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Objective The use of combined hormonal contraceptives (CHCs) worsens glucose tolerance, but the risk for glucose metabolism disorders remains controversial. Design The study is a prospective longitudinal population-based cohort study. Methods The study was based on a cohort population that comprised 1879 women born in 1966. At age 46, the women answered a questionnaire on contraceptive use and underwent an oral glucose tolerance test. Glucose metabolism indices were evaluated in current CHC (n = 153), progestin-only contraceptive (POC, n = 842), and non-hormonal contraceptive users (n = 884). Results In the entire study population, current CHC use was significantly associated with prediabetes (OR: 2.0, 95% CI: 1.3–3.2) and type 2 diabetes (OR: 3.3, 95% CI: 1.1–9.7) compared to non-hormonal contraceptive use. After 5 years of use, the prediabetes risk increased 2.2-fold (95% CI: 1.3–3.7) and type 2 diabetes risk increased 4.5-fold (95% CI: 1.5–13.5). Compared with the current POC use, current CHC use was significantly associated with prediabetes (OR: 1.9, 95% CI: 1.2–3.0). Current POC use was not associated with any glucose metabolism disorders. The results prevailed after adjusting for BMI and socioeconomic status. Conclusions CHC use in perimenopausal women was associated with a significantly increased risk of glucose metabolism disorders. This association should be considered in women with increased metabolic risk.

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 ± 2.11 mg/L) compared with EV + DNG (−0.06 ± 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. Trial Registration ClinicalTrials.gov NCT02352090

Context Limited studies have compared 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 (active control) on levels of follicle stimulating hormone (FSH), luteinizing hormone, anti-Müllerian hormone (AMH), ovarian steroids, sex hormone binding globulin (SHBG), and the free androgen index (FAI). Methods This spin-off study from a randomized trial enrolled 59 healthy, 18 to 35-year-old ovulatory women, outpatients at Helsinki and Oulu University Hospitals, Finland, who were randomized to EV 2 mg + DNG 2-3 mg (n = 20); EE 0.03 mg + DNG 2 mg (n = 20); and DNG 2 mg (n = 19) for 9 weeks. Blood samples were drawn at baseline, and at 5 and 9 weeks. Age and BMI were comparable between groups; 3 women discontinued. Results EV + DNG suppressed FSH by −27% (−51% to −3%) (median [95% CI]) vs EE + DNG, −64% (−78 to −51), P = 0.04, but AMH levels decreased similarly by −9% (−18 to −0.1) vs −13% (−28 to 0.2), P = 0.38, respectively. EV + DNG increased SHBG levels by 56% (30% to 82%) and EE + DNG by 385% (313% to 423%), P Conclusion Compared with EE + DNG, treatment with EV + DNG resulted in milder pituitary downregulation and reduced induction of hepatic SHBG synthesis—potentially carrying more beneficial health effects.

Ethinylestradiol (EE)-based combined oral contraceptives (COC) affect adrenal function by altering steroid and corticosteroid-binding globulin (CBG) synthesis that may contribute to adverse effects related to these drugs. The effects of COCs containing natural estrogens remain unclear. We compared the effects of COCs containing estradiol valerate (EV) and EE on cortisol and other adrenal steroid hormones.A spin-off study of a randomized, open-label trial. Fifty-nine healthy women were allocated to groups that engaged in the continuous use of EV+dienogest (DNG), EE+DNG, or DNG only for 9 weeks. We measured changes in adrenal steroids, CBG, and the free cortisol index (FCI).Treatment with EE+DNG increased total cortisol (mean increment 668 nmol/L, p0.001) and cortisone (10 nmol/L, p= 0.001) levels, whereas the change from the baseline was insignificant for the EV+DNG and DNG-only groups. Dehydroepiandrosterone sulfate decreased by 24% in the EE+DNG group but remained unchanged in the EV+DNG and DNG-only groups. Aldosterone and 17-hydroxyprogesterone levels did not differ between the groups. All preparations increased CBG, but the increase in the EE+DNG group (median increment 42 µg/mL, p0.001) was 9- and 49-fold higher than that in the EV+DNG and DNG-only groups, respectively. The FCI remained unchanged in all study groups, indicating that cortisol and CBG mainly increased in parallel, although some individuals demonstrated larger alterations in the cortisol-CBG balance.In COCs, EV had a milder effect on circulating CBG and adrenal steroid levels than EE; however, further research is necessary to determine the long-term effects.ClinicalTrials.gov NCT02352090 IMPLICATIONS: EV-based COC had reduced effects on circulating CBG and adrenal steroids compared to EE, probably due to a lower hepatic impact. Whether the sensitization of the adrenals to ACTH varies according to COC contents and whether it relates to experienced side effects needs to be investigated. These results encourage further research and development of contraceptives containing natural estrogens.

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. Implications Combinations of both ethinyl estradiol and natural estradiol (estradiol valerate) with dienogest (DNG), as well as DNG-only, seem metabolically safe in young and healthy women in short-term continuous use.

Objectives Research on the treatment of second-trimester miscarriages is scarce. We studied the outcomes, and the factors associated with adverse events and need for hospital resources in the medical treatment of second-trimester miscarriage. Materials and methods In these retrospective analyses we studied women treated for spontaneous fetal miscarriage with misoprostol-only (n = 24) or mifepristone and misoprostol (n = 177) in duration of gestation 12+1–21+6. Primary outcomes were the risk factors for surgical evacuation and excessive bleeding. Secondary outcomes were total misoprostol dose, time to expulsion and the length of hospital stay. Results History of surgical evacuation of the uterus increased the risk of surgical evacuation (p = 0.027). Excessive bleeding was not associated with any of the studied variables. More misoprostol was needed when the duration of gestation exceeded 17+0 weeks (p = 0.036). In multivariate analysis the time to fetal expulsion was shorter in women with history of 1–2 deliveries (hazard ratio [HR] 1.49, 95% confidence interval [CI]; 1.07–2.07), ≥3 deliveries (HR 1.63, 95% CI; 1.11–2.38) and with a two-day interval between mifepristone-misoprostol administration (HR 1.71, 95% CI; 1.05–2.81). Patients with symptoms (i.e. uterine bleeding or pain) at baseline had longer hospital stay (HR 0.66, 95% CI; 0.47–0.92). Conclusions The factors affecting the outcomes of medical treatment of second-trimester fetal miscarriage are similar to those of second-trimester induced abortion. Two-day interval between mifepristone-misoprostol administration might decrease the time to fetal expulsion and the need of hospital resources.

Over time, reductions in the ethinylestradiol (EE) dose of combined oral contraceptives (COCs) from 100 μg to 20–30 μg have resulted in a lowered risk of COC-associated venous thromboembolism (VTE). Additionally, the development and incorporation of less androgenic progestins, administered in lower doses, have improved the tolerability and metabolic impact of COCs. EE in COCs has recently been replaced with estrogens based on natural estradiol (E2). E2-based COCs are expected to cause more moderate metabolic, endocrine and hemostatic effects than EE-based COCs. However, evidence remains limited, and previous studies investigating EE versus EV are difficult to interpret since they have compared COCs that also differ based on the progestin type. A meaningful comparison of the estrogens in COCs should focus on COCs differing only by the estrogen component since the progestin component exerts its own effects in addition to modulating the effects of the estrogen. Therefore, this thesis aimed to compare the metabolic, endocrine and hemostatic effects of COCs containing E2 (esterified with valeric acid; estradiol valerate [EV]) and EE. To this end, we conducted an open-label, randomized study. Participants were allocated to nine weeks of continuous treatment with 1) EV 2 mg and dienogest (DNG) 2–3 mg, 2) EE 0.03 mg and DNG 2 mg and 3) DNG 2 mg, which was included to specify the progestin effects. Participants were assessed at baseline, five and nine weeks of treatment for changes in insulin sensitivity (the Matsuda index; study I); the lipid profile and markers of low-grade inflammation (high sensitivity C-reactive protein [hs-CRP] and pentraxin-3 [PTX-3]; study II); levels of reproductive hormones (gonadotropins and ovarian hormones) and the induction of hepatic metabolism (sex hormone-binding globulin [SHBG]; study III); and blood coagulation biomarkers (in vitro thrombin generation and markers of in vivo coagulation activation; study IV). We recruited 77 women, of whom 59 were enrolled. The main inclusion criteria were being 18–35 years of age, a two-month wash-out from previous hormonal contraceptive use and normal body weight (body mass index 19–24.9 kg/m2). Three women discontinued participation due to mild side effects. The primary endpoint measure of this study was a change in the Matsuda Index, a whole-body insulin sensitivity index derived from the oral glucose tolerance test (OGTT). The Matsuda index, as well as glucose levels during the OGTT, remained unchanged after treatment with both EV+DNG and EE+DNG. By contrast, fasting insulin levels increased within the normal ranges in the EE+DNG group by +39% (p = 0.03) and in the DNG-alone group by +45% (p = 0.01), whereas they remained unchanged in the EV+DNG group (study I). In the EV+DNG group, the lipid profile changed negligibly. The mean triglyceride levels were minimally elevated at nine weeks, increasing by 0.18 mmol/L (p = 0.02). In the EE+DNG group, triglycerides increased by 0.45 mmol/L (p < 0.001) and high-density lipoproteins by 0.20 mmol/L (p < 0.01). These changes remained within the normal ranges and demonstrated changes in the lipid profile typical for estrogen treatment. Moreover, the mean levels of hs-CRP increased by 1.1 mg/L (p < 0.01) and PTX-3 by 0.22 ng/L (p = 0.02) in the EE+DNG-group, indicative of increased low-grade inflammation. In contrast, treatment with EV+DNG and DNG alone did not trigger increases in either inflammatory marker (study II). Compared with EE+DNG, treatment with EV+DNG resulted in less marked suppression of follicle-stimulating hormone (FSH), whereas luteinizing hormone levels were equally suppressed. As expected, all participants had low progesterone levels compatible with anovulation at five and nine weeks. As an indicator of follicular arrest, anti-Müllerian hormone (AMH) levels decreased in both COC groups by -9% (EV+DNG; p = 0.04) and -13% (EE+DNG; p = 0.01), while AMH remained unchanged in the DNG-alone group. The free androgen index (FAI), a surrogate for free testosterone levels, decreased less in the EV+DNG group than in the EE+DNG group (-39% vs. -72%, p < 0.001). In the EV+DNG group, reduced hepatic impact was demonstrated through a moderate increase in SHBG levels at nine weeks compared with the EE+DNG group, in which SHBG levels increased significantly more (+56% vs. +368%, p < 0.001) (study III). The effect on blood coagulation parameters differed between the EV+DNG and EE+DNG groups. In both groups, in vitro coagulation potential (assessed by thrombin generation) increased; however, the magnitude diverged in favor of EV+DNG, which induced a smaller increase in endogenous thrombin potential (+26% vs. +64%, p < 0.01). Levels of prothrombin fragment 1+2 (F1+2) were elevated in the EE+DNG group, compatible with coagulation activation in vivo, while F1+2 levels remained unaltered in the EV+DNG group (p = 0.04). In contrast, D-dimer levels remained unchanged in all groups. Treatment with DNG alone did not affect either the in vitro or in vivo coagulation parameters. These results indicate increased coagulation potential in the EE+DNG group compared with the EV+DNG group (study IV). In conclusion, these results show that in young, healthy women, short-term treatment with EV+DNG affected markers of low-grade inflammation, lipids, the FAI, SHBG synthesis and blood coagulation parameters less than treatment with EE+DNG. In addition, EV+DNG also appeared neutral on parameters of glucose metabolism, whereas EE+DNG elevated fasting insulin levels. The clinical significance of the differing effects of EV and EE on insulin levels, lipids, and inflammatory markers remains to be explored. However, the more minor impact of EV+DNG on the coagulation parameters may be clinically significant, possibly predicting a lower risk of venous thrombosis. These results encourage further development and research of E2-based COCs. Nykyaikaiset hormonaaliset yhdistelmäehkäisyvalmisteet sisältävät pääsääntöisesti synteettistä etinyyliestradiolia yhdistettynä synteettiseen keltarauhashormoniin, progestiiniin. Etinyyliestradiolin haittavaikutukset, erityisesti sen laskimotukoksen riskiä lisäävä vaikutus, tunnetaan hyvin. Siksi etinyyliestradioliannosta on vuosien mittaan pienenetty. Tiedetään myös, että yhdistelmäehkäisyvalmisteet heikentävät sokeriaineenvaihduntaa ja lisäävät matala-asteista tulehdusta. Markkinoille on viimeisten vuosien aikana tullut luonnollista estradiolia sisältäviä yhdistelmäehkäisyvalmisteita, joilla on mahdollisesti vähemmän aineenvaihdunnallisia haittavaikutuksia ja pienempi laskimotukosriski. Väitöskirjatutkimuksessa verrattiin yhdistelmäehkäisyvalmisteita, jotka sisältävät luonnollista estradiolivaleraattia tai synteettistä etinyyliestradiolia, ja selvitettiin niiden vaikutuksia sokeri- ja rasva-aineenvaihduntaan ja matala-asteiseen tulehdukseen, lisääntymishormoneihin, ja veren hyytymisjärjestelmään. Ainoastaan keltarauhashormonia sisältävä valmiste toimi vertailuvalmisteena. Tutkimus toteutettiin satunnaistettuna kliinisenä lääkeainetutkimuksena. Tutkimukseen osallistui 59 vapaaehtoista, 18–35-vuotiasta naista. Osallistujat satunnaistettiin käyttämään joko 1) estradiolivaleraatin ja dienogestin yhdistelmää (EV 2 mg + DNG 2-3 mg), 2) etinyyliestradiolin ja dienogestin yhdistelmää (EE 0.03 mg + DNG 2 mg), tai 3) pelkkää dienogestiä (DNG 2 mg) yhtäjaksoisesti yhdeksän viikon ajan. Verikokeita otettiin ennen tutkimusjakson alkua sekä viidennen ja yhdeksännen tutkimusviikon aikana. Tutkimuksen päämuuttuja oli insuliiniherkkyys. Kummassakaan yhdistelmävalmisteryhmässä (EV+DNG ja EE+DNG) ei havaittu muutosta insuliiniherkkyydessä. Veren rasvaprofiili pysyi lähes muuttumattomana EV+DNG ryhmässä, kun taas EE+DNG ryhmässä triglyseridien ja HDL-kolesterolin pitoisuudet nousivat jonkin verran. EV+DNG ryhmässä matala-asteista tulehdusta kuvaavat merkkiaineet pysyivät muuttumattomina, mutta nousivat merkittävästi EE+DNG ryhmässä. EV+DNG ryhmässä havaittiin lievempi vaikutus follikkelia stimuloivan hormonin pitoisuuksiin. Kaikilla naisilla oli kuitenkin matalat progesteronitasot, sopien ovulaation estoon. Veren vapaa testosteroni laski vähemmän EV+DNG ryhmässä (-38 %) kuin EE+DNG ryhmässä (-72 %). Myös sukuhormoneja sitova globuliinin pitoisuus lisääntyi vähemmän EV+DNG (+56 %) ryhmässä verrattuna EE+DNG ryhmään (+368 %), osoittaen EV+DNG:n lievempää vaikutusta maksan estrogeeniherkkien proteiinien tuotantoon. EE+DNG-yhdistelmä vaikutti enemmän veren hyytymisjärjestelmään kuin EV+DNG. Plasmanäytteistä tutkittiin veren hyytymisen keskeisen entsyymin, trombiinin, tuotantoa. Kokeellisessa asetelmassa, EE+DNG-ryhmässä trombiinin tuotanto nousi lähtötilanteesta +64 % kun vastaava nousu EV+DNG-ryhmässä oli 26 %. Tulosten perusteella estradiolivaleraattia sisältävä yhdistelmäehkäisyvalmiste vaikutti vähemmän rasva-aineenvaihduntaan, matala-asteiseen tulehdukseen ja veren hyytymisjärjestelmään kuin etinyyliestradiolia sisältävä valmiste. Koska molemmilla valmisteilla on hyvä ehkäisyteho, estradiolivaleraatin lievemmät vaikutukset, varsinkin hyytymisjärjestelmään, viittaavat edullisempaan hyöty-haittasuhteseen.