Estetrol (medication)
Estetrol is an estrogen medication and naturally occurring steroid hormone which is used in combination with a progestin in combined birth control pills and is under development for various other indications. These investigational uses include menopausal hormone therapy to treat symptoms such as vaginal atrophy, hot flashes, and bone loss and the treatment of breast cancer and prostate cancer. It is taken by mouth.
Estetrol is a naturally occurring and bioidentical estrogen, or an agonist of the estrogen receptor, the biological target of estrogens like endogenous estradiol. Due to its estrogenic activity, estetrol has antigonadotropic effects and can inhibit fertility and suppress sex hormone production and levels in both women and men. Estetrol differs in various ways both from other natural estrogens like estradiol and synthetic estrogens like ethinylestradiol, with implications for tolerability and safety. For instance, it appears to have minimal estrogenic effects in the breasts and liver. Estetrol interacts with nuclear ERα in a manner identical to that of the other estrogens and distinct from that observed with Selective Estrogen Receptor Modulators.
Estetrol was first discovered in 1965, and basic research continued up until 1984. It started to be studied again as well as investigated for potential medical use in 2001, and by 2008, was of major interest for possible medical use. As of 2021, estetrol is in mid- to late-stage clinical development for a variety of indications.
Available forms
Estetrol is available in combination with drospirenone in the following formulations, brand names and indications:- Estetrol 15 mg and drospirenone 3 mg Nextstellis – combined oral contraception
- Estetrol 15 mg and drospirenone 3 mg Drovelis – combined oral contraception
- Estetrol 15 mg and drospirenone 3 mg Lydisilka – combined oral contraception
Side effects
Estetrol-containing birth control pills, similarly to estradiol-containing birth control pills, may have a lower risk of venous thromboembolism than ethinylestradiol-containing birth control pills based on studies of coagulation. However, it is likely that another decade will be required before post-marketing epidemiological studies of VTE incidence with these birth control pills are completed and able to confirm this.
Pharmacology
Pharmacodynamics
Estetrol is an agonist of the estrogen receptors, and hence is an estrogen. It has moderate affinity for ERα and ERβ, with Ki values of 4.9 nM and 19 nM, respectively. As such, estetrol has 4- to 5-fold preference for ERα over ERβ. For comparison, the potent nonsteroidal estrogen diethylstilbestrol showed higher affinities for ERs, with Ki values of 0.286 nM for ERα and 0.199 nM for ERβ. Similarly, estetrol has low affinity for ERs relative to estradiol, and thus both estetrol and the related estrogen estriol require substantially higher concentrations than estradiol to produce similar effects. The affinity of estetrol for ERs is about 0.3% to 6.25% of that of estradiol, and its in vivo potency in animals is about 2 to 3% of that of estradiol. In women, estetrol has been found to be approximately 10 to 20 times less potent orally than ethinylestradiol, the most potent oral estrogen available. The high oral potency of estetrol in women in spite of relatively low affinity for the ERs is related to its high metabolic stability and favorable pharmacokinetics.Estetrol shows high selectivity for the ERs. It showed only 11 to 15% occupation of the androgen, progesterone, and glucocorticoid receptors at a very high concentration of 10 μM. In addition, estetrol showed no affinity for a set of 124 receptors and enzymes, with the sole exception of very weak affinity for the α1B-adrenergic receptor. Due to its high selectivity for the ERs, estetrol is anticipated to have a low risk of undesirable off-target activity and associated side effects. Furthermore, estetrol showed no inhibition of the major cytochrome P450 enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 at a very high concentration of 10 μM, unlike estradiol and ethinylestradiol. Conversely, estetrol moderately stimulated CYP3A4, while estradiol strongly stimulated CYP3A4 and ethinylestradiol moderately inhibited the enzyme. These findings suggest that estetrol has a low potential for drug interactions, including a lower potential than estradiol and particularly ethinylestradiol.
Differences from other estrogens
Estetrol has potent estrogenic effects in bone, vagina, uterus, arteries, and certain areas of the brain like the pituitary gland and hypothalamus. It has comparable efficacy to ethinylestradiol on bone turnover and hot flashes and to estradiol valerate on vaginal atrophy. In addition, estetrol has stimulatory effects on the endometrium and poses a risk of endometrial hyperplasia and endometrial cancer similar to other estrogens. Conversely, the effects of estetrol in certain other tissues such as breast/mammary gland, liver, vascular tissue, and various brain areas differ, with weakly estrogenic or even antiestrogenic effects occurring in such tissues. Based on its mixed effects in different tissues, estetrol has been described as a unique, "natural" estrogen, demonstrating absence of specific membrane receptor effects, and an interaction with ERα different from SERMs.Estetrol has a low estrogenic effect in breast/mammary gland, and when administered in combination with estradiol, antagonizes the effects of estradiol. Relative to estradiol, estetrol shows 100-fold lower potency in stimulating the proliferation of human breast epithelial cells in vitro and of mouse mammary gland cells in vivo. In animal models, estetrol shows antiestrogenic effects, antagonizing the stimulatory effects of estradiol and preventing tumor development in a 7,12-dimethylbenzanthracene mammary tumor model. As such, it is anticipated that estetrol may cause minimal proliferation of breast tissue and that it may be useful in the treatment of breast cancer.
Estetrol has relatively minimal effects on liver function. In contrast to estradiol and ethinylestradiol, estetrol does not stimulate the hepatic production of SHBG in vitro. In addition, it has been found to produce minimal changes in liver protein synthesis in women relative to ethinylestradiol, including production of sex hormone-binding globulin, corticosteroid-binding globulin, angiotensinogen, ceruloplasmin, cholesterol, triglycerides, estrogen-sensitive coagulation proteins, insulin-like growth factor 1, and insulin-like growth factor-binding proteins. In a clinical study, 10 mg/day estetrol showed only 15 to 20% of the increase of 20 μg/day ethinylestradiol on SHBG and AGT levels. For comparison, it has been reported that a dosage of estradiol that is of similar potency to ethinylestradiol in terms of suppression and hot flash relief possesses about 25% of the potency of ethinylestradiol on SHBG increase and about 35% of the potency of ethinylestradiol on AGT increase. Estetrol has shown only minor effects on hemostatic biomarkers, including both on coagulation and fibrinolysis. Due to its minimal influence on liver function, estetrol is expected to have a lower risk of venous thromboembolism, a serious but rare adverse effect of all known estrogens, and other undesirable side effects. Also, oral estrogens like ethinylestradiol are associated with a reduction in lean body mass due to suppression of hepatic IGF-1 production, and this may not be expected with estetrol.
Estetrol has potent estrogenic effects in the brain in terms of relief of hot flashes, antigonadotropic effects, and ovulation inhibition. However, animal studies investigating the effects of estetrol on levels of allopregnanolone and β-endorphin in various brain areas have shown weak estrogenic effects when given alone and antiestrogenic effects in the presence of estradiol, suggesting that estetrol may have SERM-like effects in some regions of the brain by mediating weak estrogenic effects on the levels of allopregnanolone and β-endorphin when administered alone, or by causing antiestrogenic effects in the presence of estradiol in-vivo. Estetrol has mixed effects in the vascular system similarly. It has been found to have estrogenic effects on atheroma prevention in arteries, but has antiestrogenic effects against estradiol-induced endothelial nitric oxide synthase activation and acceleration of endothelial healing.