Estetrol,Molecular Chaperones,and the Epigenetics of Longevity and Cancer Resistance

Introduction

The life span in mammals varies from a few years in rodents to more than 100 years in humans. The rapid evolution of longevity in mammals suggests the involvement of relatively few genes. Also the inherent immortality of embryonic stem cells in vitro suggests that replicative senescence, possibly as organismal aging, constitutes epigenetic phenomena

The molecular chaperones are housekeeping molecules essential for the folding, repair, and transport of proteins, RNA, and DNA. That the chaperones are probably involved in the evolution of longevity is supposed from the observation that the chaperones are essential for the process of cellular immortalization and that the level of expression of the chaperones correlate with the longevity of species as well as with the life span of differentiated cells in the organism. Weakening of the chaperone defense with age probably contributes to frailty in senescence. ¹

This review presents evidence that the human fetal estrogen hormone estetrol, by promotion of chaperone functions, homeostasis, and cancer resistance, may prove useful as a supplement during senescence.

Estetrol

Estetrol is an exclusively human estrogenic steroid hormone with four hydroxyl groups (thus explaining the acronym, E4). E4 is synthesized by the fetal liver only during pregnancy. E4 enters the maternal circulation via the placenta, causing the E4 level to increase exponentially to nanomolar levels at term, reflecting a 15- to 20-fold higher level in the fetus. ² The synthesis of E4 in the newborn ceases during the first weeks after birth. Estetrol is a metabolic end-stage product and as such does not convert to other estrogens or other active metabolites. Also E4 is unique by having a high oral bioavailability and a long half-life (28 hr) and by its absence of binding to the sex hormone–binding globulin. ³

Biological effects of E4

In animal model systems, E4 behaves as an estrogen in all tissues investigated, i.e., bone, vagina, myometrium, endometrium, brain, ⁴ and the cardiovascular system. ⁵ As for other estrogens, E4 probably promotes the expression of the molecular chaperones, such as GRP78, ⁶ GRP94, ⁷ HSP27, ⁸ and HSP70, ^9,10 For instance, HSP27 has been shown to protect against atherogenesis via an estrogen-dependent mechanism. ¹¹ Also a promotion of chaperone expression might contribute to the estradiol-dependent difference in life span between genders. The search goes on to find molecules that have the beneficial effects of estradiol, but without its feminizing effects. Good candidates to meet this challenge might be found among the phytoestrogens. ¹² E4 is an obvious alternative. Thus, even at the high E4 level of the fetus, this hormone does not feminize the male conceptus. Another remarkable property of E4 is that, while other estrogens tend to promote carcinogenesis, E4 was recently observed to prevent and suppress mammary tumors induced by 7,12-dimethylbenzαanthracene (DMBA) in a rat model. ¹³

Potential Clinical Applications for Estetrol

The biological effects of E4 have led to proposals that medication with this hormone might be useful for a number of clinical applications, including hormone replacement therapy, prevention and treatment of osteoporosis, and possibly prevention and treatment of cancer. ⁴ The optimal therapeutic E4 dose for medication against any of these disorders has not been established. However, exposure of postmenopausal women to single-dose oral estetrol in the range of 0.1–100 mg of E4 demonstrates a high oral bioavailability. Also, the long half-life (28 hr) suggests a slow metabolism of E4, in addition to signs of enterohepatic recirculation. The biological potency of E4 is reflected in a strong central inhibitory and dose-dependent effect on the gonadotropins. Estetrol was well tolerated at all dose levels and no safety problems were encountered. ¹⁴

Conclusions

Estetrol is a human fetal anticarcinogenic steroid hormone that is a supplement during a critical phase of human fetal development. Evidence presented on the biological effects of estetrol suggests that this hormone might as well be useful as a supplement during human senescence.