delay development in these survivors, with 50% of this population experiencing health complications and infertility (3–6) . The lack of ovarian hormones leads to a cascade of other negative outcomes, including cardiac disease, osteopenia, growth hormone deficiency, loss of neuroprotection, dysregulated T cell function, premature epiphyseal closure, and imbalance in food intake and serum leptin levels (7–12) . The widespread systemic impact of the lost ovarian endocrine function stresses the importance of maintaining physiological feedback of ovarian hormones in female pediatric cancer survivors. Hormone replacement therapy (HRT) is the only approved treatment to induce puberty in adolescent patients in remission who experience premature ovarian insufficiency (POI) (13, 14). Using HRT for puberty induction in adolescent girls with POI has multiple limitations (15–19) . First, HRT supplies only two hormones, estradiol 1department of Biomedical engineering, University of Michigan, Ann Arbor, Mi, USA. 2division of Pediatric and Adolescent Gynecology, eunice Kennedy Shriver national institute of child health and human development, Bethesda, Md, USA. 3Program in cellular and Molecular Biology, University of Michigan, Ann Arbor, Mi, USA. 4department of chemistry, University of Michigan, Ann Arbor, Mi, USA. 5department of Pathology, case Western Reserve University cleveland, Oh, USA. 6department of Microbiology & immunology, University of Michigan, Ann Arbor, Mi, USA. 7department of Pediatrics & communicable diseases, University of Michigan, An

FAQs

What problem does the study address in pediatric cancer survivors?

Cancer treatments can damage the nonrenewable ovarian follicle reserve, leading to premature ovarian insufficiency and major downstream endocrine and health complications, including infertility.

Why is hormone replacement therapy considered insufficient in this context?

HRT provides only estradiol and progesterone at fixed levels, does not reproduce pulsatile and cyclic hormone fluctuations, and fails to mimic feedback within the hypothalamic-pituitary-gonadal axis.

How does the encapsulated xenograft approach aim to restore ovarian endocrine function?

Human ovarian tissue is implanted in an immune-isolating hydrogel capsule so it can integrate with the host hypothalamic-pituitary-gonad axis and respond to circulating gonadotropins, enabling cyclic hormone production and estrous cycling.

Sep 28, 2026

Uploaded by OmBimo