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Estretol (E4) is a relatively recently discovered (1965) human estrogenic hormone. In view of this, its effects on menopausal symptoms need to be fully established in menopause hormone therapy. Recently, Gaspard et al. [1] performed a double blind, randomized, placebo controlled study aimed at evaluating the effects of E4 15 mg on vaginal cytology, genitourinary syndrome of menopause (GSM), and health-related quality of life (HR-QoL) of postmenopausal women. For this the investigators enrolled as study group apparently healthy postmenopausal women (n= 257) aged 40 to 65 years to receive oral E4 (at different dosages) or placebo for 12 weeks, in order to compare their effects. In this paper, authors focus on the E4 15 mg dosage. The authors assessed menopausal symptoms with the Menopause Rating Scale (MRS), a menopause-specific HR-QoL questionnaire, measured vaginal pH and collected vaginal PAP smears at baseline and at the end of the study. Genitourinary symptoms were self-scored by women using an e-diary at baseline and at week 12. Vaginal dryness, vaginal and/or vulvar irritation/itching, dysuria, and vaginal pain associated with sexual activity (dyspareunia) were scored as 0 (none), 1 (mild), 2 (moderate), or 3 (severe). Regarding the MRS, three symptom domains were explored: psychological, somato-vegetative and urogenital. The study found that at the end of the study the mean percentages of parabasal and intermediate vaginal cells decreased, whereas superficial cells increased for those receiving E4. E4 also decreased intensity scores for vaginal dryness and dyspareunia, representing a decrease of 41% and 50%, respectively, and shifted to milder intensity categories. Overall MRS scores decreased in women who took E4 15 mg. The authors conclude that oral E4 15 mg demonstrated estrogenic effects in the vagina and decreased signs of atrophy, suggesting this drug as a promising treatment option for women who present important menopausal symptoms other than vasomotor.


Due to estrogen deficiency, postmenopausal women suffer from several menopausal symptoms such as hot flushes, night sweats, vulvovaginal dryness, dyspareunia, repeated urinary tract infections, dysuria, musculoskeletal pain, short term impaired memory and overall impairment of their QoL. To ameliorate their distress, estrogen represents a blessing. The 2022 update of the NAMS Hormone Therapy Position Statement confirmed that hormone therapy remains the most effective treatment for vasomotor symptoms (VMS) and the GSM [2]. E4 is produced by the human fetal liver and is a native estrogen with selective tissue activity [3]. The high oral availability of E4 and its long elimination half-life of between 24 and 32 hours are important prerequisites for administration of a once-daily oral drug. Since E4 is a promising drug its evaluation is fully warranted. Previously, oral E4 15 mg once daily demonstrated to be an effective dosage for alleviating VMS [4]. In the present commented paper is also showed a beneficial effect on vaginal cytology and maturation, vaginal dryness, vaginal pain with sexual activity, and QoL, in particular on somato-vegetative and psychological symptoms commonly observed with estrogen deprivation in postmenopausal women.

As E4 is a promising drug; the results of this study are eye opening for all. It has been reported that systemic estrogen improves genitourinary symptoms more effectively than local estrogen treatment [5]; this opinion is not universal, and not a recommendation of North American Menopause Society (NAMS) [2]. The study in question [1] clearly demonstrated that vaginal superficial cells increased at 12 weeks with oral E4 15 mg (+36.8%). This was higher than the rate reported with local treatment with E2 vaginal soft gel capsules 10 μg (+17.9%) or E2 vaginal tablets (+15%) [6]. E4 15 mg also decreased parabasal and intermediate vaginal cells, −10.81% and −20.96%, respectively. E4 at the same dosage also decreased the intensity score for vaginal dryness and dyspareunia. HR-QoL improved as determined by a decrease of the overall MRS score. Interesting, these improvements were observed since week 4 of treatment, with improvement seen in all 3 domains of the MRS, especially somato-vegetative [VMS] but not bladder problems. The aforementioned effects were maximal with E4 15 mg with significant differences observed compared to placebo at week 4.

The results of the present study [1] are in alignment with the NAMS statement indicating that local or systemic estrogen administration is the most effective therapy to alleviate GSM [7], and also with those of Palacios et al. [8] showing that QoL of menopausal women improved with systemic hormone therapy. They experienced fewer and less severe vulvovaginal symptoms compared with women who received no hormone or local therapy [8]. The only point to be noted is that the commented study could not show any direct comparison of E4 with other oral or vaginal estrogens in the global population of postmenopausal women. This limitation has been acknowledged by the authors.

In conclusion, E4 demonstrated its estrogenic effects in the vagina through decreasing signs of atrophy. Oral E4 at a dose of 15 mg therefore presents a promising new treatment option for important menopausal symptoms other than VMS. Nevertheless, there is a need for more multicenter studies to validate the beneficial effects of E4.

Shaikh Zinnat Ara Nasreen, MBBS, MPH, FCPS, MRCOG, FRCOG, FIAOG
Professor and Head of Obstetrics and Gynecology
Z H Sikder Women’s Medical College & Hospital, Daca, Bangladesh


  1. Gaspard U, Taziaux M, Jost M, et al. A multicenter, randomized, placebo-controlled study to select the minimum effective dose of estetrol in postmenopausal participants (E4Relief): part 2-vaginal cytology, genitourinary syndrome of menopause, and health-related quality of life. Menopause. 2023 Feb 21. doi: 10.1097/GME.0000000000002167.
  2. “The 2022 Hormone Therapy Position Statement of The North American Menopause Society” Advisory Panel. The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. 2022;29(7):767-794.
  3. Foidart JM, Lobo RA, Rosing J, et al. Estetrol (E4) is a unique native estrogen that does not modify coagulation markers in postmenopausal women and maintains sensitivity to activated protein C (APC). Menopause. 2019;26:1464-1465.
  4. Gaspard U, Taziaux M, Mawet M, et al. A multicenter, randomized study to select the minimum effective dose of estetrol (E4) in postmenopausal women (E4Relief): part 1. Vasomotor symptoms and overall safety. Menopause. 2020;27(8):848-857.
  5. Panay N, Palacios S, Bruyniks N, Particco M, Nappi RE; EVES Study investigators. Symptom severity and quality of life in the management of vulvovaginal atrophy in postmenopausal women. Maturitas. 2019;124:55-61.
  6. Derzko CM, Röhrich S, Panay N. Does age at the start of treatment for vaginal atrophy predict response to vaginal estrogen therapy? Post hoc analysis of data from a randomized clinical trial involving 205 women treated with 10 μg estradiol vaginal tablets. Menopause. 2020;28(2):113-118.
  7. The NAMS 2020 GSM Position Statement Editorial Panel. The 2020 genitourinary syndrome of menopause position statement of The North American Menopause Society. Menopause. 2020;27(9):976-992.
  8. Palacios S, Nappi RE, Bruyniks N, Particco M, Panay N; EVES Study Investigators. The European Vulvovaginal Epidemiological Survey (EVES): prevalence, symptoms and impact of vulvovaginal atrophy of menopause. Climacteric. 2018;21(3):286-291.

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