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The Journal of Clinical Endocrinology... Apr 2021This mini-review provides an overview of menopausal hormone therapy (HT) and cardiovascular disease (CVD) risk, with a focus on the role of hormone formulation, dose,... (Review)
Review
CONTEXT
This mini-review provides an overview of menopausal hormone therapy (HT) and cardiovascular disease (CVD) risk, with a focus on the role of hormone formulation, dose, and route of delivery.
METHODS
This summary is based on authors' knowledge in the field of menopausal HT and supplemented by a PubMed search using the terms "menopause hormone therapy," "transdermal," "estradiol," "conjugated estrogens," "bioidentical," "cardiovascular disease," "lipoproteins," "glucose," "progestogens," "low dose."
RESULTS
Available evidence indicates that oral unopposed estrogens have a favorable effect on lipoprotein levels, glycemia, insulin, and CVD risk; however, the addition of progestogens blunts the lipid-related effects. The progestogen with the smallest attenuating effect is micronized progesterone. Transdermal estrogens have less effect on coagulation, inflammation, and lipids than oral estrogens and observational studies suggest they pose a lower risk of venous thromboembolism and stroke than oral estrogens. Clinical effects of hormones were not consistently dose dependent.
CONCLUSIONS
Although HT continues to have an important role in menopause management, it is not recommended for primary or secondary CVD prevention. Different formulations, doses, and routes of delivery of HT have different effects on cardiometabolic markers and risks of clinical CVD events. However, long-term trials evaluating clinical outcomes with transdermal and other alternate HT regimens are limited.
Topics: Administration, Cutaneous; Cardiovascular Diseases; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Compounding; Estradiol; Estrogen Replacement Therapy; Female; Humans; Menopause; Risk Factors
PubMed: 33506261
DOI: 10.1210/clinem/dgab042 -
Nature Jun 2022Oestradiol establishes neural sex differences in many vertebrates and modulates mood, behaviour and energy balance in adulthood. In the canonical pathway, oestradiol...
Oestradiol establishes neural sex differences in many vertebrates and modulates mood, behaviour and energy balance in adulthood. In the canonical pathway, oestradiol exerts its effects through the transcription factor oestrogen receptor-α (ERα). Although ERα has been extensively characterized in breast cancer, the neuronal targets of ERα, and their involvement in brain sex differences, remain largely unknown. Here we generate a comprehensive map of genomic ERα-binding sites in a sexually dimorphic neural circuit that mediates social behaviours. We conclude that ERα orchestrates sexual differentiation of the mouse brain through two mechanisms: establishing two male-biased neuron types and activating a sustained male-biased gene expression program. Collectively, our findings reveal that sex differences in gene expression are defined by hormonal activation of neuronal steroid receptors. The molecular targets we identify may underlie the effects of oestradiol on brain development, behaviour and disease.
Topics: Animals; Brain; Estradiol; Estrogen Receptor alpha; Female; Gene Expression Regulation; Male; Mice; Sex Characteristics
PubMed: 35508660
DOI: 10.1038/s41586-022-04686-1 -
International Journal of Epidemiology Dec 2022Sex hormone-binding globulin (SHBG), testosterone and oestradiol have been associated with many diseases in observational studies; however, the causality of associations...
BACKGROUND
Sex hormone-binding globulin (SHBG), testosterone and oestradiol have been associated with many diseases in observational studies; however, the causality of associations remains unestablished.
METHODS
A phenome-wide Mendelian randomization (MR) association study was performed to explore disease outcomes associated with genetically proxied circulating SHBG, testosterone and oestradiol levels by using updated genetic instruments in 339 197 unrelated White British individuals (54% female) in the UK Biobank. Two-sample MR analyses with data from large genetic studies were conducted to replicate identified associations in phenome-wide MR analyses. Multivariable MR analyses were performed to investigate mediation effects of hormone-related biomarkers in observed associations with diseases.
RESULTS
Phenome-wide MR analyses examined associations of genetically predicted SHBG, testosterone and oestradiol levels with 1211 disease outcomes, and identified 28 and 13 distinct phenotypes associated with genetically predicted SHBG and testosterone, respectively; 22 out of 28 associations for SHBG and 10 out of 13 associations for testosterone were replicated in two-sample MR analyses. Higher genetically predicted SHBG levels were associated with a reduced risk of hypertension, type 2 diabetes, diabetic complications, coronary atherosclerotic outcomes, gout and benign and malignant neoplasm of uterus, but an increased risk of varicose veins and fracture (mainly in females). Higher genetically predicted testosterone levels were associated with a lower risk of type 2 diabetes, coronary atherosclerotic outcomes, gout and coeliac disease mainly in males, but an increased risk of cholelithiasis in females.
CONCLUSIONS
These findings suggest that sex hormones may causally affect risk of several health outcomes.
Topics: Female; Humans; Male; Estradiol; Gonadal Steroid Hormones; Mendelian Randomization Analysis; Sex Hormone-Binding Globulin; Testosterone
PubMed: 35218343
DOI: 10.1093/ije/dyac036 -
Central Nervous System Agents in... 2014The gonadal hormone estradiol modulates mesolimbic dopamine systems in the female rat. This modulatory effect is thought to be responsible for the observed effects of... (Review)
Review
The gonadal hormone estradiol modulates mesolimbic dopamine systems in the female rat. This modulatory effect is thought to be responsible for the observed effects of estradiol on motivated behaviors. Dopamine acting in the nucleus accumbens is thought to be important for the attribution of incentive motivational properties to cues that predict reward delivery, while dopamine in the striatum is associated with the expression of repetitive or stereotyped behaviors. Elevated concentrations of estradiol are associated with increased motivation for sex or cues associated with access to a mate, while simultaneously attenuating motivation for food. This shift in motivational salience is important for adaptive choice behavior in the natural environment. Additionally, estradiol's adaptive effects on motivation can be maladaptive when increasing motivation for non-natural reinforcers, such as drugs of abuse. Here we discuss the effect of estradiol on mesotelencephalic dopamine transmission and subsequent effects on motivated behaviors.
Topics: Animals; Dopamine; Estradiol; Feeding Behavior; Female; Humans; Male; Motivation; Sex Characteristics; Sexual Behavior
PubMed: 25540977
DOI: 10.2174/1871524914666141226103135 -
Hormones and Behavior Sep 2014A historical perspective on estradiol's enhancement of cognitive function is presented, and research, primarily in animals, but also in humans, is reviewed. Data... (Review)
Review
A historical perspective on estradiol's enhancement of cognitive function is presented, and research, primarily in animals, but also in humans, is reviewed. Data regarding the mechanisms underlying the enhancements are discussed. Newer studies showing rapid effects of estradiol on consolidation of memory through membrane interactions and activation of inter-cellular signaling pathways are reviewed as well as studies focused on traditional genomic mechanisms. Recent demonstrations of intra-neuronal estradiol synthesis and possible actions as a neurosteroid to promote memory are discussed. This information is applied to the critical issue of the current lack of effective hormonal (or other) treatments for cognitive decline associated with menopause and aging. Finally, the critical period hypothesis for estradiol effects is discussed along with novel strategies for hormone/drug development. Overall, the historical record documents that estradiol positively impacts some aspects of cognitive function, but effective therapeutic interventions using this hormone have yet to be realized.
Topics: Aging; Animals; Cognition; Cognition Disorders; Estradiol; Estrogen Replacement Therapy; Female; Humans; Memory; Menopause
PubMed: 25205317
DOI: 10.1016/j.yhbeh.2014.08.011 -
International Journal of Molecular... Jan 2022Biological sex influences disease development and progression. The steroid hormone 17β-oestradiol (E2), along with its receptors, is expected to play a major role in... (Review)
Review
Biological sex influences disease development and progression. The steroid hormone 17β-oestradiol (E2), along with its receptors, is expected to play a major role in the manifestation of sex differences. E2 exerts pleiotropic effects in a system-specific manner. Mitochondria are one of the central targets of E2, and their biogenesis and respiration are known to be modulated by E2. More recently, it has become apparent that E2 also regulates mitochondrial fusion-fission dynamics, thereby affecting cellular metabolism. The aim of this article is to discuss the regulatory pathways by which E2 orchestrates the activity of several components of mitochondrial dynamics in the cardiovascular and nervous systems in health and disease. We conclude that E2 regulates mitochondrial dynamics to maintain the mitochondrial network promoting mitochondrial fusion and attenuating mitochondrial fission in both the cardiovascular and nervous systems.
Topics: Animals; Cardiovascular System; Estradiol; Female; Gene Expression Regulation; Humans; Male; Mitochondria; Mitochondrial Dynamics; Nervous System; Receptors, Estrogen; Sex Characteristics
PubMed: 35163044
DOI: 10.3390/ijms23031118 -
Redox Biology Jun 2023Ovariectomy (OVX) conducted before the onset of natural menopause is considered to bringing forward and accelerate the process of ageing-associated neurodegeneration....
Ovariectomy (OVX) conducted before the onset of natural menopause is considered to bringing forward and accelerate the process of ageing-associated neurodegeneration. However, the mechanisms underlying memory decline and other cognitive dysfunctions following OVX are unclear. Given that iron accumulates during ageing and after OVX, we hypothesized that excess iron accumulation in the hippocampus would cause ferroptosis-induced increased neuronal degeneration and death associated with memory decline. In the current study, female rats that underwent OVX showed decreased dihydroorotate dehydrogenase (DHODH) expression and reduced performance in the Morris water maze (MWM). We used primary cultured hippocampal cells to explore the ferroptosis resistance-inducing effect of 17β-oestradiol (E). The data supported a vital role of DHODH in neuronal ferroptosis. Specifically, E alleviated ferroptosis induced by erastin and ferric ammonium citrate (FAC), which can be blocked by brequinar (BQR). Further in vitro studies showed that E reduced lipid peroxidation levels and improved the behavioural performance of OVX rats. Our research interprets OVX-related neurodegeneration with respect to ferroptosis, and both our in vivo and in vitro data show that E supplementation exerts beneficial antiferroptotic effects by upregulating DHODH. Our data demonstrate the utility of E supplementation after OVX and provide a potential target, DHODH, for which hormone therapy has not been available.
Topics: Animals; Female; Rats; Dihydroorotate Dehydrogenase; Estradiol; Ferroptosis; Hippocampus; Memory Disorders; Ovariectomy
PubMed: 37116254
DOI: 10.1016/j.redox.2023.102708 -
Frontiers in Neuroendocrinology Oct 2012Estradiol plays a pivotal role in the control of GnRH neuronal function, hence female reproduction. A series of recent studies in our laboratory indicate that rapid... (Review)
Review
Estradiol plays a pivotal role in the control of GnRH neuronal function, hence female reproduction. A series of recent studies in our laboratory indicate that rapid excitatory actions of estradiol directly modify GnRH neuronal activity in primate GnRH neurons through GPR30 and STX-sensitive receptors. Similar rapid direct actions of estradiol through estrogen receptor beta are also described in mouse GnRH neurons. In this review, we propose two novel hypotheses as a possible physiological role of estradiol in primates. First, while ovarian estradiol initiates the preovulatory GnRH surge through interneurons expressing estrogen receptor alpha, rapid direct membrane-initiated action of estradiol may play a role in sustaining GnRH surge release for many hours. Second, locally produced neuroestrogens may contribute to pulsatile GnRH release. Either way, estradiol synthesized in interneurons in the hypothalamus may play a significant role in the control of the GnRH surge and/or pulsatility of GnRH release.
Topics: Animals; Estradiol; Female; Gonadotropin-Releasing Hormone; Hypothalamus; Neurons; Receptors, Estrogen
PubMed: 22940545
DOI: 10.1016/j.yfrne.2012.08.001 -
Hormones and Behavior Apr 2020The sex steroid hormone 17β-estradiol (estradiol) regulates animal behavior as both a non-rapid hormone signal and as a rapid-acting neuromodulator. By practical...
The sex steroid hormone 17β-estradiol (estradiol) regulates animal behavior as both a non-rapid hormone signal and as a rapid-acting neuromodulator. By practical necessity, estradiol's divergent temporal actions on rodent behavior are typically studied singularly and in one sex. We hypothesized that estradiol simultaneously acts through both temporal mechanisms to sex-specifically modulate a single behavior; and furthermore, that estradiol action in one temporal domain may regulate action in another. To test this hypothesis, we utilized one of the most robust rat behaviors exhibiting sex differences and estradiol-responsiveness, voluntary wheel running. Adult female and male rats were gonadectomized and exposed to daily repeated estradiol benzoate (EB) injections. Estradiol-sensitive running behavior was continually assessed in both the rapid and non-rapid temporal domains. We found that in female rats, estradiol rapidly decreased voluntary wheel running, but only after prior daily EB injections, supporting the hypothesis that non-rapid estradiol action influences rapid estradiol actions. Males exhibited a similar but less robust response, demonstrating sex-responsiveness. This rapid estradiol-induced decrease in running contrasted to non-rapid estradiol action which overall increased running in both sexes, revealing a bidirectional nature of estradiol's temporal influence. Non-rapid estradiol action also demonstrated sex-responsiveness, as a higher dose of EB was required to induce increased running in males compared to females. These findings indicate that estradiol rapidly, non-rapidly, and bidirectionally modulates wheel running in a sex-responsive manner, and that rapid estradiol action is modulated by non-rapid estradiol action. Overall, these data illustrate estradiol as a pleiotropic sex-responsive neuromodulator of a single behavior across temporal domains.
Topics: Animals; Behavior, Animal; Estradiol; Female; Male; Motivation; Motor Activity; Rats; Rats, Sprague-Dawley; Running; Sex Characteristics; Time Factors
PubMed: 31978389
DOI: 10.1016/j.yhbeh.2020.104694 -
Hormones and Behavior May 2020This review highlights fifty years of progress in research on estradiol's role in regulating behavior(s). It was initially thought that estradiol was only involved in... (Review)
Review
This review highlights fifty years of progress in research on estradiol's role in regulating behavior(s). It was initially thought that estradiol was only involved in regulating estrus/menstrual cycles and concomitant sexual behavior, but it is now clear that estradiol also influences the higher order neural function of cognition. We provide a brief overview of estradiol's regulation of memory and some mechanisms which underlie its effects. Given systemically or directly into the hippocampus, to ovariectomized female rodents, estradiol or specific agonists, enhance learning and/or memory in a variety of rodent cognitive tasks. Acute (within minutes) or chronic (days) treatments enhance cognitive functions. Under the same treatment conditions, dendritic spine density on pyramidal neurons in the CA1 area of the hippocampus and medial prefrontal cortex increase which suggests that these changes are an important component of estrogen's ability to impact memory processes. Noradrenergic, dopaminergic and serotoninergic activity are also altered in these areas following estrogen treatments. Memory enhancements and increased spine density by estrogens are not limited to females but are also present in castrate males. In the next fifty years, neuroscientists need to determine how currently described neural changes mediate improved memory, how interactions among areas important for memory promote memory and the potential significance of neurally derived estrogens in normal cognitive processing. Answering these questions may provide significant advances for treatment of dementias as well as age and neuro-degenerative disease related memory loss.
Topics: Animals; Behavior; Cognition; Dendritic Spines; Estradiol; Estrogens; Female; Hippocampus; History, 20th Century; History, 21st Century; Humans; Learning; Male; Memory; Neuroendocrinology; Prefrontal Cortex; Rodentia
PubMed: 32035072
DOI: 10.1016/j.yhbeh.2020.104711