April 2018 Health Bulletin
Might bio-engineered ovaries soon replace menopausal hormone therapy?
A fascinating and elegant study has been reported in which 'hormone replacement' effects of an implanted bio-engineered ovary have been compared with that of giving standard hormone therapy to mature female rats that have had their own ovaries removed 1. In essence Sittadjody and collegues have investigated the possibility of a recreated ovary as an alternative to traditional menopausal hormone therapy (MHT).
Healthy premenopausal ovaries contain eggs which are surrounded by an inner layer of granulosa cells and an outer layer of thecal cells. The “look-alike” bioengineered ovaries contained cells isolated from immature rats and had an outer compartment of thecal cells and inner compartment of granulosa cells, but no eggs. Mature rats whose ovaries were surgically removed either had hormone pellets inserted to provide hormone therapy or an engineered ovary inserted into their intra-abdominal 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 high levels of the pituitary hormones FSH and LH, which are elevated at 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 the animals with ovaries removed 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 favours muscle mass over fat mass. This may well explain the observed beneficial effects on bone and body composition.
This research is a significant step towards creating a bio-ovary for management of menopause. But is this clinically feasible?
Firstly the ovaries were engineered from matching (isogenetic) cells implanted into rats of the same strain. We therefore cannot extrapolate these findings to the genetically diverse 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 own 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 their alleviate 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 body (her pituitary FSH and LH production), which in turn is under the control of higher brain networks?
With respect to safety, one needs to consider the effects of continuous hormone exposure on the breast and uterine lining. Continuous combined estradiol-progesterone therapy has been shown to increase breast cancer risk over time in large studies. In the present study, no assessments of mammary (breast) effects were presented. Although the implants did not result in adverse uterine lining effects, ensuring adequate uterine protection in women might be more complicated because different women need different levels of progesterone to prevent uterine wall thickening. Finally, although clumsy in comparison, presently available hormone therapy allows for immediate dose titration in response to symptom alleviation and side effects. Dose titration could present a major challenge with implanted ovarian constructs. Despite these potential limitations this work is pioneering and exciting.
- Sittadjody S, Saul JM, McQuilling JP, Joo S, Register TC, Yoo JJ, et al. In vivo transplantation of 3D encapsulated ovarian constructs in rats corrects abnormalities of ovarian failure. Nat Commun. 2017;8(1):1858.