A concept for a new approach to combined oral contraception from adolescence to perimenopause: Continuous use of the oral GnRH antagonist Relugolix and the fetal estrogen Estetrol.

GnRH antagonists inhibit GnRH dose‐dependently by competition with GnRH for the GnRH receptor, and can suppress follicle‐stimulating hormone (FSH) and luteinizing hormone (LH), thereby ovarian function almost completely. As a result, estrogen levels (especially Estradiol) are decreased and a persistent amenorrhea occurs. The recent introduction of the safe and effective natural fetal estrogen, Estetrol, as the estrogenic component in a COC, 5 allows adding Estetrol to relugolix for estrogen substitution to create the new combination: RE4W. Estetrol differs from Estradiol and Ethinyl Estradiol by a high oral bioavailability, little effect on liver function and coagulation, and a favorable side‐effect profile. 4 , 5 , 6 , 13 , 14 Estetrol's potential ability to preserve cardiovascular health warrants further exploration of pathways such as annexin‐A1 induction. 15 Milestones in the history of Estetrol are its identification in 1965 by Egon Diczfalusy at the Karolinska Institutet in Stockholm, Sweden, its rediscovery and clinical development since 2001 by the first author of this article at Pantarhei Bioscience in the Netherlands, the market introduction of the first Estetrol‐containing COC in 2022, 13 and the approval of Estetrol for hormone replacement therapy (HRT) by the European Medicines Agency (EMA) in January 2026. 16 A major benefit of RE4W in addition to amenorrhea will be a smooth, unnoticed, and symptomless perimenopausal transition into the postmenopausal status, creating a life cycle endocrine management approach for women. Moreover, a reduced risk of Breast cancer is an expected important long‐term preventive effect of RE4W related to the absence of luteal progesterone and progestins.

The essential mode of action of all E/P COCs is the inhibition of hypothalamic GnRH pulsatility and release by the progestins, thereby suppressing the gonadotrophic hormones FSH and LH, resulting in ovulation inhibition and suppression of ovarian function. Progestins are also needed to transform the estrogen‐stimulated endometrium into a secretory state and enable endometrial shedding after progestin discontinuation. The estrogen in a COC primarily substitutes the loss of ovarian Estradiol, which is an essential hormone for women, but is also important for the regulation of endometrial growth and supports the progestin suppression by additional negative feedback on FSH and LH.

HCB: conceptualization and supervision; HCB, CLW, KGD: writing – original draft and revisions, KA, LGB, AG, DB, TB, YO, and SP: writing – revisions. All authors commonly agreed on the final version to be submitted.

In women, the reproductive system functions from on average 11 years of age at menarche until on average 51 years of age at menopause. Thereafter, women become victims of the loss of their ovarian Estradiol. On top of the essential hormones steering reproductive function is GnRH, secreted intermittently in a pulsatile manner by some 1000 neurons in the nucleus arcuatus of the hypothalamus, thereby stimulating the synthesis and secretion of FSH and LH by the anterior pituitary gland. 17 GnRH release itself is regulated by the kisspeptin–neurokinin–dynorphin system in the hypothalamus. This pulsatile GnRH secretion is one of many remarkable systems in the human body. 18 , 19 In women, the pulse‐interval is about 90 min. 20 Continuous GnRH as well as a too low or a too high GnRH pulse frequency does not work and the reproductive system is disrupted. 21 With appropriate GnRH pulsatility, FSH stimulates follicle growth in women, whereas LH stimulates testosterone synthesis by ovarian thecal cells. 22 Testosterone is metabolized by aromatization to Estradiol, but Testosterone levels during the menstrual cycle remain up to eight times higher than Estradiol levels, since women need Testosterone for optimal health and function. 23 , 24 In summary, the system depends upon pulsatile GnRH, FSH, and LH. The effects of Estradiol and Testosterone are seen in the typical body shapes, breast development in women, the hair growth patterns, gender‐related human behavior, reproduction, and sexual function.

The composition of RE4W is a tablet containing 40 mg relugolix, known to inhibit ovulation and ovarian function in all women exposed to this dose, 34 combined with a low dose of Estetrol for estrogen replacement. RE4W has to be taken daily without pauses and aims at amenorrhea without spontaneous or withdrawal bleedings. Two Phase 2 dose‐finding studies are planned in healthy cycling women aged 18–35 years (Group 1) and aged 36–51 years (Group 2). Participants will be treated for 84 consecutive days with 40 mg relugolix, and either 4, 8, or 12 mg Estetrol. Inhibition of ovulation by 40 mg relugolix will be confirmed, and the Estetrol dose that replaces estrogen function optimally and does not cause unacceptable endometrial growth and/or breakthrough bleeding will be selected for further clinical investigations. In the Phase 2 studies, bone biochemistry using markers for resorption and formation of bone will be tested. Later in Phase 3, bone mass will be investigated in a subgroup of study participants and fracture rates will follow in postmarketing follow‐up studies. Phase 3 development will also focus on the Pearl Index (No. of pregnancies per 100 women‐years of use), assessed in an adequate number of women using RE4W for 1 year. Venous thromboembolism (VTE) is the most important risk factor of any estrogen containing oral contraceptive, especially in the older age group also targeted by RE4W. Increasing evidence suggests that the VTE risk with Estetrol is lower than with other estrogens in a COC, 14 while E4 has shown to have a limited impact on hemostasis in postmenopausal women. 36 In the RE4W studies hemostasis will be tested regularly and VTE will be registered carefully. When used as a contraceptive and pregnancy is wanted, RE4W is discontinued. As shown in relugolix CT studies, the first ovulation occurs around 3 weeks after discontinuation, 34 and therefore forgetting pills occasionally will not result in unwanted pregnancies. Return of ovulation after discontinuation of RE4W will also be investigated in the planned Phase 2 study.

We searched the literature for relevant publications, using the combination of terms as GnRH, estrogen, women's health, and contraception. The GnRH antagonist/estrogen combinations found include a progestin for endometrial safety and are also indicated to relieve endometriosis‐associated pain or heavy menstrual bleeding associated with uterine fibroids. 31 , 32 , 33 A once‐daily oral dose of relugolix combination therapy (40 mg relugolix, 1 mg Estradiol and 0.5 mg norethindrone acetate) inhibits ovulation in all women who completed the 84‐day treatment period. 34 The 1 mg Estradiol dose in relugolix Combination Therapy is considered sufficient to maintain bone health, but long‐term confirmation is required. 35

The expected benefits and concerns regarding RE4W are summarized in Box  1 . Major advantages of RE4W are: (i) the expected lower incidences of breast cancer, by avoiding progesterone from the natural cycle and progestins from E/P or P‐only contraception, (ii) a lower risk of endometriosis by avoiding tubal retrograde endometrial shedding into the abdomen, and (iii) improved symptom control and cycle management for women with established polycystic ovary syndrome (PCOS), with potential additional benefit on androgen‐related symptoms and cardiometabolic risk factors. The induced amenorrhea prevents menstrual cycle‐related disorders such as menstrual bleeding disorders, dysmenorrhea, menstrual cycle‐related migraine, premenstrual syndrome (PMS), and premenstrual dysphoric disorders (PMDD). The amenorrhea and estrogen substitution of RE4W prevent perimenopausal problems. There will be no menopause and RE4W will enable a smooth and unnoticed shift from contraception to postmenopausal estrogen treatment. The perimenopausal transition is accompanied by many symptoms such as vasomotor hot flushes, urogenital symptoms, mood disorders, and irregular bleeding, 37 , 38 all expected to be relieved by RE4W. The additional advantages of RE4W are expected to be those of E/P contraceptives, 39 and include apart from the benefits already mentioned above, the following established advantages of E/P Pills: less ovarian cysts, a lower risk of ectopic pregnancy, less uterine fibroids, a lower incidence of pelvic inflammatory disease (PID), less benign breast disease, higher bone mass and less osteoporosis, a less serious course of disease in multiple sclerosis, rheumatoid arthritis, asthma, and porphyria, and a lower risk of cancer of the ovary (up to 80%) and colon (up to 15–20%). Most of these additional E/P advantages are related to the substitution of the natural cycle by the E/P Pill cycle and no cycle at all, as is the case with RE4W, may further increase the magnitude of these beneficial effects. However, most of these effects are not subjective and contraceptives are often judged on subjective side effects such as mood and libido changes. These subjective problems may be related to the loss of testosterone, occurring with E/P COC's as well as with RE4W. This could potentially be solved by adding 50 mg dehydroepiandrosterone (DHEA) to RE4W. This dose has shown to maintain physiological free and total testosterone levels and to improve sexual function in women using EE‐COCs, known to reduce androgen levels. 23 , 24 A potential concern about RE4W without progestins is breakthrough bleeding, endometrial hyperplasia, and endometrial cancer, the latter being reduced by the E/P COC's by 25–30%. 39 This will be evaluated during the further development of RE4W and is an important reason to aim for the lowest effective dose of Estetrol. A strategy will be developed to address these issues depending on the results of clinical studies, and occasional 10–14 days progestin courses may be required to shed the endometrium once per 6–12 months. Immediate additional benefits No irregular and unpredictable menstrual bleeding No dysmenorrhea No premenstrual syndrome (PMS) No premenstrual dysphoric disorders (PMDD) No menstrual cycle‐related migraine No hyperandrogenicity Suitable as perimenopausal contraception Suitable as postpartum contraception Since it takes about 3 weeks until ovulation after discontinuation of RE4W, forgetting pills occasionally will not interfere with contraceptive efficacy. (Peri)menopause‐related beneficial effects Smooth and unnoticed transfer from the pre‐ to the postmenopausal status No menopause No perimenopausal bleeding problems or symptoms Same advantages as combined estrogen/progestin oral contraception Less ovarian cysts Relieve of symptoms of polycystic ovary syndrome (PCOS) Less endometriosis and slower progression Lower risk of ectopic pregnancy Less uterine fibroids and slower growth Lower incidence of pelvic inflammatory disease (PID) Less benign breast disease Higher bone mass and less osteoporosis Less serious course of the disease in multiple sclerosis, rheumatoid arthritis, asthma and porphyria Less ovarian cancer (up to 80% with E/P COC's) Less colon cancer (up to 20% with E/P COC's) Specific long‐term oncological effect Less breast cancer Possible concerns Endometrial safety (hyperplasia; endometrial cancer) due to the “estrogen‐only” concept Occasional induction of a withdrawal bleeding and endometrial shedding by 10–14 days progestin treatment may be necessary No irregular and unpredictable menstrual bleeding No dysmenorrhea No premenstrual syndrome (PMS) No premenstrual dysphoric disorders (PMDD) No menstrual cycle‐related migraine No hyperandrogenicity Suitable as perimenopausal contraception Suitable as postpartum contraception Since it takes about 3 weeks until ovulation after discontinuation of RE4W, forgetting pills occasionally will not interfere with contraceptive efficacy. Smooth and unnoticed transfer from the pre‐ to the postmenopausal status No menopause No perimenopausal bleeding problems or symptoms Less ovarian cysts Relieve of symptoms of polycystic ovary syndrome (PCOS) Less endometriosis and slower progression Lower risk of ectopic pregnancy Less uterine fibroids and slower growth Lower incidence of pelvic inflammatory disease (PID) Less benign breast disease Higher bone mass and less osteoporosis Less serious course of the disease in multiple sclerosis, rheumatoid arthritis, asthma and porphyria Less ovarian cancer (up to 80% with E/P COC's) Less colon cancer (up to 20% with E/P COC's) Less breast cancer Endometrial safety (hyperplasia; endometrial cancer) due to the “estrogen‐only” concept Occasional induction of a withdrawal bleeding and endometrial shedding by 10–14 days progestin treatment may be necessary

After 65 years since the introduction of the first combined oral contraceptive pill, the progestins can be replaced by the oral GnRH antagonist relugolix, and the loss of estradiol can be compensated by the human fetal estrogen estetrol. The new RE4W combination has many potential advantages, especially the absence of menstrual cycle‐related problems and disorders, and the expected lower incidences of breast cancer, endometriosis, and adenomyosis and prevention/treatment of symptoms of polycystic ovary syndrome. Phase 2 dose‐finding studies will reveal the minimal effective and endometrial safe dose of estetrol to be combined with 40 mg relugolix, known to inhibit ovarian function completely in all women treated. Final confirmation of efficacy and safety requires further Phase 3 studies, although both relugolix and estetrol already have an established safety and efficacy record in several human applications. In summary, RE4W will enable women to control their fertility, will provide continuous amenorrhea and may reduce the risk of breast cancer. It has comparable advantages to the present E/P COC's and offers a smooth transition through perimenopause into the postmenopause.

It has been 65 years now since the first combined oral contraceptive pill, Enovid, was introduced for female contraception. This remarkable invention has changed the lives of women worldwide. It enabled women to take control over their own fertility independent of their heterosexual partners. This first “Pill,” as it became known and is today, was developed in the USA through a collaborative effort of the biologists Gregory Pincus and Min Chueh Chang focusing on the scientific aspects; the Catholic gynecologist John Rock conducting clinical trials; and Catherine Dexter McCormick providing financial support. Margaret Sanger, a birth control advocate, played a key role in bringing these individuals together and initiate the project. The chemist Carl Djerassi developed several synthetic progestins used in the Pill to inhibit ovarian function. New developments in the composition of combined estrogen/progestin (E/P) oral contraceptives (COC) have focused on (i) reduction of the dose of ethinylestradiol (EE), the estrogen used in the pill since 1960, (ii) the introduction of the natural estrogens estradiol and estetrol as the estrogen component, and (iii) new progestins with potentially fewer side effects. The first pill, Enovid, contained 150 μg of the estrogen mestranol, and 9.85 mg of the progestin norethynodrel; dosages decreased soon after the introduction to 75 μg and 5 mg, respectively. Over the last 65 years, the daily dose of EE has been lowered to 10–30 μg to reduce estrogenic side effects. 1 Replacing EE by 1.5 mg Estradiol or 1–3 mg Estradiol‐valerate led to a reduction of cardiovascular and thromboembolic side effects. 2 However, due to liver metabolism, the oral bioavailability of Estradiol and Estradiol Valerate is only 5%, whereas the other 95% is metabolized into estrone and Estrone‐sulfate. 3 Since 2022, the fetal estrogen Estetrol has been available as the estrogen component in a COC. 4 , 5 , 6 Estetrol has an oral bioavailability of 70–80% and a half‐life of 20–28 h. Because progestins may have intrinsically different (anti‐)androgenic effects and cross‐reactivity with other hormone receptors, progestins often have side effects such as nausea, fatigue, headache, peripheral edema, body weight fluctuations, bloating and abdominal discomfort, breast tenderness, and acne. Therefore, after the first progestin, norethynodrel, many new progestins were developed to find a compound with fewer side effects (Table  1 ). Profile various progestins and degree of cross‐reactivity to other hormone receptors. Note : The present table is an adaptation of a table published by Zaman et al. 40 Positive effect: agonist; Weak: weak effect; No: no effect; Negative effect: antagonist. It has been shown that the natural hormone progesterone from the luteal phase of the menstrual cycle is an important cause of breast cancer. 7 When Progesterone is replaced by progestins as in COC's or in E/P postmenopausal treatment, the Breast cancer risk is the same or even somewhat higher. 8 , 9 , 10 The introduction of oral gonadotropin‐releasing hormone (GnRH) antagonists, such as relugolix, linzagolix, and enzagolix has created the possibility to replace the progestins in COC's as the suppressor of ovarian function and avoid the side effects of the progestins. 11 , 12

In addition to GnRH, FSH, LH, Estradiol, and Testosterone, there is progesterone, a sixth human hormone essential for reproduction and present only in women. Progesterone plays a vital role during the luteal phase of the menstrual cycle and throughout pregnancy and the only reason for the existence of Progesterone is to make pregnancy possible and maintain pregnancy until term. Counteracting the effect of Progesterone at any time during pregnancy results in termination of pregnancy. Progesterone is the major cause of the subjective side effects during the luteal and premenstrual phase of the menstrual cycle and during pregnancy. However, Progesterone is also the major cause of Breast cancer in women by inducing mutations in normal breast epithelium. 7 , 25 This is due to the stimulation by Progesterone of the paracrine factors WNT4 and RANKL and the upregulation of the expression of the DNA mutator enzyme APOBEC3B in normal breast epithelium during the luteal phase of the menstrual cycle. 26 These effects of P4 increase the accumulation of mutations in long‐lived mammary stem and progenitor cells. The human body has DNA repair genes such as the BRCA1 and BRCA2 to remove the mutations caused by Progesterone. These genes on chromosome 17 produce proteins that act as tumor suppressors, primarily by repairing damaged DNA and maintaining genomic stability through the homologous recombination repair pathway. Mutations in these BRCA genes compromise this repair mechanism, resulting in 55–72% Breast cancer with a BRCA1 mutation and 45–69% Breast cancer with a BRCA2 mutation by age 70 in women with mutated BRCA genes. 27 The mitotic effect of Progesterone is confirmed by breast mitotic activity determined by the Ki‐67 marker, which is highest during the midluteal phase of the menstrual cycle corresponding with the highest Progesterone levels. 28 Estrogens have only mild proliferative effects on normal breast epithelium, and are therefore, unlikely to cause Breast cancer, but can stimulate already existing estrogen receptor positive (ER+) Breast cancer. Important for differentiating between causality and stimulation is the understanding that it takes at least about 10 years from a mutation in normal breast epithelium until the resulting breast tumor has reached a diameter of about 1 cm and can be diagnosed. Just like Progesterone, progestins can cause Breast cancer by the same mutagenic effects as those of Progesterone on normal breast epithelium, but also in this case it takes at least 10 years until the progestin‐induced Breast cancer is large enough to be diagnosed. 29 Apart from causing Breast cancer, progestins can also stimulate existing Progestrone‐receptor positive Breast cancer, and different progestins may have different stimulatory effects on Progesterone receptor‐positive Breast cancer. 30 Nationwide Danish and Swedish studies confirm the stimulatory role of progestins of existing Breast cancer and reveal that the Breast cancer risk in COC users is significantly increased compared with non‐users [RR 1.21 (95% CI: 1.11–1.33) and HR 1.12 (95% CI: 1.07–1.17), respectively], and strongly related to the duration of use. 8 , 9 Duration of COC use of at least more than 10 years may induce new Breast cancers caused by progestins. 10

HCB is affiliated with the Karolinska Institutet, has retired as President of Pantarhei Bioscience, and is currently President of Pandora Endocrine Innovation BV (PEI), a company involved in the development of new female and male hormonal contraceptives. LB has served on Medical Advisory Boards and gave ad hoc invited lectures for Organon and Bayer. AG has participated in speakers' bureaus for Bromatech and Novo Nordisk; participated in advisory boards for Astellas Pharma, Mylan and Uriach; and served as a consultant for Astellas Pharma, Fagron, Mylan and Uriach. DB has provided clinical education at events sponsored by Bayer Healthcare, Besins and Mayne Pharma and received support to attend an educational event from Organon Australia. TB is President of the European Society of Contraception and Reproductive Health and Secretary of the Portuguese Society of Contraception, had received consulting fees and speaker's honoraria from Bayer HC, Exelgyn, Organon, and Gedeon Richter. SP has received consulting fees and speaker's honoraria from Shionogi and Bayer HC, Exeltis, Gedeon Richter, NovoNordisk, Procare H, Serelys, Lacer, Sandoz, Pfizer, and Theramex. KGD reports ad hoc presentations or participation on advisory boards for Bayer, Organon, Gedeon Richter, Natural Cycles, Exelgyn, Exeltis, Cirqle, RemovAid, and Obseva. CLW served as consultant to Merck, Bayer, AbbVie, Therapeutics MD, and HRAPharma; and received research support from Estetra SPRL, Sebela, Chemoresearch, Exeltis, and Medicines360, all managed through Columbia University. KGD is also director of the WHO collaborating center at Karolinska Institutet, and a member of the International Committee for contraceptive research (ICCR), Population Council, past president of the European Society of Contraception and Reproductive Health, and FIAPAC, and the FIGO council. KA and YO have nothing to declare.