Exogenous Estrogen Administration Research Articles

Comparative induction of benign prostate hyperplasia using testosterone propionate and estradiol benzoate in rabbit model

Benign prostatic hyperplasia (BPH) is a common non-cancerous enlargement of the prostate that usually occurs in aging men and some higher mammals. Many studies have been conducted to explore different treatment strategies for managing BPH. However, a suitable animal model for studying BPH is necessary. So far, only a few animal models, such as rat and dog models, have been used for this purpose. This study aimed to compare the assessment of the BPH model induced in rabbits through the administration of exogenous testosterone and estrogen post-bilateral orchidectomy. Fifteen (N=15) indigenous Nigerian rabbits were used for this experiment. The rabbits were orchiectomized and randomly divided into 3 groups: the testosterone, estrogen, and control groups. Seven days after bilateral orchidectomy, BPH was induced using exogenous subcutaneous administration of testosterone (15 mg kg-1), estrogen (0.75 mg kg-1), and normal saline (1 mL) for 4 weeks. After completion of the treatments, prostates were removed. The weight, volume, prostate index, and histologic scoring were determined. There were significant changes (p<0.05) in prostate weight, volume, and index. Testosterone and estrogen-treated groups differed significantly from the control groups. There were no significant differences in all the parameters between the testosterone and the estrogen groups. Histological evaluation revealed hyperplasia of the epithelium of the prostate gland and increased stromal connective tissues with a corresponding increase in the number of glandular units with secretory-filled fluid within the lumens of the glands. The benign prostate hyperplasia rabbit model was developed successfully using exogenous treatment with testosterone propionate. Testosterone appeared to have significant roles in the development of prostate hyperplasia when compared to estrogen.

12391 When Pressure Drops, Consequences Rise: A Case Of Pituitary Apoplexy And Watershed Infarcts

Abstract Disclosure: D. Moreno Watashi: None. H.R. Alkaissi: None. M.B. Sharma: None. Introduction: Pituitary apoplexy (PA) results from sudden hemorrhaging and infarction of the pituitary gland, typically within a pituitary adenoma. The primary symptom is a sudden, severe headache, often followed by acute endocrine dysfunction, ophthalmoplegia and visual or neurological disturbances. Case Description: A 68-year-old male with a past medical history of hypertension presented to the emergency department with acute chest and upper back pain, beginning one day prior. No history of smoking, alcohol intake or drug use. Blood pressure (BP) on arrival was 180/95 mmHg. Initial labs revealed mild electrolyte abnormalities. Troponins were normal, but ECG showed diffuse T wave inversion and ST depression. CT angiography revealed a type B aortic dissection. He was managed in the critical care unit with continuous esmolol intravenous (IV) infusion and planned for endovascular repair. During his stay, he became disoriented and hypotensive. MRI from the brain incidentally discovered a pituitary macroadenoma measuring 2.9x2.2x3cm and recent infarcts, with a distribution concerning for hypoperfusion. Fundoscopy concerning for optic chiasm compression. Labs indicated secondary hypothyroidism and hypogonadism (TSH 0.3 uUI/ml, free T4 0.88 ng/dL, total testosterone 56.3 ng/dL). Neurosurgical intervention was deferred until after aortic repair. Endovascular aortic repair was performed with episodes of hypotension. Post-procedure, the patient developed fever (39.5°C) and worsening mental status. Head CT revealed an increased suprasellar extension of the pituitary macroadenoma and vasogenic edema, consistent with hemorrhage of the lesion. He was started on stress doses of hydrocortisone, levothyroxine 125mcg and managed conservatively due to a high surgical risk. Discussion: PA's extrinsic risk factors include angiographic procedures, endocrinological dynamic tests, anticoagulation therapy, exogenous estrogen administration, orthopedic and cardiac surgeries (due to BP fluctuations). The intrinsic risk factors are non-functioning adenomas, macroadenomas and suprasellar extension. Treatment is focused on immediate correction of endocrine derangements and relieving local compression. Stress dosage of corticosteroids should be administered IV as soon as the diagnosis is confirmed to prevent life-threatening corticotropic deficiency. Neurosurgical decompression via a transsphenoidal approach is the definitive therapy to relieve local compression with severe visual loss, obtundation or rapidly progressive course. The potential outcomes are based on the extent of hemorrhage, necrosis, and edema. PA should be treated as a medical emergency in the setting of hemodynamic changes from acute corticotropic deficiency and irreversible neurological damage from acute intracranial compression. The risk factors for PA should be known to assist in early diagnosis. Presentation: 6/1/2024

GPER expression prevents estrogen-induced urinary retention in obese mice

Long-term administration of exogenous estrogen is known to cause urinary retention and marked, often fatal, bladder distention in both male and female mice. Estrogen-treated mice have increased bladder pressure and decreased urine flow, suggesting that urinary retention in estrogen-treated mice is due to infravesicular obstruction to urine outflow. Thus, the condition is commonly referred to as bladder outlet obstruction (BOO). Obesity can also lead to urinary retention. As the effects of estrogen are mediated by multiple receptors, including estrogen receptors ERα and ERβ and the G protein-coupled estrogen receptor (GPER), we sought to determine whether GPER plays a role in estrogen-induced BOO, particularly in the context of obesity. Wild type and GPER knockout (KO) mice fed a high-fat diet were ovariectomized or left ovary-intact (sham surgery) and supplemented with slow-release estrogen or vehicle-only pellets. Supplementing both GPER KO and wild type obese mice with estrogen for 8 weeks resulted in weight loss, splenic enlargement, and thymic atrophy, as expected. However, estrogen-treated obese GPER KO mice developed abdominal distension, debilitation, and ulceration of the skin surrounding the urogenital opening. At necropsy, these mice had prominently distended bladders and hydronephrosis. In contrast, estrogen-treated obese wild type mice only rarely displayed these signs. Our results suggest that, under conditions of obesity, estrogen induces BOO as a result of ERα-driven pathways and that GPER expression is protective against BOO.

Different endometrial preparation protocols on first frozen-thawed embryo transfer outcomes after hysteroscopic polypectomy: A retrospective cohort study.

To evaluate the optimal endometrial preparation protocol for frozen-thawed embryo transfer (FET) following hysteroscopic polypectomy. This was a retrospective clinical cohort study involving 464 patients who underwent their first FET after polyp resection between January 2021 and July 2023. The cohorts were categorized into three groups: the natural cycle (NC) group (n = 139), the ovarian induction (OI) group (n = 117), and the hormone replacement therapy (HRT) group (n = 208). In the initial unadjusted analysis, both NC and OI cycles exhibited similar pregnancy rates but were associated with significantly higher implantation rate (56.5%, 57.1% vs 42.0%, P < 0.001), clinical pregnancy rate (73.4%, 74.4% vs 57.2%, P = 0.001), and ongoing pregnancy rate (OPR; 67.6%, 63.2% vs 51.0%, P = 0.005) compared to the HRT group. Additionally, the three groups demonstrated comparable abortion rate (7.8%, 14.9% vs 10.9%, P = 0.299). After adjusting for potential confounders in the multiple logistic regression model, the HRT protocol resulted in a 54% significantly lower OPR compared to the NC protocol (adjusted odds ratio [aOR] = 0.46, 95% confidence interval [CI]: 0.28-0.77; P = 0.003). Meanwhile, the OPR difference between the OI protocol and the NC protocol remained insignificant (OI vs NC: aOR = 0.62, 95% CI: 0.35-1.12; P = 0.112). The ovulatory-FET scheme (NC and OI) following hysteroscopic polyp resection displayed promising clinical outcomes compared with HRT-FET scheme. The regimen without exogenous estrogen administration should be prioritized for endometrial preparation protocol after polypectomy.

A Novel Metastatic Estrogen Receptor-Expressing Breast Cancer Model with Antiestrogen Responsiveness.

Most women diagnosed with breast cancer (BC) have estrogen receptor alpha-positive (ER+) disease. The current mouse models of ER+ BC often rely on exogenous estrogen to encourage metastasis, which modifies the immune system and the function of some tissues like bone. Other studies use genetically modified or immunocompromised mouse strains, which do not accurately replicate the clinical disease. To create a model of antiestrogen responsive BC with spontaneous metastasis, we developed a mouse model of 4T1.2 triple-negative (TN) breast cancer with virally transduced ER expression that metastasizes spontaneously without exogenous estrogen stimulation and is responsive to antiestrogen drugs. Our mouse model exhibited upregulated ER-responsive genes and multi-organ metastasis without exogenous estrogen administration. Additionally, we developed a second TN BC cell line, E0771/bone, to express ER, and while it expressed ER-responsive genes, it lacked spontaneous metastasis to clinically important tissues. Following antiestrogen treatment (tamoxifen, ICI 182,780, or vehicle control), 4T1.2- and E0771/bone-derived tumor volumes and weights were significantly decreased, exemplifying antiestrogen responsivity in both cell lines. This 4T1.2 tumor model, which expresses the estrogen receptor, metastasizes spontaneously, and responds to antiestrogen treatment, will allow for further investigation into the biology and potential treatment of metastasis.

P-690 Time to bust some myths about progesterone supplementation in the luteal phase. Role of the route of administration and usefulness (or uselessness) of plasma determination

Abstract Study question Is it worth measuring plasma progesterone levels after FET? Is there any difference in results depending on the route of progesterone administration? Summary answer The administration route of progesterone supplementation after FET entails different plasmatic levels (whose determination is useless) but without any correlation with ongoing pregnancy. What is known already Embryonic aneuploidy is likely to be the major contributor to human implantation failure, but not all failures are due to embryonic defects. The need for progesterone supplementation in ART frozen-thawed cycles is well accepted. Several studies have demonstrated an increase in live birth rate with progesterone luteal support although there is a discussion on the association of Progesterone levels on day of embryo transfer and birth or pregnancy loss rates. Moreover, although the effect of route of administration of progesterone on serum levels and pregnancy rates have been thoroughly studied, there is no consensus on the optimal endometrial preparation protocol. Study design, size, duration Prospective, randomized study performed during the 2020-21. A total of 201 genetically screened blastocyst (after PGT-A) transfers were performed after endometrial preparation, performed with exogenous estrogen administration followed by progesterone administration before embryo transfer (ET) . After embryo transfer, two different Progesterone regimens were randomly administered. Group I and Group II (see “Participants”) Participants/materials, setting, methods Group I patients (n = 100): 800 mg of micronized Progesterone was administered vaginally (Cyclogest® 1-0-1). Group II patients (n = 101): vaginal administration of 400 mg of micronized progesterone was combined with the subcutaneous administration of 25 mg of Progesterone (Prolutex 25®) Plasmatic progesterone (PP) levels on day of B-HCG determination (pregnancy test) (10 days after ET) and ultrasound confirmation of pregnancy (3 weeks after ET) were determined. The relationship between progesterone levels and ongoing pregnancy rates was amalyzed. Main results and the role of chance The rate of positive pregnancy test among the 201 FET was 71,64%. The overall ongoing pregnancy was 58,71%. PP on day of pregnancy test was 24,92±1,27 ng/ml (mean±SEM). The corresponding figures por positive (n = 144) and negative (n = 57) HCG were 27,65±1,09 and 20,33±2,13 respectively (t = 2,68; p = 0,008). The PP levels on day of HCG determination were 23,12±1,48 among ongoing pregnancies whereas the levels among non-evolutive gestations were 48,78±3,55 (t = 7,19; p = 0,000). PP levels were significantly higher among group II patients (combined treatment) both, on day of B-HCG determination (28,25±1,22 ng/ml) and on day of ultrasound confirmation of a gestational sac (33,61±2,39) than among group I patients (vaginal treatment) (15,12±1,60 and 19,77±1,50 ng/ml) (t = 0651, p = 0,000 and t = 5,38, p = 0,000 respectively). But these differences do not correlate with ongoing pregnancy rates: 59 out of 101 (58,42%) in group I patients and 59 out of 100 (59%) in group II patients. Limitations, reasons for caution Even though only euploid embryos have been transferred, ee must be cautious when drawing conclusions from the present study taking into account the limited number of cases evaluated. Wider implications of the findings Since only euploid embryos have been transferred in the present study, results in terms of successful ongoing pregnancies may be influenced by endometrial factors. Although the need of progesterone supplementation among frozen-thawed cycles is accepted, some debate exists on the route of administration and the need of progesterone serum determinations Trial registration number NOT applicable

O-110 Endometrial preparation for FET: HRT vs. Natural cycle

Abstract Frozen-thawed embryo transfer (FET) cycles have increased dramatically over the past decade, mainly due to the introduction of vitrification as a more efficient method of cryopreservation, and the increase of the freeze-all strategy in order to reduce the risk of OHSS. Planning of FET cycles is a key step for the implantation of the frozen-thawed embryos since it allows the synchronization of the endometrium with the developmental stage of the embryo. Endometrial preparation can be achieved either through hormonal replacement treatment (HRT) by an artificial cycle using exogenous estrogen administration for the development of the endometrium and subsequent administration of exogenous progesterone for its secretory transformation (AC-FET) or via a natural cycle, following the detection of LH surge (NC-FET), or the trigger of ovulation with human chorionic gonadotrophin (mNC-FET). The scope of the current presentation is to provide an overview of the different methods of endometrial preparation for FET cycles, their advantages, and disadvantages, and the evidence regarding clinical but also adverse obstetrical and perinatal outcomes, following each different protocol. Trial registration number

Sex-dependent development of Kras-induced anal squamous cell carcinoma in mice.

Anal squamous cell carcinoma (SCC) will be diagnosed in an estimated 9,080 adults in the United States this year, and rates have been rising over the last several decades. Most people that develop anal SCC have associated human papillomavirus (HPV) infection (~85–95%), with approximately 5–15% of anal SCC cases occurring in HPV-negative patients from unknown etiology. This study identified and characterized the Kras-driven, female sex hormone-dependent development of anal squamous cell carcinoma (SCC) in the LSL-KrasG12D; Pdx1-Cre (KC) mouse model that is not dependent on papillomavirus infection. One hundred percent of female KC mice develop anal SCC, while no male KC mice develop tumors. Both male and female KC anal tissue express Pdx1 and Cre-recombinase mRNA, and the activated mutant KrasG12D gene. Although the driver gene mutation KrasG12D is present in anus of both sexes, only female KC mice develop Kras-mutant induced anal SCC. To understand the sex-dependent differences, KC male mice were castrated and KC female mice were ovariectomized. Castrated KC males displayed an unchanged phenotype with no anal tumor formation. In contrast, ovariectomized KC females demonstrated a marked reduction in anal SCC development, with only 15% developing anal SCC. Finally, exogenous administration of estrogen rescued the tumor development in ovariectomized KC female mice and induced tumor development in castrated KC males. These results confirm that the anal SCC is estrogen mediated. The delineation of the role of female sex hormones in mediating mutant Kras to drive anal SCC pathogenesis highlights a subtype of anal SCC that is independent of papillomavirus infection. These findings may have clinical applicability for the papillomavirus-negative subset of anal SCC patients that typically respond poorly to standard of care chemoradiation.

DOES PROLONGED ESTRACE ADMINISTRATION EFFECT ON PREGNANCY OUTCOME IN PROGRAMMED FROZEN EMBRYO TRANSFER CYCLE?

To determine whether women in frozen-thawed embryo transfer (FET) cycles, who continued prolonged estrogen administration beyond the standard 12 days due to a thin endometrial stripe exhibited lower pregnancy rates. We retrospectively analyzed the outcomes of 822 FET cycles from January 1, 2019 through March 1, 2021. Oocyte recipients or women with known intrauterine adhesions were excluded. Women received twelve days of 6 mg of oral 17 beta Estradiol (Estrace) after ovarian suppression was confirmed. If after twelve days of Estrace their endometrial stripe (ES) was equal to or less than 7 mm, then their estrogen regimen was continued until her ES was at least 7mm. Intramuscular progesterone 50mg intramuscularly was then administered and a single thawed blastocyst was transferred 132 hours later. Variables assessed included thickens of endometrium, pregnancy (serum hCG), clinical pregnancy, and implantation rate by fetal cardiac activity and pregnancy outcome. The Fisher’s Exact Test and t-test were used. A p value <0.05 was considered significant. Twenty three of 822 cycle were continued on their estrogen regimen to meet ES criteria for at least five days (range 5 to 14 days). No significant differences in age, prior failed FET cycles, and percentage of euploid blastocysts were noted between those women who did or did not requires at least five days more of exogenous estrogen. However, endometrial thickness was significantly thicker in regular FET group compared that of pushed FET cycle at day 12 (9.59 mm vs 6.16 mm, p<0.05). Furthermore, their thin endometrial thickness was significantly improved after prolonged Estrace (6.16 mm vs 7.49 mm, p<0.05). Among pushed FET cycles, five patients were pushed for 14 days and the endometrial thickness were improved from 4.78 mm to 7.08 mm (p=0.11). The pregnancy rate (positive serum hCG/total transfers), clinical pregnancy rates and implantation rate were not significantly different between regular and pushed FET cycles (73.2 %vs 75.0 %), (68.8 % vs 62.5 %), and (59.4 % vs 52.0 %), respectively. The pregnancy outcomes in two groups were similar by age group or PGT performed group. Additionally, chemical pregnancy loss or miscarriage rate did not differ between two groups (7 % vs 4%) and (7 % vs 4 %), respectively. Ongoing pregnancy/live birth rate was 60.9 % (14/23) for regular FET and 59.7 % (462/799) for pushed FET. Our findings suggest that continued exogenous estrogen administration successfully increased the endometrial thickness in all patients with a thin ES and did not adversely affect pregnancy outcome.

Investigating the role of endogenous estrogens, hormone replacement therapy, and blockade of estrogen receptor-\u03b1 activity on breast metabolic signaling

PurposeMenopause is associated with an increased risk of estrogen receptor-positive (ER +) breast cancer. To characterize the metabolic shifts associated with reduced estrogen bioavailability on breast tissue, metabolomics was performed from ovary-intact and ovariectomized (OVX) female non-human primates (NHP). The effects of exogenous estrogen administration or estrogen receptor blockade (tamoxifen treatment) on menopause-induced metabolic changes were also investigated.MethodsBilateral ovariectomies were performed on female cynomolgus macaques (Macaca fascicularis) to model menopause. OVX NHP were then divided into untreated (n = 13), conjugated equine estrogen (CEE)-treated (n= 13), or tamoxifen-treated (n = 13) subgroups and followed for 3 years. Aged-matched ovary-intact female NHP (n = 12) were used as a premenopausal comparison group. Metabolomics was performed on snap-frozen breast tissue.ResultsChanges in several different metabolic biochemicals were noted, particularly in glucose and fatty acid metabolism. Specifically, glycolytic, Krebs cycle, acylcarnitines, and phospholipid metabolites were elevated in breast tissue from ovary-intact NHP and OVX + CEE in relation to the OVX and OVX + tamoxifen group. In contrast, treatment with CEE and tamoxifen decreased several cholesterol metabolites, compared to the ovary-intact and OVX NHP. These changes were accompanied by elevated bile acid metabolites in the ovary-intact group.ConclusionAlterations in estrogen bioavailability are associated with changes in the mammary tissue metabolome, particularly in glucose and fatty acid metabolism. Changes in these pathways may represent a bioenergetic shift in gland metabolism at menopause that may affect breast cancer risk.

Should Exogenous Estrogens Be Stopped for Surgery in Transgender Women?

Should Exogenous Estrogens Be Stopped for Surgery in Transgender Women?

Abstract 1701: Estrogen receptor beta agonists as anti-tumor and immune-modulatory agents in malignant glioma

Abstract High grade, or malignant gliomas are Grade III and IV primary brain tumors that are among the most treatment-resistant human cancers. They have the worst prognosis of any central nervous system malignancy with a median survival of only 14 months and a 5-year survival rate of less than 5%. The standard-of-care (SOC) for high-grade glioma has remained unchanged for over a decade and more than half of newly diagnosed patients do not see any therapeutic benefit with existing regimens. Targeted immunotherapies have not improved the prognosis for glioma patients due to tumor-mediated mechanisms of immune evasion and suppression. Estrogen, or 17β- estradiol (E2), is a sex steroid hormone that inhibits development of gliomas in animal models and mediates its effects via Estrogen Receptor alpha (ERα), beta (ERβ), and the G-protein Coupled Estrogen Receptor (GPER). Early studies indicated that exogenous administration of estrogen mediates protection against glioma development in animal models, but estrogen therapy has adverse side effects due to non-specific targeting of Estrogen Receptors (ER) (α and β). In contrast to ERα, ERβ is a tumor-suppressor in gliomas, with lower expression correlating to increased tumor aggressiveness and worse prognosis. Thus, we have developed a novel, potent, and selective ERβ agonist, ent-28, and our data demonstrate its anti-glioma functions in patient cell lines in vitro, patient-derived xenografts, and orthotopic syngeneic models in vivo. While the more selective ERβ agonists have 200 to 1000-fold selectivity for ERβ, ent-28 has a 9000-fold beta-selectivity. Thus, the specificity of ent-28 for ERβ over ERα will allow us to minimize side-effects of non-selective ER-targeted therapy and maximize therapeutic benefit. ERβ agonists also have anti-inflammatory effects through inhibiting NF-κB activity and decreasing subsequent inflammatory cytokine secretion. Our preliminary gene set analyses indicate that immune signaling pathways are highly enriched in ent-28-treated patient cells compared to vehicle control, suggesting that ent-28 has immune-modulatory effects. To further elucidate the extrinsic effects of ERβ agonism on the tumor microenvironment (TME), we have assessed infiltration of immune subsets between ent-28 and vehicle-treated syngeneic tumor-bearing mice using immunohistochemistry (IHC). Here, we have demonstrated that ERβ agonists have anti-tumor activity in animal models of glioma and modulate the brain TME. Lack of immune infiltration and suppression within the glioma TME are a major barrier to immunotherapy responsiveness; thus, ERβ-mediated immune modulation may sensitize patients to immune-based therapies. Citation Format: Jordan Fredriksen Isaacs, Divya Ravi, Carmen L. del Genio, Zachary A. Shalit, Glenn C. Micalizio, Arti B. Gaur. Estrogen receptor beta agonists as anti-tumor and immune-modulatory agents in malignant glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1701.

Imaging in gynecomastia.

Gynecomastia (GM) is the benign proliferation of glandular tissue in the male breast. It is a common condition, which may occur physiologically and shows three age peaks during a male's lifespan: infancy, puberty, and senescence. An underlying pathology may be revealed in 45%-50% of adult men with GM, such as aggravating medications, systemic diseases, obesity, endocrinopathies, or malignancy. To discuss the role of imaging in the evaluation of GM and its contribution to therapeutic decision-making. The current literature was reviewed through PubMed, Scopus, and CENTRAL electronic databases to identify the best available evidence concerning imaging modalities in patients with GM. Most male breast lesions can be diagnosed on clinical grounds; however, in certain cases, when physical examination is inconclusive, imaging may be helpful. The main purpose of evaluating a patient with GM is to establish the diagnosis and differentiate true GM from pseudogynecomastia, exclude breast cancer, and detect the possible cause. GM is seen in mammography as a subareolar opacity and three mammographic patterns of GM are described: nodular, dendritic, and diffuse, corresponding to florid GM of early onset, fibrous persistent GM, and GM due to exogenous estrogen administration, respectively. In ultrasound (US), florid GM is depicted as a disk-shaped, hypoechoic area underlying the areola, whereas echogenicity of the lesions increases as fibrosis develops. Data on the use of MRI in the evaluation of the male breast and GM are still limited. Imaging findings can be classified according to the BIRADS (breast imaging reporting and data system) based on their malignant potential. Both mammography and US are sensitive and specific to diagnose GM and distinguish it from breast cancer. When clinical findings are suggestive of malignancy or imaging findings are inconclusive, a histological confirmation should be sought.

Tumors modulate fenestrated vascular beds and host endocrine status.

Allograft and xenograft transplantation into a mouse host is frequently utilized to study cancer biology, tumor behavior, and response to treatment. Preclinical studies employing these models often focus solely upon the intra-tumoral effects of a given treatment, without consideration of systemic toxicity or tumor-host interaction, nor whether this latter relationship could modulate the toxicologic response to therapy. Here it is demonstrated that the implantation and growth of a range of human- and mouse-derived cell lines leads to structural vascular and, potentially, functional changes within peripheral endocrine tissues, a process that could conceivably ameliorate the severity of anti-angiogenic-induced fenestrated vessel attenuation. Observations suggest a multifactorial process, which may involve host- and tumor-derived cytokines/growth factors, and the liberation of myeloid-derived suppressor cells. Further investigation revealed a structurally comparable response to the administration of exogenous estrogen. These findings, in addition to providing insight into the development of clinical anti-angiogenic "adaptation," may be of significance within the "cancer-cachexia" and cancer-related anemia syndromes in man.

FROZEN-THAWED EMBRYO TRANSFERS ARE ASSOCIATED WITH A HIGHER RISK OF LARGE FOR GESTATIONAL AGE NEWBORNS

Improvements in cryopreservation techniques associated with the possible impairment in endometrial receptivity due to the supra-physiologic hormonal levels observed during conventional controlled ovarian stimulation (COS) have increased the implementation of frozen-thawed embryo transfers (FET). Perinatal outcomes of fresh embryo transfers (ET) and FET have shown to be similar. However, several studies associate FET with a higher risk of large-for-gestational-age (LGA), thereby, increasing risk of adverse obstetric and neonatal outcomes. This study aims to assess whether FET is associated with a higher risk of large for gestational age newborns, compared with fresh ET in our population. Retrospective, single center study performed from 2017 to 2019. A total of 561 patients who became pregnant after fresh and frozen embryo transfers. A first study group included all IVF cycles where fresh embryo transfer resulted in a singleton live birth (fresh group n=254). A second cohort included FET that led to a singleton live birth (FET group n= 307). All embryos were transferred at a blastocyst stage and vitrification was the only cryopreservation method. In all FET the endometrium was artificially prepared through the administration of exogenous estrogen and progesterone. Data was collected from telephone surveys. We compared the number of LGA newborns and weight differences in both groups. z-test was applied for statistical analysis. A p value <0.05 was considered significant. The median gestational age in both groups was 38 weeks. The mean adjusted birth weight after FET group was higher by 109.26 g, than the fresh group (3269.32 g vs 3160.13 g respectively, p=0.285). The incidence of newborns that weighted ≥ p50 was significantly higher for FET group (142 vs 75 for FET and fresh respectively, p= 0.000048). Moreover, the incidence of LGA livebirths was significantly higher in the FET group (p=0.0226) (23 from the FET group vs 8 from fresh ET). No difference in female to male ratio for LGA newborns or preterm birth rate was identified between groups. FET is associated with increased risk of LGA in our population. FET has become an important technique in IVF; however, whether it should be the first choice for ET requires further analysis. An individual approach should remain when deciding between fresh or frozen embryo transfers. Longer-term potential health effects remain to be evaluated.

Iron-Deficiency and Estrogen Are Associated With Ischemic Stroke by Up-Regulating Transferrin to Induce Hypercoagulability.

Epidemiological studies have identified an associate between iron deficiency (ID) and the use of oral contraceptives (CC) and ischemic stroke (IS). To date, however, the underlying mechanism remains poorly understood. Both ID and CC have been demonstrated to upregulate the level and iron-binding ability of Tf (transferrin), with our recent study showing that this upregulation can induce hypercoagulability by potentiating FXIIa/thrombin and blocking antithrombin-coagulation proteases interactions. To investigate whether Tf mediates IS associated with ID or CC and the underlying mechanisms. Tf levels were assayed in the plasma of IS patients with a history of ID anemia, ID anemia patients, venous thromboembolism patients using CC, and ID mice, and in the cerebrospinal fluid of some IS patients. Effects of ID and estrogen administration on Tf expression and coagulability and the underlying mechanisms were studied in vivo and in vitro. High levels of Tf and Tf-thrombin/FXIIa complexes were found in patients and ID mice. Both ID and estrogen upregulated Tf through hypoxia and estrogen response elements located in the Tf gene enhancer and promoter regions, respectively. In addition, ID, administration of exogenous Tf or estrogen, and Tf overexpression promoted platelet-based thrombin generation and hypercoagulability and thus aggravated IS. In contrast, anti-Tf antibodies, Tf knockdown, and peptide inhibitors of Tf-thrombin/FXIIa interaction exerted anti-IS effects in vivo. Our findings revealed that certain factors (ie, ID and CC) upregulating Tf are risk factors of thromboembolic diseases decipher a previously unrecognized mechanistic association among ID, CC, and IS and provide a novel strategy for the development of anti-IS medicine by interfering with Tf-thrombin/FXIIa interactions.

Role of sex steroid hormones in pelvic organ prolapse.

Pelvic organ prolapse (POP) affects a significant percentage of women and contributes to major healthcare costs both in the United States and worldwide. This review examines the current understanding of the role of sex steroid hormones (estrogens, androgens, and progesterone) in POP in premenopausal, perimenopausal, and postmenopausal women. We reviewed the relevant studies on POP related to estrogens, androgens, and progesterone in both animal models and humans. Estrogen has a profound influence on the synthesis and metabolism of pelvic connective tissues, and may have the ability to both prevent POP and improve prognosis if used therapeutically. There is limited research regarding the role of androgens and progesterone and their receptors in POP and results so far have been contradictory, warranting further study to determine whether changes in androgen and progesterone receptor expression are a cause or effect of POP. Because of the role that estrogen plays in maintaining the integrity of pelvic floor connective tissues, we propose that rigorous and well-controlled studies are needed on the role of exogenous estrogen administration as a form of POP prevention. : Video Summary:http://links.lww.com/MENO/A583.

Predictive value of C-reactive protein level and pregnancy rate in intracytoplasmic sperm injection cycle

Objective The aim was to determine the possible relation between the maternal serum C-reactive protein (CRP) level and outcome of controlled ovarian stimulation and pregnancy rate in patients undergoing in-vitro fertilization (IVF) or intracytoplasmic sperm injection. Background Controlled ovarian hyperstimulation is apparently a key factor in the success of IVF embryo transfer. CRP is a sensitive marker in the inflammatory process rises following hormonal stimulation and does not have diurnal alterations but administration of exogenous estrogen increases its level. Materials and methods This prospective cohort study was conducted at the outpatient clinic in a Private Infertility Unit, Menoufia, Egypt, from November 2018 to August 2019. This study included 100 infertile patients who were candidates for IVF/intracytoplasmic sperm injection and fulfilled the inclusion and exclusion criteria. Full history was taken. Participants underwent CRP measuring at three times, at the day of beginning of ovarian stimulation, ovum pickup, and the day of transfer. Two groups were identified for those who get pregnant and those who did not get pregnant. Results Patients whose CRP level decreased on transfer day (19 cases) 14 got pregnant (73.7%), whereas only five failed to get pregnant (26.3%). Patients whose CRP level increased on transfer day (81 cases) 52 got pregnant (64%), whereas 29 failed to get pregnant (36%). Conclusion Ovulation induction is an inflammatory process leading to increased levels of CRP but with different patterns. These patterns of changes failed to be used as markers of successful outcome of IVF treatment.

Estrogen Receptor 1 (ESR1) Agonist Induces Ovarian Differentiation and Aberrant Müllerian Duct Development in the Chinese Soft-shelled Turtle, Pelodiscus sinensi.

Estrogens play critical roles in ovarian and reproductive organ development, but the molecular signaling pathways in non-mammalian vertebrates are not well understood. Studies of reptiles have indicated that administration of exogenous estrogens during embryonic development causes ovarian differentiation and presumptive male to female sex-reversal. The Chinese soft-shelled turtle, Pelodiscus sinensis, belongs to the family Trionychidae and exhibits genotypic sex determination system with ZZ/ZW sex chromosomes. In order to assess the role of estrogens and their signaling pathway on sex determination and differentiation, P. sinensis eggs were given a single administration of endogenous estrogen,17β-estradiol (E2) or a synthetic estrogen receptor 1 (ESR1) agonist, 4,4',4"-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol (PPT) in ovo during gonadal differentiation, and the subsequent effects were examined during a final developmental stage prior to hatching. The administration of both E2 and PPT induced ovarian differentiation in genetic male embryos. Intriguingly, PPT but not E2 induced the Müllerian duct enlargement and aberrant glandular development. These data suggest that ovarian differentiation and reproductive tract anomalies induced by the exogenous estrogen exposure act through ESR1 in the Chinese soft-shelled turtles.

Значення замісної гормональної терапії при ранній менопаузі

Substitution of estrogen is a proven way of correcting disorders that are associated with menopause. The question of the optimal method for the administration of estrogens, given changes in the cardiovascular system and psychological maladaptation, is controversial. The objective: to study the effect of alternative schemes of exogenous estrogen administration on the state of endothelial regulation and psychological adaptation of women with RM. Material and methods. Under observation, there were 74 patients who asked the gynecologist about the termination of menstrual function at the age of less than 40 years. Patients were divided into 3 subgroups – 25 patients of subgroup Ia received classic cyclic hormone replacement therapy, 25 subgroup Ib patients received exogenous drugs in combination oral contraceptives, 24 patients of the subgroup Ic received exogenous estrogens as transdermal patches. In all groups, the level of reactive and personality anxiety was determined prior to the start of treatment on a special scale. For the study of endothelial regulation, the activity of vascular motor expansion of the shoulder artery under the influence of hyperemia was investigated, the base diameter of the shoulder artery Db was estimated, the shoulder artery diameter after decompression Dd and the increase in the diameter of the shoulder artery after decompression,%, Δ 1. All of these indicators were studied in patients of all subgroups in 3, 6 and 12 months after initiating the administration of exogenous estrogens. The Kolmogorov-Smirnov criterion (level of psychological adaptation) and Student’s criterion (indicators of endothelial regulation) were used to assess the statistical differences between the groups. Results. Among all methods of exogenous use of estrogen, oral administration of them in a continuous mode has the most powerful positive effect on psychological adaptation – after 6 and 12 months of therapy, 52% and 76% of patients achieved a low level of situational anxiety, while 48% and 72% personal anxiety, in other subgroups, these proportions were significantly smaller (not more than 42%). The effect on endothelial dysfunction was also more pronounced in patients of the Ia subgroup – they reported a significant increase in the growth of the diameter of the brachial artery during the first year of therapy during the 6 months after starting treatment. Such changes in endothelial regulation are not the same or even the tendency towards them in the groups of other forms of administration of estrogens. Conclusions. 1. The application of different schemes of exogenous estrogen assignment has a different effect on the psychological adaptation and regulation of cardiovascular function in patients with early menopause. 2. Thus, during 6 months of treatment, 52% of patients taking estrogens in continuous hormone replacement therapy had a low level of situational anxiety, while patients taking hormonal contraceptive cyclical estrogens in only 32 % showed a low level of anxiety, and women who took exogens in the form of a transdermal patch – a lice of 25%. After 12 months, the disagreements became even higher – 76, 40, and 41.6% respectively. 3. The tendency to reduce the level of personal anxiety, outlined after 6 months of treatment, in women who received estrogens in continuous hormone therapy (48% vs. 32 and 33.3% in hormonal contraceptives and transdermal patches), became statistically probable due to year of treatment (72, 40 and 45.8% respectively). 4. In the subgroup receiving estrogens in the mode of continuous substitution hormone therapy, improvement of endothelial function in the form of increase in the growth of the diameter of the brachial artery after decompression was noted during 6 months of treatment, this trend was not found in other subgroups Key words: early menopause, situational, personality anxiety, endothelial regulation, estrogen therapy.