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Loss of ovarian function (e.g., due to menopause) leads to profound physiological effects in women including changes in sexual function and osteoporosis. Hormone therapies are a known solution, but their use has significantly decreased due to concerns over cardiovascular disease and certain cancers. We recently reported a tissue-engineering strategy for cell hormone therapy (cHT) in which granulosa cells and theca cells are encapsulated to mimic native ovarian follicles. cHT improved physiological outcomes and safety compared to pharmacological hormone therapies in a rat ovariectomy model. However, cHT did not achieve estrogen levels as high as ovary-intact animals. In this report, we examined if hormone secretion from cHT constructs is impacted by incorporation of bone marrow-derived mesenchymal stem cells (BMSC) since these cells contain regulatory factors such as aromatase necessary for estrogen production. Incorporation of BMSCs led to enhanced estrogen secretion in vitro. Moreover, cHT constructs with BMSCs achieved estrogen secretion levels significantly greater than constructs without BMSCs in ovariectomized rats from 70 to 90 days after implantation, while also regulating pituitary hormones. cHT constructs with BMSC ameliorated estrogen deficiency-induced uterine atrophy without hyperplasia. The results indicate that inclusion of BMSC in cHT strategies can improve performance.

Safe clinical hormone replacement (HR) will likely become increasingly important in the growing populations of aged women and cancer patients undergoing treatments that ablate the ovaries. Cell-based HRT (cHRT) is an alternative approach that may allow certain physiological outcomes to be achieved with lower circulating hormone levels than pharmacological means due to participation of cells in the hypothalamus-pituitary-ovary feedback control loop. Here we describe the in vivo performance of 3D bioengineered ovarian constructs that recapitulate native cell-cell interactions between ovarian granulosa and theca cells as an approach to cHRT. The constructs are fabricated using either Ca ++ or Sr ++ to crosslink alginate. Following implantation in ovariectomized (ovx) rats, the Sr ++ -cross-linked constructs achieve stable secretion of hormones during 90 days of study. Further, we show these constructs with isogeneic cells to be effective in ameliorating adverse effects of hormone deficiency, including bone health, uterine health, and body composition in this rat model.