Estrogen Administration Research Articles

Estrogen as a Safe Therapeutic Adjunct in Reducing the Inflammatory Storm in Trauma Hemorrhagic Shock Patients

Trauma is a major cause of death and disability throughout the world. It is a leading cause of death with or without sepsis in about 50% of patients. Limited therapeutic options are available besides definitive care with a mortality benefit. Preclinical studies have demonstrated the mortality benefit of estrogen in trauma hemorrhagic shock (THS). Based on encouraging results from preclinical studies, we hypothesized that early administration of estrogen in male THS patients may reduce the inflammatory storm, prevent sepsis-associated problems, and subsequently reduce mortality. The authors studied the safety of early administration of estrogen as a therapeutic adjunct in the emergency department (ED) and its effects on the inflammatory storm, prevention of sepsis, and mortality during the intensive care unit stay. Forty THS patients were recruited. THS patients were divided into experimental and placebo control groups based on the estrogen administration in the ED. Serum levels of cytokines and immune cells were measured at different time points on days 0, 3, 7, and 14 in both groups of THS patients. The experimental group received intravenous estrogen (25 mg) at a single time point in the ED beside standard of care as per advanced trauma life support guidelines. Patients did not develop any major or minor adverse events and showed favorable clinical outcomes in the experimental group. The levels of T regulatory cells, monocytes, and systemic cytokines significantly reduced and showed a balanced inflammatory response in THS patients who received estrogen.In conclusion, this preliminary study showed that intravenous estrogen therapy is safe and reduced the inflammatory insult due to trauma hemorrhagic shock. It may protect THS patients from sepsis-associated complications. Future clinical trials are required to study the efficacy and mechanistic pathway.

Differential effects of estradiol on neural and emotional stress response in postmenopausal women with remitted Major Depressive Disorder

<h3>Introduction</h3> Ovarian hormones can influence neural systems involved in mood regulation, suggesting a pathway explaining why women have a greater incidence of Major Depressive Disorder (MDD) than men primarily beginning at puberty. Estrogen fluctuations may contribute to MDD risk through effects on brain networks important in emotion processing, stress responding, and mood regulation. Although there is evidence to support the use of ovarian hormone treatment for peri-menopausal depression, postmenopausal use has not been as well examined. As the neural systems involved in emotional processing and stress response are altered in MDD, it is possible that the effect of estrogen treatment on these systems may differ between postmenopausal women with and without a history of MDD. The objective of this study was to investigate whether estrogen modulation of the neural and emotional cognitive responses to stress differs between postmenopausal women with and without MDD vulnerability. <h3>Methods</h3> 60 postmenopausal women completed this fMRI study including a psychosocial stress task, the Montreal Imaging Stress Task (MIST), after receiving no drug or 3 months of daily 2mg 17β estradiol (E2). Participants included women with no personal history of MDD by SCID interview and women with remitted MDD with at least one episode in the last ten years and no depressive episodes within the last year. There were 4 participant groups: 1) MDD+/E2+ (n=10), 2) MDD+/E2- (n=12), 3) MDD-/E2= (n=20), 4) MDD-/E2- (n=18). All groups were euthymic at the time of study with non-clinical scores on the Beck Depression and Anxiety Inventories. Subjective mood response to the MIST was assessed as change score on the Stress-Arousal Checklist (SACL stress) before and after the MIST. fMRI analyses examined activity differences between the "stress and "control" conditions of the MIST using SPM 12. Second level analyses included 2 × 2 interactions (MDD history X E2 administration), whole-brain (gray matter masked), and cluster threshold corrected for multiple comparisons (p<0.005, K >102, FDR<0.05) for differences in activity during the MIST between the 4 groups and the relationship between activity during the MIST and SACL stress score in each group. <h3>Results</h3> E2 administration was associated with different effects in post-menopausal women with or without a history of MDD. In accordance with our previous work, the MDD-/E2+ group had a more negative mood response (higher SACL stress score) to the stress task than the MDD-/E2- group. In contrast, this effect was reversed in women with a history of MDD, where the MDD+/E2+ group had a less negative mood response than the MDD+/E2- group. Additionally, both groups who exhibited more negative mood responses also showed greater activity in emotional perception areas (left inferior frontal and left angular gyri) during the stress condition of the task than the groups which showed less negative mood responses. Group differences were also observed on fMRI. Women who did not receive E2 showed a positive correlation between greater right inferior frontal activity and higher SACL stress score, while the MDD+/E2- group additionally showed a positive correlation between right insula activity and SACL score. The MDD+/E2+ group showed negative correlations between activity in each area and SACL stress score in both the "stress" and "control" conditions of the MIST, while the MDD-/E2+ did not show significant correlations between activity in any area and SACL stress Score. <h3>Conclusions</h3> These results support a differential effect of estrogen administration on emotional and neural responses to psychosocial stress in postmenopausal women with and without a history of MDD. We had previously show that in women without a history of MDD, E2 is associated with a more negative mood response to stress than placebo. The results of this study replicated those findings in women without a history of MDD and show that E2 is also associated with increased activity in brain areas involved in emotion perception and response. Additionally, the result of this study support that the effect of E2 is reversed in women with a history of MDD, such that E2 is associated with a less negative mood response to stress and a differential relationship between activity in brain areas involved in emotion response. This suggests that women with a history of MDD, even while currently euthymic, have both a different mood and neural response to psychosocial stress and may show a beneficial mood effect E2 that is not seen in women without a history of MDD. These results may provide a neurological basis for recurrence risk and the beneficial mood effects of post-menopausal hormone treatment in women with a history of MDD. <h3>Funding</h3> This work was supported by the National Institutes of Aging R01AG021476, the National Institutes of Mental Health H110598, and Vanderbilt CTSA grant UL1 TR002243 from National Center for Advancing Translational Sciences.

Estrogen administration attenuates post-stroke depression by enhancing CREB/BDNF/TrkB signaling in the rat hippocampus.

A previous study demonstrated that 17β-estradiol (E2), which is an antidepressant, can ameliorate post-stroke depression (PSD); however, the underlying mechanisms governing this remain largely unknown. Therefore, the present study developed a PSD model in rats, which was induced by left middle cerebral artery occlusion followed by exposure to chronic mild stress for 2 weeks. The results revealed that the activity of the cAMP response element-binding protein (CREB), a cellular transcription factor, and the associated brain-derived neurotrophic factor (BDNF)/tyrosine kinase B (TrkB) signaling were all attenuated in the hippocampus in PSD rats. The depression-like behaviors were significantly improved after treatment with E2, along with increased CREB and the BDNF/TrkB signaling activity. These results provide novel insight into the molecular basis of PSD, and suggest the potential involvement of CREB/BDNF/TrkB signaling in E2-mediated improvement of PSD in rats.

Effect of ovariectomy induced osteoporosis on metaphysis and diaphysis repair process.

The fracture repair process is known to be delayed in postmenopausal women, under estrogen-deficient status. Osteoporotic fracture mainly occurs in the metaphyseal region of the long bone; however, most studies on fracture healing have focused on the diaphyseal region. In this study, we compared the repair process between metaphysis and diaphysis of ovariectomized (OVX) and Sham mice, and analyzed the effects of short-term estrogen administration in OVX mice. Mice were divided into four experimental groups, including Sham, OVX, OVX+vehicle, and OVX+17β-estradiol (E2). Bone apertures were formed in the tibial metaphysis and diaphysis. The samples were collected and examined by micro-computed tomography, and using histological, histochemical, and immunohistochemical analysis at different time points after the surgery. The cartilaginous callus was formed at the diaphysis site of both the groups, which was sequentially replaced by bone on the periosteum side. Medullary callus was formed in all the groups; however, the volume of the callus in OVX mice was significantly lesser (˜30%) than that in Sham mice. Furthermore, in the metaphysis, no differences were observed in the medullary callus and bone mineral density between the two groups from day 21 to 28. The diaphysis of OVX group was not completely repaired even by day 28. In both the sites of OVX mice, ALP activity and disappearance of Gr-1 positive cells were delayed compared to that of Sham. Estrogen administration improved medullary callus formation in the diaphysis, however not in the metaphysis. The effect of ovariectomy on the repair process in diaphysis was greater than that in metaphysis. Our findings clarify the differences between the metaphysis and diaphysis repair process using OVX mouse model and suggest that the estrogen sensitivities differ between the sites during the bone repair process.

Effect of transdermal estrogen dose regimen for endometrial preparation of frozen-thawed embryo transfer on reproductive and obstetric outcomes.

PurposePrevious studies have reported different methods of estrogen administration during endometrial preparation for frozen‐thawed embryo transfer (FET). This study aimed to investigate a beneficial regimen of transdermal estrogen administration for FET.MethodsWe investigated the reproductive and obstetric outcomes of FET by comparing the increasing dose (ID) group that mimics changes in serum estradiol during the menstrual cycle and the constant dose (CD) group. Transdermal patches were used for estrogen administration in both groups. In our hospital, we targeted 315 cycles of the ID group in which FET was performed in 2017 and 324 cycles of the CD group in which FET was performed in 2018. In all cases, single embryo transfer was performed.ResultsAll were singleton pregnancies. There was no difference in clinical pregnancy rate (28.9% vs 28.2%, P =.837) and live birth rate (17.3% vs 21.4%, P =.201) between the ID and CD groups. Spontaneous abortion rate was significantly lower in the CD group than in the ID group (37.2% vs 23.0%, P =.041). There was no difference in obstetrical outcomes.ConclusionsIt was considered that the simple CD regimen may be more beneficial than the complicated ID regimen.

Potential role of fenugreek Trigonella foenum-graecum)in the prevention of skin aging

Skin aging is a process influenced by several factors, including estrogen. Estrogen modulates the physiology of the skin, and its deficiency in postmenopausal women accelerates skin aging. Administration of estrogen can delay the skin aging process. Phytoestrogens are estrogen-like compounds derived from plants that administered via oral as well astopical routes. Trigonella foenum-graecum, commonly known as fenugreek, is one plants containing phytoestrogens. Several studies have been conducted on the phytoestregonic activity of fenugreek. Fenugreek extract exhibits estrogenic activity, as observed in the study of mouse and rat reproductive organs. Fenugreek exhibits estrogenic activity in the reproductive organs of a rat, as well as demonstrates positive effects on the skin by topical administration. This review explored the fenugreek as the source of phytoestrogens and its role in delaying skin aging.

Striatal dopamine D2-type receptor availability and peripheral 17β-estradiol.

Research using rodent models has established a relationship between the steroid hormone estrogen and dopamine function, by revealing changes throughout the estrous cycle and by directly manipulating neuroendocrine signaling through ovariectomy and administration of estrogen. However, a direct link between estrogen levels and dopamine signaling had not been established in humans. The goal of this study, therefore, was to assess the relationship between circulating 17β-estradiol and dopamine signaling in the human brain by testing for a relationship between two proxies for these variables: peripheral 17β-estradiol and striatal dopamine D2-type receptor availability, measured with [18F]fallypride and positron emission tomography (PET). Sixteen (23-45 years of age) women were tested on 2 days of the menstrual cycle estimated prospectively to occur during (a) the early follicular phase, when estrogen levels are near their nadir, and (b) the periovulatory phase, when estrogen levels peak. PET scans with [18F]fallypride were performed on these 2 days, and serum 17β-estradiol was measured using radioimmunoassay. Dopamine D2-type receptor availability did not differ significantly in the whole striatum or the caudate, putamen, or accumbens subregions during the high-estrogen vs. the low-estrogen phases of the menstrual cycle. We conclude that circulating estrogen levels do not affect dopamine D2-type receptor availability in the human striatum although other indices of dopaminergic function may be affected.

Induction of short-term pseudopregnancy in gilts by the administration of estradiol benzoate or estradiol dipropionate to achieve ovulatory synchronization for embryo collection.

A study was conducted to investigate whether ovulation in gilts could be synchronized for embryo collection by the administration of estradiol benzoate (EB) or estradiol dipropionate (EDP) to induce pseudopregnancy, followed by the treatment with prostaglandin F2α (PGF2α ) on 10days after. Ten gilts each received a total of 20mg of EB or EDP on Day 10 or EB on Day 10 and 14 to induce pseudopregnancy (Day 0=onset of estrus). Donors received PGF2α 10 or 15days (as a control) after the first administration of estrogens and subsequently eCG and hCG, and were then inseminated artificially. The embryos were collected 7days after the administration of hCG, and assessed for embryo yield and their developmental stages. All protocols resulted in good embryo yield (9.8-13.2 embryos in average), and the embryos showed average ability to develop to the expanded blastocyst stage (3.29-4.03 as developmental scores) without any significant differences among the protocols. These results suggest that the administration of PGF2α 10days after the treatment of gilts with EB or EDP would allow synchronization of ovulation and embryo collection, as well as shortening the period from estrus detection to embryo collection, thus improving embryo collection efficiency.

Estrogen modulates the skeletal muscle regeneration process and myotube morphogenesis: morphological analysis in mice with a low estrogen status.

The purpose of this study was to elucidate the functions of estrogen and two estrogen receptors (ERs; ERα and ERβ) in the myoregeneration process and morphogenesis. Cardiotoxin (CTX) was injected into the tibialis anterior (TA) muscles of ovariectomized (OVX) mice to induce muscle injury, and subsequent myoregeneration was morphologically assessed. The diameter of regenerated myotubes in OVX mice was significantly smaller than that in intact mice at all time points of measurement. OVX mice also showed lower muscle recovery rates and slower speeds than did intact mice. ER protein levels showed a predominance of ERβ over ERα in both intact and OVX states. The ERβ level was increased significantly at 7 days after CTX injection in OVX mice and remained at a high level until 14 days. In addition, continuous administration of E2 to OVX mice in which muscle injury was induced resulted in a significantly larger diameter of regenerated myotubes than that in mice that did not receive estrogen. The results indicate that estrogen is an essential factor in the myoregeneration process since estrogen depletion delayed myoregeneration in injured muscles and administration of estrogen under the condition of a low estrogen status rescued delayed myoregeneration. The results strongly suggested that ERβ may be a factor that promotes myoregeneration more than does ERα.

The gut microbiota during the progression of atherosclerosis in the perimenopausal period shows specific compositional changes and significant correlations with circulating lipid metabolites

ABSTRACT Atherosclerosis (AS) is exacerbated in the perimenopausal period, which significantly increases the incidence rate of cardiovascular disease. The disruption of the gut microbiota has been associated with AS or menopause, but the specific changes of AS-associated gut microbiota in the perimenopausal period remain largely unknown. As lipid abnormalities are mainly responsible for AS, the relationship between lipid metabolism abnormalities and gut microbiota disruptions during menopause is rarely reported hitherto. In the present study, ApoE−/- mice fed with a high-fat diet (HFD) were subjected to ovariectomy and supplemented with estrogen. The ovariectomized HFD-fed ApoE−/- mice underwent significant AS damage, hepatic lipid damage, hyperlipidemia, and changes of lipid metabolism- and transport-related enzymes. There was significantly higher abundance of some lipid metabolites in the plasma of ovariectomized HFD-fed ApoE−/- mice than in non-ovariectomized ones, including cholesterol esters, triglycerides, phospholipids, and other types of lipids (free fatty acids, acylcarnitine, sphingomyelins, and ceramides). The administration of estrogen significantly reduced the contents of most lipid metabolites. The diversity and composition of gut microbiota evidently changed in ovariectomized HFD-fed ApoE−/- mice, compared to HFD-fed ApoE−/- mice without ovariectomy. In contrast, with estrogen supplementation, the diversity and composition of gut microbiota were restored to approach that of non-ovariectomized HFD-fed ApoE−/- mice, and the relative abundances of some bacteria were even like those of C57BL/6 mice fed with a normal diet. On the other hand, the transplantation of feces from C57BL/6 mice fed with normal diet to ovariectomized HFD-fed ApoE−/- mice was sufficient to correct the hyperlipidemia and AS damage, and to reverse the characteristics changing of lipid metabolomics in ovariectomized HFD-fed ApoE−/- mice. These phenomena were also been observed after transplantation of feces from estrogen-treated ovariectomized HFD-fed ApoE−/- mice to ovariectomized HFD-fed ApoE−/- mice. Moreover, the gut microbiota and lipid metabolites were significantly correlated, demonstrating that the changes of serum lipids may be associated with the gut microbiota disruptions in the perimenopausal period. In conclusion, the gut microbiota during the progression of AS in the perimenopausal period showed specific compositional changes and significant correlations with circulating lipid metabolites. Estrogen supplementation may exert beneficial effects on gut bacteria and lipid metabolism.

Role of nuclear and membrane estrogen signaling pathways in the male and female reproductive tract

Estrogen signaling through the main estrogen receptor, estrogen receptor 1 (ESR1; also known as ERα), is essential for normal female and male reproductive function. Historically, studies of estrogen action have focused on the classical genomic pathway. Although this is clearly the major pathway for steroid hormone actions, these hormones also signal through rapid non-classical effects involving cell membrane actions. Reports of rapid effects of estrogens extend for more than half a century, but recent results have expanded understanding of the identity, structure, function and overall importance of membrane receptors in estrogen responses. Key findings in this field were the immunohistochemical detection of ESR1 in cell membranes and demonstration that a portion of newly synthesized ESR1 is routed to the membrane by palmitoylation. These receptors in the membrane can then signal through protein kinases and other mechanisms following ligand binding to alter cell function. Another crucial advance in the field was development of transgenic mice expressing normal amounts of functional nuclear ESR1 (nESR1) but lacking membrane ESR1 (mESR1). Both male and female transgenic mice lacking mESR1 were infertile as adults, and both sexes had extensive reproductive abnormalities. Transgenic mice lacking mESR1 were highly protected from deleterious effects of neonatal estrogen administration, and estrogen effects on the histone methyltransferase Enhancer of Zeste homolog 2 that are mediated through mESR1 could have significant effects on epigenetic imprinting. In summary, signaling through mESR1 is essential for normal male and female reproductive function and fertility, and is a critical enabler of normal estrogen responses in vivo. Although the precise role of mESR1 in estrogen responses remains to be established, future research in this area should clarify its mechanism of action and lead to a better understanding of how mESR1 signaling works with classical genomic signaling through nESR1 to promote full estrogenic responses.

Progesterone Intramuscularly or Vaginally Administration May Not Change Live Birth Rate or Neonatal Outcomes in Artificial Frozen-Thawed Embryo Transfer Cycles.

BackgroundsPrevious studies suggested that singletons from frozen-thawed embryo transfer (FET) were associated with higher risk of large, post-date babies and adverse obstetrical outcomes compared to fresh transfer and natural pregnancy. No data available revealed whether the adverse perinatal outcomes were associated with aberrantly high progesterone level from different endometrium preparations in HRT-FET cycle. This study aimed to compare the impact of progesterone intramuscularly and vaginally regimens on neonatal outcomes in HRT-FET cycles.MethodsA total of 856 HRT-FET cycles from a fertility center from 2015 to 2018 were retrospectively analyzed. All patients had their first FET with two cleavage-staged embryos transferred. Endometrial preparation was performed with sequential administration of estrogen followed by progesterone intramuscularly 60 mg per day or vaginal gel Crinone 90 mg per day. Pregnancy outcomes including live birth rate, singleton birthweight, large for gestational age (LGA) rate, small for gestational age (SGA) rate, and preterm delivery rate were analyzed. Student’s t test, Mann-Whitney U-test, Chi square analysis, and multivariable logistic regression were used where appropriate. Differences were considered significant if p < 0.05.ResultsNo significant difference of live birth rate was found between different progesterone regimens (Adjusted OR 1.128, 95% CI 0.842, 1.511, p = 0.420). Neonatal outcomes like singleton birthweight (p = 0.744), preterm delivery rate (Adjusted OR 1.920, 95% CI 0.603, 6.11, p = 0.269), SGA (Adjusted OR 0.227, 95% CI 0.027, 1.934, p = 0.175), and LGA rate (Adjusted OR 0.862, 95% CI 0.425, 1.749, p=0.681) were not different between two progesterone regimens. Serum P level >41.82 pmol/L at 14 day post-FET was associated with higher live birth rate than serum P level ≤41.82 pmol/L in HRT-FET cycles when progesterone was intramuscularly delivered (Adjusted OR 1.690, 95% CI 1.002, 2.849, p = 0.049). But singleton birthweight, preterm delivery rate, SGA and LGA rate were not different between these two groups.ConclusionsRelatively higher serum progesterone level induced by intramuscular regimen did not change live birth rate or neonatal outcomes compared to vaginal regimen. Monitoring serum progesterone level and optimizing progesterone dose of intramuscular progesterone as needed in HRT-FET cycles has a role in improving live birth rate without impact on neonatal outcomes.

Menopause, the gut microbiome, and weight gain: correlation or causation?

The gut microbiome is a key regulator of metabolism and influences the metabolism of estrogens, however, the microbiome's role in the changes in body composition and metabolic risk factors experienced by menopausal women remains largely unexplored. Menopause has been shown to alter the gut microbiome, and rodent studies suggest that microbiome changes postovariectomy are associated with increased adiposity, decreased metabolic rate, and insulin resistance, changes attenuated by estrogen administration. Given these data, a deeper understanding of the gut microbiome's relationship to menopause-induced changes in body composition and metabolism is warranted and may offer opportunity for novel therapeutic interventions.The microbiome is central to both systemic and estrogen metabolism, and is altered by the menopausal transition, suggesting an important role of the microbiome in the increased metabolic risk faced by menopausal women. Although additional research is needed to establish a causal link, the interrelationship between menopause and the gut microbiome may represent a new frontier to address menopause-related metabolic risk.

The safety of oral versus transdermal estrogen.

There exists a growing number of treatment options available to women who choose hormone therapy for management of systemic menopause symptoms. Choosing the product that is the "best fit" for each individual woman can be a challenging task. One of these decisions pertains to the optimal route of estrogen administration. This Practice Pearl will explore some of the differences between oral and transdermal estrogens.

Reply to Jakovac: Sex differences in COVID-19 course and outcome: progesterone should not be neglected.

Reply to Jakovac: Sex differences in COVID-19 course and outcome: progesterone should not be neglected.

A single dose of estrogen during hemorrhagic shock protects against Kidney Injury whereas estrogen restoration in ovariectomized mice is ineffective

The protective effect of estrogens against chronic glomerular diseases is admitted but remains debated during acute kidney injury (AKI). Using a model of resuscitated hemorrhagic shock in C57/Bl6 female mice, this study evaluated at 1 and 21 days the renal effect of (1) endogenous estrogen, using ovariectomized mice with or without chronic estrogen restoration, or (2) exogenous estrogen, using a single administration of a pharmacological dose during shock resuscitation. In both ovariectomized and intact mice, hemorrhagic shock induced epithelial cell damages (assessed by KIM-1 renal expression) with secondary renal fibrosis but without significant decrease in GFR at day 21. Ovariectomy with or without estrogen restoration have no significant effect on renal damages and dysfunction. This lack of effect was associated with a marked (> 80%) reduction of total kidney GPR30 expression. By contrast, a single high dose of estradiol in intact mice reduced renal KIM-1 expression by 2/3, attenuated the severity of cell death related to pyroptosis, and prevented the increase of fibrosis by 1/3. This provides a rationale to investigate the benefits of a single administration of estrogen or estrogen modulators during acute kidney injuries in males. Furthermore, the cost/benefit ratio of such administration should be investigated in Human.

Current treatment options for genitourinary syndrome

At the onset of menopause, the urogenital symptoms begin to develop simultaneously with vasomotor symptoms: vaginal soreness, itching and dryness, dyspareunia, etc. The development of atrophic changes in the urogenital tract greatly reduces the quality of life and is a risk factor for the development of recurrent urinary tract infections. More than 60% of postmenopausal women, who do not take systemic menopausal hormone therapy (MHT), suffer from vaginal atrophy experience symptoms. The article discusses and evaluates effectiveness of various therapies for genitourinary syndrome of menopause (GSM). Nonhormonal lubricating gels are recommended as the first-line therapy. Local intravaginal administration of estrogens is used in moderate to severe vulvovaginal atrophy and in the absence of contraindications. Women with estrogen-dependent cancers can use low doses of local estrogen against the background of Tamoxifen therapy. New promising therapies for GSM are presented: ospemifene, an oral active selective estrogen receptor modulator (SERM), laser therapy, dehydroepiandrosterone. Even though the urogenital atrophy is a common disease, administration frequency of local estrogens as therapy is low. Basic principles for treatment of urogenital atrophy include alleviation of symptoms and restoration of normal blood supply to the vaginal epithelium and urothelium wall and mucous membrane. The therapy should be initiated early and the response time to therapy will depend on the degree of baseline atrophy. Vaginal moisturizers and lubricants can be used in combination with or separately from natural estrogens in cases when patients have medical contraindications to estrogen treatment.

Early uterine development in pigs

The capacity of pig uterine tissues to recognize and respond to maternal and conceptus signals determines whether pregnancy can be established and defines the environment in which embryonic and fetal growth occur. Limits of uterine capacity may be defined genetically. However, the extent to which functional uterine capacity approaches genetic potential may be determined, in part, by the success of organizational events associated with growth, morphogenesis and cytodifferentiation of uterine tissues. It is important, therefore, that these events be identified and evaluated with respect to their potential effect on adult uterine function. Histogenesis of the pig uterus begins prenatally, but is completed postnatally. Transformation of the uterine wall from histoarchitectural infancy to maturity occurs between birth and day 120. Morphogenetic events characteristic of the first 60 days of neonatal life proceed normally in gilts ovariectomized at birth. These events include appearance and proliferation of uterine glands, development of endometrial folds, and growth of the myometrium. Endometrial development during this period involves alterations in patterns of epithelial and stromal DNA synthesis, coordinated changes in the distribution and biosynthesis of extracellular matrix glycosaminoglycans and cell surface glycoconjugates, and specific alterations in patterns of uterine protein secretion. The ovary-independent, spatially coordinated nature of these events suggests that neonatal uterine development is regulated locally via dynamic cell-cell and cell-extracellular matrix interactions. The extent to which such potentially critical interactions must be preserved to ensure developmental success remains unknown. However, the normal pattern of ovary-independent cellular and molecular events associated with development of the uterine wall was disrupted by treating neonatal gilts with oestradiol valerate, and daily administration of oestrogen to gilts from birth to day 13 did not affect ovulation rate, but did reduce embryonic survival by 22% on day 45 of gestation in adults that were exposed to oestrogen neonatally. These observations support the idea that some organizational events associated with development of the neonatal uterine wall must be allowed to proceed without interruption to ensure that adult uterine function is not compromised. Efforts to identify specific developmental determinants of uterine capacity may be facilitated by examining the consequences of xenobiotically induced interruption of uterine development on adult uterine function. Such studies may also contribute to identification of uterine factors affecting embryonic survival and fetal growth.

Effects chronic administration of corticosterone and estrogen on HPA axis activity and telomere length in brain areas of female rats

Chronic stress is related to the acceleration of telomere shortening. Recent work showed a correlation between chronic psychosocial stress and reduced telomere length in certain cells. The exposure of T lymphocytes to cortisol promoted a significant reduction in telomerase activity. Although stress can promote changes in telomere length, whether increased glucocorticoid concentrations alter telomere length in brain tissue cells is unclear. In addition to modulating the activity of the stress system, estrogen also influences telomere length. The objective of this study was to verify whether chronic exposure to glucocorticoids promotes changes in the telomere length of encephalic areas involved in the control of HPA axis activity and whether estrogen affects these changes. Wistar rats were ovariectomized and treated with estradiol cypionate [(50 or 100 μg/kg, subcutaneously)] or oil and 20 mg/kg corticosterone or vehicle (isotonic saline with 2% Tween 80, subcutaneously) for 28 days. On the day after the end of the hormonal treatment, the animals were euthanized for collection of blood, brain and pituitary gland samples. Estrogen modulated the activity of the HPA axis. CRH, AVP and POMC mRNA levels were reduced by estrogen. At least in doses and treatment time used, there was no correlation between effects of exposure to glucocorticoids and estrogen on telomere length in the brain areas of female rats. However, estrogen treatment reduced the telomere length in the central amygdala and dorsal hippocampus, but not in the PVN, indicating a variation of reaction of telomeres for estrogen in different brain areas.

The protective role of estrogen on endothelial and glycocalyx barriers after shock conditions: A microfluidic study

BackgroundSexual dimorphism has been demonstrated after major trauma and hemorrhage shock with protective effects related to female sex or estrogen. Traumatic endotheliopathy is an important component of trauma-induced coagulopathy. Components of endothelial barrier dysfunction include degradation of the endothelial glycocalyx and endothelial cellular injury. Estrogen modulates endothelial function via its membrane and cellular receptors. The effects of estrogen on the vascular endothelial barrier after trauma and hemorrhage shock are, however, unknown. This topic was studied in an in vitro model under flow conditions. MethodsMonolayers of human umbilical vein endothelial cells were established in microfluidic flow devices. After overnight perfusion, cell monolayers were subjected to normoxic or hypoxic perfusion and then treated with either estrogen (as estradiol), testosterone (as dihydrotestosterone), or media alone. Endothelial activation/injury was indexed by soluble thrombomodulin and glycocalyx degradation by syndecan-1 and hyaluronic acid shedding as well as measurement of the thickness of the glycocalyx layer. The coagulation phenotype of the human umbilical vein endothelial cells was indexed by the relative values of the activities of tissue plasminogen activator and plasminogen activator inhibitor-1. Vascular endothelial growth factor was measured in cell culture supernatants using a solid-phase enzyme-linked immunosorbent assay. ResultsTreatment with estrogen but not testosterone mitigated the adverse effect of shock on endothelial and glycocalyx barrier properties. Our biomimetic model suggests a beneficial effect of estrogen administration after trauma and hemorrhage shock on the glycocalyx and endothelial barriers. ConclusionEarly estrogen treatment after trauma and hemorrhage shock may be a useful adjunct to mitigating the development of traumatic endotheliopathy.