Changes in the Serum Levels of Estradiol and Changes in Expression of Estrogen Receptor Alpha in the Bone Tissue of Ovariectomized Wistar Rats

Estradiol is an estrogen steroid hormone and is produced basically within the follicles of the ovaries. The decrease in serum estrogens concentration at menopause disrupts the metabolic balance, changes the lipid profile leading to visceral obesity, which caused an increase in serum estradiol levels, through aromatase activity. Estrogen deficiency also is a reason for the development of osteoporosis.We investigated the serum estradiol levels and changes in bone alpha estrogen receptor expression in ovariectomized rats. For this purpose, we used 20 female Wistar rats at reproductive age - 2 months divided into 2 groups: group 1 (G1)-10 animals were ovariectomized and group 2 (G2)-10 of which were sham-operated. All animals of G1 showed weight gain compared to group G2. The results showed that the values of serum 17β-estradiol in rats of G1 statistically increased compared to G2 (p <0.05). Immunohistochemical analysis revealed no difference in estrogen receptor expression between the both groups. Histomorphological analysis of femur from G1 showed the presence of pronounced osteoporosis. Ovariectomy led to the development of obesity, which caused an increase in serum estradiol levels, through aromatase activity, but this process did not prevent bone tissue from developing osteoporosis.

Cancer chemopreventive and antioxidant activities of seed, skin, and pulp of Maximo hybrid grapes (IAC 138-22) at five different ripening stages

ABSTRACT: This study evaluated the composition and the cancer chemopreventive and antioxidant activities of the seed, skin, and pulp of Maximo hybrid grapes (IAC 138-22) harvested at different ripening stages. The content of total phenolic compounds and tannins were determined by the Folin-Ciocaulteau method, and total anthocyanins were determined using the differential pH method. Different chemical methods assessed the antioxidant activity. Cell viability (macrophage and melanoma skin cancer) and cancer chemopreventive activity were tested in cell lines by quinone reductase induction assay, TNF-α-induced NF-κB inhibitory activity assay, and aromatase inhibitory activity assay. The hybrid grape had high phenolic contents in both seeds and skin, significantly reduced upon ripening. The results showed that fruit ripening significantly affected both the composition and the antioxidant and cancer chemopreventive activities. Except for the anthocyanin content, the most significant results were observed for green seeds, with the greenest stage showing the best results. The green seeds showed the highest antioxidant activity, even when compared to free resveratrol. In the assessment of cancer chemopreventive activity, the green seeds showed the ability to inhibit N-FκB and aromatase activity, important factors for the early stage of cancer development. Besides, no extracts showed cytotoxicity. Therefore, this grape’s green seeds showed strong antioxidant and cancer chemopreventive activities confirmed herein, suggesting beneficial health effects.

Local Biomarkers Involved in the Interplay between Obesity and Breast Cancer

Obesity is associated with an increased risk of breast cancer, which is the most common cancer in women worldwide (excluding non-melanoma skin cancer). Furthermore, breast cancer patients with obesity have an impaired prognosis. Adipose tissue is abundant in the breast. Therefore, breast cancer develops in an adipose-rich environment. During obesity, changes in the local environment in the breast occur which are associated with breast cancer. A shift towards a pro-inflammatory state is seen, resulting in altered levels of cytokines and immune cells. Levels of adipokines, such as leptin, adiponectin, and resistin, are changed. Aromatase activity rises, resulting in higher levels of potent estrogen in the breast. Lastly, remodeling of the extracellular matrix takes place. In this review, we address the current knowledge on the changes in the breast adipose tissue in obesity associated with breast cancer initiation and progression. We aim to identify obesity-associated biomarkers in the breast involved in the interplay between obesity and breast cancer. Hereby, we can improve identification of women with obesity with an increased risk of breast cancer and an impaired prognosis. Studies investigating mammary adipocytes and breast adipose tissue in women with obesity versus women without obesity are, however, sparse and further research is needed.

Pathogenesis Based Diagnosis and Treatment of Endometriosis

Understanding the pathophysiology of endometriosis is changing our diagnosis and treatment. Endometriosis lesions are clones of specific cells, with variable characteristics as aromatase activity and progesterone resistance. Therefore the GE theory postulates GE incidents to start endometriosis, which thus is different from implanted endometrium. The subsequent growth in the specific environment of the peritoneal cavity is associated with angiogenesis, inflammation, immunologic changes and bleeding in the lesions causing fibrosis. Fibrosis will stop the growth and lesions look burnt out. The pain caused by endometriosis lesions is variable: some lesions are not painful while other lesions cause neuroinflammation at distance up to 28 mm. Diagnosis of endometriosis is made by laparoscopy, following an experience guided clinical decision, based on history, symptoms, clinical exam and imaging. Biochemical markers are not useful. For deep endometriosis, imaging is important before surgery, notwithstanding rather poor predictive values when confidence limits, the prevalence of the disease and the absence of stratification of lesions by size, localization and depth of infiltration, are considered. Surgery of endometriosis is based on recognition and excision. Since the surrounding fibrosis belongs to the body with limited infiltration by endometriosis, a rim of fibrosis can be left without safety margins. For deep endometriosis, this results in a conservative excision eventually with discoid excision or short bowel resections. For cystic ovarian endometriosis superficial destruction, if complete, should be sufficient. Understanding pathophysiology is important for the discussion of early intervention during adolescence. Considering neuroinflammation at distance, the indication to explore large somatic nerves should be reconsidered. Also, medical therapy of endometriosis has to be reconsidered since the variability of lesions results in a variable response, some lesions not requiring estrogens for growth and some being progesterone resistant. If the onset of endometriosis is driven by oxidative stress from retrograde menstruation and the peritoneal microbiome, medical therapy could prevent new lesions and becomes indicated after surgery.

Effects of bone morphogenetic protein 4, gremlin, and connective tissue growth factor on estradiol and progesterone production by bovine granulosa cells

Bone morphogenetic proteins (BMP) are members of the transforming growth factor β (TGFβ) family of proteins that have been implicated in the paracrine regulation of granulosa cell (GC) function, but whether responses to BMPs change with follicular size or interact with connective tissue growth factor (CTGF) or BMP antagonists (e.g., gremlin) to directly affect GC function of cattle is unknown. Therefore, to determine the effects of BMP4 on proliferation and steroidogenesis of GC and its interaction with gremlin or CTGF, experiments were conducted using bovine GC cultures. In vitro, BMP4 (30 ng/mL) inhibited (P &lt; 0.05) follicle-stimulating hormone (FSH) plus insulin-like growth factor 1 (IGF1)-induced progesterone and estradiol production by large- and small-follicle GC but the inhibitory effect of BMP4 on estradiol production was much more pronounced in large-follicle GC. In small-follicle GC, BMP4 had no effect (P &gt; 0.10) on IGF1-induced proliferation, but gremlin inhibited (P &lt; 0.05) cell proliferation and estradiol and progesterone production in IGF1 plus FSH-treated GC. In large-follicle GC, BMP4 (10-30 ng/mL) increased (P &lt; 0.05) GC numbers and gremlin (100 ng/mL) blocked this effect. In large-follicle GC, CTGF inhibited (P &lt; 0.05) FSH plus IGF1-induced progesterone and estradiol production, and CTGF blocked the stimulatory effect of BMP4 on GC proliferation. These results indicate that BMP4, gremlin, and CTGF inhibit GC aromatase activity and progesterone production. Also, the stimulatory effect of BMP4 on GC proliferation and the inhibitory effects of BMP4 on GC steroidogenesis are more pronounced in large versus small follicles.

Male Subclinical Hypogonadism: Mechanisms with Interplay of Reproductive Hormones, Undercarboxylated Osteocalcin and Endothelial Dysfunction

BackgroundPathogenesis and endothelial function in subclinical hypogonadism (SCH) are unknown. Undercarboxylated osteocalcin (ucOC) participate in atherosclerosis and reproduction. We studied interplay of endothelial function, unOC and reproductive hormones with SCH.Methodsamong SCH, late onset hypogonadism (LOH), and healthy eugonadal male (HC) groups, we measured sex hormones and unOC, calculated luteinizing hormone/testosterone (LH/T), LH.T product and estradiol/T (E/T) as indicators of impaired leydig cell, androgen sensitivity index (ASI) & aromatase activity respectively and regulators for LH set point. We assessed flow mediated dilation of brachial artery (FMD%), carotid- intima media thickness (CIMT) and aortic stiffness index (AS) as markers of subclinical atherosclerosis.ResultsContrary to LOH, SCH had higher ASI, lower E/T ratio& similar T, follicle stimulating hormone and sex hormone binding globulin (SHBG) compared to HC, LH/ T was significant higher in LOH and lower in HC than SCH . Similar to LOH, SCH had significant lower FMD% and higher CIMT, AS, unOC & inflammatory marker and atherogenic lipid profile than HC. LH, LH/T & ucOC negatively while T positively FMD% meanwhile. LH, LH/T & ucOC positively while testosterone negatively correlated with CIMT. LH and LH/T positively while estradiol and E/T negatively related to AS. ucOC positively correlated to LH, LH/T, E SHBG & negatively correlated with T. Independent predictors were LH for FMD% & AS meanwhile LH and LH/T for CIMT.ConclusionsSCH as not impaired testicular function state is characterized by androgen insensitivity, impaired aromatase activity, compensatory elevated unOC and atherogenic role of LH in endothelial dysfunction.

Rapid changes in brain estrogen concentration during male sexual behavior are site and stimulus specific

Classically, estrogens regulate male sexual behavior through effects initiated in the nucleus. However, neuroestrogens, i.e., estrogens locally produced in the brain, can act within minutes via membrane-initiated events. In male quail, rapid changes in brain aromatase activity occur after exposure to sexual stimuli. We report here that local extracellular estrogen concentrations measured by in vivo microdialysis increase during sexual interactions in a brain site- and stimulus-specific manner. Indeed, estrogen concentrations rose within 10 min of the initiation of sexual interaction with a female in the medial preoptic nucleus only, while visual access to a female led to an increase in estrogen concentrations only in the bed nucleus of the stria terminalis. These are the fastest fluctuations in local estrogen concentrations ever observed in the vertebrate brain. Their site and stimulus specificity strongly confirm the neuromodulatory function of neuroestrogens on behavior.

Regulation of estradiol synthesis by aromatase interacting partner (AIPB)

Estradiol is essential for the development of female sex characteristics and fertility. Postmenopausal women and breast cancer patients have high estradiol. Aromatase catalyzes estradiol synthesis; however, the factors regulating aromatase activity are unknown. We identified a new 22-kDa protein, aromatase interacting partner in breast (AIPB), from the endoplasmic reticulum of human breast tissue. AIPB expression is reduced in tumorigenic breast and further reduced in triple negative tumors. Like aromatase, AIPB expression is induced by nonsteroidal estrogen. We found that AIPB and aromatase interact in nontumorigenic and tumorigenic breast tissues and cells. Conditional AIPB over expression decreased estradiol and blocking AIPB availability with an AIPB binding antibody increased estradiol in tumorigenic cells. Estradiol synthesis is highly increased in AIPB knockdown cells, suggesting that the newly identified AIPB protein is important for aromatase activity and a key modulator of estradiol synthesis. Thus, a change in AIPB protein expression may represent an early event in tumorigenesis and be predictive of an increased risk of developing breast cancer.