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DOI: 10.1177/1933719109353205

2010 17: 320Reproductive SciencesBoy Torres, Giuseppe Rago, Pietro Litta and Felice Petraglia

Pasquale Florio, Massimo Gabbanini, Lavinia E. Borges, Lorella Bonaccorsi, Serena Pinzauti, Fernando M. Reis, PauloReviews: Activins and Related Proteins in the Establishment of Pregnancy

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REVIEWS

Activins and Related Proteins in the Establishment of PregnancyPasquale Florio, MD, PhD, Massimo Gabbanini, MD,

Lavinia E. Borges, MD, PhD, Lorella Bonaccorsi, PhD,Serena Pinzauti, MD, Fernando M. Reis, MD, PhD,

Paulo Boy Torres, MD, PhD, Giuseppe Rago, MD, PhD Student,Pietro Litta, MD, and Felice Petraglia, MD

Activin A and related proteins (inhibins, follistatin [FS], follistatin-related gene [FLRG], endometrial

bleeding associated factors [ebaf]) are involved in the complex mechanisms allowing the establishment and

the maintenance of pregnancy. As a consequence of ovarian progesterone stimuli, activin A is expressed

and secreted by the stromal endometrial cells, which locally induces the decidualization process, a

prerequisite for implantation. Moreover, activin A does influence the implantation phase, also enhancing

cytotrophoblast differentiation, indirectly, by increasing the expression of other molecules involved in

embryo implantation, such as matrix metalloproteinases (MMPs) and leukemia inhibitory factor (LIF).

The local derangement of activin A pathway in some pregnancy disorders (incomplete and complete

miscarriages, recurrent abortion, and ectopic pregnancy [EP]) further sustains the hypothesis that

activin A and its related proteins play a relevant role in the establishment of pregnancy.

KEY WORDS: activin A, endometrium, decidualization, embryo implantation, pregnancy,

miscarriage, ectopic pregnancy, abortion.

INTRODUCTION

Human endometrium is a highly specialized tissue,

providing an optimal environment for implantation of the

semiallogeneic embryo. Following the estrogen-induced

proliferation, progesterone involves the cyclic adenosine

monophosphate (cAMP) signaling pathway and induces

differentiative events within all compartments of the endo-

metrium, creating a receptive environment for blastocyst

attachment and invasion.1,2 Endometrial epithelial glands

undergo morphological and functional differentiation and

commence active secretion of a complex nutritive and

growth factor–rich media, contributing to uterine fluid and

providing support to blastocyst growth and development

before endometrial attachment.3,4 The endometrium repre-

sents not only a target for hormones but also an endocrine

organ itself, synthesizing several substances that influence the

local environment in an autocrine and paracrine manner.5

A growing number of data are currently pointing to

the role of activins and related proteins in the physiology

of the human endometrium.6 Activins are expressed and

secreted by the human endometrium and locally modu-

late stromal decidualization, a prerequisite for implanta-

tion; this effect results from a complex network of

interactions between activins and other locally regulating

processes.7,8 This complex scenario suggests a pivotal role

of activins in endometrial physiological changes, allowing

the establishment of pregnancy.

BIOCHEMISTRY

Activins are members of the transforming growth factor b(TGF-b) superfamily, which are structurally related

From the Department of Pediatrics, Obstetrics and Reproductive Medicine,

Section of Obstetrics and Gynecology, University of Siena, Siena, Italy (PF,

MG, LEB, LB, SP, FMR, PBT, GR, FP); and Department of Gynecological

Science and Human Reproduction, University of Padua, School of Medicine,

Padua, Italy (PL).

Address correspondence to: Pasquale Florio, PhD, MD, Department of

Pediatrics, Obstetrics and Reproductive Medicine, Section of Obstetrics and

Gynecology, University of Siena, Policlinico ‘‘Le Scotte,’’ Viale Bracci, 53100

Siena, Italy. E-mail: [email protected].

Reproductive Sciences Vol. 17 No. 4 April 2010 320-330DOI. 10.1177/1933719109353205# 2010 The Author(s)

320 at Univ di Siena on December 20, 2010rsx.sagepub.comDownloaded from


proteins involved in the control of cell proliferation,

differentiation, apoptosis, metabolism, homeostasis, differ-

entiation, immune response, and endocrine function.9

Activins possess a cysteine knot scaffold and are secreted as

homodimers or heterodimers of inhibin b-subunits.

Although 4 b-subunit genes (bA, bB, bC, and bE) have

been described in humans, only dimers composed of bA/

bA (activin A), bB/bB (activin B), and bA/bB (activin

AB) subunits have been shown to bebiologically active.10,11

Activins signal to their targets by interacting with 2

transmembrane serine/threonine receptor kinases (type

I and type II receptors). Activin binds first to its type II

receptor, ActRII or ActRIIB, leading to the recruitment,

phosphorylation, and subsequent activation of the type I

receptor (activin-like kinase 4, ALK4).12 On activation,

ALK4 phosphorylates a subset of cytoplasmic Smad pro-

teins (Smad2 and Smad3), which form part of the postre-

ceptor signal transduction system.13 Then, they undergo

homotrimerization and form heterometric complexes

with Smad 4; these activated complexes translocate into

the nucleus and, in conjunction with other nuclear cofac-

tors, regulate the transcription of target genes (Figure 1).

Access of activins to the cell is regulated by various

extracellular binding proteins.14 Follistatin (FS) binds

activins with high affinity (50-500 pmol/L) to form

biologically inactive complexes (Figure 1). It consists of

a 63-residue amino (N)-terminal segment, followed by

3 successive FS domains of 73 to 75 amino acids contain-

ing 10 cysteine residues termed FS-1, FS-2, and FS-3.

Alternative splicing generates 2 FS isoforms: FS288,

ebafAlk4

ActrRII

FLRG

βA βA

Activin AFS

Alk4

ActrRII

inhibitsbinding to receptor

inhibitsbinding to receptor

βA

Activin A

ActrRII

Alk4

P Smad 2/3 Smad 4

Smad 2/3 Smad 4

P

Genes expression

Inhibin A

β-glycan

βA βA

Activin A

ActrRII

A

B

DC

βA

Figure 1. Graphic representation of activin A signaling and interactions with its related peptides. A, Activin dimer first binds to the type II

(ActRII) receptor, which then recruits and phosphorylates type I (Alk4) receptor. These in turn phosphorylate receptor-activated Smads 2/3 that

subsequently form a complex with Smad 4 and is translocated to the nucleus, where it regulates the transcription of target genes. B, Activin

antagonists (follistatin-related gene [FLRG] and follistatin [FS]) bind activin A in the extracellular space, blocking its access to receptors. C,

Endometrial bleeding associated factor binds the activin receptor type II (ActRII), preventing the phosphorylation of Smad proteins and the

subsequent signaling pathway. D, Inhibin a subunit interacts with b-glycans promoting the binding of the inhibin b subunit to the ActRII,

which prevents activin A access.

Activin A is Implicated in Human Reproduction Reproductive Sciences Vol. 17, No. 4, April 2010 321



which binds heparan sulfate proteoglycans with high affi-

nity via residues in FS-1 and is considered a local regulator

of activin actions, and FS315, which does not bind cell-

surface proteoglycans and is the predominant circulating

form of the protein.15,16

Follistatin-related gene (FLRG), also known as

FS-related protein or FS-like 3, is a recently characterized

member of the FS family, which binds activin with relatively

high affinity.17 Follistatin-related gene differs from FS by

lacking the third FS domain and a consensus heparin-

binding sequence. In this regard, FLRG is thought to act

as a circulating activin-binding protein, much like FS315.

Outside the 26 conserved cysteine residues, murine FLRG

and FS share about 40% amino acid identity.18 Because both

proteins bind and neutralize activin (Figure 1), it seems likely

that the residues that are important for binding activins are

located in these conserved regions. Intriguingly, expression

and regulation studies suggest that FS and FLRG might not

be complete functional homologs.18

Other proteins are relevant in counteracting activins by

displacing it from its own receptors. This is the case of

inhibins and endometrial bleeding associated factors (ebaf;

Figure 1). Like activins, inhibins are members of the TGF-bsuperfamily consisting of ana subunit that can dimerize with

either bA or bB subunit to form inhibin A (a-bA) or B

(a-bB).19 They operate as potent selective antagonists of

activins and their function is tightly related to the presence

of b-glycans, membrane-anchored proteoglycans that act

as inhibin coreceptors. The interaction of b-glycans with

inhibina subunit promotes the binding of the inhibinb sub-

unit to the ActRII, preventing activin access (Figure 1).20,21

Endometrial bleeding associated factor (ebaf) is

another member of the TGF-b family, recently renamed

left-right determination, factor A (LEFTY-A).22 It is a

protein of 370 amino acids, which presents a 65% similar-

ity with activin A structure. It binds to the activin recep-

tor type II B (ActRIIB), preventing the phosphorylation

of Smad proteins and the subsequent signaling pathway

(Figure 1).23

THE HUMAN ENDOMETRIUM AS A SOURCE OF ACTIVIN ANDRELATED PROTEINS

Activins were originally isolated in the ovary and

identified as a gonadal protein due to its action on pitui-

tary follicle-stimulating hormone (FSH) synthesis and

secretion.24 Subsequently, it was detected in several other

organs, but the main source of circulating protein levels is

still unknown.8

ActivinbA messenger RNA (mRNA) is expressed both

in endometrial glands and in stromal cells25-27; the immunos-

taining along the menstrual cycle is widely different

(Figure 2).28 A specific and predominant bA immunostain-

ing in the cytoplasm of luminal and glandular epithelial cells

with an inconsistent staining pattern alongside the glandular

cells during the proliferative phase and a more intense and

uniform staining pattern in the secretory phase have been

described. The glandular immunostaining progressively

increases across the secretory phase, reaching a maximum

in the late secretory phase.29 The staining also tended to be

more intense in the glandular cells near the luminal

epithelium.30 However, the stromal cells are weakly immu-

noreactive from the menstrual to the midsecretory phase and

become stronger in the late secretory phase. Additional

immunostaining is present in the vascular endometrium and

in subsets of infiltrating leukocytes.28,31,32

Activins B and AB are also endometrial products.

Indeed, normal endometrium also expresses the activin

bB subunit, with the staining intensity being strongest

in the late secretory phase compared to proliferative and

early secretory phase secretions (Figure 3).31,32

Inhibin a subunit is detected in normal human endo-

metrium, predominantly localized in the glandular and

luminal epithelium, thus suggesting an endometrial pro-

duction of inhibins A and B. Inhibin a subunit showed

no or minimal expression during the proliferative phase,

increasing during the secretory phase.28,33,34 Indeed, the

expression of inhibin a subunit evaluated by immunohis-

tochemistry was significantly higher during the early

and late secretory phase than in the proliferative phase

(Figure 2).33,35,36 b-glycan, fundamental for inhibin’s

action, is localized in stromal and epithelial cells and the

staining is particularly abundant in the basal and apical

borders of the cell.37

Follistatin expression is also detected in endometrial

stromal and epithelial cells,38,39 even if both its mRNA

and protein expression is low across the menstrual cycle,

with a peak only in early pregnant decidua (Figure 2).40

The pattern of activin A and FS expression are resembled

by secretion of the proteins into the uterine lumen.

Indeed, activin A, but not FS, is secreted in higher

amounts by the endometrium in the secretive than in the

proliferative phase of the menstrual cycle. Furthermore,

activin A levels in washing uterine fluids significantly cor-

relate with endometrial thickness and with the day of the

menstrual cycle.25 There are no assays available for acti-

vins B and AB.

Follistatin-related gene is strongly localized in epithe-

lial cells of glands and vessel walls, both in cytoplasma and

322 Reproductive Sciences Vol. 17, No. 4, April 2010 Florio et al



nucleus, whereas it is detectable only in the nucleus of the

stromal cells.39,41 The expression of FLRG mRNA does

not change throughout the menstrual cycle but is

significantly higher in early pregnancy and, in this condi-

tion also, the stromal cells show both nuclear and cyto-

plasmic positive FLRG immunostaining (Figure 2).42

Early Late Early LateProliferative Secretory

ActivinβA

- -

+ +

- + - +

++- + - +

Stroma

Glands

Inhibinα

Activinreceptors

Follistatin

-

+

-

+ ++

+ +

+ +

-

+ +

-

-

- +

-

- +

+

- -

+

-

+ + + +

-

Stroma

Glands

Stroma

Glands

Stroma

Glands

Follistatinlike-3

+

-

+ ++ ++

++-

Stroma

Glands

ebaf-

- -

-

- + +

- -

Stroma

Glands

+

++

+ ++

++

Stroma

Glands

ActivinβB

Figure 2. Changes in the intensity of immunohistochemical staining of bA, bB, and a subunits, activin receptors, FS, FLRG, and ebaf across

the menstrual cycle (early–late proliferative phases and early–late secretory phases) in the endometrial stromal cells (upper bar) and in the

glandular epithelial cells (lower bar).




Endometrial bleeding associated factor is expressed

differently during the menstrual cycle. Immunohisto-

chemical stainings show a low level of immunoreactivity

in the early, mid- and late proliferative and early and mid-

secretory endometrium. A strong immunoreactivity for

ebaf is reported in the stroma and to lesser extent in the

endometrial glands in late secretory and menstrual

endometrium (Figure 2).43,44 A similar increase in ebaf

mRNA occurs in explants from proliferative endome-

trium cultured in the absence of ovarian steroids.45

The various activin receptor subtypes have been

detected in the endometrial stromal cells (ESCs) but not

in the surface of glandular epithelium at any stage of the

cycle.40,46 Protein expression of the respective receptors

is maintained throughout the secretory phase with a

strong staining in decidual cells, during mid- to late secre-

tory phase and in early pregnancy (Figure 2).39 Therefore,

expression of activin receptors increases in the prolifera-

tive phase of endometrial cycle and this increase contin-

ues throughout the secretive phase, whereas FS remains

constant during the menstrual cycle.

LOCAL EFFECTS OF ACTIVIN A IN THE HUMANENDOMETRIUM

Exquisite mechanisms control the processes that drive

endometrium through proliferative and secretive phases,

thus preparing this tissue for implantation. In the late

secretory phase of the menstrual cycle, decidual

transformation of ESCs is a prerequisite for human

implantation.1-4 It commonly occurs in stromal cells

surrounding the spiral arteries about 10 days after the

postovulatory rise in progesterone levels and is character-

ized by the transformation of the ESCs in elongated

fibroblast-like cells, the decidualized ESCs (human ESCs

[HESCs]). Decidualization is independent of the presence

of an implanting blastocyst but occurs in response to pro-

gesterone and involves the cAMP signaling pathway.47

However, in the absence of conception, falling circulat-

ing progesterone levels in the late secretory phase of the

cycle elicit sloughing of the decidualized superficial

endometrial layer and menstruation. When pregnancy

occurs, the decidual reaction extends to the basal endo-

metrial layer and it is critical for trophoblast invasion and

placenta formation. Activin A has been recognized as a

decidualization factor (Figure 3).5,8,48

Endometrial expression of activin A and its related

peptides is locally regulated by steroid ovarian hormones

and other factors involved in decidualization of the

human endometrium.6 In an in vitro model of HESCs,

it was demonstrated that high concentrations of dimeric

activin A after decidualization, induction with estradiol

(E2) and medroxyprogesterone acetate (MPA) are pro-

duced.49 In this regard, it was revealed that progesterone

(10�7 mol/L, 10–6 mol/L) significantly increased activin

A secretion and mRNA expression from HESCs, while

E2 did not show remarkable effects.50 Other than secre-

tion, activin A locally modulates HESC function. Indeed,

the addition of activin A to HESCs resulted in a dose-

dependent increase in prolactin (PRL) production, an

established marker of decidualization51 and such an effect

was inhibited by the cotreatment with FS.52 To further

explore the relevance of activin A in decidualization, it was

found that neutralization of endogenous activins signifi-

cantly reduced the decidual response. Indeed, Tierney and

Giudice53 decidualized HESCs with cAMP, and associated

increasing concentrations of FS for 48 hours resulted in a

dose-dependent inhibition of insulin-like growth factor

binding protein (IGFBP) 1 (a marker of decidualization)54

secretion. These data have suggested that activin A is a

component of endometrial stromal decidualization, thus

modulating the implantation process.

Other studies suggest that activin A may affect decid-

ual transformation of HESCs by modulating matrix

metalloproteinases (MMPs; Figure 4).52 Matrix metallo-

proteinases constitute a family of zinc endopeptidases that

are involved in degradation of the extracellular matrix

IL-β+ Activin A

Decidualization

+MMPs

Cytotrophoblastdifferentiation

Embryo

Decidua

Derangement ofactivin A pathway in

- implantation failure- recurrent abortion- ectopic pregnancy

+ LIF

OvaryProgesterone

Figure 3. Biological actions of activin A in the human endome-

trium in preimplantation phase and in early pregnancy. IL indicates

interleukin; LIF ¼ leukemia inhibitory factor; MMPs ¼ matrix

metalloproteinases.




(ECM) components and are thus implicated in connec-

tive tissue remodeling associated with various biologic

processes.55 The proteolytic activity of the MMPs is pre-

cisely regulated by their main endogenous protein inhibi-

tors (tissue inhibitors of metalloproteinases [TIMPs]) and

the disruption of this MMP-TIMP balance can result in

pathologies such as tumor growth, tumor-cell invasion,

and metastasis. In the endometrium, numerous types of

MMPs are expressed and they play a role in the endome-

trial breakdown during menstruation, decidualization,

and implantation processes.55,56 Indeed, during the

secretory phase, the expression and activity of MMPs in

endometrial stromal/decidual cells is inhibited by proges-

terone and its withdrawal reverses the inhibition of many

MMPs, which then can degrade the interstitial collagens

of the ECM. The increase and activation of MMPs,

mainly MMP-2, are considered key elements for men-

struation.57 Matrix metalloproteinases are also involved

in the proteolytic process required for decidual cell

differentiation. In this context, activin A stimulates

endometrial expression of pro-MMP-2, -3, -7, -9, and

active MMP-2. Activin upregulation with decidualiza-

tion parallels MMP-2, -3, and -9 increase. Furthermore,

pro-MMP-2 production is stimulated when decidualiza-

tion is accelerated by activin A and suppressed when

activin A is neutralized, attenuating decidualization.52

Endometrial bleeding associated factor is a protein

mainly expressed by menstrual endometrium and is

suggested to be involved in the mechanisms leading to

menstruation. Indeed, an increase in ebaf mRNA expres-

sion occurs in proliferative endometrium in the absence

of ovarian steroids. Using in vitro culture system, it has

been shown that a parallel increase in ebaf and pro-

MMP-3 and -7, which normally appear during menstrua-

tion, occurs and that progesterone exerts a dual block on

ebaf action, by preventing the increase in ebaf mRNA

concentration and by inhibiting ebaf-induced MMP

expression.44 A possible role of ebaf in the decidualization

process is suggested by the evidence that its expression is

remarkably elevated in stromal cells that are undergoing

decidualization, representing an intrinsic feature of the

differentiated decidualized state of stromal cells.45

ACTIVIN A AND IMPLANTATION

Implantation is a complex process that initially requires

the interaction between blastocyst and endometrium.58

The members of the molecular repertoire that make

endometrium receptive are gradually being recognized

and among these are cytokines (like interleukin [IL]

1b), integrins, heat shock proteins, leukemia inhibitory

factor (LIF), tastin, and trophonin.59-61 The expression

of a second set of genes including tumor necrosis factor

a (TNF-a) and ebaf may constitute the appropriate signal

for the closure of the ‘‘implantation window,’’ making

the endometrium refractory to implantation and prepar-

ing it for the menstrual shedding.62,63

Activin A seems to be involved in implantation

phase. Interleukin 1b is one of the mediators in the dialo-

gue between the blastocyst and the endometrium during

implantation, because it is secreted by the implanting

embryo and it is able to induce localized changes in the

endometrium before adhesion, stimulating trophoblast

implantation.61,64 The addition of IL-1b significantly

triggers activin A secretion and mRNA expression but

not that of FS. This finding suggests that activin A may

be involved in the complex cross talk between ovary

(through progesterone secretion) and embryo (through

IL-1b production; Figure 3).60,65 In line with this

hypothesis are the in vitro data regarding the modulatory

role of activin A on the expression of LIF,66 an endome-

trial protein mediating interactions between maternal

decidual leukocytes and invading trophoblast cells.59

The open question is the putative role of activin A in

implanting cytotrophoblast. Invasive extravillous cytotro-

phoblasts (EVT) differentiate from progenitor cytotro-

phoblasts in anchoring cell columns on contact with

maternal decidua and either invade the decidua as inter-

stitial (i) EVTs or specifically target and enter maternal

arteries as endovascular (v) EVTs. Exogenous addition

of activin A to villous explant cultures promotes the rapid

transition from relatively static explants, which maintain

the structure of a floating type chorionic villus, into a

villus, which sprouted migrating cytotrophoblast cells that

ultimately differentiated into invasive EVT cells, expres-

sing the markers human leukocyte antigen (HLA)-G and

MMP-9 (Figure 3).67 A significant early effect of activin

on the villous explants is also the induction of MMP-2

expression.68 Immunohistochemical data support these

data, showing that MMP-2 expression is strikingly

upregulated in cytotrophoblast cells as they contact and

invade through the activin-rich decidua.52

ACTIVINS AND CLINICAL IMPLICATIONS

The endometrium undergoes cyclical changes and the

appropriate factors required for this communication are

expressed at a specific time of the cycle, which is known




as the ‘‘implantation window.’’ In light of the fact that

activin A is a well-known regulator of the differentiation

of proliferative cytotrophoblast into extravillous invasive

trophoblast cells of the anchoring villi, we and others

hypothesized that interactions between activin A and its

related proteins in the endometrium may have a funda-

mental role at implantation.5,8,69 The derangement of

activin A machinery has, therefore, the potential to be

correlated with impairments of endometrial receptivity

needed for implantation to occur, suggesting that some

types of infertility may be associated with dysregulated

endometrial expression of activin A (Figure 3).

In addition, a dysregulated expression of ebaf in the

endometrium of a subset of women with infertility during

the receptive phase of the menstrual cycle has been

shown.70 Indeed, abundantly secreted protein is present

in the endometrium of these women during the

implantation window and during the critical period of

endometrial receptivity; ebaf is more abundant in patients

with endometriosis, who did not conceive than in

patients who became pregnant.70 In this regard, it was

evaluated whether activin A may be an in vivo marker

of endometrial receptivity. Therefore, it was examined

whether activin A concentrations in uterine washing fluid

differ between women who become pregnant after

intrauterine insemination (IUI) and those who did not.

Activin A levels were significantly higher in the endome-

trial wash fluid collected from women who later become

pregnant than in those who did not and correlated with

endometrial thickness.25 Furthermore, activin A repre-

sented a marker to predict pregnancy, because in patients

submitted to IUI, the probability of pregnancy was near

to 100% in patients with high activin A level whereas this

percentage decreased to 20% in patients with low activin

A level.71

In agreement with the hypothesis that activin A is

involved in implantation, data derived from the evalua-

tion of the expression of activin bA and bB subunits and

FS in the endometrium of women with implantation

failure was compared with a fertile control group. It was

demonstrated that the endometrium of women with

implantation failure shares an altered activin A–FS

interaction pathway (Figure 3), because FS expression

was significantly reduced in the endometrial epithelial

glandular cells in women with implantation failure

compared with control group of healthy fertile women.

However, this reduction did not appear to translate into

an expected increase in endometrial activin expression,

because activin subunits’ staining was not significantly dif-

ferent.72 In any case, this finding may represent an altered

activin FS interactive pathway, probably involved in the

mechanism related to implantation failure.

The impairment of endometrial activin pathway

seems to be involved in ectopic pregnancy (EP; Figure 3).

Ectopic pregnancy is an important cause of maternal

deaths in early pregnancy and its diagnosis is based on the

positive visualization of an extrauterine pregnancy out-

side the uterus. Factors affecting decidualization and/or

embryo transport inside the uterus have the potential to

cause EP. The intensity of expression of bA and bB

subunits, type IIA and type IIB receptors, and FS was

stronger in the EP group when compared with the

pseudopregnant group; however, quantitative reverse

transcriptase polymerase chain reaction (RT-PCR)

showed a significant decrease in mRNA levels of these

proteins, with the exception of bB-subunit with an

apparent paradox of high concentration of protein but

low mRNA expression.73 The hypothesis of a reduced

local protein secretion was proposed on the basis of the

findings reporting low serum concentrations of activin

A in women with EP.74 Indeed, activin A measurement

was performed at the initial visit in early pregnancies of

unknown location (PULs; n ¼ 536), in whom there was

no clear ultrasound evidence of an intrauterine preg-

nancy. The diagnosis of a normal intrauterine pregnancy

was made on follow-up by the demonstration of an

intrauterine gestational sac on the scan, while EP was

diagnosed later at laparoscopy and on histological exam-

ination of the surgical specimens. Serum activin A levels

were lowest in women with PUL, later diagnosed as hav-

ing an EP and, at the cutoff of 0.37 ng/mL, activin A

combined a sensitivity and a specificity of 100% and

99.6%, respectively, for prediction of EP.74

Likewise, the analysis of activin B expression in

decidualized endometrium from ectopic pregnancies

showed low levels when compared with that of ongoing

pregnancies or miscarriages. However, activin B was

lower in the serum of women with ectopic pregnancies

than in viable intrauterine gestations, with a clear correla-

tion between serum activin B and the degree of

decidualization.75

Because activin A and inhibin A are also produced by

the human placenta,76 their serum concentrations were

measured in women with incomplete and complete mis-

carriage, with the aim of evaluating their putative clinical

usefulness as marker of early pregnancy viable placenta-

tion.77 It was found that activin A levels significantly

decreased in complete miscarriage, whereas inhibin A

concentrations were significantly lower both in incom-

plete and complete miscarriages, with the lowest




concentrations in complete miscarriage.77 This study

prompted to evaluate whether the serum activin A and

inhibin A measurement may provide additional tools for

the prediction of pregnancy viability in women with

vaginal bleeding due to threatened abortion and failing

pregnancies.78 It was found that (1) serum activin A and

inhibin A were significantly lower in nonviable pregnan-

cies than in women with threatened abortion but

ongoing pregnancy; (2) low levels of inhibin A and acti-

vin A occur in patients with threatened abortion whose

pregnancy failed after 3 weeks; (3) inhibin A measure-

ment was identified as the best marker in detection of

early pregnancy viability. Indeed, inhibin A at the best

cutoff detected by the receiver operating curve analysis

achieved the best accuracy for prediction of failing preg-

nancy, showing a sensitivity of 90.6% and a specificity of

99.5%.77

On the basis of the above-mentioned data, a putative

role for activin A has also been supposed in the mechan-

ism related to recurrent miscarriage, whose etiology is in

large part unknown, because causes vary from chromoso-

mal anomalies to luteal phase defects.79 In this regard, it

was demonstrated that the endometrial expression of FS

and activin bA subunit in the ESCs collected from

women with recurrent miscarriage was significantly

lower than in control women, and this evidence has

reinforced the idea that the alterations of endometrial

functions are locally accompanied by a dysregulation of

activin A pathway (Figure 3).80,81

CONCLUSIONS

Activins and related regulatory proteins (inhibin, ebaf, FS,

FLRG, b-glycan) are endometrial factors whose expres-

sion is dynamically and tightly regulated according to

endometrial cycle. In particular, activin A is a decidualiz-

ing growth factor and its mRNA and protein expression

is part of the complex series of events allowing

implantation.

The derangement of endometrial activin pathway

may be part of the complex repertoire of local molecular

events and therefore involved both in infertility and dis-

orders of early pregnancy, such as miscarriage and EP.

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