Estradiol Substitution Research Articles

The Effect of Ovariectomy and Estradiol Substitution on the Metabolic Parameters and Transcriptomic Profile of Adipose Tissue in a Prediabetic Model.

Menopause brings about profound physiological changes, including the acceleration of insulin resistance and other abnormalities, in which adipose tissue can play a significant role. This study analyzed the effect of ovariectomy and estradiol substitution on the metabolic parameters and transcriptomic profile of adipose tissue in prediabetic females of hereditary hypertriglyceridemic rats (HHTgs). The HHTgs underwent ovariectomy (OVX) or sham surgery (SHAM), and half of the OVX group received 17β-estradiol (OVX+E2) post-surgery. Ovariectomy resulted in weight gain, an impaired glucose tolerance, ectopic triglyceride (TG) deposition, and insulin resistance exemplified by impaired glycogenesis and lipogenesis. Estradiol alleviated some of the disorders associated with ovariectomy; in particular, it improved insulin sensitivity and reduced TG deposition. A transcriptomic analysis of perimetrial adipose tissue revealed 809 differentially expressed transcripts in the OVX vs. SHAM groups, mostly pertaining to the regulation of lipid and glucose metabolism, and oxidative stress. Estradiol substitution affected 1049 transcripts with overrepresentation in the signaling pathways of lipid metabolism. The principal component and hierarchical clustering analyses of transcriptome shifts corroborated the metabolic data, showing a closer resemblance between the OVX+E2 and SHAM groups compared to the OVX group. Changes in the adipose tissue transcriptome may contribute to metabolic abnormalities accompanying ovariectomy-induced menopause in HHTg females. Estradiol substitution may partially mitigate some of these disorders.

Cardiovascular, Metabolic and Inflammatory Changes after Ovariectomy and Estradiol Substitution in Hereditary Hypertriglyceridemic Rats.

Background: If menopause is really independent risk factor for cardiovascular disease is still under debate. We studied if ovariectomy in the model of insulin resistance causes cardiovascular changes, to what extent are these changes reversible by estradiol substitution and if they are accompanied by changes in other organs and tissues. Methods: Hereditary hypertriglyceridemic female rats were divided into three groups: ovariectomized at 8th week (n = 6), ovariectomized with 17-β estradiol substitution (n = 6), and the sham group (n = 5). The strain of abdominal aorta measured by ultrasound, expression of vascular genes, weight and content of myocardium and also non-cardiac parameters were analyzed. Results: After ovariectomy, the strain of abdominal aorta, expression of nitric oxide synthase in abdominal aorta, relative weight of myocardium and of the left ventricle and circulating interleukin-6 decreased; these changes were reversed by estradiol substitution. Interestingly, the content of triglycerides in myocardium did not change after ovariectomy, but significantly increased after estradiol substitution while adiposity index did not change after ovariectomy, but significantly decreased after estradiol substitution. Conclusion: Vascular and cardiac parameters under study differed in their response to ovariectomy and estradiol substitution. This indicates different effects of ovariectomy and estradiol on different cardiovascular but also extracardiac structures.

Estradiol-dependent gene expression profile in the amygdala of young ovariectomized spontaneously hypertensive rats.

Estrogen plays a role in cardiovascular functions, emotional health, and energy homeostasis via estrogen receptors expressed in the brain. The comorbid relationship between rising blood pressure, a decline in mood and motivation, and body weight gain after menopause, when estrogen levels drop, suggests that the same brain area(s) contributes to protection from all of these postmenopausal disorders. The amygdala, a major limbic system nuclear complex known to express high estrogen receptor levels, is involved in the regulation of such physiological and psychological responses. We hypothesized that elevated estrogen levels contribute to premenopausal characteristics by activating specific genes and pathways in the amygdala. We examined the effect of 1 mo of estradiol treatment on the gene expression profile in the amygdala of ovariectomized young adult female spontaneously hypertensive rats. Estradiol substitution significantly decreased blood pressure, prevented body weight gain, and enhanced the voluntary physical activity of ovariectomized rats. In the amygdala of ovariectomized rats, estradiol treatment downregulated the expression of genes associated with estrogen signaling, cholinergic synapse, dopaminergic synapse, and long-term depression pathways. These findings indicate that the transcriptomic characteristics of the amygdala may be involved in estrogen-dependent regulation of blood pressure, physical activity motivation, and body weight control in young adult female spontaneously hypertensive rats.

Chronic UVB-irradiation actuates perpetuated dermal matrix remodeling in female mice: Protective role of estrogen.

Chronic UVB-exposure and declined estradiol production after menopause represent important factors leading to extrinsic and intrinsic aging, respectively. Remodeling of the extracellular matrix (ECM) plays a crucial role in both responses. Whether the dermal ECM is able to recover after cessation of UVB-irradiation in dependence of estradiol is not known, however of relevance when regarding possible treatment options. Therefore, the endogenous sex hormone production was depleted by ovariectomy in female mice. Half of the mice received estradiol substitution. Mice were UVB-irradiated for 20 weeks and afterwards kept for 10 weeks without irradiation. The collagen-, hyaluronan- and proteoglycan- (versican, biglycan, lumican) matrix, collagen cleavage products and functional skin parameters were analyzed. The intrinsic aging process was characterized by increased collagen fragmentation and accumulation of biglycan. Chronic UVB-irradiation additionally augmented the lumican, versican and hyaluronan content of the dermis. In the absence of further UVB-irradiation the degradation of collagen and accumulation of biglycan in the extrinsically aged group was perpetuated in an excessive matter. Whereas estradiol increased the proteoglycan content, it reversed the effects of the perpetuated extrinsic response on collagen degradation. Suspension of the intrinsic pathway might therefore be sufficient to antagonize UVB-evoked long-term damage to the dermal ECM.

Effect of subcutaneous injection of estradiol on feeding and drinking behaviors and body weight in basolateral amygdaloid lesioned rats.

Estradiol is known to inhibit food intake (FI), water intake (WI) and body weight (BW) across the species including women and it is most evident in rats. Ovariectomy in rats and menopause in women produce hyperphagia and obesity. Estradiol substitution in ovariectomized (OVX) rats and hormone replacement in women reverses these changes suggesting that lack of estradiol causes eating related disorders. However, the neurobiological target/s for estradiol mediating effects remains largely unknown. While lesions of basolateral amygdala (BLA) also produce hyperphagia, polydipsia and obesity in female rats suggesting BLA normally inhibits these behaviors. Since ovariectomy is a useful model to study postmenopausal obesity in women, we have investigated the role of BLA in ovariectomy induced ingestive behaviors. Ovariectomy and stereotaxic lesions in experimental group (n = 6) whereas sham operations in control group (n = 6) were carried out in female rats. Estradiol was injected subcutaneously (s.c) before and after lesions in experimental group and vehicle was injected in control group. Data from the present study shows that there was an additional increase in FI, WI and BW in OVX animals following BLA lesions, but this additive effect was small compared to sham operated controls. Conversely, OVX rats with lesions have shown small but significant reductions in FI, WI, and lost less BW, following s.c injection of estradiol compared to rats with intact BLA. These findings suggest that ovariectomy and estradiol induced changes on ingestive behaviors and body weight are partly mediated via BLA.

Low Estrogen Exposure and/or Defective Estrogen Signaling Induces Disturbances in Glucose Uptake and Energy Expenditure

Correlations between estrogen signaling and human morbidity seems to be very unclear and difficult topic. Nowadays, the opinions of scientists have been partially changed regarding “estrogen induced diseases”, but the overwhelming literary data are still contradictory. Physiological estrogen levels in healthy premenopausal women supply protection against insulin resistance, hypertension, cardiovascular diseases and malignancies as compared with men of the same age. However, after menopause a decreased ovarian estrogen synthesis will rapidly deteriorate the glucose sensitivity and increases the prevalence of life threatening diseases. New findings on the functions of tissular estrogen receptors (ERs) indicate that estradiol plays important role in the maintenance of glucose homeostasis and energy expenditure. Diverse disorders associated with insulin resistance are usually well treatable by estradiol substitution both in pre- and postmenopausal women as well as in animal experiments. ERs seem to have balanced interplay in the maintenance of adaptation to the momentarily changing intra and extracellular stimuli. This equilibrium may be shattered in case of a defective estrogen supply or by the derangement of ER signaling pathways. Understanding the crosstalk and interplay between ERs illuminates the fact that there is no good or bad ER isoform, but they construe a complex system so as to achieve an ideal internal milieu. Considering the regulatory effects of ERs on food intake, insulin secretion, glucose uptake and metabolic processes, estrogen administration may be a therapeutic avenue to repair insulin sensitivity in patients with dysmetabolism and diabetes mellitus.

Rare missense P450c17 (CYP17A1) mutation in exon 1 as a cause of 46,XY disorder of sexual development (DSD): implications of breast tissue “unresponsiveness” despite adequate estradiol substitution

Rare missense P450c17 (CYP17A1) mutation in exon 1 as a cause of 46,XY disorder of sexual development (DSD): implications of breast tissue “unresponsiveness” despite adequate estradiol substitution

The effects of long-term raloxifene and estradiol treatments on bone in a patient with congenital aromatase deficiency

Introduction In adult aromatase-deficient men, estrogen treatment has always resulted in a rapid skeletal maturation with epiphyseal closure and improved BMD. Raloxifene is a SERM with proven estrogen agonist action on bone that leads to an improvement in BMD and a reduction in bone turnover. The present study reports the effects of raloxifene and transdermal estradiol treatment, respectively, on epiphyseal closure and BMD in an aromatase-deficient man, over a 24-month follow-up, with the aim of obtaining further insight into the role of estrogens in the male skeletal homeostasis. Materials and methods A 25-year-old Caucasian man with aromatase deficiency, a bone age of 15.3 years, unfused epiphyses and an impaired BMD was initially administered raloxifene (60 mg/day per os) for 12 months, while transdermal estradiol (25 μg twice weekly) was administered for the subsequent 12 months. During the follow-up, the effects of the two treatments on epiphyseal closure, BMD and bone turnover markers were investigated. An iliac crest bone biopsy was performed only before and after the raloxifene treatment, but it was not repeated after transdermal estradiol treatment. Results No changes in bone age were observed after raloxifene therapy, whereas a complete epiphyseal closure was achieved with transdermal estradiol treatment. Compared with baseline values, raloxifene treatment led to improved BMD both at the ultradistal forearm and 33% radius; the transdermal estradiol treatment resulted in a further slight increase in BMD at the 33% radius, but not at the ultradistal forearm. The baseline bone biopsy showed elevated bone remodelling in trabecular bone, while the second biopsy following raloxifene treatment revealed a decrease in remodelling. Discussion This study shows that the management of aromatase deficiency in the male cannot consider raloxifene as a first choice treatment, but should be still based on estrogen replacement treatment since in this patient the completion of bone maturation has only been obtained once estradiol substitution was performed. The present case also demonstrates that raloxifene is able to improve BMD in aromatase-deficient men.

Aging Reduces the Efficacy of Estrogen Substitution to Attenuate Cardiac Hypertrophy in Female Spontaneously Hypertensive Rats

Clinical trials failed to show a beneficial effect of postmenopausal hormone replacement therapy, whereas experimental studies in young animals reported a protective function of estrogen replacement in cardiovascular disease. Because these diverging results could in part be explained by aging effects, we compared the efficacy of estrogen substitution to modulate cardiac hypertrophy and cardiac gene expression among young (age 3 months) and senescent (age 24 months) spontaneously hypertensive rats (SHRs), which were sham operated or ovariectomized and injected with placebo or identical doses of 17beta-estradiol (E2; 2 microg/kg body weight per day) for 6 weeks (n=10/group). Blood pressure was comparable among sham-operated senescent and young SHRs and not altered by ovariectomy or E2 treatment among young or among senescent rats. Estrogen substitution inhibited uterus atrophy and gain of body weight in young and senescent ovariectomized SHRs, but cardiac hypertrophy was attenuated only in young rats. Cardiac estrogen receptor-alpha expression was lower in intact and in ovariectomized senescent compared with young SHRs and increased with estradiol substitution in aged rats. Plasma estradiol and estrone levels were lower not only in sham-operated but surprisingly also in E2-substituted senescent SHRs and associated with a reduction of hepatic 17beta-hydroxysteroid dehydrogenase type 1 enzyme activity, which converts weak (ie, estrone) into potent estrogens, such as E2. Aging attenuates the antihypertrophic effect of estradiol in female SHRs and is associated with profound alterations in cardiac estrogen receptor-alpha expression and estradiol metabolism. These observations contribute to explain the lower efficiency of estrogen substitution in senescent SHRs.

Combined Effects of Physical Activity, Dietary Isoflavones and 17β-Estradiol on Movement Drive, Body Weight and Bone Mineral Density in Ovariectomized Female Rats

Reduced estrogen levels occurring during menopause in woman are accompanied by a variety of disorders, e. g., hot flushes, depressions, osteoporosis, increase of body weight, and reduced movement drive. In this study we investigated the combined effects of physical activity, estradiol substitution, and a phytoestrogen-rich diet on bone mineral density, increase of body weight, and movement drive in an animal model. Ovariectomized (OVX) female Wistar rats were either fed an isoflavone-rich diet (IRD) or substituted with 17beta-estradiol (E2) for 3 months. Sham-operated rats (Sham) and vehicle-treated OVX animals served as controls. One half of the animals had the opportunity of voluntary wheel running. OVX rats displayed an eight times lower movement activity than Sham animals. E2 treatment, but not IRD, significantly increased the movement activity of OVX rats. During 3 months the lowest increase of body weight was observed in Sham animals, the highest rate in OVX animals. Along with running activity E2 treatment, but not IRD, also lowered the increase of body weight significantly compared to OVX animals. Bone mineral density (BMD) in the trabecular area of the tibia was strongly reduced in OVX rats compared to Sham animals. In contrast to IRD, E2 substitution resulted in a protection of BMD in this area compared to OVX animals. Our data demonstrate that body weight, movement drive, and BMD are positively influenced by E2. The steroid estrogen acts in the trabecular area of the tibia in a bone-protective manner, increases movement drive and antagonizes the increase of body weight. All these effects could not be observed in animals fed an isoflavone-rich diet.

Wirkung von transdermaler oder oraler Östradiolgabe auf die Ausscheidung vasoaktiver Mediatoren bei postmenopausalen Frauen

Fragestellung: Wirken die transdermale (n = 20) und die orale (n = 20) Östradiolsubstitution auf die renale Ausscheidung von vasoaktiven Substanzen bei postmenopausalen Frauen? Methode: Als vasoaktive Substanzen wurden Prostazyklin und Thromboxan, zyklisches Guanosinmonophosphat, das die systemische Stickstoffmonoxidproduktion reflektieren kann, Serotonin, Relaxin, Insulin und Melatonin im 8-Stunden-Nachturin vor und nach 2- und 4wöchiger Östradiolbehandlung bestimmt. Ergebnisse: Die Ausscheidung von Prostazyklin und Thromboxan wurde, als Prostazyklin/Thromboxan-Quotient berechnet, durch beide Anwendungsformen zugunsten der Prostazyklinproduktion erhöht. Für die Ausscheidung von zyklischem Guanosinmonophosphat wurden nur geringgradige Veränderungen beobachtet. Die Produktion von Serotonin, Relaxin und Insulin wurde nur unter transdermaler Behandlung gesteigert. Für Melatonin wurden keine Veränderungen registriert. Schlussfolgerungen: Die hormonelle Substitutionstherapie mit Östradiol bei postmenopausalen Frauen kann, sowohl bei transdermaler als auch bei oraler Gabe, die Ausscheidung verschiedener vasoaktiver Substanzen erhöhen, welche auf vasorelaxierende Östrogenwirkungen hinweisen. Durch die transdermale Applikation wurde dabei eine höhere Wirksamkeit erzielt, obwohl wesentlich geringere Dosen verabreicht wurden. Möglicherweise lässt sich dies durch die bei transdermaler Applikation erfolgende kontinuierliche Einwirkung auf die östrogenen Endorgane erklären.

No difference in improvement of flow mediated dilation after oral or transdermal estradiol substitution after surgical induced menopause

No difference in improvement of flow mediated dilation after oral or transdermal estradiol substitution after surgical induced menopause

Transdermal estradiol substitution therapy for the induction of puberty in female hypogonadism

Fifteen patients aged 14.5-27.3 years (mean +/- SE 18.8 +/- 0.9) with pubertal development failure underwent replacement therapy with estradiol (E2) using a transdermal therapeutic system (TTS). Fourteen of them were affected by hypogonadotropic hypogonadism (11 with thalassemia major, 3 with multiple pituitary hormone deficiency), the 15th patient had an asymmetric gonadal dysgenesis (karyotype 45, X 0/46, XY). Two sizes (5 and 10 cm2) of E2 TTS, delivering respectively 25 and 50 micrograms of E2 a day for 3 1/2 days, were used in this study. All patients were initially given the lower dose of 25 micrograms, twice weekly for 3 weeks each month; 6 months after starting therapy, 5-10 mg oral medroxyprogesterone acetate (MPA) daily was added during the third week. Later, the following sequence was used: 25 micrograms E2 TTS (twice weekly), on days 1 through 14, and 50 micrograms E2 TTS (twice weekly), on days 15 through 25 of each month. On days 15 through 25, 5 mg daily of MPA were administered orally. The period of treatment ranged from 0.5 to 3 years. Breast development was obtained in all cases. The vaginal maturation index rose. Ultrasonography showed an increase of uterine size and uterine shape became of pubertal type. Withdrawal bleeding occurred in all patients. Plasma E2 levels rose to normal levels, estrone (E1) levels increased slightly. No change in plasma SHBG levels was observed. Urinary E2, E1 and estriol rose to maximum levels the 3rd day after the application of each system. Neither systemic side effects nor adverse metabolic effects were observed except for an increased sensitivity to the platelet aggregating agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Transdermal estradiol substitution therapy for female hypogonadism in thalassemia major

The efficacy and metabolic effects of estradiol (E2) administered by a transdermal therapeutic system (TTS) in the replacement therapy of hypogonadism, was evaluated in five women (aged 17–22.1 years) with β-thalassemia major and hypogonadism. Two sizes of TTS (5 and 10 cm2) were used in this study delivering, respectively, 25 and 50 μg E2 daily for 3 1/2 days. The systems were applied to the skin and were changed twice weekly for 3 weeks a month. Using this sequence, the lower dose of 25 μg E2 TTS was administered in all patients for 6–12 months. In addition, two of the patients were given 50 μg E2 transdermally in combination with an oral progestogen for 4 months. The administration of 25 μg TTS resulted in breast development in all cases. The vaginal cells reached pubertal maturity. Uterine size, measured by pelvic ultrasound, progressively increased but no withdrawal bleeding occurred. In the two patients receiving 50 μg E2 TTS and oral progestogen, breast tissue and uterine size further progressed and withdrawal bleeding occurred. Plasma estradiol levels rose during E2 TTS administration in every patient. The patches were well tolerated and no systemic side effects were reported. No adverse metabolic effects were observed, except for an increased sensitivity to the aggregating agents in two cases.

GABA and gonadal hormones

Summary The effects of alterations in the androgen status of male rats was investigated with respect to the possible involvement of hormones in GABAergic regulation. The methods used to study this hormone-GABA relationship revealed: (1) Long term castration of rats caused a decrease in GABA concentration in the amygdala and septal area, while a slight but consistent increase in concentration was found in the midbrain. (2) Testosterone substitution was effective in reversing this decrease in GABA associated with castration, but had no discriminable effect on the midbrain steady state concentrations. (3) Estradiol substitution reversed the reduction in GABA found with castration and further increased GABA concentrations in the midbrain. (4) Dihydrotestosterone had no effect on amygdaloid or septal concentrations but was effective in reducing GABA concentration in the midbrain. (5) After GABA transaminase inhibition by aminooxyacetic acid the concentration of GABA in castrated animals was lower compared to sham animals in all 3 brain regions. Testosterone reversed this reduction in all areas. The findings suggest that castration causes a decrease in GABA synthesis in several brain regions and that this is an effect of a reduction in circulating testosterone and/or estradiol concentrations. Castration may also cause a decrease in turnover of GABA in the midbrain which is reversed by dihydrotestosterone and/or testosterone.