Fernando M. Reis

Growth factors and myometrium: biological effects in uterine fibroid and possible clinical implications

BACKGROUND Growth factors are proteins secreted by a number of cell types that are capable of modulating cellular growth, proliferation and cellular differentiation. It is well accepted that uterine cellular events such as proliferation and differentiation are regulated by sex steroids and their actions in target tissues are mediated by local production of growth factors acting through paracrine and/or autocrine mechanisms. Myometrial mass is ultimately modified in pregnancy as well as in tumour conditions such as leiomyoma and leiomyosarcoma. Leiomyomas, also known as fibroids, are benign tumours of the uterus, considered to be one of the most frequent causes of infertility in reproductive years in women. METHODS For this review, we searched the database MEDLINE and Google Scholar for articles with content related to growth factors acting on myometrium; the findings are hereby reviewed and discussed. RESULTS Different growth factors such as epidermal growth factor (EGF), transforming growth factor-α (TGF-α), heparin-binding EGF (HB-EGF), acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF) and TGF-β perform actions in myometrium and in leiomyomas. In addition to these growth factors, activin and myostatin have been recently identified in myometrium and leiomyoma. CONCLUSIONS Growth factors play an important role in the mechanisms involved in myometrial patho-physiology.

Endometriosis: hormone regulation and clinical consequences of chemotaxis and apoptosis

BACKGROUND The recruitment of immune cells by chemokines and the regulation of endometrial cell apoptosis are critical aspects of endometriosis biology. Here, we review the local (paracrine) and systemic hormone (endocrine) modulation of these two specific, but highly related phenomena. METHODS We searched Pubmed for items published in English between September 1991 and September 2011 and selected the studies evaluating the effects of hormones on chemokines or apoptosis in normal human endometrium and endometriosis. RESULTS Estradiol has proinflammatory and antiapoptotic effects in endometrial cells, and these effects appear to be exacerbated in women with endometriosis. In these women, physiological estradiol concentrations are able to induce an enhanced inflammatory response mediated by local chemokine production and to reinforce mechanisms of cell survival mediated by extracellular signal-regulated kinases and Bcl-2. The main effect of progestogens is to inhibit interleukin-8 and other chemokines in stromal cells from both eutopic and ectopic endometrium. Progesterone is also effective in inducing apoptosis in endometrial and endometriotic cells through the inhibition of Bcl-2 and nuclear factor-κB. CONCLUSIONS Estrogens and progestogens modulate chemotaxis and apoptosis in human endometrium and endometriotic cells and tissues. These endocrine and paracrine pathways are perturbed in women with endometriosis, contributing to inflammatory responses, abnormal tissue remodeling, therapeutic refractoriness and disease persistence. Ultimately, they promote adhesion formation and the clinical symptoms of pelvic pain and infertility. A more detailed understanding of the molecular mechanisms involved will offer new opportunities for novel pharmacological strategies to diagnose and treat endometriosis.

Putative role of placental corticotropin-releasing factor in the mechanisms of human parturition.

Corticotropin-releasing factor is a 41-amino-aic neuropeptide synthesized in the paraventicular nucleus of the hypothalamus and released in response to stress. Its major role is the regulation of the hypothalamus-pituitary-adrenal axis by stimulation of ACTh release from the anterior pituitary gland. In addition, corticotropin-releasing factor modulates behavioral, vascular, and immune responses to stress. Corticotropin-releasing factor was first detected in the extracts of human placentas obtained at full term from spontaneous deliveries. Placental corticotropin-releasing factor content and messenger RNA expression progressively increase during normal pregnancy, and corticotropin-releasing factor levels in maternal plasma have a similar time course. The addition of corticotropin-releasing factor to primary trophoblast cell cultures stimulates ACTH secretion in a dose-dependent manner, and its action is mediated by cyclic adenosine monophosphate as second messenger. In addition, corticotropin-releasing factor is a potent local regulator of myometrial contractility and of membrane prostaglandin release. The effects of corticotropin-releasing factor in these various tissues are mediated by specific receptors. Placental corticotropin-releasing factor is also secreted into the fetal circulation and the stimulation of fetal pituitary ACTH and fetal adrend gland dehydroepiandrosterone sulfate release in vitro has been shown. Recently, urocortin, a new peptide related to corticotropin-releasing factor, has been found in human placenta. Corticotropin-releasing factor and urocortin share some of their biologic effects, acting on the same receptors. A large-molecular-weight corticotropin-releasing factor-binding protein modulates the activity of both these peptides. Plasma corticotropin-releasing factor levels are low in nonpregnant women and become higher during the second trimester of pregnancy, rising steadily until about 35 weeks, and then increasing more rapidly until term. Vaginal delivery is a condition associated with the highest values of maternal corticotropin-releasing factor levels. Corticotropin-releasing factor is also measurable in fetal plasma (20-fold lower than in maternal circulation) and in amniotic fluid. Increased maternal plasma corticotropin-releasing factor levels characterize some gestational diseases. Women with chronic hypertension and preeclampsia have high corticotropin-releasing factor levels, and intrauterine growth retardation is associated with an activation of the hypothalamus-pituitary-adrenal axis, reflected by increased fetal plasma concentrations of ACTH, cortisol, and corticotropin-releasing factor. The role of corticotropin-releasing factor in preterm labor is uncertain, but midgestational plasma corticotropin-releasing factor levels may be higher in women delivering preterm. In these various pathologic states, maternal plasma corticotropin-releasing factor-binding proten levels undergo opposite changes, decreasing to very low levels. The endocrine-paracrine corticotropin-releasing factor/corticotropin-releasing factor-binding protein pathways may play a major role in the mechanism of human parturition.

Uterine Fibroids: Pathogenesis and Interactions with Endometrium and Endomyometrial Junction

Uterine leiomyomas (fibroids or myomas) are benign tumors of uterus and clinically apparent in a large part of reproductive aged women. Clinically, they present with a variety of symptoms: excessive menstrual bleeding, dysmenorrhoea and intermenstrual bleeding, chronic pelvic pain, and pressure symptoms such as a sensation of bloatedness, increased urinary frequency, and bowel disturbance. In addition, they may compromise reproductive functions, possibly contributing to subfertility, early pregnancy loss, and later pregnancy complications. Despite the prevalence of this condition, myoma research is underfunded compared to other nonmalignant diseases. To date, several pathogenetic factors such as genetics, microRNA, steroids, growth factors, cytokines, chemokines, and extracellular matrix components have been implicated in the development and growth of leiomyoma. This paper summarizes the available literature regarding the ultimate relative knowledge on pathogenesis of uterine fibroids and their interactions with endometrium and subendometrial myometrium.

Lack of Effect of Psychosocial Stress on Maternal Corticotropin-Releasing Factor and Catecholamine Levels at 28 Weeks' Gestation

OBJECTIVE: Corticotropin-releasing factor (CRF) and catecholamines are among the major hormones activated during the adaptive response to stressful stimuli. In pregnant women, serum CRF and catecholamines levels increase during labor and preterm delivery. The aim of the present study was to evaluate whether psychosocial stress measures are correlated with serum CRF or urinary catecholamine ie, epinephrine, norepinephrine (NE), dopamine (DA)/ levels in healthy midtrimester pregnant women. METHODS: A large group of white pregnant women (n = 382) participated in the present study. The Work Conditions Questionnaire and the Psychiatric Epidemiology Research Interview were administered to measure job stress and general life stress, respectively. Urine and blood specimens were collected at 28 weeks of gestation at the time of psychosocial evaluation. Epinephrine, NE, and DA were quantified in the urine by a highly sensitive method based on an amperometric detector. Serum CRF and cortisol levels were measured in blood specimens by using specific radioimmunoassays. RESULTS: Serum CRF and cortisol levels did not vary between patients with high and low scores on psychological tests, and no correlation was found between CRF and cortisol levels. One job stress measure, low job latitude, was signnficantly associated with a mild increase in NE and DA levels in the afternoon and night (P <. 05, analysis of variance). Serum cortisol levels were inversely correlated with NE in the morning (r= -0. 447; P = .002) and night segments (r = -0.391; P = .007) and with DA in the night period (r = -0.367; P = .013). CONCLUSION: The absence of a signficant relationship between CRF/cortisol and psychosocial stress measures in pregnant women suggests that the hypothalamic-pituitary-adrenal response to psychosocial stress may be masked at midtrimester by the constantly high levels of placental CRF, whose control is beyond the influence of environmental stressors.

The addition of activin A and inhibin A measurement to uterine artery Doppler velocimetry to improve the early prediction of pre-eclampsia

To evaluate whether the measurement of maternal serum activin A and inhibin A adds any clinically relevant information for the prediction of pre‐eclampsia in women with altered uterine artery Doppler velocimetry at 24 weeks of gestation.

Duration of rhythmic EEG patterns in neonates: new evidence for clinical and prognostic significance of brief rhythmic discharges.

OBJECTIVE This study aimed at identifying the characteristics - especially the duration - of rhythmic discharges in neonatal EEG, and their association with clinical neonatal problems. Specifically, we aimed at testing the diagnostic and prognostic validity of using 10 s as minimal duration for defining electroencephalographic seizures. DESIGN AND METHODS The polysomnographies of 340 neonates were reviewed, and episodes of rhythmic discharges were identified, analyzed, and quantified. The study sample was divided into 3 groups: one in which the maximal duration of rhythmic discharges was shorter than 10 s (brief rhythmic discharges, BRD), a second one in which there were rhythmic discharges longer than 10 s (long rhythmic discharges, LRD), and finally a group in which no rhythmic discharge was found (No-RD). These 3 groups of subjects were compared for the baseline and outcome clinical data. RESULTS From the 340 neonates studied, 210 did not present any form of rhythmic discharge, 67 (19. 7%) had only BRD episodes, and 63 (18.5%) had at least one LRD episode. Prevalence of rhythmic discharges was low among healthy full term newborns, and was significantly higher among preterm and high-risk newborns. Electrophysiological characteristics of rhythmic discharges did not differ between healthy neonates and high-risk ones. Accompanying clinical manifestations were present in 26.3% of the LRD group, but also in 15.9% of the BRD group. The presence of BRD was significantly associated with leukomalacia and with hypoglycemia in the cross-sectional analysis of baseline data, and with an increased risk for abnormal neurodevelopmental outcome after a mean follow-up period of 47 months (adjusted relative risk=4.90, P<0.01). CONCLUSIONS The present data demonstrate an association between BRD and clinical history of hypoxic-ischemic encephalopathy, especially when complicated by leukomalacia, and also with a prognosis of increased risk for abnormal neurodevelopmental outcome. The clinical and prognostic significance of isolated BRD justifies the need to include these brief episodes in future studies of neonatal seizures.

Activin, inhibin and the human breast.

Activins and inhibins are growth factors involved in cell differentiation and proliferation. Human breast tissues such as normal mammary tissue, fibroadenoma, and breast cancer express inhibin and activin mRNA and proteins. Activin A and its binding protein, follistatin, are also present in human milk during the first week of lactation. Using immunohistochemistry, we have observed that the inhibin/activin alpha, betaA, and betaB subunits are present in normal breast tissue regardless of menstrual cycle phase or menopause, as well as in fibrocystic disease, and breast tumors. The mRNAs encoding all three activin/inhibin subunits are expressed in breast carcinoma, fibroadenoma, and normal mammary tissue. The betaA subunit gene expression is higher in either local or metastatic breast carcinoma than in normal tissue. In addition, dimeric activin A is detectable in homogenates of breast cancer tissue at concentrations twice as high as in non-neoplastic adjoining tissue. Recent evidence suggests that some of the activin A produced by breast carcinoma is released into systemic circulation. In women with breast cancer, serum activin A levels are often elevated, and a significant decrease is observed in the first and second days following tumor excision. The role of activin and inhibin as endocrine and/or paracrine factors in the breast is still uncertain. Activin has complex effects on cell growth during branching morphogenesis, but it is generally considered as an inhibitor of cell proliferation as in vitro studies have shown that activin A treatment of breast cancer cells arrests cell growth. Inhibin is generally considered as a tumor suppressor, but its possible role in the breast is less understood.

Angiogenesis and Endometriosis

A comprehensive review was performed to survey the role of angiogenesis in the pathogenesis of endometriosis. This is a multifactorial disease in which the development and maintenance of endometriotic implants depend on their invasive capacity and angiogenic potential. The peritoneal fluid of patients with endometriosis is a complex suspension carrying inflammatory cytokines, growth factors, steroid hormones, proangiogenic factors, macrophages, and endometrial and red blood cells. These cells and their signaling products concur to promote the spreading of new blood vessels at the endometriotic lesions and surroundings, which contributes to the endometriotic implant survival. Experimental studies of several antiangiogenic agents demonstrated the regression of endometriotic lesions by reducing their blood supply. Further studies are necessary before these novel agents can be introduced into clinical practice, in particular the establishment of the safety of anti-angiogenic medications in women who are seeking to become pregnant.

Placental Corticotropin‐Releasing Factor An Update

Abstract: Corticotropin‐releasing factor (CRF) produced in placenta has paracrine effects within placenta, decidua, and myometrium and endocrine effects on mother and fetus. CRF is a potent local regulator of myometrial contractility and of prostaglandin release, Recently, urocortin, a new member of the CRF family, has been localized in human placenta and membranes. Urocortin mimics some of the local effects of CRF in intrauterine tissues, that is, increase of adrenocorticotrophic hormone (ACTH) and prostagiandin release and myometrial contractility. A local CRF‐BP modulates the paracrine effects of CRF and urocortin. The various CRF receptor subtypes are well distributed in placenta and membranes. CRH also acts on placental blood vasculature and has an action on fetal adrenal gland to stimulate the productlon of the steroid DHEA‐S. In nonpregnant women, plasma CRF levels are low; they become higher during the first and second trimesters of pregnancy. A clear increase is evident at term and when CRF‐BP levels decrease. Women with preterm labor show high CRF and low CRF‐BP levels, supporting an involvement of this pathway in mechanism of parturition.