Activin A and follistatin are dynamically regulated during human pregnancy.

Activin A (beta A-beta A) and activin B (beta B-beta B) are related dimeric proteins that regulate numerous cellular activities. Activin activity is bioneutralized by follistatin, a specific and high-affinity binding protein. Recently, our group developed specific and sensitive enzyme-linked immunosorbent activin assays that do not detect either activin isoform when bound to follistatin, therefore, the assays are specific for biologically relevant ligands. Activin A is measurable in the serum of pregnant women (cross-sectional sample collection), while activin B is not detected in maternal serum. However, activin B is measurable in amniotic fluid and cord blood sera. The purpose of this study was to measure serum activin A, activin B, and follistatin prospectively in longitudinally collected samples during pregnancy. This study design offered observations of relative changes in serum hormone concentration with each person serving as an internal reference. Serum samples were collected bimonthly from seven pregnant women beginning within the second month of gestation, and up to, but not including, the onset of labor. Six of the seven women had normal labor and delivery. One patient required pitocin (an oxytocin agonist) for induction of labor which led to delivery. Activin A, activin B, total follistatin, free follistatin, human chorionic gonadotropin, estradiol, progesterone, FSH, and LH were measured in maternal serum samples using specific assays. Serum activin A levels increased in the final month of pregnancy in the six patients who delivered following normal labor (< 0.78 ng/ml (first trimester) to 1-6 ng/ml (term)). Activin B was not detected in any serum sample (< 0.78 pg/ml). Total serum follistatin (free follistatin, follistatin-activin, and follistatin-inhibin) increased 10- to 45-fold in the final month of pregnancy in four of the women undergoing normal labor (10 ng/ml (first trimester) to 100-450 ng/ml (final month)). Total follistatin was high and variable in two women throughout pregnancy. Total follistatin returned to basal serum concentration in three of the patients during the last 2 weeks of pregnancy. Free follistatin was detected throughout pregnancy (range < 2-35 ng/ml). Free follistatin represented a small percentage of the total follistatin throughout the time of pregnancy and did not rise coincident with the rise in total follistatin. Serum activin A and activin B were not detected during the entire course of pregnancy in the one patient who did not have normal labor and total follistatin did not rise in the last trimester of pregnancy. Gonadotropin and steroid hormones were measured in all patients and were within normative ranges for human pregnancy (inclusive of the non-laboring patient). The results suggest that immunodetectable activin A is present in the third trimester of pregnant women who have normal onset labor. The total follistatin assay results suggest that follistatin-activin (or -inhibin) complexes are upregulated during the third trimester of pregnancy. Importantly, activin A production exceeds the binding capacity of circulating follistatin. Because binding protein free activin A is biologically active we conclude that the activin A detected in late pregnancy is biologically relevant. The findings are consistent with our hypothesis that activin A is an endocrine factor during the last trimester of human pregnancy and may be involved in normal labor.

Pregnancy rates after operative endoscopic treatment of total (neosalpingostomy) or near total (salpingostomy) distal tubal occlusion.

OBJECTIVE: To determine the efficacy of the endoscopic treatment of complete distal tubal occlusion or moderate to severe tubal phimosis and to analyze outcome using contemporary statistical methodologies. DESIGN: Prospective cohort analysis. SETTING: Tertiary-care institution. PATIENTS: One hundred thirteen consecutive patients undergoing a neosalpingostomy or salpingostomy. INTERVENTIONS: KTP/532 laser (Laserscope, Santa Clara, CA) laparoscopy. Additional infertility factors were treated postoperatively. MAIN OUTCOME MEASURES: Crude pregnancy rate (PR), monthly fecundity rate, monthly probability of pregnancy, cure rate, and cumulative PRs. Outcome was compared on the basis of the surgical procedure performed. The impact of endometriosis as well as other fertility factors was analyzed. RESULTS: Twenty-three patients conceived yielding a crude PR of 20.4%, a monthly fecundity rate of 2.6%, a monthly probability of pregnancy of 6.4%, and a cure rate of 52.4%. There were six ectopic pregnancies (5.3%). A significant difference was found among the cumulative pregnancy curves. The cumulative pregnancy curve for unilateral salpingostomy differed significantly from that of unilateral neosalpingostomy. Patients with endometriosis and no other infertility factors had a significantly better cumulative pregnancy curve compared with patients without endometriosis or other factors as well as compared with patients with no endometriosis but with other infertility factors. Patients undergoing bilateral neosalpingostomy had a cure rate of 9.0% whereas patients undergoing bilateral salpingostomy had a cure rate of 34.2%. CONCLUSIONS: Operative endoscopy yields PRs that are comparable to those reported in the literature for laparotomy. The presence of complete bilateral distal tubal occlusion has a negative impact on outcome.

Inhibin suppresses human chorionic gonadotropin secretion in term, but not first trimester, placenta.

Inhibin is produced by the placenta, with serum concentrations rising throughout pregnancy. In contrast, hCG serum concentrations peak in the first trimester and are 80-90% lower at term. This study was designed to determine the effect of inhibin on hCG secretion both early and late in gestation. Villus tissue from 3 term and 3 first trimester (8-10 week) placentas was maintained in an in vitro explant culture model for 5 days. Tissue from each placenta was incubated with control medium in 24 replicate wells for the first 72 h. During the final 48 h, 12 wells received control medium, and 12 wells received medium containing 1% rabbit antiserum raised against the alpha-subunit (residues 1-32) of the human inhibin peptide. The antiserum demonstrated biological activity by increasing serum FSH concentrations in an immature female rat bioassay. The relative increase in hCG secretion at the conclusion of days 4 and 5 in control and antiserum-treated groups for each first trimester and term placenta were compared to pretreatment hCG concentrations on day 3. The relative increases in hCG secretion of first trimester control groups on day 4 (mean +/- SD, 34 +/- 11%) and day 5 (63 +/- 23%) were compared to those in antiserum-treated groups on day 4 (39 +/- 13%) and day 5 (54 +/- 5%) and showed no significant difference between groups on either day. The same comparison in term cultures showed the relative increases in hCG secretion of control groups on day 4 (31 +/- 10%) and day 5 (64 +/- 50%) to be significantly lower than those in antiserum-treated groups on day 4 (100 +/- 41%) and day 5 (150 +/- 108%; P less than 0.001). These findings suggest that inhibin suppresses hCG secretion in term, but not first trimester, placentas.