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Journal für Reproduktionsmedizin und Endokrinologie – Journal of Reproductive Medicine and Endocrinology –

Andrologie • Embryologie & Biologie • Endokrinologie • Ethik & Recht • Genetik Gynäkologie • Kontrazeption • Psychosomatik • Reproduktionsmedizin • Urologie

Estetrol, a Fetal for the Treatment of Adults Coelingh Bennink HJT, Foidart J-M J. Reproduktionsmed. Endokrinol 2015; 12 (4), 399-403

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Wir freuen uns auf Sie! , a Fetal Steroid for the Treatment of Adults

H. J. T. Coelingh Bennink, J.-M. Foidart on behalf of Pantarhei Bioscience, the Netherlands and Mithra Pharmaceuticals, Belgium

Estetrol (E4) is a natural fetal . This steroid molecule has been discovered in 1965 by the group of Egon Diczfalusy at the Karolinska Institute in Swe- den and as a drug for human use in 2001 by the group of Herjan Coelingh Bennink at Pantarhei Bioscience in the Netherlands. Estetrol is structurally closely

related to the predominant natural estron (E1), (E2) and (E3), but with a number of different and potentially favorable features. In comparison to E2, E4 displays much higher upon and its elimination is considerably slower. Moreover, E4 is a metabolic endproduct and not metabolized into other estrogenic metabolites as happens after oral intake of E2. Consequently, stable therapeutic blood concentrations are rapidly achieved upon oral administration. E4 has been shown to interact exclusively with the estrogen receptors with some preference for the alpha . Estetrol interacts minimally with function and steroid- and drug-metabolizing liver , suggesting among others less interference with hemostasis compared to other estrogens and potentially a lower risk of venous thromboembolism (VTE). These features indicate the particular feasibil-

ity and anticipated safety of E4 as an oral therapy in a once-daily dosing regimen. Data from preclinical pharmacology studies support the safe use of E4 in humans and suggest therapeutic effects such as menopausal hormone treatment (MHT) of vasomotor symptoms (VMS) and vulvovaginal atrophy (VVA), prevention of , as well as application in contraceptive regimen. Estetrol

antagonized E2 in in vitro models and prevented and inhibited growth of mammary tumors in an experimental rat model, suggesting a more -friendly profile compared to other estrogens and suitability of E4 as estrogen add-back treatment during anti-hormonal endocrine therapy of , endome- triosis and .

After 28-days daily oral administration of 2, 10, 20, or 40 mg to postmenopausal women, E4 has been shown to reduce the occurrence of VMS, to reverse the -induced VVA and to exert -preserving changes by decreasing bone turnover, especially bone-resorption, suggesting positive bone forma-

tion. Endometrial proliferation, to an extent similar to 2 mg E2-valerate (E2V), was found at E4 doses of 10 mg/day. Estetrol was safe and had minimal effects on the synthesis of lipoproteins, SHBG and parameters of hemostasis, supporting the favorable profile with respect to VTE. At present dose-finding studies

with E4 are prepared for the treatment of VMS and VVA. Estetrol at a daily oral dose of 15 or 20 mg has been shown to be suitable as the estrogen component of combined oral contraceptives in a full phase II development program in collaboration with Jean-Michel Foidart in Belgium, demonstrating excellent , safety and cycle control, while minimally in-

terfering with a number of metabolic parameters. Further phase III development of the oral contraceptive application of E4 will be performed by Mithra Phar- maceuticals in Liège, Belgium. J Reproduktionsmed Endokrinol_Online 2015; (4): 399–401.

Key words: Estetrol, E4, natural fetal estrogen, contraception, VMS, VVA, add-back treatment

 Introduction the of pregnant women, the devel- mental model of hot flushes [6], and to opment of a drug containing E4 is not ex- inhibit [7]. Estetrol has a vaso-

The estrogen Estetrol (E4) is produced in pected to carry additional environmental relaxing effect on isolated rat large quantities by the fetal liver during risks. [8]. The effect on breast tumor is human only. The molecule summarized later in this paper. was discovered in 1965 at the Karolinska  Preclinical Development Institute in Stockholm [1]. Estetrol dif- In in vitro studies, Pantarhei has demon- fers from other natural estrogens by an Pantarhei Bioscience has discovered that strated that E4 is capable of binding to additional alpha-hydroxy (OH) group at E4 is suitable as a drug for human use. both ER-alpha as well as ER-beta, with a position 15 of the molecule. It has been Pantarhei first demonstrated that E4 is four- to fivefold preference for ER-al- demonstrated that this minor structural orally bioavailable in the rat with a re- pha. Estetrol displayed a relatively low difference has important implications, markably long elimination half-life for affinity compared to EE and E2, but E4 since this single additional OH group as the rat of 2–3 hours [3]. Subsequently did not bind to other steroid receptors compared to estriol (E3) extends the the pharmacological profile of E4 was and to a panel of 130 other drug targets elimination half-life in the human from characterized in detail in a number of [5].

10 minutes for E3 to 20–28 hours for E4 studies. In these studies, E4 was adminis-

[2]. The half-life of E4 is also much lon- tered orally and compared to oral ethi- of E4 in human liver cells ger than those of other natural estrogens, nyl-estradiol (EE), a synthetic estrogen. was found to be slow. Importantly, and in including natural 17-estradiol (E2) and Comparison with E2 and E3 was not fea- agreement with historical isotope studies micronized E2, for which half-lifes of sible given the rapid deactivation of these carried out in the early seventies, no ac-

1–2 hours and 10–12 hours have been re- natural estrogens by the rat liver. The re- tive metabolites of E4 have been detected ported respectively. In addition, E4 is sults of Pantarhei’s pharmacological to date, and E4 is excreted in an inactive more efficiently absorbed than E2 upon studies indicate that E4 acts as an estro- form by the liver and kidney following oral administration, as it is much less gen on the [3], the [3] and conjugation to sulphate and/or glucuro- subject to pre-systemic and first-pass bone [4]. Estetrol shows limited interac- nide [5]. In this respect E4 substantially metabolism. These features of E4 are im- tion with the liver, both kinetically and differs from E2, which after oral adminis- portant prerequisites for the develop- dynamically [5]. Furthermore, E4 was tration is extensively metabolized, pre- ment of a once-a-day oral drug. Being a found to suppress the naloxone-induced dominantly into (E1) and estrone natural estrogen excreted abundantly in tail skin temperature increase, an experi- sulphate (E1S), as well as into a large

Received and accepted: September 4th, 2015. Correspondence: Prof. Dr. Herjan J. T. Coelingh Bennink, Pantarhei Bioscience, NL-3700 AL Zeist, Boslaan 11, The Netherlands; e-mail: [email protected]

J Reproduktionsmed Endokrinol_Online 2015; 12 (4) 399 For personal use only. Not to be reproduced without permission of Krause & Pachernegg GmbH. Estetrol

number of other E1- and E2-derived me- Pharmacokinetic simulations have shown oral doses of 10 mg E4 decreased levels tabolites [9]. that the 24-hour exposure of the human of CTX-1 to a similar extent as E2V

to E4 at term pregnancy equals a 2.0 mg/day, whereas the decrease of

As expected in view of the high levels of daily human oral dose of 50–55 mg E4, osteo calcin with E4 was much less, sug-

E4 during human pregnancy, E4 seems to suggesting that such a dose may be ex- gesting a net effect and positive bone for- be very safe. In animal pharmacology pected to be safe in the human. mation. This may qualify E4 not only for studies, in which doses of up to 10 mg/ prevention, but also for treatment of kg/day were used for four weeks, E4 did A multiple rising dose phase IB/IIA osteo porosis. not cause any relevant side effect. The study with E4 was performed in healthy safety profile of E4 was further con- postmenopausal women to evaluate safe- Estetrol in the oral dose range of 2– firmed in a number of studies addressing ty, and pharmacody- 10 mg/day for a period of 28 days had the interaction of E4 with human hepato- namic parameters. Doses of 2, 10, 20 and minimal effects on liver-protein synthe- cytes [5], which is of particular signifi- 40 mg E4 were evaluated after daily oral sis. At 2.0 mg/day no effect on SHBG cance given the known and well-docu- administration for 28 days and the lowest was observed, while at 10 mg/day simi- mented side effects and interactions of 2 mg dose of E4 was compared head-to- lar effects as induced by 2.0 mg/day E2V estrogens on liver function. Contrary to head with 2 mg estradiol-valerate (E2V). were observed. E4 did not affect the syn-

EE and E2, E4 did not increase the syn- thesis of , in contrast to E2V, thesis of Binding Globu- Estetrol at an oral dose of 10 mg/day for and was furthermore associated with no line (SHBG) and did not change the ac- a short period of 28 days was shown to changes or small decreases in LDL-cho- tivity of the five most relevant Cyto- be effective in reducing (~ 40%) the fre- lesterol (considered favorable) and total chrome P-450-related liver enzymes [5]. quency of hot flushes (HF) in women , a small and favorable in- Furthermore, and different from other suffering from such complaints. Estetrol crease in HDL-cholesterol and a result- estrogens, E4 appeared not to bind to appeared somewhat more effective than ing small decrease in the ratio cholester-

SHBG [10]. E2V 2 mg/day. Full evaluation of the ef- ol/HDL-cholesterol. Hemostatic factors

fect of E4 for vasomotor symptoms and activities, including F1+2, tPA and Extensive information on the history and (VMS) requires treatment periods of at nAPCr, were all minimally influenced, the preclinical and clinical profile of E4 least 12 weeks. suggesting a limited effect on the risk of is available in several review papers [11– VTE. 14] and most of the pharmacological Vaginal cytology revealed dose-depen- studies performed by Pantarhei have dent estrogenic effects (vaginal matura- No serious adverse events occurred at been published in Supplement I of the tion), with a dose of 2 mg E4 per day E4 any E4 dose, and no significant changes journal Climacteric in 2008. showing similar effects as E2V 2 mg/day. were observed in vital signs, body In the case of vulvovaginal atrophy weight, physical examination or ECG-  Toxicology (VVA) the full estrogenic effect of E4 readings either. was obtained after 4 weeks treatment al- A complete toxicology program was per- ready. Estetrol may be suitable as the estrogen formed in rat and monkey. The results in combined oral contraceptives (COCs), showed that the toxicology of E4 is large- Ultrasound measurement of endometrial for the treatment of menopausal symp- ly determined by its estrogenic action, thickness did not show an effect of E4 at toms, for prevention of osteoporosis and leading to exaggerated pharmacological 2 mg/day, in contrast to E2V 2 mg/day for estrogen add-back therapy during responses at excessively high exposures. and E4 10 mg/day. Biopsies taken from treatment with inhibitors and

No specific toxicity of E4 has been ob- subjects displaying a > 50% increase in tamoxifene in women with breast cancer served. endometrial thickness revealed the ex- and in men with prostate cancer treated pected proliferative changes. This data with GnRH analogues.  Clinical Development suggest that low dose oral E4 treatment Phase I/IIA of VVA may not require endometrial  Combined Oral Contra- progestin protection, but higher doses of ception (COC) A single rising dose phase IA study has E4 will require a progestin. To avoid the been performed in healthy post-meno- increased breast cancer risk related to the A complete phase II clinical develop- pausal women. Estetrol showed high and use of oral progestins, higher doses of E4 ment has been performed for oral contra- dose-proportional oral bioavailability should preferably be combined with an ception. In summary, E4 inhibits ovula- with a long elimination half-life of 28 intra-uterine levonorgestrel-releasing in- tion effectively when combined with a hours [2], thereby confirming its poten- tra-uterine device (IUD) or with the pro- standard COC dose of a progestin [15]. tial as an oral therapeutic. A dose-depen- gestin dydrogesterone, which is the pro- Estetrol COCs have better cycle control dent peak was found to occur within 15 gestin closest to natural . than the E2/dienogest comparator. Its to 30 minutes after oral administration, safety profile is favorable in phase I and which was followed by a sharp decline of Estetrol was associated with a dose-de- phase II clinical trials. No relevant side the E4 blood level and a secondary rise pendent decrease in the levels of osteo- effects have been observed in more than and slow elimination of E4 thereafter, calcin and type I collagen telopeptide 300 women taking 15 or 20 mg E4 for six suggesting gastro-intestinal recircula- (CTX-1), parameters of bone formation COC cycles in combination with a pro- tion. No side effects were observed. and bone resorption respectively. Daily gestin.

400 J Reproduktionsmed Endokrinol_Online 2015; 12 (4) Estetrol

Estetrol has significantly less effect on liver [16] and hemostasis parameters compared to EE and E2, whatever the progestin used in the combination, sug- gesting a lower risk of VTE compared to other COCs. Estetrol seems a more breast-friendly estrogen, since it exhibits estrogen-antagonistic effects in preclini- cal and clinical studies, especially in the presence of E2. Moreover, in contrast to orally administered E2, E4 does not yield a large pool of E1S, which constitutes a potential source of unwanted E2-resyn- thesis in the breast.

 Menopausal (MHT)

According to the present standard of care Figure 1. In the rat hot fl ush model E4 causes a dose dependent decrease of the naloxone induced tail temperature raise. Mod. from [6]. © Pantarhei Bioscience. for MHT, Pantarhei has focused on oral

E4 treatment of early post-menopausal women with moderate to serious com- plaints due to estrogen deficiency such as hot flushes and sweatings, urogenital atrophy, dyspareunia caused by vaginal dryness, arthralgia, loss of bone mass and an increased risk of fractures and de- creasing cognition.

Major clinical advantages of E4 in MHT Figure 2. Doses of 2 and 10 mg E4 cause compared to presently used estrogens are a signifi cant decrease of the number of hot fl ushes in postmenopausal women, where- a lower incidence of side effects and as both doses are as effective as the 2 mg lower risks of VTE and gallbladder dis- dose of the comparator E2V. © Pantarhei ease. In addition the estrogen-antagonis- Bioscience. tic effect of E4 on the breast may result in a better safety profile in relation to breast Figure 1 shows the dose-related effect of Figure 3 shows that in the Allen-Doisy cancer (BC). E4 in an experimental hot flush model in test all doses of E4 induce full vaginal the rat. Complete inhibition of the tail cornification in the ovariectomized Since the oral synthetic progestins seem temperature rise is obtained at a dose- (OVX) rat. to be more important than the estrogens level 10× higher than EE. for the risk to develop BC, the objective For use in the human this suggests that a is to develop MHT drugs without addi- Figure 2 shows the effect of E4 on hot very low dose of E4 may be effective, al- tion of a progestin. This will be achieved flushes in the multiple rising dose phase though the time to achieve the full effect by developing a low dose of oral E4 for IB/IIA study in postmenopausal women may be somewhat longer compared to

VVA that does not stimulate the endome- with at least 50 hot flushes per week (the higher doses of E4. trium and therefore does not require ad- FDA criterion). In this 28-day-study E4 dition of a progestin. For VMS a higher is as effective as E2V. As mentioned be- Table 1 shows the effect of E4 on the dose of oral E4 may be required, that will fore, the final judgement of efficacy of E4 vaginal cytology in the multiple rising induce endometrial proliferation. To pro- requires a treatment period of at least 12 dose phase IB/IIA study in postmeno- tect the and to avoid oral weeks. Such a 12-week E4 dose-finding pausal women. In this 28-day-study E4 progestins and their increased BC risk, study in women with moderate to severe has the full effect and is as effective as an intra-uterine levonorgestrel-releasing vasomotor symptoms is needed to esti- E2V.

IUD is preferred. mate the optimal dose of E4 for this ap- plication.  Add-back Treatment  Vasomotor Symptoms (VMS)  Vulvovaginal Atrophy The terminology “add-back treatment” is (VVA) used for adding back an estrogen after The therapeutic potential of E4 for complete pharmacological suppression the treatment of VMS is supported by The therapeutic potential of E4 for of endogenous estrogen synthesis by an- Figures 1 and 2. the treatment of VVA is supported by ti-estrogenic treatment of diseases such Figure 3 and Table 1. as breast and prostate cancer and serious

J Reproduktionsmed Endokrinol_Online 2015; 12 (4) 401 Estetrol

add-back treatment in combination with anti-estrogenic treatments such as aro- matase inhibitors, tamoxifene and GnRH analogues.

 Preclinical Studies related to Breast Cancer During the pharmacological profiling of

E4 in human breast cancer (BC) cell lines and in the DMBA rat model, Pantarhei

has demonstrated that E4 can act as an estrogen antagonist in breast tumor tis- sue.

The estrogen antagonism of E4 has been

Figure 3. E4 induces cornifi cation of the vaginal in ovariectomised rat with all doses tested. Lower doses confirmed in in vitro models by the are also effective, but require more time to achieve the full effect. Mod. from [3]. © Pantarhei Bioscience. groups of Gompel in Paris, Simoncini and Genazzani in Pisa and Greene in

Table 1. After 28 days of E4 treatment in early postmenopausal women, all E4 do- Chicago. ses (2, 10 and 20 mg/day) induce a normal physiological cytology of the vagina with a low percentage of parabasal cells and high percentages of intermediate and su- In three separate experiments in the perfi cial cells. The effect is comparable to 2 mg E V. © Pantarhei Bioscience. 2 DMBA animal model, Pantarhei has

Parabasal (%) Intermediate (%) Superfi cial (%) shown that E4 can dose-dependently pre- vent and treat breast tumors [17, 18]. E -val – 2 mg 0 (0–3) 74 (51–92) 26 (15–49) 2 Figure 4 shows data from the DMBA E – 2 mg 2 (0–15) 80 (53–94) 18 (6–47) 4 treatment study demonstrating that E4 at E – 10 mg 8 (0–17) 45 (23–78) 47 (5–77) 4 the highest dose (10 mg/kg) removes E – 20 mg 0 (0) 60 (17–88) 40 (12–83) 4 breast tumors as effectively as OVX. Even when this effect would have been obtained by complete suppression of

ovarian function and extinction of E2

only, it shows that E4 at a high dose does not promote tumor growth. However it is

more likely that the effect of E4 at this dose is a cytotoxic effect, also known

from other estrogens such as EE, E2 and DES at high doses. A major difference with these other estrogens is the expect-

ed superior of E4 at higher

doses, allowing the clinical use of E4 at such high dose levels.

Very recently the group of Foidart in

Liége has demonstrated that E4 is acting as an estrogen via the genomic pathway, Figure 4. The therapeutic potential of E4 to inhibit growth of pre-existing mammary tumors was investigated in the whereas it acts as an anti-estrogen via DMBA rat model. Eight weeks after tumor induction, animals that had developed palpable mammary tumors were either ovariectomized (OVX) or treated orally with a vehicle (saline administration only), tamoxifene (TAM), or different the non-genomic pathway [19]. This doses of E4 (1 mg, 3 mg and 10 mg; all per kg) daily during four weeks. The number of palpable mammary tumors before unique combination of properties classi- (“Baseline”) and after (“Treatment Week 4”) four weeks of treatment was compared. Standard errors of the mean are fies E4 as the first known natural SERM indicated. A signifi cant disappearance of mammary tumors was observed after ovariectomy and dose-dependently (selective modulator) after E4 treatment. With the dose of TAM used (1 mg/kg) no increase or decrease was observed, but higher doses of TAM may be effective. Mod. from [17, 18]. © Pantarhei Bioscience. and explains why in preclinical and clin-

ical studies E4 exhibits anti-estrogenic endometriosis. Since the side effects of As Pantarhei has demonstrated in phar- effects on breast cancer. It implies that removing estrogens are often unaccept- macological and clinical studies that E4 E4 might be safer for the breast than oth- able and interfere with compliance to the acts as an estrogen on vagina [3], er estrogens. This, in combination with anti-estrogenic drugs, adding back an es- bone [4] and [6], whereas E4 has the liver-friendly profile of E4 and its trogen at a low dose has been introduced estrogen-antagonistic effects on breast very favorable safety profile, suggests as a solution for this problem. Actually tumor tissue (see below), the mixed ago- that E4 containing new drugs are expect- one may consider add-back treatment as nistic/antagonistic profile of E4 seems ed to exhibit a very beneficial benefit- a special type of MHT. highly attractive for its use as estrogen risk ratio.

402 J Reproduktionsmed Endokrinol_Online 2015; 12 (4) Estetrol

 Conflict of Interest

H. J. T. Coelingh Bennink is the inven-

tor of E4 and CEO and shareholder of Pantarhei Bioscience, the company de-

veloping E4 for several human applica- tions in collaboration with Mithra Phar- maceuticals, consulted by J.-M. Foidart.

References: 1. Hagen AA, Barr M, Diczfalusy E. Metabolism of 17-oestra- diol-4-14C in early infancy. Acta Endocrinol 1965; 49: 207–220. 2. Visser M, Holinka CF, Coelingh Bennink HJT. First human ex- posure to exogenous single-dose oral estetrol in early post- menopausal women. Climacteric 2008; 11 (Suppl I): 31–40. 3. Heegaard A-M, Holinka CF, Kenemans P, Coelingh Bennink HJT. Estrogenic uterovaginal effects of oral estetrol in the modi- fi ed Allen-Doisy test. Climacteric 2008; 11 (Suppl I): 22–8. 4. Coelingh Bennink HJT, Heegaard A-M, Visser M, Holinka CF, Figure 5. The effect of E on estrogen receptors in breast tumor tissue. © Pantarhei Bioscience. Christiansen C. Oral bioavailability and bone-sparing effects of 4 estetrol in an osteoporosis model. Climacteric 2008; 11 (Suppl I): 2–14.  Clinical Study in Women the serious side effects caused by the ex- 5. Visser M, Foidart J-M, Coelingh Bennink HJT. In vitro effects treme estrogen deficiency induced by the of estetrol on receptor binding, drug targets and human liver cell with Breast Cancer metabolism. Climacteric 2008; 11 (Suppl I): 64–8. AI’s and (hot flushes, vaginal 6. Holinka CF, Brincat M, Coelingh Bennink HJT. Preventive ef- A prospective, double-blind, placebo-con- dryness, bone loss, arthralgia, cognition fect of oral estetrol in a menopausal hot fl ush model. Climacteric trolled, randomised, 14 days, pre-opera- problems). However it should not inter- 2008; 11 (Suppl I): 15–21. 7. Coelingh Bennink HJT, Skouby S, Bouchard P, Holinka CF. Ovu- tive, neo-adjuvant study was performed fere with the efficacy of the AI’s and lation inhibition by estetrol in an in vivo model. Contraception 2008; 77: 186–90. in 15 pre- and 15 postmenopausal wom- tamoxifen. The combination of E4 with en with estrogen-receptor positive early an AI seems especially attractive, since 8. Hilgers RHP, Oparil S, Wouters W, Coelingh Bennink HJT. Vasorelaxing effects of Estetrol (E4) on rat arteries. J Endocrinol BC in the “Vienna General Hospital”, the mechanism of action of both drugs is 2012; 215: 97–106. Austria. Results have been published re- entirely different i.e. receptor antago- 9. Stanczyk FZ, Archer DF, Bhavnanic BR. Ethinyl estradiol and 17-estradiol in combined oral contraceptives: pharmacokinet- cently [20] and showed that E4 had a sig- nism and inhibition of synthesis respec- ics, pharmacodynamics and risk assessment. Contraception nificant pro-apoptotic effect on tumor tively. The combination might even 2013; 87: 706–27. tissue while Ki67 expression remained prove to be complementary when E4 10. Hammond G, Hogeveen K, Visser M, Coelingh Bennink HJT. Estetrol does not bind sex hormone binding globulin or increase unchanged. Estetrol increased SHBG would have estrogen-antagonistic effects its production by human HepG2 cells. Climacteric 2008; 11 significantly thereby reducing the con- under these conditions. (Suppl I): 41–6. 11. Coelingh Bennink HJT, Holinka CF, Diczfalusy E. Estetrol re- centrations of bioavailable E2. FSH lev- view: profi le and potential clinical applications. Climacteric 2008; els decreased in postmenopausal women  Estetrol add-back in Pros- 11 (Suppl I): 47–58. only and LH levels remained unchanged. tate Cancer treated with 12. Holinka CF, Diczfalusy E, Coelingh Bennink HJT. Estetrol: a Systemic IGF-1 levels decreased signifi- unique steroid in human pregnancy. J Steroid Biochem Mol Biol GnRH 2008; 110: 138–43. cantly. The most intriguing finding of the 13. Visser M, Coelingh Bennink HJT. Clinical applications for es- study was that intratumoral epithelial GnRH agonists are used for antihormon- tetrol. J Steroid Biochem Mol Biol 2009; 114 (1–2): 85–9. ER-alpha expression decreased signifi- al treatment of prostate cancer (PC) by 14. Visser M, Coelingh Bennink HJT. Estetrol, the new natural estrogen for clinical use in women. Ref Gynecol Obstet 2011; cantly and a trend was found towards an inhibition of the gonadotrophins FSH 14: 1–10. increased expression of ER-beta (Fig. 5). and especially LH, which stimulates the 15. Duijkers I, Klipping C, Zimmerman Y, Appels N, Jost M, et Since ER-alpha is related to proliferation synthesis of , that stimulates al. Inhibition of ovulation by administration of estetrol in combi- nation with or levonorgestrel: results of a phase II and ER-beta to anti-proliferation, the ob- tumor growth. Also in males this type of dose-fi nding pilot study. Eur J Contracept Reprod Health Care 2015 (accepted for publication). served effect of E4 may offer an addition- treatment causes typical “climacteric- 16. Mawet M, Maillard C, Klipping C, Zimmerman Y, Foidart JM, al explanation for the unexpected estro- like” complaints caused by estrogen de- Coelingh Bennink HJ. Unique effects on hepatic function, lipid gen-antagonistic effect of E4. ficiency such as hot flushes and sweat- metabolism, bone and growth endocrine parameters of estetrol in combined oral contraceptives. Eur J Contracept Reprod Health ings, arthralgia, loss of bone mass, an in- Care 2015; 29: 1–13.  Estetrol add-back in creased fracture risk and cognition prob- 17. Coelingh Bennink HJT, Singer C, Simoncini T, Genazzani A, Breast Cancer treated lems. These “climacteric-like” problems Kubista E. Estetrol, a pregnancy-specifi c human steroid, pre- vents and suppresses mammary tumor growth in a rat model. with Aromatase Inhibi- might be counteracted by E4 treatment. Climacteric 2008; 11 (Suppl I): 29. tors or Tamoxifen 18. Visser M, Kloosterboer H.J, Coelingh Bennink HJT. Estetrol In addition, the inhibitory effect of E on prevents and suppresses mammary tumors induced by DMBA in 4 a rat model. Horm Mol Biol Clin Invest 2012; 9: 95–103. Based on its antagonistic activity in gonadotrophins may support the effect of 19. Gérard C, Mestdagt M, Tskitishvili E, Communal L, Gompel breast tissue, E4 has the potential to be the GnRH agonist. Estetrol may even A, et al. Combined estrogenic and anti-estrogenic properties of estetrol on breast cancer may provide a safe therapeutic win- developed for add-back treatment in suppress or inhibit the unwanted initial dow for the treatment of menopausal symptoms. Oncotarget breast cancer in estrogen receptor (ER) rise of gonadotrophins occurring at the 2015; 6: 17621–36. positive patients treated with aromatase start of GnRH agonist treatment and 20. Singer C, Coelingh Bennink HJT, Natter C, Steurer S, Rudas M, et al. Antiestrogenic effects of the fetal estrogen estetrol in inhibitors (AI’s) or tamoxifene. Estrogen therefore E4 seems the perfect match for women with estrogen-receptor positive early breast cancer. add-back has the purpose to counteract estrogen add-back in men with PC. Carcinogenesis 2014; 35: 2447–51.

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