Welcome Estetrol – No Longer an Orphan Estrogen

Contraception, menopause, and cancer

After many years of neglect, estetrol has found applications in oral contraception, hormone replacement therapy, and maybe there is more to come. Is it crazy to hope that this natural estrogen can boost treatment of breast and prostate cancer? But, first, I will wind history back to the beginning of the story.

A family of three natural estrogens emerged a century ago from sex hormone research. The firstborn was E1, then came E2, and finally E3 for estrone, estradiol, and estriol, respectively. Water insolubility stymied formulation in pills until synthetic estrogens and conjugated equine estrogens (Premarin). A fourth estrogen was discovered in 1965 in a Karolinska Institute lab in Stockholm led by the eminent reproductive endocrinologist, Egon Diczfalusy. Elio Gurpide at the Rockefeller Institute in NYC also worked on this new steroid, calling it estetrol (E4) in 1966 because its synthesis in the human fetal liver involved enzymatic addition of a fourth hydroxyl group to the estriol molecule at position 15-alpha. No other tissue in humans or any in animals produces E4, which seeps across the placenta from the fetal circulation and vanishes soon after birth in mother and baby’s urine.

I have forgotten if I ever read about E4 earlier in my career. I’m sure I never mentioned it in lectures or books. And I suspect if I had taken an interest, no grant agency would have paid to study a molecule with no known function and reviewers would scoff at a “weak” estrogen. E4 was like a book no one wanted to read, lying forgotten on the top shelf of a library until a perceptive reader took it down.

I already knew Herjan Coelingh Bennink before he visited me in 2002 in Norfolk, Virginia. He came bearing news of a career change after leading a research division at Organon in the Netherlands. He described the frustration when company executives cancel promising compounds to avoid competition for sales with an existing product. The year before we met, Herjan made an exciting if risky leap out of the corporate world to launch his own company and develop drugs for reproductive endocrinology and oncology. He called it Pantarhei Bioscience (everything flows), recalling Heraclitus maxim that “no man ever steps in the same river twice.” Neither does science stop moving forward.

He made E4 a lead compound when pilot studies revealed it had intriguing properties. By 2008, he had enough data from animals and human subjects to publish a paper coauthored with Egon (retired by this stage) and Chris Holinka (with whom I collaborated on fetal mortality). Herjan had met Egon as head of the reproductive branch at the WHO many times during his office at Organon. Egon expressed joy at the revival of his discovery of estetrol during celebrations of Pantarhei’s fifth anniversary in Amsterdam in 2006.

The Pantarhei team found E4 is orally bioavailable in rats and humans and sufficiently water-soluble for a pill. After absorption, it circulates for many hours in the blood before elimination in the urine. It had minimal side effects on the liver, implying a low risk of blood clotting or drug interactions. Although not very potent biologically, it has trophic estrogenic effects on the uterus and suppresses pituitary gonadotropins like other steroid contraceptives. The two classical estrogen receptors and a non-genomic pathway mediate these actions. The minimal effects of the molecule on breast tissue captured more interest. It has an anti-estrogenic effect like raloxifene, a Selective Estrogen Receptor Modulator (SERM), and both can counteract the demineralization of bone from postmenopausal estrogen deficiency.

The case grew for E4 as an alternative to Premarin for HRT in combination with a progestin. HRT enjoyed huge popularity in the 1990s, but Herjan’s hopes fell victim to a scientific storm that threw estrogens on the rocks.

In 1991, the NIH’s Women’s Health Initiative (WHI) launched the largest women’s health research program in history (the program announced last week for the chopping block in a purge of federal funding). News headlines in 2002 were ablaze with interim results from a long study of women aged 50-70 taking HRT or a placebo. The hopes of program managers were dashed when estrogen failed to reduce coronary heart disease, which claims the lives of many women. Worse still, HRT-users had more strokes and breast cancer, and not much improvement in bone mineral density. An extensive study of women with hysterectomies treated with estrogen alone found a lower risk of mortality from breast cancer.

When data proved the risks of hormone therapy outweighed the benefits, the NIH canceled the program. Federal health authorities discouraged HRT for lessening the risks of heart disease or osteoporosis, assigning it a D score. Across the world, millions of women discarded the pills for alternative ways of controlling hot flashes and vaginal dryness.

The news forced Herjan to swing his goal from HRT to contraception. Laboratory tests and human subject studies showed it provided highly efficient defense against pregnancy with a progestin. It was well-tolerated, and the estrogen avoided breakthrough bleeding in the cycle. After 20 years of basic research and clinical trials, the new pill was approved by the FDA and in other territories. With that triumph under his belt, he returned to HRT, where the climate of scientific opinion had changed. Close examination of WHI data and follow-up studies have adjusted the balance of benefits versus hazards. It is now deemed safe for women under 60 to use HRT for short-term relief of symptoms, although reuptake remains low because good news seldom gets as much media attention as bad publicity.

E4 research is now fashionable. At my last count, there were 267 original or review papers cited in PubMed from numerous centers. Not a bad rate of adoption, even before a possible entry for reproductive cancer.

To claim that estrogen might help breast cancer patients may sound perverse outside a circle of reproductive endocrinologists. The original members of the estrogen family promote the disease in the 70% of estrogen receptor-positive cases. But why should E4 be any safer than the others? I already alluded to its “weakness,” responsible for past neglect, but that turns out to be an advantage. By competing with more potent estrogens for binding to receptors while only 1% as potent, it can serve as an anti-estrogen for existing breast cancer.

If it seems odd that an estrogen can neutralize other estrogens, it may sound more bizarre to use what is commonly called the female hormone for men with prostate cancer. But this is no paradox because estrogens have important roles in male physiology, albeit at low concentrations. Testosterone is the major driver of prostatic hypertrophy and carcinogenesis until target cells are unresponsive in advanced disease, so it made sense in the past to suppress gonadotropic stimulation of testicular androgens with E2 (or DES). However, patients were squeamish about the side-effects, so GNRH analogs are welcome alternatives for inducing hypoandrogenism instead of estrogens or physical castration. Since sex hormone deficiency causes bone demineralization, E4 might yet serve as an adjuvant with GNRH to reduce the risk of fractures in men too. This brings me to a cutting edge of research. Since the prostate has estrogen receptors, E4 might target cancer directly. We can’t predict whether positively or negatively, but the prospect excites me as a man at an age when risks of the disease are climbing fast. Research offers hope before shining light.

In an earlier article on Substack, I lamented the dawdling pace of contraceptive technology. Of course, there are many effective devices and drugs available but we haven’t had a major innovation in a long time. Drug companies are cautious about investing in new methods, easily discouraged by low efficiency or low compliance and by the need for extreme safety standards for young, healthy users. The launch of estetrol for contraception and HRT is therefore a cause for celebration, not so much for a novel technology or mechanism, but as the first new estrogen to enter clinical service in 50 years. A story that began with a leap of scientific curiosity about an orphan steroid required years of faith in patient study and investment before arriving for clinical service. I expect other worthy molecules are waiting on shelves for an inquisitive mind to take a close look at them.

Further reading in the current issue of Menopause.

Declaration: The author has no vested financial interest in Pantarhei or its affiliates. This article has been checked for accuracy by Prof. Dr. Coelingh Bennink.

Traditional gel chromatography for steroids (created with DALL-E).

Egon, Aless Graz, and Herjan (left to right) at the Menopause Congress in Amsterdam in 2010.