Estradiol Valerate Vs. Ethinylestradiol In Combined Oral Contraceptives : Effects On The Pituitary-Ovarian Axis

Context There are limited studies comparing the effects of combined oral contraceptives (COCs) containing natural estrogens and synthetic ethinylestradiol (EE) on reproductive hormones. Objective To compare estradiol valerate (EV)+dienogest (DNG), EE+DNG, and DNG alone (an active control) on levels of follicle stimulating hormone (FSH), luteinizing hormone, Anti-Mullerian hormone (AMH), ovarian steroids, sex hormone binding globulin (SHBG), and the Free Androgen Index (FAI). Design Spin-off study from a randomized trial. Setting Outpatient setting at Helsinki and Oulu University Hospitals, Finland. Participants 59 healthy, 18-35-year-old ovulatory women were enrolled. Three women discontinued. The groups were comparable as regards age and body mass index. Interventions EV 2mg+DNG 2-3mg (n=20), EE 0.03mg+DNG 2mg (n=20) and DNG 2mg (n=19) were used continuously for nine weeks. Blood samples were drawn at baseline, and at 5 and 9 weeks. Main Outcome Measures EV+DNG suppressed FSH by -27% (-51:-3) (median [95%CI]) vs. EE+DNG, -64% (-78: -51), P=0.04, but AMH levels decreased similarly by -9% (-18: -0.1) vs. -13% (-28:0.2), P=0.38, respectively. EV+DNG increased SHBG levels by 56% (30:82) and EE+DNG by 385% (313:423), PPeer reviewe

Oral and Vaginal Hormonal Contraceptives Induce Similar Unfavorable Metabolic Effects in Women with PCOS: A Randomized Controlled Trial

This clinical trial aims to compare hormonal and metabolic changes after a 9-week continuous use of oral or vaginal combined hormonal contraceptives (CHCs) in women with polycystic ovary syndrome (PCOS). We recruited 24 women with PCOS and randomized them to use either combined oral (COC, n = 13) or vaginal (CVC, n = 11) contraception. At baseline and 9 weeks, blood samples were collected and a 2 h glucose tolerance test (OGTT) was performed to evaluate hormonal and metabolic outcomes. After treatment, serum sex hormone binding globulin (SHBG) levels increased (p < 0.001 for both groups) and the free androgen index (FAI) decreased in both study groups (COC p < 0.001; CVC p = 0.007). OGTT glucose levels at 60 min (p = 0.011) and AUCglucose (p = 0.018) increased in the CVC group. Fasting insulin levels (p = 0.037) increased in the COC group, and insulin levels at 120 min increased in both groups (COC p = 0.004; CVC p = 0.042). There was a significant increase in triglyceride (p < 0.001) and hs-CRP (p = 0.032) levels in the CVC group. Both oral and vaginal CHCs decreased androgenicity and tended to promote insulin resistance in PCOS women. Larger and longer studies are needed to compare the metabolic effects of different administration routes of CHCs on women with PCOS

Combined oral contraceptives containing estradiol valerate vs ethinylestradiol on coagulation : A randomized clinical trial

Introduction Contraceptives containing ethinylestradiol (EE) induce changes in the coagulation system and are associated with a risk of venous thromboembolism. However, studies comparing the effects of combined oral contraceptives containing EE and low-potency estrogens (ie, estradiol [E-2] and estradiol valerate [EV]) on coagulation biomarkers are limited. This study represents secondary outcomes of a randomized trial comparing combined oral contraceptives containing EV + dienogest (DNG), EE + DNG, and DNG alone on selected coagulation biomarkers. We could compare the specific effects of the different estrogen components owing to the inclusion of preparations containing the same progestin. Material and methods We enrolled 59 healthy, 18- to 35-year-old, non-smoking women, of whom three discontinued. The participants were randomly allocated to 9 weeks of continuous treatment with EV 2 mg + DNG 2-3 mg (n = 20), EE 0.03 mg + DNG 2 mg (n = 20), or DNG 2 mg (n = 19). Blood samples were collected at baseline and after 9 weeks. We assessed coagulation in vitro by thrombin generation using the Calibrated Automated Thrombogram. Thrombin generation was evaluated by lag time, time to thrombin peak, thrombin peak, and endogenous thrombin potential in response to tissue factor (1 pm). In vivo coagulation assessment was based on levels of prothrombin fragment 1 + 2 (F1 + 2) (thrombin generation) and D-dimer (fibrin turnover). Clinical trial registration: NCT02352090. Results Lag time and time to thrombin peak remained unaltered after exposure to EV + DNG, whereas EE + DNG shortened both lag time (mean percentage change -24%, 95% confidence interval [CI] -32% to -15%; p < 0.01) and time to thrombin peak (-26%, 95% CI -37% to -16%; p < 0.01). EV + DNG induced lower thrombin peak and endogenous thrombin potential than EE + DNG (peak; +45%, 95% CI 22%-67% vs +147%,95% CI 96%-198%; p < 0.01, and endogenous thrombin potential; +26%, 95% CI 15%-38% vs +64%, 95% CI 51%-76%; p < 0.01). Median F1 + 2 levels remained unchanged with EV + DNG (p = 0.22) but increased within normal ranges with EE + DNG (from 152 pmol/L, 95% CI 127-206] pmol/L to 194 pmol/L, 95% CI 149-250 pmol/L, p = 0.04). The within-group change in D-dimer levels was not significant in any of the groups. DNG alone did not affect these biomarkers. Conclusions Both in vitro and in vivo thrombin generation was lower after exposure to EV + DNG compared with EE + DNG. The lower thrombin generation measures after treatment with EV + DNG indicate less enhancement of coagulation potential and suggest that EV may be favorable to EE as a component of combined oral contraceptives.Peer reviewe

Combined oral contraceptives containing estradiol valerate vs ethinylestradiol on coagulation : A randomized clinical trial

Introduction Contraceptives containing ethinylestradiol (EE) induce changes in the coagulation system and are associated with a risk of venous thromboembolism. However, studies comparing the effects of combined oral contraceptives containing EE and low-potency estrogens (ie, estradiol [E-2] and estradiol valerate [EV]) on coagulation biomarkers are limited. This study represents secondary outcomes of a randomized trial comparing combined oral contraceptives containing EV + dienogest (DNG), EE + DNG, and DNG alone on selected coagulation biomarkers. We could compare the specific effects of the different estrogen components owing to the inclusion of preparations containing the same progestin. Material and methods We enrolled 59 healthy, 18- to 35-year-old, non-smoking women, of whom three discontinued. The participants were randomly allocated to 9 weeks of continuous treatment with EV 2 mg + DNG 2-3 mg (n = 20), EE 0.03 mg + DNG 2 mg (n = 20), or DNG 2 mg (n = 19). Blood samples were collected at baseline and after 9 weeks. We assessed coagulation in vitro by thrombin generation using the Calibrated Automated Thrombogram. Thrombin generation was evaluated by lag time, time to thrombin peak, thrombin peak, and endogenous thrombin potential in response to tissue factor (1 pm). In vivo coagulation assessment was based on levels of prothrombin fragment 1 + 2 (F1 + 2) (thrombin generation) and D-dimer (fibrin turnover). Clinical trial registration: NCT02352090. Results Lag time and time to thrombin peak remained unaltered after exposure to EV + DNG, whereas EE + DNG shortened both lag time (mean percentage change -24%, 95% confidence interval [CI] -32% to -15%; p < 0.01) and time to thrombin peak (-26%, 95% CI -37% to -16%; p < 0.01). EV + DNG induced lower thrombin peak and endogenous thrombin potential than EE + DNG (peak; +45%, 95% CI 22%-67% vs +147%,95% CI 96%-198%; p < 0.01, and endogenous thrombin potential; +26%, 95% CI 15%-38% vs +64%, 95% CI 51%-76%; p < 0.01). Median F1 + 2 levels remained unchanged with EV + DNG (p = 0.22) but increased within normal ranges with EE + DNG (from 152 pmol/L, 95% CI 127-206] pmol/L to 194 pmol/L, 95% CI 149-250 pmol/L, p = 0.04). The within-group change in D-dimer levels was not significant in any of the groups. DNG alone did not affect these biomarkers. Conclusions Both in vitro and in vivo thrombin generation was lower after exposure to EV + DNG compared with EE + DNG. The lower thrombin generation measures after treatment with EV + DNG indicate less enhancement of coagulation potential and suggest that EV may be favorable to EE as a component of combined oral contraceptives.Peer reviewe

Niche matters : The comparison between bone marrow stem cells and endometrial stem cells and stromal fibroblasts reveal distinct migration and cytokine profiles in response to inflammatory stimulus

Objective Intrinsic inflammatory characteristics play a pivotal role in stem cell recruitment and homing through migration where the subsequent change in niche has been shown to alter these characteristics. The bone marrow mesenchymal stem cells (bmMSCs) have been demonstrated to migrate to the endometrium contributing to the stem cell reservoir and regeneration of endometrial tissue. Thus, the aim of the present study was to compare the inflammation-driven migration and cytokine secretion profile of human bmMSCs to endometrial mesenchymal stem cells (eMSCs) and endometrial fibroblasts (eSFs). Materials and methods The bmMSCs were isolated from bone marrow aspirates through culturing, whereas eMSCs and eSFs were FACS-isolated. All cell types were tested for their surface marker, proliferation profiles and migration properties towards serum and inflammatory attractants. The cytokine/chemokine secretion profile of 35 targets was analysed in each cell type at basal level along with lipopolysaccharide (LPS)-induced state. Results Both stem cell types, bmMSCs and eMSCs, presented with similar stem cell surface marker profiles as well as possessed high proliferation and migration potential compared to eSFs. In multiplex assays, the secretion of 16 cytokine targets was detected and LPS stimulation expanded the cytokine secretion pattern by triggering the secretion of several targets. The bmMSCs exhibited higher cytokine secretion of vascular endothelial growth factor (VEGF)A, stromal cell-derived factor-1 alpha (SDF)-1 alpha, interleukin-1 receptor antagonist (IL-1RA), IL-6, interferon-gamma inducible protein (IP)-10, monocyte chemoattractant protein (MCP)1, macrophage inflammatory protein (MIP) 1 alpha and RANTES compared to eMSCs and/or eSFs after stimulation with LPS. The basal IL-8 secretion was higher in both endometrial cell types compared to bmMSCs. Conclusion Our results highlight that similar to bmMSCs, the eMSCs possess high migration activity while the differentiation process towards stromal fibroblasts seemed to result in loss of stem cell surface markers, minimal migration activity and a subtler cytokine profile likely contributing to normal endometrial functionPeer reviewe

Women with polycystic ovary syndrome present with altered endometrial expression of stanniocalcin-1

Stanniocalcin-1 (STC-1) is a pro-survival factor that protects tissues against stressors, such as hypoxia and inflammation. STC-1 is co-expressed with the endometrial receptivity markers, and recently endometrial STC-1 was reported to be dysregulated in endometriosis, a condition linked with endometrial progesterone resistance and inflammation. These features are also common in the endometrium in women with polycystic ovary syndrome (PCOS), the most common endocrine disorder in women. Given that women with PCOS present with subfertility, pregnancy complications, and increased risk for endometrial cancer, we investigated endometrial STC-1 expression in affected women. Endometrial biopsy samples were obtained from women with PCOS and controls, including samples from overweight/obese women with PCOS before and after a 3-month lifestyle intervention. A total of 98 PCOS and 85 control samples were used in immunohistochemistry, reverse-transcription polymerase chain reaction, or in vitro cell culture. STC-1 expression was analyzed at different cycle phases and in endometrial stromal cells (eSCs) after steroid hormone exposure. The eSCs were also challenged with 8-bromo-cAMP and hypoxia for STC-1 expression. The findings indicate that STC-1 expression is not steroid hormone mediated although secretory-phase STC-1 expression was blunted in PCOS. Lower expression seems to be related to attenuated STC-1 response to stressors in PCOS eSCs, shown as downregulation of protein kinase A activity. The 3-month lifestyle intervention did not restore STC-1 expression in PCOS endometrium. More studies are warranted to further elucidate the mechanisms behind the altered endometrial STC-1 expression and rescue mechanism in the PCOS endometrium. Summary sentence Endometrial expression of STC-1 in the secretory phase is blunted in women with PCOS, suggesting impaired protection against stress.Peer reviewe

Lapsuuden itseisarvo : Lapsuuden itseisarvon toteutuminen käytännön tasolla varhaiskasvatuksessa

Tässä tutkimuksessa tarkastelin, kuinka lapsuuden itseisarvo toteutuu käytännön tasolla varhaiskasvatuksessa. Varhaiskasvatussuunnitelman perusteissa on luokiteltuna kuusi arvoa, joista yksi on lapsuuden itseisarvo. Se sisältää hyvän ja turvallisen lapsuuden sekä lapsen ainutlaatuisuuden, arvokkuuden ja oikeuden tulla kuulluksi, nähdyksi ja huomioon otetuksi yksilönä ja yhteisön jäsenenä. Arvot Varhaiskasvatussuunnitelman perusteisiin on johdettu osittain YK:n Lapsen oikeuksien sopimuksesta. Tutkimuskysymyksiä minulla oli kolme ja ne olivat 1) miten Varhaiskasvatussuunnitelman perusteissa esitetty lapsuuden itseisarvo tulee esiin käytännön tasolla varhaiskasvatuksessa, 2) mikä merkitys lapsuuden itseisarvon toteutumisella varhaiskasvattajien kokemuksen mukaan on lapselle ja 3) onko lapsuuden itseisarvon toteuttaminen varhaiskasvatuksessa tiedostettua vai tiedostamatonta. Keräsin tutkimusaineiston haastattelulomakkeen avulla syksyllä 2020. Haastattelulomakkeen jaoin sosiaalisessa mediassa kahdessa varhaiskasvattajille tarkoitetuissa Facebook-ryhmässä. Aineistoni koostui yhteensä seitsemästä vastaajasta. Tutkimusotteeni oli fenomenologis-hermeneuttinen, sillä tutkimukseni myötä toin näkyväksi asioita, joita varhaiskasvattajat ovat havainneet tai kokeneet, mutta eivät välttämättä tietoisesti ajatelleet. Keräsin aineistoni puolistrukturoituna teemahaastatteluna. Aineistoa analysoin teemoittelun avulla. Luokittelin tutkimukseni tulokset lapsuuden itseisarvon määrittelyn sisällön mukaisesti. Tuloksista ilmeni, että lapsuuden itseisarvon toteutuminen käytännön tasolla on sidoksissa hyvin arkikokemuksellisiin asioihin. Lapsuuden itseisarvon toteutuminen varhaiskasvatuksessa vahvistaa lapsen itsetuntoa ja kokemusta turvallisuudesta sekä luo perustan demokratialle. Lapsuuden itseisarvo toteutuu osittain tiedostamattomasti, mutta turvallisuuteen liittyvät tekijät ovat tiedostetumpia. Tutkimukseni johtopäätöksenä voidaan todeta, että lapsuuden itseisarvon toteutumisen mahdollistajia ovat hyvä tiimityöskentely, aikuisten läsnäolo, positiivinen suhtautuminen lapseen, sensitiivisyys, osallisuus, leikki sekä yksilöllisyys

Estradiol valerate versus ethinylestradiol in combined contraceptives:effects on blood proteome, lipids, inflammation, and steroid hormones

Abstract Millions of women globally use combined oral contraceptives (COCs) for contraception and the treatment of various conditions. As women may use these preparations for decades, it is essential that they are provided with products that are both effective and safe with minimal side effects. Traditional ethinylestradiol (EE)-based COCs are known to affect metabolism, inflammation, hepatic protein synthesis, and blood coagulation. COCs containing natural estrogens have recently been introduced to the market, offering an interesting new alternative to EE-based COCs. The present studies aimed to investigate the differences of EE- and estradiol valerate (EV)-based COCs in the serum proteome, inflammation, lipids, and ovarian and adrenal hormones. The studies were based on a randomized, controlled, multicenter clinical trial, SYLVI. Altogether, 59 healthy young women were randomized to use either EE+dienogest (DNG) (n=20), EV+DNG (n=20), or DNG only (n=19) continuously for 9 weeks. Fasting serum samples were collected at baseline and the fifth and ninth weeks. We performed an untargeted proteomic analysis and analyzed changes in the inflammatory markers high-sensitivity CRP and pentraxin 3, lipid measurements, gonadotropins, ovarian and adrenal steroids, anti-Müllerian hormone, sex hormone-binding globulin (SHBG), and corticosteroid-binding globulin (CBG). Our results showed that the number of affected proteins in the circulation during EE+DNG use was multifold compared with the natural estrogen-based EV+DNG and DNG-only preparations. The pathways most affected during EE+DNG use were the complement pathway, acute phase signaling response, metabolism-related pathways, and coagulation system. A natural-estrogen-based COC also had significantly milder effects on low-grade inflammation, lipid profile, gonadotropins, androgens, cortisol, and binding protein (SHBG, CBG) synthesis compared with the synthetic EE+DNG preparation. This thesis highlights the neutral effects of natural estrogen in a COC compared with the synthetic and highly potent EE. To date, the choice of COC is based mainly on the properties of progestin components. However, emerging data, suggesting the milder metabolic impact of natural estrogens, promote the consideration of estrogen when prescribing COCs. The results encourage further research and development of natural-estrogen-based COCs.Tiivistelmä Miljoonat naiset käyttävät yhdistelmäehkäisyvalmisteita sekä raskauden ehkäisyyn että erilaisten gynekologisten oireiden hoitoon usein jopa vuosikymmenten ajan. Näin ollen on tärkeää kehittää tehokkaita ja turvallisia valmisteita, joilla on mahdollisimman vähän sivuvaikutuksia. Perinteisesti yhdistelmäehkäisyvalmisteet ovat sisältäneet etinyyliestradiolia (EE), jonka on todettu heikentävän muun muassa rasva-aineenvaihduntaa ja korostavan matala-asteista tulehdusta. Hiljattain kehitetyt, luonnollisempia estrogeeneja sisältävät valmisteet tarjoavat uuden, mielenkiintoisen vaihtoehdon aiemmille yhdistelmille. Väitöskirjan pohjana on satunnaistettu ja kontrolloitu kliininen lääketutkimus SYLVI. 59 naista käyttivät 9 viikkoa yhtäjaksoisesti yhtä seuraavista valmisteista: EE+dienogesti (DNG, n=20), estradiolivaleraatti (EV)+DNG (n=20) tai pelkkä DNG (n=19). Paastoverinäytteet otettiin ennen valmisteen käyttöä sekä viidennellä ja yhdeksännellä käyttöviikolla. Valmisteiden vaikutuksia selvitettiin kohdentamattomalla proteomiikka-analyysillä sekä mittaamalla tulehdusmerkkiaineita ja rasva-arvoja. Hormonisäätelymuutoksia selvitettiin mittaamalla munasarjojen ja lisämunuaiskuoren steroidihormoneja, gonadotropiinit, anti-Müller-hormoni, sukupuolihormoneja sitova proteiini (SHBG) ja kortikosteroideja sitova proteiini (CBG). Tutkimusjakson aikana EE-pohjaisen valmisteen muuttamien proteiinien määrä oli moninkertainen verrattuna estradiolipohjaiseen valmisteeseen ja pelkkään progestiiniin. Nämä muuttuneet proteiinit liittyivät komplementtijärjestelmään, akuutin faasin signalointiin, aineenvaihdunnan säätelyyn sekä veren hyytymistekijöihin. Luonnollisemmalla estradiolipohjaisella yhdistelmällä oli lievemmät vaikutukset myös matala-asteiseen tulehdukseen, rasva-arvoihin, gonadotropiineihin sekä steroidihormoneihin ja näiden kuljettajaproteiineihin (SHBG, CBG) verrattuna synteettiseen EE-yhdistelmään. Tämä väitöskirjatutkimus korostaa luonnolliseen estrogeeniin pohjautuvan yhdistelmäehkäisyn neutraalimpia kokonaisvaikutuksia synteettiseen ja hyvin tehokkaaseen EE:iin verrattuna. Tähän saakka yhdistelmäehkäisyvalmisteen valinta on perustunut lähinnä eri progestiinien ominaisuuksiin, mutta karttuvan tiedon valossa myös estrogeenikomponentti tulisi huomioida. Tutkimustulokset kannustavat tutkimaan ja kehittämään luonnollista estrogeenia sisältäviä valmisteita

Ethinyl estradiol vs estradiol valerate in combined oral contraceptives - Effect on glucose tolerance : A randomized, controlled clinical trial

Objective: To compare the effects of two formulations of combined oral contraceptives (COCs), estradiol valerate (EV) and ethinyl estradiol (EE) combined with dienogest (DNG), and DNG-only, on glucose tolerance. Study Design: We performed a randomized, controlled 9-week clinical trial. Inclusion criteria were: age 18-35 years, regular menstrual cycle (28 +/- 7 days), no polycystic ovaries, non-smoking, no contraindications for COC use and a 2-month wash-out from hormonal contraceptive use. The women were randomized to EV + DNG (n = 20), EE + DNG (n = 20), and DNG-only (n = 19), and evaluated at baseline, at 4-5 weeks and 8-9 weeks of treatment. Study medications were used continuously for 63 days. Primary outcome measure was change in the whole-body insulin sensitivity index (Matsuda index) derived from the oral glucose tolerance test (OGTT) over the treatment period. Secondary outcome measures were area under curves (AUC) of glucose and insulin, homeostatic model assessment - insulin resistance (HOMA-IR) and Insulin Sensitivity Index (ISI). Results: Fifty-nine women enrolled, and 56 women completed the study. The Matsuda index changed from baseline as follows (mean percentage change, mean change [95%CI]): DNG-only -12%, -1.45 [95%CI -3.22-0.325] P = 0.10; EV + DNG + 2.7%, -0.10 [-1.34 to 1.14] P = 0.86; EE + DNG -5.5%, -1.02 [-2.51 to 0.46] P = 0.16, comparing the groups P = 0.27. There were no clinically significant differences in glucose tolerance between the COC groups, but the DNG-only group showed an improvement in the 2-h glucose levels (5.5 [95%CI 5.0-6.0] to 4.7 mmol/l [4.2-5.2], P = 0.001). Conclusion: We found no clinically significant differences between EV and EE combined with DNG and DNG-only on glucose tolerance in healthy, young, normal-weight women, indicating that these preparations appear close to neutral regarding glucose metabolism when used continuously for nine weeks. (C) 2020 Elsevier Inc. All rights reserved.Peer reviewe

Estradiol Valerate in COC Has More Favorable Inflammatory Profile Than Synthetic Ethinyl Estradiol : A Randomized Trial

Context: Combined oral contraceptives (COCs) alter inflammatory status and lipid metabolism. Whether different estrogens have different effects is poorly understood. Objective: We compared the effects of COCs containing ethinyl estradiol (EE) or estradiol valerate (EV) and dienogest (DNG) with those containing DNG only on inflammation and lipid metabolism. Design: Randomized, controlled, open-label clinical trial. Setting: Two-center study in Helsinki and Oulu University Hospitals. Participants: Fifty-nine healthy, young, nonsmoking women with regular menstrual cycles. Age, body mass index, and waist-to-hip ratio were comparable in all study groups at the beginning. Fifty-six women completed the study (EV + DNG, n = 20; EE + DNG, n = 19; DNG only, n = 17). Interventions: Nine-week continuous use of COCs containing either EV + DNG or EE + DNG, or DNG only as control. Main Outcome Measures: Parameters of chronic inflammation (high-sensitivity C-reactive protein [hs-CRP], and pentraxin 3 [PTX-3]) and lipid profile (high-density lipoprotein [HDL], low-density lipoprotein [LDL], triglycerides, and total cholesterol). Results: Serum hs-CRP increased after 9-week use of EE + DNG (mean change +/- standard deviation 1.10 t 2.11 mg/L) compared with EV + DNG (-0.06 t 0.97 mg/L, P = 0.001) or DNG only (0.13 +/- 0.68 mg/L, P= 0.021). Also, PTX-3 increased in the EE + DNG group compared with EV + DNG and DNG-only groups (P = 0.017 and P = 0.003, respectively). In the EE + DNG group, HDL and triglycerides increased compared with other groups (HDL: EE + DNG 0.20 +/- 0.24 mmol/L vs EV + DNG 0.02 +/- 0.20 mmol/L [P = 0.002] vs DNG 0.02 +/- 0.18 mmol/L [P = 0.002]; triglycerides: EE + DNG 0.45 +/- 0.21 mmol/L vs EV + DNG 0.18 +/- 0.36 mmol/L [P= 0.003] vs DNG 0.06 +/- 0.18 mmol/L [P <0.001]). Conclusions: EV + DNG and DNG only had a neutral effect on inflammation and lipids, while EE + DNG increased both hs-CRP and PTX-3 levels as well as triglycerides and HDL.Peer reviewe