This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Florio, P. Articles by Petraglia, F. Search for Related Content PubMed PubMed Citation Articles by Florio, P. Articles by Petraglia, F. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CHORIONIC GONADOTROPIN PROGESTERONE Medline Plus Health Information High Risk Pregnancy Related Collections Female Endocrinology

Single Serum Activin A Testing to Predict Ectopic Pregnancy

Obstetrics and Gynecology, Department of Paediatrics, Obstetrics and Reproductive Medicine, University of Siena, 53100 Siena, Italy

Address all correspondence and requests for reprints to: Felice Petraglia, Chair of Obstetrics and Gynecology, Department of Pediatrics, Obstetrics and Reproductive Medicine, University of Siena, Policlinico "Le Scotte," viale Bracci, 53100 Siena, Italy. E-mail: petraglia{at}unisi.it.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: Ectopic pregnancy (EP) is an important cause of maternal deaths in early pregnancy because most fatal cases result from delayed diagnosis and inappropriate investigation.

Objective: We evaluated whether the measurement of activin A may be useful in the diagnosis of EP in women with unknown pregnancy location.

Design: The study was designed as an open observational study.

Setting: The study was set in a tertiary referral center for obstetric care.

Patients: Patients were women with unknown pregnancy location (n = 536) who had complaints of bleeding, pain, or cramping.

Interventions: Interventions included clinical examination; transvaginal ultrasound scan; human chorionic gonadotropin (hCG), progesterone, and activin A measurements; laparoscopy; uterine curettage; and histological examination.

Main Outcome Measures: Main outcome measures were pregnancy outcomes and evaluation of sensitivity, specificity, and predictive values of hCG, progesterone, and activin A as diagnostic tests for the detection of EP.

Results: Pregnancy outcomes included 155 (28.9%) viable intrauterine pregnancies (IUP), 305 (56.9%) first-trimester spontaneous abortion (SAB), and 76 (14.2%) EP. SAB had the lowest (P < 0.0001) hCG and progesterone concentrations, significantly lower than EP (P < 0.001) and IUP (P < 0.001). In EP, levels were significantly (P < 0.001) lower than in IUP. On the contrary, activin A levels were lowest (P < 0.0001) in EP, significantly lower than in SAB (P < 0.001) and IUP (P < 0.001). IUP had significantly (P < 0.001) lower activin A levels than SAB. When evaluated by the receiver operating curve analysis, activin A at the cutoff of 0.37 ng/ml combined a sensitivity and a specificity of 100 and 99.6%, respectively, for prediction of EP. When activin A concentrations were below the cutoff, the positive predictive value for EP was 97.43%, and 0% for concentrations higher than 0.37 ng/ml.

Conclusions: Activin A measurement may identify patients at risk of EP with a high sensibility and specificity.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
ECTOPIC PREGNANCY (EP) is an important cause of maternal deaths in early pregnancy because most fatal cases result from delayed diagnosis and inappropriate investigation (1). The diagnosis of EP should be based on the positive visualization of an extrauterine pregnancy outside the uterus, rather than the absence of an intrauterine pregnancy (IUP), and the use of transvaginal sonography (TVS) is the method of choice for the initial assessment of women with suspected EP (1, 2). Indeed, with the use of TVS a normal IUP can be identified at 4 wk and 3 d in a woman with a regular 28-d cycle (3). However, in 8–31% of women with suspected abnormal early pregnancies who are referred for assessment, the diagnosis cannot be made by TVS at the initial visit (1). In these women, either surgical or biochemical assessment is used to reach the correct diagnosis (1, 4, 5). With respect to the biochemical assessment, it is usually based on the measurement of serum levels of human chorionic gonadotropin (ß-hCG) (6, 7) and progesterone (8, 9, 10). However, because none of the current methods combines accuracy, reproducibility, and simplicity to become a universal predictive marker of EP (1), there continues to be a compelling demand for new markers and also for new algorithms that extract the best information of current screening methods.

In the present study, we have evaluated whether activin A measurement at the initial visit may be useful in the diagnosis of EP in early pregnancies of unknown location (UPL). Activin A is a dimeric glycoprotein belonging to the TGF-ß superfamily, a group of structurally similar but functionally diverse growth factors involved in cellular proliferation, differentiation, and cell fate determination (11). During pregnancy, the placenta is the main source of activin A (12); activin A serum levels in maternal circulation are higher than in nonpregnant women and increase throughout pregnancy until delivery (13). Moreover, the addition of activin A to primary cultures of human placental cells increases progesterone production and potentiated the GnRH-induced release of hCG (14), supporting the hypothesis that activin A plays a pivotal role in the endocrine physiology of human pregnancy.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We did a prospective observational study of pregnant women with UPL (n = 536) who were referred for assessment by either general practitioners or hospital consultants at our tertiary referral center for obstetric care, presenting with complaints of bleeding, pain, or cramping. Patients were enrolled from November 2004 to September 2005.

All women included in the study conceived spontaneously and were not taking exogenous progestogens. A full medical history was documented, and clinical examination was carried out by the attending physician. A transvaginal ultrasound scan was then performed using a 4.5–7.0 MHz probe (Real Time Ultrasound Scan Equipment, Siemens Sonoline ELEGRA Millenium Edition; Siemens, Erlangen, Germany).

The diagnosis of UPL was made at the initial visit in all cases where there was no clear ultrasound evidence of an IUP, retained products of conception, or an EP. The definition of UPL did not include women with an early pregnancy-like structure within the uterine cavity, which required follow-up for verification, the identification of an adnexal mass that was believed to be an EP, clinically unstable patients, and patients with indirect signs of a specific pregnancy location such as the presence of hemoperitoneum or those with product of conception that could be visualized on speculum examination. Ultrasound examinations were performed by either general practitioners or hospital consultants that visited the patients, but all cases were reviewed and reanalyzed by one physician (F.M.S.). In any case, no differences were noted among several operators.

Patients were advised not to travel, to avoid sexual intercourse, and to return immediately if they experienced significant increase in abdominal pain. The women were reviewed every 3 d until a final diagnosis was reached. Follow-up included clinical assessment, serial measurement of the serum hCG levels, and repeated transvaginal ultrasound scans. Surgical intervention was indicated in women on the basis of hCG ratio (rate of change in hCG over 48 h) (15) or because of worsening clinical symptoms.

The diagnosis of a normal IUP was made on follow-up by the demonstration of an intrauterine gestational sac on the scan. In these cases, another ultrasound scan was performed 2 wk later and demonstrated the presence of a live embryo. The diagnosis of a miscarriage was made histologically after surgical evacuation of the uterine contents. EP was diagnosed at laparoscopy and on histological examination of the surgical specimens. Spontaneous resolution of pregnancy was defined as a decrease of hCG levels to less than 5 IU/liter with the disappearance of symptoms.

Informed consent was obtained from all patients before inclusion in the study, for which local Human Investigation Committee approval was obtained.

Commercially available assays were used to analyze serum samples for quantitative hCG (EURO/DPC Ltd., Glyn Rhonwy, Llanberis, Gwynedd, UK), progesterone (DRG International, Minneapolis, MN), and activin A (Serotec, Kidlington, Oxford, UK), according to manufacturers’ instructions. Assays were done in samples collected at the initial visit, without knowledge of pregnancy outcomes, and results did not influence treatment.

Measurements were performed in duplicate. hCG assay had a sensitivity of 1.1 IU/liter, with a within-assay coefficient of variation (CV) of 2.1%, and an interassay CV of 3.1%; no cross-reactivity to LH, FSH, and TSH was shown. The progesterone assay detection limit was 0.05 ng/ml, with a CV less than 3.6% for intraassay and less than 3.5% for the interassay, and the cross-reaction with 17-OH progesterone, estriol, 17ß estradiol, testosterone, dehydroepiandrosterone sulfate, cortisol, and pregnenolone was less than 0.3%. Activin A assay had a limit of detection less than 100 pg/ml, with intraassay and interassay CV for quality control samples of 2.0 and 4.5%, respectively. Cross-reaction with the various inhibin-related proteins was less than 0.5%.

Statistical analysis

All data were analyzed with Prism software (GraphPad Software Inc., San Diego, CA) and were expressed as mean ± SD. The Kolmogorov-Smirnov test confirmed that the distributions of hCG, progesterone, and activin A concentrations were not Gaussian. Therefore, we used Kruskal-Wallis test followed by Dunn’s post hoc test to compute statistical significance, and ² and Fisher exact test to analyze differences between proportions.

The sensitivity, specificity, predictive value, and likelihood ratios (LR) of hCG, progesterone, and activin A as diagnostic tests for the detection of EP in women with UPL were assessed by using the receiver operating curve (ROC) test (16). Therefore, the probability of EP after having none or one test positive (higher than the cutoff point) was estimated and compared with the pretest probability, defined as the prevalence of EP in the whole group of patients (17).

ROC analysis was performed by using MedCalc (version 8.2.1.0; MedCalc Software, 9030 Mariakerke, Belgium), and statistical significance was set at P < 0.05.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Clinical findings

Pregnancy outcomes included 155 (28.9%) viable IUP, 305 (56.9%) first-trimester spontaneous abortion (SAB), and 76 (14.2%) EP. Seventy-two EP (94.7%) were tubal, three (4.0%) were ovarian, and one (1.3%) was interstitial.

Demographic information and clinical characteristics are given in Table 1. There were no significant differences in race, gravidity, parity, and symptoms prevalence. However, the mean age of subjects with EP was significantly higher than that of patients with IUP (P < 0.001) and SAB (P < 0.05) (Table 1), and the estimated length of gestation (days) was significantly higher in EP than SAB (P < 0.001) and IUP (P < 0.05) women (Table 1).

hCG, progesterone, and activin A levels were measurable in all samples. In details, hCG concentrations were the lowest (P < 0.0001) in women with SAB at follow-up, being significantly lower than in patients with EP (P < 0.001) and IUP (P < 0.001). In addition, levels in EP were significantly (P < 0.001) lower than those in IUP (Table 1 and Fig. 1).

View larger version (21K): [in this window] [in a new window]   FIG. 1. Serum levels of hCG (A), progesterone (B), and activin A (C) in women with UPL (n = 536) who, at follow-up, had a SAB (n = 305), a normal IUP (n = 155), or an EP (n = 76).

On the contrary, activin A levels were the lowest (P < 0.0001) in EP, significantly lower than in patients with SAB (P < 0.001) and IUP (P < 0.001) (Table 1 and Fig. 1). Finally, women with IUP had significantly (P < 0.001) lower activin A levels than those who underwent SAB (Fig. 1).

Diagnostic accuracy of hCG, progesterone, and activin A measurement for EP

The sensitivity/specificity, positive/negative predictive values, positive and negative LR and the area under the curve (AUC) of hCG, progesterone, and activin A as diagnostic tests were evaluated by the ROC curve.

In details, hCG at the cutoff of 658 IU/liter achieved a sensitivity of 75.0% [95% confidence interval (CI_95%), 63.7–84.2] and a specificity of 76.1% (CI_95%, 71.9–79.9) as a single marker for EP prediction in patients with UPL [ROC AUC: 0.806 (CI_95%, 0.77–0.839)], with a positive and negative LR of 3.14 and 0.33, respectively (Fig. 2 and Table 2).

View larger version (23K): [in this window] [in a new window]   FIG. 2. ROC curve analysis of serum concentrations of hCG, progesterone, and activin A for the prediction of EP. Activin A at the cutoff of 0.37 ng/ml achieved the best accuracy for prediction of EP in women with UPL, showing a sensitivity of 100% (CI95%, 95.2–100%) and a specificity of 99.6% (CI95%, 98.4–99.9%; area under the ROC curve: 1.00). The area under the ROC curve of activin A was significantly higher than that of hCG (P = 0.000; difference between areas, 0.194; CI95%, 0.133–0.255) and progesterone (P = 0.000; difference between areas, 0.378; CI95%, 0.307–0.449).

On the contrary, activin A at the cutoff of 0.37 ng/ml combined a sensitivity of 100% (CI_95%, 95.2–100) with a specificity of 99.6% (CI_95%, 98.4–99.9) for prediction of PE, with a ROC AUC of 1.0 (CI_95%, 0.993–1.00), and positive and negative LR of 230.0 and 0.0, respectively (Fig. 2 and Table 2).

The ROC AUC of activin A was significantly higher than that of hCG (P = 0.000; difference between areas, 0.194; CI_95%, 0.133–0.255) and of progesterone (P = 0.000; difference between areas, 0.378; CI_95%, 0.307–0.449), as evaluated by pair-wise comparison of ROC curves.

Computation of the probability to have an EP

The probability of EP after having none or one test positive was calculated in the whole group of patients and compared with the pretest probability of the disease in the population evaluated. Seventy-six of 536 patients had EP, giving an overall prevalence of the disease in the study population of 14.18% (CI_95%, 11.2–17.1%). This was the predicted probability of developing EP before having performed hormones measurement (pretest probability).

With respect to the early prediction of EP, when hCG levels were found high (i.e. above the thresholds defined by the ROC curve analysis), the probability of having EP (positive predictive value) was as high as 34.13% (CI_95%, 26.9–41.3%), whereas with hCG values below the cutoff, the probability of having an EP was 5.14% (CI_95%, 2.1–7.4%) (Fig. 3).

View larger version (13K): [in this window] [in a new window]   FIG. 3. Probability of having an EP among all patients (pretest probability) and after different test results (posttest probability). Data are reported as percentage, and the error bars indicate the CI95% for each probability.

On the contrary, if serum activin A concentrations were low (i.e. below the thresholds defined by the ROC curve analysis), its positive predictive value for EP was as high as 97.43% (CI_95%, 93.9–100%) (Fig. 3), but if activin A concentrations were within reference intervals, that probability was as low as 0% (CI_95%, 0–1.9%).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The present study first shows that, in spontaneously conceived UPL, activin A levels are lowest in women with EP, and lower than in those who will progress to term delivery (IUP) or who will have a SAB. The finding of low activin A concentrations in EP and SAB patients are novel, and lead us to suggest that an impaired secretion of activin A occurs in the presence of problems related to trophoblast invasion and implantation. Indeed, during pregnancy, the human placenta is the main source of activin A in maternal bloodstream (12) because serum levels in maternal circulation progressively increase throughout pregnancy until delivery (13). Furthermore, variations in maternal activin A levels occurring in trophoblast diseases are believed to be part of the adaptive response of the placenta to adverse environmental conditions, probably representing a nonspecific functional counterpart of structural placental changes such as proliferation of trophoblast cells and/or placental dysfunction, that are part of the evolving diseases (18). Indeed, activin A levels are reduced in the presence of nonviable trophoblast, as happens in complete miscarriage (19, 20, 21); increase when disrupted placentation and placental ischemia occur, as in the case of preeclampsia (22), fetal growth restriction (23), and abruption placentae (24); and are dramatically boosted in the presence of excessive trophoblast proliferation and implantation, as takes place in hydatidiform mole (25). This evidence suggests that a reduction of activin A secretion in EP may signal the difficulty of the trophoblast to correctly implant. Indeed, in vitro data on the role of activin A in facilitating endometrial decidualization (26, 27) and the fact that decidualization is a requisite for successful implantation collectively lead us to hypothesize that an impairment of activin A synthesis and release may take place in the placenta, causing the lack of a well-vascularized and appropriately constructed endometrium and, therefore, trophoblast implantation outside the uterus.

Finally, the role of the endometrium as a relevant source of activin A needs to be considered because the main difference between IUP/SAB and EP is essentially in the ground of implantation (28). During the secretory phase of the menstrual cycle (at the time of blastocyst implantation), activin A is present in the uterine fluid of cycling women in higher amounts than the proliferative phase, and levels correlate with endometrial thickness (29). It has been suggested (26) that such an increase of endometrial activin A and secretion at the time of blastocyst apposition may have an important role as a local endometrial phenomenon involved in embryo implantation, because activin A is a well-known regulator of the differentiation of proliferative cytotrophoblast into extravillous invasive trophoblast cells of the anchoring villi (30). These findings lead us to suggest that the lack of an adequate endometrial secretion of activin A may be related to the lack of appropriate messages to the placenta for a right implantation.

Whatever the source of reduced activin A concentrations in EP, the clinical usefulness of its measurement in the case of a UPL needs to be discussed. Indeed, the distinction between UPLs that are developing EP, IUP, and SAB based on the interpretation of hormonal markers is the most difficult diagnostic problem. Although the vast majority will be SAB and early IUPs, it is the group of women with an EP too early to visualize that poses the greatest concern (1). Currently single progesterone measurement followed by hCG surveillance and/or ultrasound is used to detect EP with relatively high success (1). Indeed, serum progesterone concentrations are higher in women with viable IUP than in those with EP or pregnancies who will progress as SAB, as also confirmed by our findings.

In the present study the clinical usefulness of single serum hCG, progesterone, and activin A measurement for discriminating the presence of EP in a selected groups of at risk pregnant women was evaluated. As expected (1, 7, 8), the discriminative capacity of a single measurement both of hCG and progesterone is insufficient to diagnose EP with certainty. With respect to the potential advantage of using activin A as a single marker for identifying EP, we have found that, at the cutoff identified by the ROC curve analysis, its measurement reached a sensitivity of 100% and a specificity of 99.6% for recognition of EP. In other words, measuring activin A yields positive (97.4%) and negative (0%) predictive values that differ materially from the overall prevalence of EP (14.18%) in the study population. It means that the probability of having an EP may be estimated more precisely and more quickly if activin A measurement is performed. These findings are of relevance because a highly sensitive and specific test to identify EP would be useful in a clinical setting when women present with symptoms and decision regarding treatment must be made quickly. Furthermore, the time delay necessary for distinguishing a woman with EP from the remaining is often distressing to patients and practitioners when women present with symptoms in an emergency setting.

In conclusion, we found that, in women with UPL, maternal serum activin A levels are lowest in those with an EP, and that single activin A measurement may identify patients at risk of EP with a high sensibility and specificity. These findings may open up a new cue for biochemical markers assessment in maternal bloodstream to select pregnancies at higher risk of EP earlier and possibly to prevent unnecessary interventions.

	Footnotes

 
This work was supported by grants to F.P. from the Italian Ministry of University and Scientific Research and the University of Siena (Siena, Italy).

Disclosure Statement: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript. The authors have no financial connection with activin A manufacturers. The authors have nothing to disclose.

First Published Online March 6, 2007

Abbreviations: AUC, Area under the curve; CI_95%, 95% confidence interval; CV, coefficient of variation; EP, ectopic pregnancy; hCG, human chorionic gonadotropin; IUP, intrauterine pregnancy; LR, likelihood ratio; ROC, receiver operating curve; SAB, spontaneous abortion; TVS, transvaginal sonography; UPL, unknown pregnancy location.

Received October 6, 2006.

Accepted February 22, 2007.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Farquhar CM 2005 Ectopic pregnancy. Lancet 366:583–591[CrossRef][Medline]
2. Brown DL, Doubilet PM 1994 Transvaginal sonography for diagnosing ectopic pregnancy: positivity criteria and performance characteristics. J Ultrasound Med 13:259–266[Abstract]
3. Fossum GT, Davajan V, Kletzky OA 1988 Early detection of pregnancy with transvaginal ultrasound. Fertil Steril 49:788–791[Medline]
4. Barnhart KT, Gosman G, Ashby R, Sammel M 2003 The medical management of ectopic pregnancy: a meta-analysis comparing "single dose" and "multidose" regimens. Obstet Gynecol 101:778–784[CrossRef][Medline]
5. Buster JE, Carson SA 1995 Ectopic pregnancy: new advances in diagnosis and treatment. Curr Opin Obstet Gynecol 7:168–176[Medline]
6. Barnhart KT, Sammel MD, Rinaudo PF, Zhou L, Hummel AC, Guo W 2004 Symptomatic patients with an early viable intrauterine pregnancy: HCG curves redefined. Obstet Gynecol 104:50–55[CrossRef][Medline]
7. Mol BW, Hajenius PJ, Engelsbel S, Ankum WM, Van der Veen F, Hemrika DJ, Bossuyt PM 1998 Serum human chorionic gonadotropin measurement in the diagnosis of ectopic pregnancy when transvaginal sonography is inconclusive. Fertil Steril 70:972–981[CrossRef][Medline]
8. Mol B, Lijmer T, Ankum W, Van Der Veen F, Bossuyt P 1998 The accuracy of single serum progesterone measurement in the diagnosis of ectopic pregnancy: a meta-analysis. Hum Reprod 13:3220–3227[Abstract/Free Full Text]
9. McCord ML, Muram D, Buster JE, Arheart KL, Stovall TG, Carson SA 1996 Single serum progesterone as a screen for ectopic pregnancy: exchanging specificity and sensitivity to obtain optimal test performance. Fertil Steril 66:513–516[Medline]
10. Stovall TG, Ling FW, Carson SA, Buster JE 1992 Serum progesterone and uterine curettage in differential diagnosis of ectopic pregnancy. Fertil Steril 57:456–457[Medline]
11. Luisi S, Florio P, Reis FM, Petraglia F 2001 Expression and secretion of activin A: possible physiological and clinical implications. Eur J Endocrinol 145:225–236[CrossRef][Medline]
12. Petraglia F, Sawchenko P, Lim AT, Rivier J, Vale W 1987 Localization, secretion, and action of inhibin in human placenta. Science 237:187–189[Abstract/Free Full Text]
13. Florio P, Luisi S, Ciarmela P, Severi FM, Bocchi C, Petraglia F 2004 Inhibins and activins in pregnancy. Mol Cell Endocrinol 225:93–100[CrossRef][Medline]
14. Petraglia F, Vaughan J, Vale W 1989 Inhibin and activin modulate the release of gonadotropin-releasing hormone, human chorionic gonadotropin, and progesterone from cultured human placental cells. Proc Natl Acad Sci USA 86:5114–5117[Abstract/Free Full Text]
15. Condous G, Okaro E, Khalid A, Timmerman D, Lu C, Zhou Y, Van Huffel S, Bourne T 2004 The use of a new logistic regression model for predicting the outcome of pregnancies of unknown location. Hum Reprod 19:1900–1910[Abstract/Free Full Text]
16. Stephan C, Wesseling S, Schink T, Jung K 2003 Comparison of eight computer programs for receiver-operating characteristic analysis. Clin Chem 49:433–439[Abstract/Free Full Text]
17. Richardson WS, Wilson MC, Guyatt GH, Cook DJ, Nishikawa J 1999 Users’ guides to the medical literature: XV. How to use an article about disease probability for differential diagnosis. Evidence-based medicine working group. JAMA 281:1214–1219[Free Full Text]
18. Florio P, Cobellis L, Luisi S, Ciarmela P, Severi FM, Bocchi C, Petraglia F 2001 Changes in inhibins and activin secretion in healthy and pathological pregnancies. Mol Cell Endocrinol 180:123–130[CrossRef][Medline]
19. Luisi S, Florio P, D’Antona D, Severi FM, Sanseverino F, Danero S, Petraglia F 2003 Maternal serum inhibin A levels are a marker of a viable trophoblast in incomplete and complete miscarriage. Eur J Endocrinol 148:233–236[Abstract]
20. Florio P, Luisi S, D’Antona D, Severi FM, Rago G, Petraglia F 2004 Maternal serum inhibin A levels may predict pregnancy outcome in women with threatened abortion. Fertil Steril 81:468–470[CrossRef][Medline]
21. Muttukrishna S, Jauniaux E, Greenwold N, McGarrigle H, Jivraj S, Carter S, Elgaddal S, Groome N, Regan L 2002 Circulating levels of inhibin A, activin A and follistatin in missed and recurrent miscarriages. Hum Reprod 17:3072–3078[Abstract/Free Full Text]
22. Reis FM, D’Antona D, Petraglia F 2002 Predictive value of hormone measurements in maternal and fetal complications of pregnancy. Endocr Rev 23:230–257[Abstract/Free Full Text]
23. Wallace EM, Schneider-Kolsky ME, Edwards A, Baker L, Jenkin G 2003 Maternal serum activin A levels in association with intrauterine fetal growth restriction. BJOG 110:306–310[Medline]
24. Florio P, Severi FM, Bocchi C, Luisi S, Petraglia F 2003 Abruptio placentae and highest maternal serum activin A levels at mid-gestation: a two cases report. Placenta 24:279–280[CrossRef][Medline]
25. Florio P, Severi FM, Cobellis L, Danero S, Bome A, Luisi S, Petraglia F 2002 Serum activin A and inhibin A. New clinical markers for hydatidiform mole. Cancer 94:2618–2622[CrossRef][Medline]
26. Florio P, Rossi M, Sigurdardottir M, Ciarmela P, Luisi S, Vigano P, Grasso D, Fiore G, Cobellis L, Di Blasio AM, Petraglia F 2003 Paracrine regulation of endometrial function: interaction between progesterone and corticotropin-releasing factor (CRF) and activin A. Steroids 68:801–807[CrossRef][Medline]
27. Dimitriadis E, White CA, Jones RL, Salamonsen LA 2005 Cytokines, chemokines and growth factors in endometrium related to implantation. Hum Reprod Update 11:613–630[Abstract/Free Full Text]
28. Norwitz ER, Schust DJ, Fisher SJ 2001 Mechanisms of disease: implantation and the survival of early pregnancy. N Engl J Med 345:1400–1408[Free Full Text]
29. Florio P, Severi FM, Luisi S, Ciarmela P, Calonaci G, Cobellis L, Petraglia F 2003 Endometrial expression and secretion of activin A, but not follistatin, increase in the secretory phase of the menstrual cycle. J Soc Gynecol Investig 10:237–243[CrossRef][Medline]
30. Caniggia I, Lye SJ, Cross JC 1997 Activin is a local regulator of human cytotrophoblast cell differentiation. Endocrinology 138:3976–3986[Abstract/Free Full Text]

This article has been cited by other articles:

				E. Kirk, A. T. Papageorghiou, B. Van Calster, G. Condous, N. Cowans, S. Van Huffel, D. Timmerman, K. Spencer, and T. Bourne The use of serum inhibin A and activin A levels in predicting the outcome of 'pregnancies of unknown location' Hum. Reprod., October 1, 2009; 24(10): 2451 - 2456. [Abstract] [Full Text] [PDF]

				P. B. Torres, P. Florio, L. Galleri, F. M. Reis, L. E. Borges, and F. Petraglia Activin A, Activin Receptor Type II, Nodal, and Cripto mRNA Are Expressed by Eutopic and Ectopic Endometrium in Women With Ovarian Endometriosis Reproductive Sciences, August 1, 2009; 16(8): 727 - 733. [Abstract] [PDF]

				J. Cartwright, W C. Duncan, H. O D Critchley, and A. W Horne Serum biomarkers of tubal ectopic pregnancy: current candidates and future possibilities Reproduction, July 1, 2009; 138(1): 9 - 22. [Abstract] [Full Text] [PDF]

				A.W. Horne, W.C. Duncan, A.E. King, S. Burgess, P.C. Lourenco, P. Cornes, P. Ghazal, A.R. Williams, L. Udby, and H.O.D. Critchley Endometrial cysteine-rich secretory protein 3 is inhibited by human chorionic gonadotrophin, and is increased in the decidua of tubal ectopic pregnancy Mol. Hum. Reprod., May 1, 2009; 15(5): 287 - 294. [Abstract] [Full Text] [PDF]

				A. W. Horne, S. van den Driesche, A. E. King, S. Burgess, M. Myers, H. Ludlow, P. Lourenco, P. Ghazal, A. R. Williams, H. O. D. Critchley, et al. Endometrial Inhibin/Activin {beta}-B Subunit Expression Is Related to Decidualization and Is Reduced in Tubal Ectopic Pregnancy J. Clin. Endocrinol. Metab., June 1, 2008; 93(6): 2375 - 2382. [Abstract] [Full Text] [PDF]

				B. Refaat, S. Amer, B. Ola, N. Chapman, and W. Ledger The Expression of Activin- A- and - B-Subunits, Follistatin, and Activin Type II Receptors in Fallopian Tubes Bearing an Ectopic Pregnancy J. Clin. Endocrinol. Metab., January 1, 2008; 93(1): 293 - 299. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Florio, P. Articles by Petraglia, F. Search for Related Content PubMed PubMed Citation Articles by Florio, P. Articles by Petraglia, F. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CHORIONIC GONADOTROPIN PROGESTERONE Medline Plus Health Information High Risk Pregnancy Related Collections Female Endocrinology