Sittadjody and colleagues  have undertaken a fascinating and elegant study in which they have compared the ‘hormone replacement’ effects of an implanted bioengineered ovary with that of exogenous hormone therapy in mature females rats that have had their own ovaries removed. In essence, they have investigated the possibility of a recreated ovary as an alternative to traditional menopausal hormone therapy (MHT). Healthy premenopausal ovaries contain oocytes (eggs) which are surrounded by granulosa cells and an outer layer of thecal cells. The bioengineered ovaries contained cells isolated from immature rats and had an outer compartment of thecal cells and an inner compartment of granulosa cells, but no oocytes. Mature rats whose ovaries were surgically removed either had hormone pellets inserted or an engineered ovary inserted into their intra-fat. The animals were monitored for 90 days and hormone levels compared with those of untreated animals with intact ovaries. As expected, the animals whose ovaries were removed and did not receive any therapy had very low sex hormone levels (estradiol, progesterone and testosterone) and low levels of inhibin, a hormone produced by healthy ovaries. They also had elevated levels of the pituitary hormones FSH and LH, which characterize menopause. Over 90 days, the animals that received the bioengineered ovaries had levels of estradiol, progesterone, testosterone and inhibin that were intermediate between synthetic hormone replacement of oophorectomized animals and intact animals. They also had maintenance of bone health and body composition ( were less likely to gain central fat) despite lower estradiol and progesterone levels. The implanted ovarian constructs also produced testosterone, which is anabolic in bone and favors muscle mass over fat mass. This may well explain the observed beneficial effects on bone and body composition. The researchers hypothesized that the bioengineered ovary recreated a feedback loop between the pituitary and the implanted cells. This is perhaps a bit fuzzy – FSH and LH levels fell but then what trophic factors were stimulating the ongoing sex steroid production of the implanted cells? This research is a significant step towards creating a bio-ovary for management of menopause. But is this clinically feasible?
First, the ovaries were engineered from isogenetic cells implanted into rats of the same strain. We therefore cannot extrapolate these findings to the genetically heterogeneous human population. Not only do women have large differences in their ovarian sex hormone production, but they are also have very variable responses to their endogenous hormones, as well as to sex steroid therapy. For example, some women have complete resolution of their menopausal symptoms with extremely low-dose estrogen therapy, but experience breast fullness and pain with low doses, whereas other women need very high-dose estrogen to alleviate their symptoms and do not experience adverse effects with high-dose therapy.
The question is whether a bioengineered ovary would produce hormones in amounts pre-programmed by the cells contained in the capsule or in response to stimulation from each individual woman’s FSH and LH production, which in turn is under the control of hypothalamic networks? With respect to safety, one needs to consider the effects of continuous hormone exposure on the breast and endometrium. Continuous combined estradiol-progesterone therapy has been shown to increase breast cancer risk over time in large observational studies. In the present study, no assessments of mammary (breast) effects were presented. Although the implants did not result in adverse endometrial effects, ensuring adequate endometrial protection in women might be more complicated because different women need different levels of progesterone to prevent endometrial proliferation. Finally, although clumsy in comparison, exogenous hormone therapy allows for immediate dose titration in response to alleviation of symptoms and side-effects. Dose titration could present a major challenge with implanted ovarian constructs. Despite these potential limitations this work is pioneering and exciting.
Susan R. Davis
Women’s Health Research Program, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
Sittadjody S, Saul JM, McQuilling JP, et al. In vivo transplantation of 3D encapsulated ovarian constructs in rats corrects abnormalities of ovarian failure. Nat Commun 2017;8:1858