Filiberto Maria Severi

Changes in inhibins and activin secretion in healthy and pathological pregnancies

Inhibin-related proteins are involved in the control of the feto-maternal communication required to maintain pregnancy. Human placenta, decidua, and fetal membranes are the major sites of production and secretion of activin A, inhibin A and inhibin B in maternal serum, amniotic fluid, and cord blood. The availability of suitable assays developed in the last years has enabled the measurement of inhibins and activin A in their dimeric forms, in order to investigate their role in physiological conditions of pregnancy. The studies conducted on inhibin-related proteins and human pregnancy suggested the possibility of an involvement of inhibin A and activin A in the pathogenesis of gestational diseases. In fact, several lines of evidence underline the potential role and the clinical usefulness of inhibin-related proteins measurement in the diagnosis, prevention, prognosis and follow-up of different gestational pathologies such as early pregnancy viability, Downs syndrome, fetal demise, pre-eclampsia, pregnancy-induced hypertension, preterm delivery and intrauterine growth restriction. The measurement of inhibin A and activin A into the biological fluids of pregnancy will offer in the future, further possibilities in the early diagnosis, prediction, and monitoring diseases of pregnancy.

Inhibins and activins in pregnancy

Human placenta, decidua, and fetal membranes are the major sites of production and secretion of inhibin A and activin A in maternal serum, amniotic fluid, and umbilical cord blood. These tissues also express follistatin-related gene and betaglycan, the binding proteins of activin A and inhibin A, respectively, recently identified. They show a different expression throughout pregnancy, suggesting new functional roles into gestational tissues. The availability of suitable assays for measuring inhibin A and activin A lead us the possibility to investigate their secretion in healthy pregnancy. In addition, several evidences underline the potential role and the clinical usefulness of their measurement in the diagnosis, prevention, prognosis and follow-up of different gestational pathologies such as: threatened abortion, placental tumors, hypertensive disorders of pregnancy, intrauterine growth restriction, fetal hypoxia. The measurement of inhibin A and activin A into the biological fluids of pregnancy will offer in the future further possibilities in early diagnosis, prediction, and monitoring pregnancy diseases.

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.

Placental stress factors and maternal-fetal adaptive response : The corticotropin-releasing factor family ()

The placenta and its accessory membranes amnion and chorion undertake the role of intermediary barriers and active messengers in the maternal-fetal dialog. They synthesize, metabolize, and serve as target to numerous hormones that regulate maternal and fetal physiology during pregnancy. Among these factors, corticotropin-releasing factor (CRF) has been one of the more investigated in the last decade. Increasing evidence indicates that in the event of acute or chronic metabolic, physical, or infectious stress, maternal or fetal physiologic and pathologic conditions may influence placental secretion of CRF. The current opinion is that the placenta actually takes part in a stress syndrome by releasing CRF, which may help to influence uterine perfusion, maternal metabolism, fluid balance, and possibly uterine contractility, thereby protecting the fetus from a hostile environment.

Endometrial expression and secretion of activin A, but not follistatin, increase in the secretory phase of the menstrual cycle

Objective: Activin A is a growth factor expressed by human endometrium, and its biologic effects are counteracted by follistatin. We evaluate whether activin A and follistatin mRNA and peptide expression as well as protein secretion from human endometrium change throughout the menstrual cycle. Methods: In 25 healthy fertile patients, uterine washing fluid was retrieved by hydrosonography. In a subgroup (n = 13), endometrial tissue samples were collected by hysteroscopy during the proliferative (n = 6) or secretory (n = 7) phase of the menstrual cycle. Activin and follistatin mRNA and peptide expression were evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR) and by immunohistochemistry (IHC), respectively. Activin A and follistatin levels were assayed in uterine washing fluids by specific enzyme-linked immunosorbent assays and evaluated according to the endometrial thickness and menstrual cycle days. Results: Both activin A and follistatin mRNAs were expressed by human endometrium, and their peptides immunolocalized both in proliferative and secretory endometrial epithelial and stromal cells. A significant increase in immunoreactive activin βA but not in follistatin was observed in glandular epithelium during the secretory phase. Activin A but not follistatin was significantly (P < .0001) higher in the washing fluids collected during the secretory than proliferative phase of the menstrual cycle. In addition, a significant correlation was found between activin A, but not follistatin, and menstrual cycle days (P < .0001) or endometrial thickness (P < .0001). Conclusion: Both activin A and follistatin mRNAs are expressed by human endometrium; however, activin A but not follistatin peptide expression and secretion were increased in the secretory phase of the menstrual cycle, suggesting an important role in human endometrium.

Amniotic fluid S100B protein in mid-gestation and intrauterine fetal death

Fetal death in the mid-trimester of pregnancy is unexplained and no reliable markers are available to identify at-risk women. We aimed to assess use of alpha fetoprotein and S100B concentrations in amniotic fluid as markers. We did a case-control study in 758 healthy women undergoing amniocentesis at mid-gestation, of whom 12 had a spontaneous intrauterine fetal death before 28 weeks, and 746 matched controls. Concentrations were corrected for gestational age by conversion to multiples of median (MoM) of healthy controls of the same gestational age. Concentrations of S100B, but not alpha fetoprotein, were significantly higher (p<0.0001) in women who later had spontaneous fetal death (median 4.431 MoM [95%CI 3.605-6.197]) than in controls (1.000 MoM [1.062-1.121]). Sensitivity, specificity, and positive and negative predictive values of S100B as a diagnostic test were 100%, suggesting that measurement of this protein at amniocentesis could be useful to identify at-risk women.

Women with endometriosis at first pregnancy have an increased risk of adverse obstetric outcome

Abstract Objective: To evaluate pregnancy, delivery and neonatal outcome in singleton primiparous versus multiparous women with/without endometriosis. Methods: Multicentric, observational and cohort study on a group of Caucasian pregnant women (n = 2239) interviewed during their hospitalization for delivery in five Italian Gynecologic and Obstetric Units (Siena, Rome, Padua, Varese and Florence). Results: Primiparous women with endometriosis (n = 219) showed significantly higher risk of small for gestational age fetuses (OR: 2.72, 95% CI 1.46–5.06), gestational diabetes (OR: 2.13, 95% CI 1.32–3.44), preterm premature rupture of membranes (OR: 2.93, 95% CI 1.24–6.87) and preterm birth (OR: 2.24, 95% CI 1.46–3.44), and were hospitalized for a longer period of time (p < 0.0001) comparing with control group (n = 1331). Multiparous women with endometriosis (n = 97) delivered significantly more often small for gestational age fetuses (OR: 2.93, 95% CI 1.28–6.67) than control group (n = 592). Newborns of primiparous women with endometriosis needed more frequently intensive care (p = 0.05) and were hospitalized for a longer period of time (p < 0.0001). Conclusions: Women with endometriosis at first pregnancy have an increased risk of impaired obstetric outcome, while a reduced number of complications occur in the successive gestation. Therefore, it is worthy for obstetricians to increase the surveillance in nulliparous women with endometriosis during pregnancy.

Activin-A and Myostatin Response and Steroid Regulation in Human Myometrium: Disruption of Their Signalling in Uterine Fibroid

CONTEXT Investigation of activin-A (A) and myostatin (M) in human myometrium (HM) and leiomyoma (HL) will explain their involvement in human myometrial pathophysiology. OBJECTIVE We aimed to investigate A and M response and steroid regulation in HM. We also evaluated A and M expression and response in HL. DESIGN Tissues were analyzed and cultured. PATIENTS Patients included fertile (in proliferative phase) and menopausal women undergoing hysterectomy. INTERVENTIONS HM explant cultures were treated with A and M (for Smad-7 mRNA quantification) or estrogen and progesterone (for A and M mRNA quantification). A and M expression levels were also evaluated in menopausal (physiological absence of steroids) HM specimens. A and M and their receptors were evaluated in HL (n = 8, diameter 5-8 cm) compared with their matched HM. HL explants cultures were treated with A and M (for Smad7 mRNA quantification), and, to explain the absence of response, the levels of follistatin, follistatin-related gene (FLRG), and Cripto were evaluated. RESULTS A and M increased Smad7 expression in HM explants. A and M mRNAs were both reduced after estradiol treatment, unchanged after progesterone treatment, but were higher in menopausal than fertile (in proliferative phase) specimens. A, M, and FLRG were expressed at higher levels in HL compared with adjacent HM, whereas the receptors, follistatin, and Smad7 mRNAs resulted unchanged. Cripto mRNA was expressed only in HL. CONCLUSIONS A and M act on human HM and are regulated by steroids. In HL there is an increase of A, M, FLRG, and Cripto expression.

Pre-eclampsia with fetal growth restriction: placental and serum activin A and inhibin A levels

Activin A (βAβA) and inhibin A (αβA) are dimeric glycoproteins secreted from early to term pregnancy in the maternal circulation. They circulate in higher amounts in women with gestational hypertension and/or pre-eclampsia, the most important gestational diseases also causing fetal growth restriction (FGR). Since no data are available in patients with pre-eclampsia and superimposed FGR, by using two-site immunoassays we evaluated serum activin A and inhibin A levels in serum samples collected from: healthy normotensive pregnant controls (n = 42); and women with pre-eclampsia with (n = 19) or without superimposed FGR (n = 21). In addition, by quantitative reverse transcriptase-polymerase chain reaction the changes of α- and βA-subunit mRNA expression in placentas collected from healthy controls (n = 7) and pre-eclamptic pregnancies with (n = 6) or without (n = 6) superimposed FGR was also investigated. Activin A and inhibin A serum levels were significantly higher in pre-eclampsia, and the presence of FGR did not significantly modify these concentrations. Similarly, inhibin-subunit mRNA levels in placentas from pre-eclampsia were significantly higher than in controls, and FGR did not significantly affect this expression. The present data suggest that the increased placental expression of inhibin subunit mRNAs is part of the mechanism leading to increased serum activin A and inhibin A levels.

Melanocytic skin lesions and pregnancy: digital dermoscopy analysis.

Background: Very few studies have tried to clarify how pregnancy influences the morphology of pigmented skin lesions (PSL). Our purpose was to objectively determine, by digital dermoscopy analysis (DDA), any dermoscopic changes of acquired melanocitic nevi during pregnancy and after 1 year from delivery.