Oestrogen-androgen crosstalk in the pathophysiology oferectile dysfunction

<abstract>Ageing in man is associated with a decline in testosterone following changes in the hypothalamo-pituitary testicular axis. This may offset the physiologic equilibrium between oestrogen and androgen and at some point when the ratio of free testosterone to oestradiol reaches a critical level, the oestrogenic gonadotropin suppressive effect predominates with decreased release of FSH and LH. Adding to this endocrinal complexity is the continued peripheral conversion to oestradiol through aromatisation. Although the androgen deficiency is not the sole cause for impotence in the elderly, there is a gradual decrease in nocturnal penile tumescence (NPT) and spontaneous morning erections with ageing. Despite the age related increase in oestrogen levels, the information on the pathophysiological role of the 'female hormone' in erectile dysfunction has been scanty. Together with our identification of oestrogen receptors within the penile cavernosum, we have delineated dysfunctional changes on male erection mediated by oestradiol. These findings parallel the recent concerns over environmental oestrogens on fertility declines in young men. Oestrogenic activity is also present in plants and thereby in human diet. These phytoestrogens are structurally and functionally similar to oestradiol and more potent than the environmental oestrogenic chemicals such as organochlorine and phenolic compounds. Thus in the light of growing concerns of possible compromising effects on sexuality by endogenous and environmental oestrogens, we are faced with the scientific need to delineate their role on the mechanism of male erectile pathway in health and disease for clinical correlates and prognostics.

The differential effects of prostate stromal cells derived from different zones on prostate cancer epithelial cells under the action of sex hormones

It is well known that prostate cancer （PCa） occurs predominantly in the peripheral zone （PZ）, whereas benign prostatic hyperplasia （BPH） typically develops in the transition zone. To identify possible mechanisms underlying zonal differences, we compared the effects of prostate stromal cells derived from the peripheral zone （PZsc） and the transition zone （TZsc） on a PCa epithelial cell line （PC3） in the presence of sex hormones. First, we observed that androgen receptor （AR） mRNA was more highly expressed in PZsc than TZsc when the cells were treated with dihydrotestosterone （DHT） and β-oestradiol （E2） （P〈0.05）. By ELISA, we looked for differences in the secretion of peptide growth factors from PZsc and TZsc. We found that keratinocyte growth factor （KGF） secretion increased with increasing concentrations of DHT （P〉0.01） and was higher in PZsc than TZsc. Under treatment with DHT plus E2, PZsc secreted more transforming growth factor-β1 （TGF-β1） than TZsc, but this pattern was reversed when the cells were treated with E2 only. With increasing concentrations of DHT, insulin-like growth factor-1 （IGF-1） secretion increased in PZsc but decreased in TZsc. To further characterize the effects of PZsc and TZsc on PC3 cells, we developed a coculture model and performed MTT assays, Western blot analysis and real-time RT-PCR. We found that PZsc promoted PC3 cell proliferation and progression better than TZsc, particularly when treated with 10 nmoll^- 1 DHT plus 10 nmoll^-1 E2. In conclusion, our data suggest that PZsc may have a greater capacity to induce PCa development and progression than TZsc via growth factors regulated by sex hormones. These findings provide possible mechanisms underlying zonal differences in prostate diseases, which may aid the search for novel therapeutic targets for PCa.

The association of aromatase （CYP19） gene variants wil sperm concentration and motility

The irreversible transformation of androgens into oestrogens is catalysed by cytochrome P450 aromatase. In the present study, we explored the contribution of the （TTTA）n polymorphism in the aromatase gene （CYP19） to sperm concentration and motility. Ninety normozoospermic and 60 oligospermic men were examined during infertility examinations. DNA was extracted from spermatozoa, and the CYP19（TTTA）n polymorphism was genotyped by PCR. Genotype analysis revealed six CYP19（TTTA）n alleles with 7-12 repeats. The allelic distribution of the CYP19（TTTA）n polymorphism differed between normozoospermic and oligospermic men （P〈0.01）. Oligospermic men less frequently had long CYP19 alleles than did normozoospermic men （25 and 37.8%, respectively; P〈0.02）. The higher frequency of short CYP19alleles in oligospermic men compared to normozoospermic men （43.3 and 28.3%, respectively; P〈0.01） was primarily due to the distribution of the CYP19 （TTTA）7 allele. The CYP19 （TTTA）7 allele was associated with lower sperm concentration in normozoospermic men {P〈0.01） and in the total study population {P〈0.01）; it was also associated with lower sperm motility in normozoospermic men （P〈0.05） and in the total study population （P〈0.01）. In conclusion, the CYP19 （TTTA）7 allele probably impairs aromatase activity, which in turn alters aromatase and oestrogen levels in the testis, leading to decreased sperm concentration and motility. These findings support the significance of cytochrome P450 aromatase in human spermatogenesis and consequently in semen quality.

Sex differences and effects of oestrogen in rat gastric mucosal defence

AIM To evaluate sex differences and the effects of oestrogen administration in rat gastric mucosal defence.METHODS Sex differences in gastric mucus thickness and accumulation rate, absolute gastric mucosal blood flow using microspheres, the integrity of the gastric mucosal epithelium in response to a chemical irritant and the effects of oestrogen administration on relative gastric mucosal blood flow in an acute setting was assessed in an in vivo rat experimental model. Subsequently, sex differences in the distribution of oestrogen receptors and calcitonin gene related peptide in the gastric mucosa of animals exposed to oestrogen in the above experiments was evaluated using immunohistochemistry.RESULTS The absolute blood flow in the GI-tract was generally higher in males, but only significantly different in the corpus part of the stomach (1.12 ± 0.12 m L/min·g in males and 0.51 ± 0.03 m L/min·g in females) (P = 0.002). After removal of the loosely adherent mucus layer the thickness of the firmly adherent mucus layer in males and females was 79 ± 1 μm and 80 ± 3 μm respectively. After 60 min the mucus thickness increased to 113 ± 3 μm in males and 121 ± 3 μm in females with no statistically significant difference seen between the sexes. Following oestrogen administration(0.1 followed by 1 μg/kg·min), mean blood flow in the gastric mucosa decreased by 31% [68 ± 13 perfusion units (PFU)] in males which was significantly different compared to baseline(P = 0.02). In females however, mean blood flow remained largely unchanged with a 4% (5 ± 33 PFU) reduction. The permeability of the gastric mucosa increased to a higher level in females than in males (P = 0.01) after taurocholate challenge. However, the calculated mean clearance increase did not significantly differ between the sexes [0.1 ± 0.04 to 1.1 ± 0.1 m L/min·100 g in males and 0.4 ± 0.3 to 2.1 ± 0.3 m L/min·100 g in females(P = 0.065)]. There were no significant differences between 17β-Estradiol treated males (mean ratio of positive staining ± SEM)(0.06 ± 0.07) and females(0.11 ± 0.11) in the staining of ERα (P = 0.24). Also, there were no significant differences between 17β-Estradiol treated males (0.18 ± 0.21) and females (0.06 ± 0.12) in the staining of ERβ (P = 0.11). Finally, there were no significant differences between 17β-Estradiol treated males (0.04 ± 0.05) and females (0.11 ± 0.10) in the staining of CGRP(P = 0.14).CONCLUSION Gastric mucosal blood flow is higher in male than in female rats and is reduced in male rats by oestrogen administration.

Colorectal cancers and chlorinated water

Published reports have revealed increased risk of colorectal cancers in people exposed to chlorinated drinking water or chemical derivatives of chlorination. Oestrogen plays a dual positive functions for diminishing the possibilities of such risk by reducing the entrance, and increasing the excretion, of these chemicals. In addition, there are supplementary measures that could be employed in order to reduce this risk further, such as boiling the drinking water, revising the standard concentrations of calcium, magnesium and iron in the public drinking water and prescribing oestrogen in susceptible individuals. Hypo-methylation of genomic DNA could be used as a biological marker for screening for the potential development of colorectal cancers.

Puberty, Pregnancy, Parturition, Puerperium—Surveillance by Intertwined Innumerable Neurohumoral Factors;Prevention, Postponement, Termination of Pregnancy, Precipitation of Parturition, Hysterectomy [Except for Post Partum Hemorrhage, Cancer Uteri]—Deleterious—Proof of Basic Concept Study by Retrospective Analysis

Case 1: In 1990, a 23-year-old woman, married for two years, with primary infertility, was brought by her husband, with ultrasonography of abdomen, pelvis report stating multiple tiny cysts in both ovaries, infantile uterus;so husband claimed he was cheated to marry a woman with an infantile uterus, he wanted to divorce her on medical grounds. Analysing the problem revealed the woman had irregular menstruation before marriage due to polycystic ovaries;the husband took a prescription of oral contraceptive pills from a clinician, for one cycle to regularise menstruation of his wife;which he continued to administer for 2 years, with a desire to enable conception of his wife not understanding oral contraceptive pills with their exogenous oestrogen, suppress endogenous oestrogen preventing ovulation to conceive, produce withdrawal bleeding, due to suppressed endogenous oestrogen-suppressed uterine development resulting in infantile uterus. Case 2: In 1996, a 25-year-old woman underwent lower segment Cesarian section, 10 days prior to her EDC [expected date of child birth], as per the request of her husband who desired to see the baby before boarding his flight overseas;lower segment Cesarian section was performed by a urologist, general surgeon, but the mother expired on the theatre table, probably because the woman’s expected date of childbirth range would have fallen into the 15 days after expected date of childbirth norm, when her oestrogen would not have dipped, oxytocin would not have been released, to prevent postpartum haemorrhage. Case 3: In 1998, a 27-year-old woman presented with postpartum haemorrhage of one hour duration, following vaginal delivery of foeto placental unit;with haemoglobin of 3 gm%;immediately hysterectomy of the soft uterus was performed, mobilising 10 units of blood;once bleeding uterus was severed, all the 10 units of blood were transfused immediately, she survived. Case 4: In 1999 woman of 32 years [without antenatal screening] was delivering a twin breech presentation, she was detected to be hepatitis B surface antigen positive, she had jaundice total bilirubin 3 mg/dl, anaemia-haemoglobin of 6.5 gm%, her twins were managed at higher centres, for jaundice during pregnancy;she received 3 units of packed red blood cells, during postpartum;she returned for next pregnancy in the second trimester, with both twins crawling at her sides, Hepatitis B surface antigen had turned negative. Case 5: In 2003, a 32-year-old woman presented to emergency with dyspnoea with desaturation of 60%, she was ventilating but oxygen saturation was low;she had consumed hormonal pills for 3 days to postpone her menstruation to enable her to attend a wedding;she had undergone puerperal sterilisation in the past;her electrocardiography showed S1, Q3, T3 changes suggesting pulmonary embolism;thrombolysis, heparinisation was initiated, intubated, ventilated without improvement in oxygen saturation;hence saddle thrombus possibility was considered and she was referred to higher centres but she succumbed. This persons contraception status increases thrombogenicity due to reduced endogenous oestrogen status secondary to germ cells destruction by contraception, over that her consumption of hormonal pills to postpone menstruation further decreases endogenous oestrogen, increased vulnerability for pulmonary thromboembolism. Case 6: In 2014, a 29-year-old woman presented with unconsciousness of 30 minutes duration to emergency;she had infertility for 11 years and had delivered a precious baby, 34 days prior to admission;due to social ignorance [to enhance mothers milk baby shark food helps] she had consumed baby shark food one hour prior to admission;on examination she had quadriparesis, she was unresponsive. Her Magnetic Resonance Imaging [MRI] brain, with arteriogram, venogram showed multiple vessel narrowing suggesting vasculitis with bilateral asymmetrical, multifocal infarcts. She was treated with IV immunoglobulin, [0.4 gm/kg/day*5 days] needed ventilatory support, antiedema measures, anti-epileptics, parenteral hydration, enabling a slow recovery, on referral to higher centres.

Expression of oestrogen receptor-α and oestrogen receptor-β in prostate cancer

Background Recent studies have suggested that estrogens are involved in normal and abnormal prostate growth, though their exact role is still controversial. Oestrogens exert inhibitory and stimulatory effects on prostate gland, but the expression of oestrogen receptor-α （ERα） and oestrogen receptor-β （ERβ） in malignant prostate tissue remains unresolved. We determined ERa and ERβ in prostate cancer and investigated the relationship between expression of ER and pathological features of prostate carcinoma. Methods Thirty-two cases of prostate cancer, 12 cases of normal prostate tissue and 32 cases of benign prostate hyperplasia were analyzed for the expression of ERa and ERβ using semiquantitative, reverse transcription polymerase chain reaction （RT-PCR） and the products sequenced. Results Comparisons of the normal, hyperplastic and tumour prostate tissues indicated an overexpression of ERa in tumour specimens （P〈0.01）. However, the expression of ERβ significantly reduced in tumour tissues compared with normal and hyperplastic specimens （P〈0.01）, suggesting that severe pathological features of prostate cancer were associated with lower ERβ expression. Spearman analysis showed negative correlation between ERβ expression and tumour stage, grade （-0.67, -0.43, respectively, both P〈0.05）, and a positive correlation between ERα expression and tumour stage, grade （0.51, 0.57, respectively, both P〈0.01）. Our analysis also showed that hormone refractory, prostate cancer, compared with hormone dependent, prostate cancer, displayed a decreased expression of ERβ （P〈0.01） and an increased expression of ERa. Conclusions ERα and ERβ may play important roles in the development of prostate cancer. The decrease in ERβ expression is associated with higher Gleason grade tumours and prostate cancer with higher metastatic potential. The loss of ERβ could be one of the key processes leading to uncontrolled growth of prostate epithelial cells.

The influence of sex steroid hormones on the response to trauma and burn injury

Trauma and related sequelae result in disturbance of homeostatic mechanisms frequently leading to cellular dysfunction and ultimately organ and system failure. Regardless of the type and severity of injury, gender dimorphism in outcomes following trauma have been reported, with females having lower mortality than males, suggesting that sex steroid hormones (SSH) play an important role in the response of body systems to trauma. In addition, several clinical and experimental studies have demonstrated the effects of SSH on the clinical course and outcomes following injury. Animal studies have reported the ability of SSH to modulate immune, inflammatory, metabolic and organ responses following traumatic injury. This indicates that homeostatic mechanisms, via direct and indirect pathways, can be maintained by SSH at local and systemic levels and hence result in more favourable prognosis. Here, we discuss the role and mechanisms by which SSH modulates the response of the body to injury by maintaining various processes and organ functions. Such properties of sex hormones represent potential novel therapeutic strategies and further our understanding of current therapies used following injury such as oxandrolone in burn-injured patients.