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Contraception Apr 2021To evaluate the effect on endocrine and metabolic parameters of a new combined oral contraceptive (COC) containing estetrol (E4) and drospirenone (DRSP). (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
To evaluate the effect on endocrine and metabolic parameters of a new combined oral contraceptive (COC) containing estetrol (E4) and drospirenone (DRSP).
STUDY DESIGN
Randomized, open-label, controlled, 3-arm, parallel study. Healthy subjects received either E4 15 mg/DRSP 3 mg (E4/DRSP) (n = 38), or ethinylestradiol (EE) 30 µg/levonorgestrel (LNG) 150 µg (n = 29), or EE 20 µg/DRSP 3 mg (n = 31) for 6 treatment cycles. Median percentage change from baseline to cycle 3 and to cycle 6 were evaluated for endocrine parameters, liver proteins, lipid profile, and carbohydrate metabolism.
RESULTS
At cycle 6, E4/DRSP treatment had less effect on gonadotropins (follicle stimulating hormone [FSH] +30.5%, luteinizing hormone [LH] -7.5%) compared to EE/LNG (FSH -84.0%, LH -92.0%) and EE/DRSP (FSH -64.0%, LH -90.0%). With E4/DRSP increases in total cortisol (+26.0%) and cortisol binding globulin ([CBG] (+40.0%) were less compared to EE/LNG (cortisol +109.0%, CBG +152.0%) and EE/DRSP (cortisol +107.0%, CBG +140.0%). Liver proteins, except CRP, increased, but the effect was less pronounced with E4/DRSP for angiotensinogen (+75.0%) compared to EE/LNG (+170.0%) and EE/DRSP (+206.5%) and for sex hormone binding globulin ([SHBG] +55.0%), compared to EE/LNG (+74.0%) and EE/DRSP (+251.0%). E4/DRSP had minimal impact on lipid parameters; the largest effect was observed for triglycerides (+24.0%), which was less compared to EE/LNG (+28.0%) and EE/DRSP (+65.5%). E4/DRSP had no effect on carbohydrate metabolism.
CONCLUSIONS
E4/DRSP treatment has limited effects on endocrine and metabolic parameters. The effects on gonadotropins, cortisol, CBG, angiotensinogen, SHBG and triglycerides were less pronounced compared to EE-containing products.
IMPLICATIONS STATEMENT
Combining E4 15 mg with DRSP 3 mg resulted in a COC with a different metabolic profile in comparison to EE-containing products. The clinical relevance of these findings needs to be further assessed, using clinical endpoints to establish the safety profile of this new COC.
Topics: Androstenes; Contraceptives, Oral, Combined; Estetrol; Estrogens; Ethinyl Estradiol; Female; Humans; Levonorgestrel; Sex Hormone-Binding Globulin
PubMed: 33428907
DOI: 10.1016/j.contraception.2021.01.001 -
Medical Science Monitor : International... Apr 2022BACKGROUND We aimed to insure the accuracy and reproducibility of alpha-fetoprotein (AFP), free beta-human chorionic gonadotropin (free ß-hCG), and unconjugated estriol...
External Quality Assessment of Maternal Serum Levels of Alpha-Fetoprotein, Free Beta-Human Chorionic Gonadotropin, and Unconjugated Estriol in Detecting Down Syndrome and Neural Tube Defects in the Second Trimester of 87 Maternal Serum Samples, Based on 105-139 Days.
BACKGROUND We aimed to insure the accuracy and reproducibility of alpha-fetoprotein (AFP), free beta-human chorionic gonadotropin (free ß-hCG), and unconjugated estriol (uE3) concentrations for the screening for trisomy 21 (T21) and neural tube defects (NTD) in the second trimester. We conducted an external quality assessment of 6 laboratories, using maternal serum specimens. MATERIAL AND METHODS Serum specimens collected from 87 women of singleton pregnancies (4 with T21, 5 with NTD, and 78 with normal fetuses) were divided into 6 equivalent-volume fractions and transported to 6 laboratories (A, B, C, D, E, and F). All laboratories used the time-resolved fluorescence analyzer and supporting reagents to measure concentrations of AFP, free ß-hCG, and uE3. The screening efficacies of T21 and NTD were compared with the certified or accredited status of the participants' quality systems. RESULTS Concentrations of AFP measured by laboratory F were low compared with those determined by the other 5 laboratories, and the differences were significant (P<0.01). There was no statistically significant difference in the free ß-hCG and uE3 concentrations measured by the 6 laboratories (P>0.05). The correlation coefficients for the 3 multiples of the median values were all >0.900. The McNemar paired chi-squared test showed the differences in the positivity and detection rates were not statistically significant (P=1.000). CONCLUSIONS AFP, free ß-hCG, and uE3 values measured by the other 5 laboratories were comparable with those of laboratory A, with good linear correlation. When used in the maternal prenatal screening of T21 and NTD, the test results met the clinical requirements.
Topics: Biomarkers; Chorionic Gonadotropin, beta Subunit, Human; Down Syndrome; Estriol; Female; Humans; Neural Tube Defects; Pregnancy; Pregnancy Trimester, Second; Prenatal Diagnosis; Reproducibility of Results; alpha-Fetoproteins
PubMed: 35414638
DOI: 10.12659/MSM.935573 -
Structure (London, England : 1993) Nov 2004Sterol 14alpha-demethylases (CYP51) are essential enzymes in sterol biosynthesis in eukaryotes and drug targets in antifungal therapy. Here, we report CYP51 structures...
Sterol 14alpha-demethylases (CYP51) are essential enzymes in sterol biosynthesis in eukaryotes and drug targets in antifungal therapy. Here, we report CYP51 structures in ligand-free and estriol bound forms. Using estriol as a probe, we determined orientation of the substrate in the active site, elucidated protein contacts with the invariant 3beta-hydroxy group of a sterol, and identified F78 as a key discriminator between 4alpha-methylated and 4alpha,beta-dimethylated substrates. Analysis of CYP51 dynamics revealed that the C helix undergoes helix-coil transition upon binding and dissociation of a ligand. Loss of helical structure of the C helix in the ligand-free form results in an unprecedented opening of the substrate binding site. Upon binding of estriol, the BC loop loses contacts with molecular surface and tends to adopt a closed conformation. A mechanism for azole resistance in the yeast pathogen Candida albicans associated with mutations in the ERG11 gene encoding CYP51 is suggested based on CYP51 protein dynamics.
Topics: Amino Acid Sequence; Cytochrome P-450 Enzyme System; Estriol; Ligands; Models, Molecular; Molecular Probes; Molecular Sequence Data; Oxidoreductases; Protein Conformation; Sequence Homology, Amino Acid; Sterol 14-Demethylase; Substrate Specificity
PubMed: 15530358
DOI: 10.1016/j.str.2004.08.009 -
International Journal of Molecular... Jan 2022Keratoconus (KC) is a progressive corneal thinning disease that manifests in puberty and worsens during pregnancy. KC onset and progression are attributed to diverse...
Keratoconus (KC) is a progressive corneal thinning disease that manifests in puberty and worsens during pregnancy. KC onset and progression are attributed to diverse factors that include: environmental, genetics, and hormonal imbalances; however, the pathobiology remains elusive. This study aims to determine the role of corneal stroma sex hormone receptors in KC and their interplay with estrone (E1) and estriol (E3) using our established 3D in vitro model. Healthy cornea stromal cells (HCFs) and KC cornea stromal cells (HKCs), both male and female, were stimulated with various concentrations of E1 and E3. Significant changes were observed between cell types, as well as between males and females in the sex hormone receptors tested; androgen receptor (AR), progesterone receptor (PR), estrogen receptor alpha (ERα), and estrogen receptor beta (ERβ) using Western blot analysis. E1 and E3 stimulations in HCF females showed AR, PR, and ERβ were significantly upregulated compared to HCF males. In contrast, ERα and ERβ had significantly higher expression in HKC's females than HKC's males. Our data suggest that the human cornea is a sex-dependent, hormone-responsive tissue that is significantly influenced by E1 and E3. Therefore, it is plausible that E1, E3, and sex hormone receptors are involved in the KC pathobiology, warranting further investigation.
Topics: Biomarkers; Cells, Cultured; Corneal Stroma; Disease Susceptibility; Estriol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrone; Gonadal Steroid Hormones; Humans; Keratoconus; Receptors, Androgen; Receptors, Progesterone; Receptors, Steroid
PubMed: 35055103
DOI: 10.3390/ijms23020916 -
Molecular Psychiatry Nov 2020Elevated latent prenatal steroidogenic activity has been found in the amniotic fluid of autistic boys, based on measuring prenatal androgens and other steroid hormones....
Elevated latent prenatal steroidogenic activity has been found in the amniotic fluid of autistic boys, based on measuring prenatal androgens and other steroid hormones. To date, it is unclear if other prenatal steroids also contribute to autism likelihood. Prenatal oestrogens need to be investigated, as they play a key role in synaptogenesis and corticogenesis during prenatal development, in both males and females. Here we test whether levels of prenatal oestriol, oestradiol, oestrone and oestrone sulphate in amniotic fluid are associated with autism, in the same Danish Historic Birth Cohort, in which prenatal androgens were measured, using univariate logistic regression (n = 98 cases, n = 177 controls). We also make a like-to-like comparison between the prenatal oestrogens and androgens. Oestradiol, oestrone, oestriol and progesterone each related to autism in univariate analyses after correction with false discovery rate. A comparison of standardised odds ratios showed that oestradiol, oestrone and progesterone had the largest effects on autism likelihood. These results for the first time show that prenatal oestrogens contribute to autism likelihood, extending the finding of elevated prenatal steroidogenic activity in autism. This likely affects sexual differentiation, brain development and function.
Topics: Adult; Autistic Disorder; Estradiol; Estriol; Estrogens; Female; Fetus; Humans; Male; Maternal Age; Paternal Age; Pregnancy; Prenatal Exposure Delayed Effects; Progesterone
PubMed: 31358906
DOI: 10.1038/s41380-019-0454-9 -
Laboratory Investigation; a Journal of... Aug 2023In multiple sclerosis (MS), demyelination occurs in the cerebral cortex, and cerebral cortex atrophy correlates with clinical disabilities. Treatments are needed in MS...
In multiple sclerosis (MS), demyelination occurs in the cerebral cortex, and cerebral cortex atrophy correlates with clinical disabilities. Treatments are needed in MS to induce remyelination. Pregnancy is protective in MS. Estriol is made by the fetoplacental unit, and maternal serum estriol levels temporally align with fetal myelination. Here, we determined the effect of estriol treatment on the cerebral cortex in the preclinical model of MS, experimental autoimmune encephalomyelitis (EAE). Estriol treatment initiated after disease onset decreased cerebral cortex atrophy. Neuropathology of the cerebral cortex showed increased cholesterol synthesis proteins in oligodendrocytes, more newly formed remyelinating oligodendrocytes, and increased myelin in estriol-treated EAE mice. Estriol treatment also decreased the loss of cortical layer V pyramidal neurons and their apical dendrites and preserved synapses. Together, estriol treatment after EAE onset reduced atrophy and was neuroprotective in the cerebral cortex.
Topics: Pregnancy; Female; Mice; Animals; Neuroprotection; Encephalomyelitis, Autoimmune, Experimental; Multiple Sclerosis; Estriol; Cerebral Cortex; Neurodegenerative Diseases; Atrophy; Mice, Inbred C57BL
PubMed: 37245852
DOI: 10.1016/j.labinv.2023.100189 -
British Medical Journal Mar 1972In a sextuplet pregnancy which followed gonadotrophin therapy the principal problems were threatened abortion, premature labour, and placental insufficiency. Delivery...
In a sextuplet pregnancy which followed gonadotrophin therapy the principal problems were threatened abortion, premature labour, and placental insufficiency. Delivery was by caesarean section soon after the onset of labour at 32 weeks. The five liveborn babies thrived. The sixth was a macerated stillbirth.
Topics: Abortion, Threatened; Cesarean Section; Chorionic Gonadotropin; Estriol; Estrone; Female; Fetal Death; Humans; Infant, Newborn; Infertility, Female; Male; Obstetric Labor, Premature; Postpartum Period; Pregnancy; Pregnancy, Multiple; Pregnanediol
PubMed: 5014254
DOI: 10.1136/bmj.1.5803.787 -
Women's Health (London, England) Mar 2008'Bioidentical hormones' is a term created by the lay media to refer to chemicals derived from plants that are modified to be structurally identical to endogenous human... (Review)
Review
'Bioidentical hormones' is a term created by the lay media to refer to chemicals derived from plants that are modified to be structurally identical to endogenous human hormones. These compounds include estradiol, estrone, estriol, progesterone, testosterone and dehydroepiandrosterone when prescribed for menopausal women. Patients assume bioidentical hormones are natural and safer than synthetic hormones with regard to the risk of developing breast cancer and other diseases, but there is little evidence to support this belief. Proponents of this therapy also support the use of salivary hormone measurements to adjust doses of these hormones instead of adjustment based on improvement or lack of improvement in menopausal symptoms. In this review, the rationale behind the use of bioidentical hormones is discussed, along with the evidence supporting the use of compounded and FDA-approved bioidentical products.
Topics: Administration, Cutaneous; Drug Compounding; Estradiol; Estriol; Estrogens; Female; Hormone Replacement Therapy; Humans; Menopause; Phytotherapy; Plant Extracts; Progesterone; Testosterone
PubMed: 19072518
DOI: 10.2217/17455057.4.2.163 -
Fertility and Sterility Nov 2016To study the current literature on the association between IVF treatment and maternal serum screening marker levels and nuchal translucency thickness. (Review)
Review
OBJECTIVE
To study the current literature on the association between IVF treatment and maternal serum screening marker levels and nuchal translucency thickness.
DESIGN
Systematic review.
SETTINGS
Not applicable.
PATIENT(S)
Eligible studies included those with an exposed group of pregnant women that used IVF with or without intracytoplasmic sperm injection to conceive and a control group of pregnant women who conceived spontaneously.
INTERVENTION(S)
IVF treatment to conceive.
MAIN OUTCOME MEASURE(S)
Outcomes evaluated included maternal serum screening markers (pregnancy-associated plasma protein A [PAPP-A], alpha-fetoprotein, hCG, unconjugated estriol, dimeric inhibin-A) and nuchal translucency thickness.
RESULT(S)
Database searches identified 4,118 titles and abstracts that were independently screened, which resulted in 76 articles that were assessed for eligibility. Additionally, one study was added for consideration based on expert knowledge. There were 29 cohort and 11 case-control studies in the descriptive review. The most commonly reported markers were PAPP-A and free β-hCG, which were reported in 28 and 26 studies, respectively. The studies that reported effect sizes for PAPP-A and free β-hCG were not statistically significant.
CONCLUSION(S)
A decrease in PAPP-A and an increase in total hCG was consistently reported among the included studies. However, owing to the variability in the levels of the other maternal serum screening markers reported and the inability to conduct a meta-analysis, we were unable to generalize about the differences between prenatal screening results in the IVF population.
Topics: Biomarkers; Chorionic Gonadotropin; Chromosome Disorders; Estriol; Female; Fertility; Fertilization in Vitro; Humans; Infertility; Inhibins; Nuchal Translucency Measurement; Predictive Value of Tests; Pregnancy; Pregnancy Trimester, First; Pregnancy-Associated Plasma Protein-A; Reproducibility of Results; Sperm Injections, Intracytoplasmic; Treatment Outcome; alpha-Fetoproteins
PubMed: 27530061
DOI: 10.1016/j.fertnstert.2016.07.1120 -
Experimental Gerontology Aug 2017Estrogens are potent and efficacious neuroprotectants both in vitro and in vivo in a variety of models of neurotoxicity. We determined the structural requirements for... (Review)
Review
Estrogens are potent and efficacious neuroprotectants both in vitro and in vivo in a variety of models of neurotoxicity. We determined the structural requirements for neuroprotection in an in vitro assay using a panel of >70 novel estratrienes, synthesized to reduce or eliminate estrogen receptor (ER) binding. We observed that neuroprotection could be enhanced by as much as 200-fold through modifications that positioned a large bulky group at the C2 or C4 position of the phenolic A ring of the estratriene. Further, substitutions on the B, C or D rings either reduced or did not markedly change neuroprotection. Collectively, there was a negative correlation between binding to ERs and neuroprotection with the more potent compounds showing no ER binding. In an in vivo model for neuroprotection, transient cerebral ischemia, efficacious compounds were active in protection of brain tissue from this pro-oxidant insult. We demonstrated that these non-feminizing estrogens engage in a redox cycle with glutathione, using the hexose monophosphate shunt to apply cytosolic reducing potential to cellular membranes. Together, these results demonstrate that non-feminizing estrogens are neuroprotective and protect brain from the induction of ischemic- and Alzheimer's disease (AD)-like neuropathology in an animal model. These features of non-feminizing estrogens make them attractive compounds for assessment of efficacy in AD and stroke, as they are not expected to show the side effects of chronic estrogen therapy that are mediated by ER actions in the liver, uterus and breast.
Topics: Animals; Brain; Estradiol; Estriol; Estrogens; Humans; Molecular Structure; Neurons; Neuroprotective Agents; Oxidation-Reduction; Oxidative Stress; Receptors, Estrogen; Structure-Activity Relationship
PubMed: 27818250
DOI: 10.1016/j.exger.2016.10.013