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Zona pellucida 3 (ZP3) expression is classically found in the ZP-layer of the oocytes, lately shown in ovarian and prostate cancer. A successful ZP3 ovarian cancer immunotherapy in transgenic mice suggested its use as an attractive therapeutic target. The biological role of ZP3 in cancer growth and progression is still unknown. We found that ~88% of the analyzed adenocarcinoma, squamous and small cell lung carcinomas to express ZP3. Knockout of ZP3 in a ZP3-expressing lung adenocarcinoma cell line, significantly decreased cell viability, proliferation, and migration rates in vitro. Zona pellucida 3 knock out (ZP3-KO) cell tumors inoculated in vivo in immunodeficient non-obese diabetic, severe combined immunodeficient mice showed significant inhibition of tumor growth and mitigation of the malignant phenotype. RNA sequencing revealed the deregulation of cell migration/adhesion signaling pathways in ZP3-KO cells. This novel functional relevance of ZP3 in lung cancer emphasized the suitability of ZP3 as a target in cancer immunotherapy and as a potential cancer biomarker.
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The role of estradiol (E2; an estrogen) in men needs to be more appreciated. In this review, we address the clinical situations that allow the study of the clinical consequences of E2 deficiency in men and discuss the effects of restoration of levels of this reproductive steroid hormone. In men with advanced prostate cancer (PCa) undergoing androgen deprivation therapy (ADT), E2 is suppressed along with testosterone, leading to side effects affecting the quality of life. These include hot flashes, arthralgia, fatigue, mood changes, cognition problems, weight gain, bone loss, and increased risk of cardiovascular disease. Transdermal E2 alone for ADT has shown equivalent testosterone suppression compared to gonadotropin-releasing hormone (GnRH) agonists while also preventing estrogen-deficiency side effects, including hot flashes and bone loss. Co-treatment of ADT with fetal estrogen estetrol (E4) has shown significant improvements of estrogen-deficiency symptoms. These observations emphasize the need to raise awareness of the importance of estrogens in men among clinicians and the lay public.
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PURPOSE: This review presents an update of the non-contraceptive health benefits of the combined oral contraceptive pill. METHODS: We conducted a literature search for (review) articles that discussed the health benefits of combined oral contraceptives (COCs), in the period from 1980 to 2023. RESULTS: We identified 21 subjective and/or objective health benefits of COCs related to (i) the reproductive tract, (ii) non-gynaecological benign disorders and (iii) malignancies. Reproductive tract benefits are related to menstrual bleeding(including anaemia and toxic shock syndrome), dysmenorrhoea, migraine, premenstrual syndrome (PMS), ovarian cysts, Polycystic Ovary Syndrome (PCOS), androgen related symptoms, ectopic pregnancy, hypoestrogenism, endometriosis and adenomyosis, uterine fibroids and pelvic inflammatory disease (PID). Non-gynaecological benefits are related to benign breast disease, osteoporosis, rheumatoid arthritis, multiple sclerosis, asthma and porphyria. Health benefits of COCs related to cancer are lower risks of endometrial cancer, ovarian cancer and colorectal cancer. CONCLUSIONS: The use of combined oral contraceptives is accompanied with a range of health benefits, to be balanced against its side-effects and risks. Several health benefits of COCs are a reason for non-contraceptive COC prescription.
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Anticoncepcionais Orais Combinados , Humanos , Feminino , Anticoncepcionais Orais Combinados/uso terapêutico , Anticoncepcionais Orais Combinados/efeitos adversos , NeoplasiasRESUMO
Background: Expression of Zona Pellucida glycoprotein 3 (ZP3) in healthy tissue is restricted to the extracellular Zona Pellucida layer surrounding oocytes of ovarian follicles and to specific cells of the spermatogenic lineage. Ectopic expression of ZP3 has been observed in various types of cancer, rendering it a possible therapeutic target. Methods: To support its validity as therapeutic target, we extended the cancer related data by investigating ZP3 expression using immunohistochemistry (IHC) of tumor biopsies. We performed a ZP3 transcript specific analysis of publicly available RNA-sequencing (RNA-seq) data of cancer cell lines (CCLs) and tumor and normal tissues, and validated expression data by independent computational analysis and real-time quantitative PCR (qPCR). A correlation between the ZP3 expression level and pathological and clinical parameters was also investigated. Results: IHC data for several cancer types showed abundant ZP3 protein staining, which was confined to the cytoplasm, contradicting the extracellular protein localization in oocytes. We noticed that an alternative ZP3 RNA transcript, which we term 'ZP3-Cancer', was annotated in gene databases that lacks the genetic information encoding the N-terminal signal peptide that governs entry into the secretory pathway. This explains the intracellular localization of ZP3 in tumor cells. Analysis of publicly available RNA-seq data of 1339 cancer cell lines (CCLs), 10386 tumor tissues (The Cancer Genome Atlas) and 7481 healthy tissues (Genotype-Tissue Expression) indicated that ZP3-Cancer is the dominant ZP3 RNA transcript in tumor cells and is highly enriched in many cancer types, particularly in rectal, ovarian, colorectal, prostate, lung and breast cancer. Expression of ZP3-Cancer in tumor cells was confirmed by qPCR. Higher levels of the ZP3-Cancer transcript were associated with more aggressive tumors and worse survival of patients with various types of cancer. Conclusion: The cancer-restricted expression of ZP3-Cancer renders it an attractive tumor antigen for the development of a therapeutic cancer vaccine, particularly using mRNA expression technologies.
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Many factors, including reproductive hormones, have been linked to a woman's risk of developing breast cancer (BC). We reviewed the literature regarding the relationship between ovulatory menstrual cycles (MCs) and BC risk. Physiological variations in the frequency of MCs and interference with MCs through genetic variations, pathological conditions and or pharmaceutical interventions revealed a strong link between BC risk and the lifetime number of MCs. A substantial reduction in BC risk is observed in situations without MCs. In genetic or transgender situations with normal female breasts and estrogens, but no progesterone (P4), the incidence of BC is very low, suggesting an essential role of P4. During the MC, P4 has a strong proliferative effect on normal breast epithelium, whereas estradiol (E2) has only a minimal effect. The origin of BC has been strongly linked to proliferation associated DNA replication errors, and the repeated stimulation of the breast epithelium by P4 with each MC is likely to impact the epithelial mutational burden. Long-lived cells, such as stem cells, present in the breast epithelium, can carry mutations forward for an extended period of time, and studies show that breast tumors tend to take decades to develop before detection. We therefore postulate that P4 is an important factor in a woman's lifetime risk of developing BC, and that breast tumors arising during hormonal contraception or after menopause, with or without menopausal hormone therapy, are the consequence of the outgrowth of pre-existing neoplastic lesions, eventually stimulated by estrogens and some progestins.
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Neoplasias da Mama , Progesterona , Feminino , Humanos , Neoplasias da Mama/etiologia , Neoplasias da Mama/genética , Ciclo Menstrual/fisiologia , Estrogênios , Estradiol , Preparações FarmacêuticasRESUMO
Background: Androgen deprivation therapy (ADT) for prostate cancer (PCa) is accompanied by side effects affecting health-related quality of life (HRQL). Objective: To assess the effects of the fetal estrogen estetrol (E4) on symptoms related to estrogen and androgen deficiency, and on HRQL measured using the validated Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire. Design setting and participants: This was a phase 2, double-blind, randomized, placebo-controlled study in patients with advanced PCa. Intervention: Patients receiving ADT were randomly assigned at a 2:1 ratio to daily treatment with a high dose of E4 (HDE4; n = 41) or placebo (n = 21) for 24 wk. Outcome measurements and statistical analysis: The primary outcome was the effect of HDE4 cotreatment on hot flushes (HFs). Secondary outcomes were the Q-Man questionnaire for evaluation of the effect on estrogen and androgen deficiency symptoms, and the FACT-P questionnaire for evaluating HRQL. Results and limitations: At 24 wk, the number of patients experiencing HFs was significantly lower in the HDE4 group than in the placebo group (14.3% vs 60.0%; p < 0.001). HDE4 treatment was associated with lower incidence of night sweats, arthralgia, and fatigue, but more nipple tenderness and gynecomastia. At 24 wk, the mean HRQL score favored HDE4 over placebo for the FACT-P total score (122.2 ± 12.3 vs 118.7 ± 19.7) and for several other FACT subscales. Conclusions: Daily HDE4 coadministration almost completely prevented HFs in patients with advanced PCa treated with ADT. HDE4 also had positive effects on HRQL and counteracted other estrogen deficiency symptoms caused by ADT. These data support the dual efficacy concept of ADT and HDE4 to improve HRQL and increase the antitumor effect of ADT. Patient summary: For patients on androgen deprivation therapy for advanced prostate cancer, cotreatment with a high dose of estetrol almost completely prevents the occurrence of hot flushes and improves quality of life and well-being, but nipple sensitivity and an increase in breast size may occur.
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The purpose of androgen deprivation therapy (ADT) in prostate cancer (PCa), using luteinizing hormone-releasing hormone agonists (LHRHa) or gonadotrophin-releasing hormone antagonists, is to suppress the levels of testosterone. Since testosterone is the precursor of estradiol (E2), one of the major undesired effects of ADT is the concomitant loss of E2, causing among others an increased bone turnover and bone loss and an increased risk of osteoporosis and fractures. Therefore, the guidelines for ADT indicate to combine ADT routinely with bone-sparing agents such as bisphosphonates, denosumab or selective estrogen receptor modulators. However, these compounds may have side effects and some require inconvenient parenteral administration. Co-treatment with estrogens is an alternative approach to prevent bone loss and at the same time, to avoid other side effects caused by the loss of estrogens, which is the topic explored in the present narrative review. Estrogens investigated in PCa patients include parenteral or transdermal E2, diethylstilbestrol (DES), and ethinylestradiol (EE) as monotherapy, or high-dose estetrol (HDE4) combined with ADT. Cardiovascular adverse events have been reported with parenteral E2, DES and EE. Encouraging effects on bone parameters have been obtained with transdermal E2 (tE2) and HDE4, in the tE2 development program (PATCH study), and in the LHRHa/HDE4 co-treatment study (PCombi), respectively. Confirmation of the beneficial effects of estrogen therapy with tE2 or HDE4 on bone health in patients with advanced PCa is needed, with special emphasis on bone mass and fracture rate.
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INTRODUCTION: Estrogens used in women's healthcare have been associated with increased risks of venous thromboembolism (VTE) and breast cancer. Estetrol (E4), an estrogen produced by the human fetal liver, has recently been approved for the first time as a new estrogenic component of a novel combined oral contraceptive (E4/drospirenone [DRSP]) for over a decade. In phase 3 studies, E4/DRSP showed good contraceptive efficacy, a predictable bleeding pattern, and a favorable safety and tolerability profile. AREAS COVERED: This narrative review discusses E4's pharmacological characteristics, mode of action, and the results of preclinical and clinical studies for contraception, as well as for menopause and oncology. EXPERT OPINION: Extensive studies have elucidated the properties of E4 that underlie its favorable safety profile. While classical estrogens (such as estradiol) exert their actions via both activation of nuclear and membrane estrogen receptor α (ERα), E4 presents a specific profile of ERα activation: E4 binds and activates nuclear ERα but does not induce the activation of membrane ERα signaling pathways in specific tissues. E4 has a small effect on normal breast tissue proliferation and minimally affects hepatic parameters. This distinct profile of ERα activation, uncoupling nuclear and membrane activation, is unique.
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Estetrol , Anticoncepção , Anticoncepcionais Orais Combinados , Estetrol/efeitos adversos , Estrogênios/efeitos adversos , Feminino , Humanos , MenopausaRESUMO
The expression of the zona pellucida glycoprotein 3 (ZP3), originally thought to be specific for oocytes, was recently extended to ovarian, prostate, colorectal and lung cancers. Earlier successful ZP3 immunization of a transgenic mouse model carrying a ZP3 positive ovarian tumor emphasized the suitability of ZP3 for cancer immunotherapy. This study was carried out to determine whether any other normal tissues besides the ovary in healthy human and mouse tissues may express ZP3, considered important to exclude off-target effects of ZP3 cancer immunotherapy. Strong ZP3 expression was found in normal human and mouse testis. ZP3 protein and mRNA transcripts were localized in spermatogonia, spermatocytes and round and elongated spermatids of both human and mouse testis, as well as in a mouse spermatogonial cell line, but absent in testicular Sertoli, Leydig, spermatogonial stem and progenitor cells. All other normal human and mouse tissues were ZP3 negative. This surprising testicular ZP3 expression has implications for the development of ZP3 cancer immunotherapies, and it also alludes to the potential of using ZP3 as a target for the development of a male immunocontraceptive.
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Testículo/metabolismo , Regulação para Cima , Glicoproteínas da Zona Pelúcida/genética , Glicoproteínas da Zona Pelúcida/metabolismo , Adulto , Animais , Linhagem Celular , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Células de Sertoli/metabolismo , Espermátides/metabolismo , Espermatócitos/metabolismo , Espermatogônias/metabolismo , Distribuição TecidualAssuntos
COVID-19 , Neoplasias da Próstata , Estrogênios , Humanos , Masculino , SARS-CoV-2 , TestosteronaRESUMO
BACKGROUND: Androgen deprivation therapy (ADT) for prostate cancer with luteinizing hormone-releasing hormone (LHRH) agonists can be improved. OBJECTIVE: To assess safety, the frequency and severity of hot flushes (HFs), bone health, and antitumor effects of high-dose estetrol (HDE4) when combined with ADT. DESIGN SETTING AND PARTICIPANTS: A phase II, double-blind, randomized, placebo-controlled study was conducted in advanced prostate cancer patients requiring ADT (the PCombi study). INTERVENTION: Patients receiving LHRH agonist treatment were randomized 2:1 to 40 mg HDE4 (n = 41) or placebo (n = 21) cotreatment for 24 wk. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Coprimary endpoints were frequency/severity of HFs and levels of total and free testosterone (T). Secondary endpoints included assessments of bone metabolism (osteocalcin and type I collagen telopeptide [CTX1]), prostate-specific antigen (PSA), and follicle-stimulating hormone (FSH). Efficacy analysis was based on the selected per-protocol (PP) population. RESULTS AND LIMITATIONS: Of 62 patients included in the study, 57 were suitable for a PP analysis (37 HDE4; 20 placebo). No E4-related serious cardiovascular adverse events occurred at 24 wk. Weekly HFs were reported by 13.5% of patients with HDE4 and 60.0% with placebo (p < 0.001). Daily HFs occurred in 5.9% versus 55%. Bone turnover parameters decreased significantly with HDE4 (p < 0.0001). Total and free T decreased earlier (p < 0.05), and free T was suppressed further (p < 0.05). PSA suppression was more profound and earlier (p < 0.005). FSH levels were suppressed by 98% versus 57% (p < 0.0001). Estrogenic side effects were nipple sensitivity (34%) and gynecomastia (17%). CONCLUSIONS: HDE4 cotreatment of ADT patients with advanced prostate cancer was well tolerated, and no treatment-related cardiovascular adverse events were observed at 24 wk. HFs and bone turnover were substantially reduced. Suppression of free T, PSA, and FSH was more rapid and profound, suggesting enhanced disease control by HDE4 cotreatment. Larger and longer-lasting studies are needed to confirm the results of the study reported here. PATIENT SUMMARY: Cotreatment of androgen deprivation therapy with high-dose estetrol in advanced prostate cancer patients results in fewer occurrences of hot flushes, bone protection, and other antitumor benefits. Nipple sensitivity and gynecomastia may occur as side effects.
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PURPOSE: The aim of this study (the ABCE4 study) was to assess dose-limiting toxicity (DLT), safety, tolerability and preliminary efficacy of high doses of the fetal estrogen estetrol (E4) in postmenopausal patients with heavily pretreated, locally advanced and/or metastatic ER+/HER2-breast cancer, resistant to anti-estrogens. METHODS: This was a multicenter, open-label, phase IB/IIA, dose-escalation study with a 3 + 3 cohort design, whereby successive cohorts of three patients received 20 mg, 40 mg or 60 mg E4 per day for 12 weeks by oral administration. DLTs, safety and wellbeing were evaluated after 4, 8 and 12 weeks of treatment. Anti-tumor effects were investigated by computer tomography scanning and evaluated according to RECIST criteria before and after 12 weeks of treatment. Wellbeing was judged weekly by the investigator and by quality-of-life questionnaires by the patients. In view of the small number of patients, no statistical testing was performed. RESULTS: All 12 patients enrolled had progressive, heavily pre-treated advanced breast cancer. No treatment-related serious adverse events or DLTs occurred during the first 4 weeks of E4 treatment allowing the investigation of all three doses. Five of nine patients completing 12 weeks of E4 treatment showed objective anti-tumor effects and six of nine patients reported improved wellbeing. CONCLUSION: High doses of estetrol seem to be safe and are well tolerated during 12 weeks of treatment without dose-limiting toxicity and with anti-tumor effects in five of nine heavily treated patients with progressive, anti-estrogen resistant, advanced breast cancer.
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Neoplasias da Mama/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Estetrol/administração & dosagem , Estetrol/efeitos adversos , Idoso , Neoplasias da Mama/patologia , Progressão da Doença , Relação Dose-Resposta a Droga , Estetrol/farmacologia , Feminino , Humanos , Dose Máxima Tolerável , Pessoa de Meia-Idade , Metástase Neoplásica , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacosRESUMO
We have searched the literature for information on the risk of breast cancer (BC) in relation to gender, breast development, and gonadal function in the following 8 populations: 1) females with the Turner syndrome (45, XO); 2) females and males with congenital hypogonadotropic hypogonadism and the Kallmann syndrome; 3) pure gonadal dysgenesis (PGD) in genotypic and phenotypic females and genotypic males (Swyer syndrome); 4) males with the Klinefelter syndrome (47, XXY); 5) male-to-female transgender individuals; 6) female-to-male transgender individuals; 7) genotypic males, but phenotypic females with the complete androgen insensitivity syndrome, and 8) females with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome (müllerian agenesis). Based on this search, we have drawn 3 major conclusions. First, the presence of a Y chromosome protects against the development of BC, even when female-size breasts and female-level estrogens are present. Second, without menstrual cycles, BC hardly occurs with an incidence comparable to males. There is a strong correlation between the lifetime number of menstrual cycles and the risk of BC. In our populations the BC risk in genetic females not exposed to progesterone (P4) is very low and comparable to males. Third, BC has been reported only once in genetic females with MRKH syndrome who have normal breasts and ovulating ovaries with normal levels of estrogens and P4. We hypothesize that the oncogenic glycoprotein WNT family member 4 is the link between the genetic cause of MRKH and the absence of BC women with MRKH syndrome.
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Neoplasias da Mama Masculina/etiologia , Neoplasias da Mama/etiologia , Transtornos do Desenvolvimento Sexual , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Neoplasias da Mama Masculina/epidemiologia , Neoplasias da Mama Masculina/genética , Transtornos do Desenvolvimento Sexual/complicações , Transtornos do Desenvolvimento Sexual/epidemiologia , Transtornos do Desenvolvimento Sexual/genética , Feminino , Estudos de Associação Genética , Disgenesia Gonadal/complicações , Disgenesia Gonadal/epidemiologia , Disgenesia Gonadal/genética , Disgenesia Gonadal 46 XY/epidemiologia , Disgenesia Gonadal 46 XY/genética , Humanos , Hipogonadismo/complicações , Hipogonadismo/congênito , Hipogonadismo/epidemiologia , Hipogonadismo/genética , Síndrome de Kallmann/complicações , Síndrome de Kallmann/epidemiologia , Síndrome de Kallmann/genética , Masculino , Fatores de Risco , Transexualidade/complicações , Transexualidade/epidemiologia , Transexualidade/genética , Síndrome de Turner/complicações , Síndrome de Turner/epidemiologia , Síndrome de Turner/genéticaRESUMO
OBJECTIVE: The aim of this study was to select the minimum effective dose of estetrol (E4) for the treatment of vasomotor symptoms in postmenopausal women. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study. Postmenopausal women (nâ=â257, of whom 32 were hysterectomized) aged 40 to 65 years, with ≥7 moderate to severe hot flushes (HFs) per day, or 50 or more moderate to severe HFs weekly, received 2.5, 5, 10, or 15âmg E4, or placebo once-daily for a period of 12 weeks. Efficacy was assessed by recording the frequency and severity of HFs. Overall safety was assessed by recording adverse events, measuring endometrial thickness, and monitoring bleeding patterns. Treatment groups were compared using analysis of covariance. RESULTS: The frequency of moderate to severe HFs decreased with all E4 doses. The difference in the percentage change of weekly HF frequency was significant for 15âmg E4 versus placebo at both W4 (-66% vs -49%, Pâ=â0.032) and W12 (-82% vs -65%, Pâ=â0.022). The decrease in severity of HFs was significantly more pronounced for 15âmg E4 than for placebo at both W4 (-0.59 vs -0.33, Pâ=â0.049) and W12 (-1.04 vs -0.66, Pâ=â0.049); the other doses failed to achieve statistical significance. In nonhysterectomized women, endometrial thickness increased during treatment and normalized following progestin treatment at study completion. No endometrial hyperplasia was observed. CONCLUSIONS: Estetrol 15âmg is considered to be the minimum effective daily oral dose for treatment of vasomotor symptoms. Its current seemingly favorable safety profile is further to be confirmed in phase 3 clinical development. : Video Summary:http://links.lww.com/MENO/A591.
Video Summary:http://links.lww.com/MENO/A591.
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Hiperplasia Endometrial , Estetrol , Adulto , Idoso , Método Duplo-Cego , Estrogênios , Feminino , Fogachos/tratamento farmacológico , Humanos , Pessoa de Meia-Idade , Pós-Menopausa , Resultado do TratamentoRESUMO
Context: Luteinizing hormone-releasing hormone (LHRH) agonists have replaced estrogens for endocrine treatment of advanced prostate cancer (PC) because of cardiovascular side effects. The fetal estrogen estetrol (E4) may be safer for PC treatment and is expected to decrease testosterone (T) and prevent estrogen deficiency. Objective: To investigate the safety and T-suppressive effect of E4 in healthy men. Design: Double-blind, randomized, placebo-controlled, dose-escalating study. Setting: The study was conducted at a phase I clinical unit (QPS, Netherlands). Participants: Healthy male volunteers aged 40 to 70 years. Intervention(s): Three treatment cohorts of 15 volunteers with placebo (n = 5) and E4 (n = 10). Estetrol doses tested were 20, 40, and 60 mg/d. Subjects were treated for 4 weeks. Main Outcome Measures: Subjective side effects, pharmacodynamic effects on hemostatic variables, lipids, glucose, bone parameters, and endocrine parameters related to T metabolism. Results: Total and free T decreased dose-dependently and significantly. Nipple tenderness occurred in 40% and decrease of libido occurred in 30% of E4-treated men. The unwanted estrogenic effects on hemostasis were small, dose dependent, and in some cases significant. Lipid and bone parameters showed a favorable trend. Conclusion: The effect of E4 on testosterone levels is insufficient for standalone PC treatment. Taking all clinical and pharmacodynamic variables into consideration, a daily dose of 40 mg E4 seems safe for further evaluation of endocrine PC treatment in combination with LHRH analogs.
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Antineoplásicos Hormonais/administração & dosagem , Estetrol/administração & dosagem , Adulto , Idoso , Antagonistas de Androgênios/administração & dosagem , Antagonistas de Androgênios/efeitos adversos , Antagonistas de Androgênios/farmacologia , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/farmacologia , Biomarcadores/sangue , Glicemia/metabolismo , Remodelação Óssea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Estetrol/efeitos adversos , Estetrol/farmacologia , Terapia de Reposição de Estrogênios/métodos , Voluntários Saudáveis , Hemostasia/efeitos dos fármacos , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Testosterona/sangueRESUMO
OBJECTIVES: This study evaluated acceptability, user satisfaction, body weight control and general well-being of estetrol (E4) combined with either drospirenone (DRSP) or levonorgestrel (LNG). METHODS: In this open-label, multi-centre, dose-finding, 6-cycle study, 396 healthy women of reproductive age were randomised into five treatment groups in a 24/4-day regimen: 15 mg or 20 mg E4 combined with either 3 mg DRSP or 150 µg LNG, and as reference estradiol valerate (E2V) combined with dienogest (DNG). Data on acceptability, user well-being, satisfaction and body weight were collected. RESULTS: The number of completers was the highest in the 15 mg E4/DRSP group (91.1%), and the lowest for 20 mg E4/LNG (70.1%). The largest proportion of treatment satisfaction was reported for 15 mg E4/DRSP (73.1%), and the lowest for 15 mg E4/LNG (50.6%). The number of women willing to continue with the assigned study treatment was the highest in the 15 mg E4/DRSP group (82.1%) and the lowest for 20 mg E4/LNG (58.3%). Well-being with E4/DRSP combinations was statistically significantly better than with E4/LNG combinations: OR (95% CI) 2.00 (1.13; 3.53) and 1.93 (1.06; 3.56) for 15 and 20 mg E4, respectively, and comparable to E2V/DNG. Proportion of women with a 2 kg or more weight loss after 3 and 6 cycles was the highest in the 15 mg E4/DRSP group (30.7 and 36.7%, respectively). CONCLUSIONS: The present study shows that 15 mg estetrol combined with 3 mg DRSP is associated with a high-user acceptability and satisfaction, and with a favourable body weight control.
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Androstenos/uso terapêutico , Anticoncepcionais Orais Combinados/uso terapêutico , Anticoncepcionais Orais Hormonais/uso terapêutico , Estetrol/uso terapêutico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Satisfação do Paciente , Adolescente , Adulto , Androstenos/administração & dosagem , Peso Corporal , Anticoncepcionais Orais Combinados/administração & dosagem , Anticoncepcionais Orais Hormonais/administração & dosagem , Estetrol/administração & dosagem , Feminino , Finlândia , Humanos , Análise de Intenção de Tratamento , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Satisfação do Paciente/estatística & dados numéricos , Inquéritos e Questionários , Hemorragia Uterina/fisiopatologia , Adulto JovemRESUMO
OBJECTIVE: Estetrol (E4) is an estrogen produced exclusively by the human fetal liver during pregnancy. In this study the pharmacodynamic effects of escalating doses of E4 in postmenopausal women were investigated. METHODS: This was a partly randomized, open-label, multiple-rising-dose study in 49 postmenopausal women. Participants were randomized to receive either 2âmg E4 or 2âmg estradiol-valerate (E2âV) for 28 days. Subsequent dose-escalation groups were (non-randomized): 10, 20 and 40âmg E4. Blood samples were collected regularly for measuring endocrine and hemostasis variables, lipids and lipoproteins, fasting glucose and bone turnover markers. RESULTS: Estetrol treatment resulted in a decrease of follicle-stimulating hormone and luteinizing hormone and an increase of sex-hormone binding globulin. Changes in hemostasis variables were small. A lowering effect on low-density lipoprotein cholesterol was accompanied with an increase in high-density lipoprotein cholesterol and no or minimal changes in triglycerides. The considerable decrease in osteocalcin levels in the three highest E4 dose groups and the small decrease in C-telopeptide levels were comparable to the E2âV control group and suggest a preventive effect on bone loss. All changes observed were dose-dependent. CONCLUSIONS: In this study, estetrol treatment showed dose-dependent estrogenic effects on endocrine parameters, bone turnover markers, and lipids and lipoproteins. The effect on triglycerides was small as were the effects on hemostatic variables. These results support the further investigation of estetrol as a candidate for hormone therapy. Quantitatively, the effects of 10âmg estetrol were similar to the study comparator 2âmg estradiol valerate.