Anne-Marie Schindler

In vitro production of pregnancy-associated plasma protein A by human decidua and trophoblast

Immunohistochemical techniques and direct measurements of pregnancy-associated plasma protein A (PAPP-A) have demonstrated the presence of PAPP-A in trophoblast and decidua. The purpose of the present study was to investigate the possibility that these tissues are capable of producing PAPP-A in vitro. Trophoblast and decidua were obtained from term deliveries and from legal surgical terminations of pregnancy (7 to 12 weeks). In addition to trophoblast and decidua, myometrium was also obtained during two hysterectomies in the first trimester of pregnancy. Tissues were incubated in medium 199 at 37 degrees C under an oxygen/carbon dioxide atmosphere. Media containing either pregnancy-associated serum or non-pregnancy-associated serum were changed after 8 hours of incubation in medium 199 alone. In addition to PAPP-A, human placental lactogen (hPL) and prolactin (Prl) were measured in homogenates and media by radioimmunoassays in order to confirm the viability of the cultured tissues. Addition of pregnancy-associated serum to the media induced a significant release of PAPP-A from trophoblast and decidua when compared to that in control cultures. Non-pregnancy-associated serum had no effect. Myometrium did not release any measurable PAPP-A into the medium even in the presence of pregnancy-associated serum. Cycloheximide added to pregnancy-associated serum significantly inhibited the release of PAPP-A from trophoblast and decidua. These last tissues, irrespective of the culture condition, released significantly more PAPP-A as well as hPL and Prl than was initially present in the tissue. These data demonstrate that PAPP-A is released in vitro by trophoblast and decidua (but not by myometrium) and that this release can be magnified by a factor present only in pregnancy-associated serum. The release of PAPP-A, hPL, and Prl is considered as a de novo production since concentration of these proteins are higher in media and tissues after incubation compared to concentrations initially present in the tissue before culture and since cycloheximide significantly inhibits the release of PAPP-A, Prl, and hPL from the cultured tissues.

Effects of the antiprogesterone RU 486 in early pregnancy and during the menstrual cycle

The antiprogesterone RU 486 produces an abortifacient effect during the early stages of most, but not all, pregnancies. The rate of complication appears similar to that occurring in spontaneous abortions. At this time there is no definitive explanation for failures.

Tissue and plasma concentrations of pregnancy-associated plasma protein-A (PAPP-A): comparison with other fetoplacental products.

Summary. Human placental lactogen (hPL), α‐fetoprotein (AFP), prolactin (PRL) and pregnancy‐associated plasma protein‐A (PAPP‐A) were measured by radioimmunoassay in plasma, in homogenates of trophoblast, decidua, chorion, amnion and in amniotic fluid from 10 patients after non‐complicated term delivery. Plasma samples and homogenates of trophoblast and decidua were also collected from 10 patients undergoing surgical termination of pregnancy between 7 and 12 weeks gestation. In addition, plasma and endometrial samples from 10 patients undergoing hysterectomy for other indications than malignancy were analysed for comparison. The highest tissue concentrations of hPL, AFP and PRL corresponded in each case to the known site of synthesis. For PAPP‐A the highest concentration was found in maternal plasma at term [238·8±75·6 (SEM)μg/ml]. The highest tissue concentration was found at term in the decidua (57·0±2·0 μg/g), more than three times higher than that in the trophoblast (16·9±5·4 μg/g). The concentrations of PAPP‐A in endometrial samples from non‐pregnant women (1·9±0·6 μg/g) was 40 times higher than that in the corresponding plasma samples (0·05±0·02 μg/ml). These observations point to the decidua as a possible source of PAPP‐A.

Histochemical Localization of Pregnancy-Associated Plasma Protein A in Fetal, Infant, and Adult Organs and Comparison between Antisera

Histochemical localization of pregnancy-associated plasma protein A (PAPP A) was performed on various genital and extragenital organs from fetuses, infants, and adults. Three types of PAPP A reactive cells were found: endocrine, epithelial, and hematopoietic cells. Positive endocrine organs included the decidua and the fetal adrenal and Leydig cells. Positive epithelial cells were found in actively proliferating tissues, such as fetal renal tubules, fetal intestinal mucosa, and adult proliferative endometrial glands. In bone marrow, red cell precursors were PAPP A positive. Comparison of a commercially available antiserum with one raised in our own laboratory revealed significant differences in histochemical staining. The biological relevance of these findings remains to be determined.

Endometrial and plasma concentrations of pregnancy‐associated plasma protein‐A (PAPP‐A)

Summary. Pregnancy‐associated plasma protein‐A (PAPP‐A), oestradiol and progesterone levels have been measured by radioimmunoassay in plasma and in endometrial homogenates of 30 women undergoing hysterectomy. Results were grouped according to the histological stages of the endometrium. In plasma, oestradiol and progesterone concentrations changed from proliferative to secretory stages in the well‐established pattern of the menstrual cycle, but PAPP‐A levels did not change. In endometrium, oestradiol levels were high during the proliferative stage and low in inactive and secretory endometrium. Endometrial PAPP‐A and progesterone concentrations increased from inactive to secretory stages, but only the increase in PAPP‐A was statistically significant. A positive correlation observed between endometrial PAPP‐A concentrations and plasma oestradiol/progesterone ratio suggests a possible hormonal control for the presence of PAPP‐A in the uterus.

Pregnancy‐associated plasma protein‐A (PAPP‐A): concentration in uterine fluid and immunohistochemical localization in the endometrium

Summary. Pregnancy‐associated plasma protein‐A (PAPP‐A) was localized immunohistochemically in the endometrium and measured in uterine fluid of non‐pregnant women. The variations of PAPP‐A concentrations in uterine fluid during the menstrual cycle paralleled those found in the endometrium. In patients receiving hormone therapy there was a significant correlation between the uterine fluid PAPP‐A concentration and the progestogen to oestrogen potency ratio of the hormonal treatment. The presence of PAPP‐A in the uterine fluid cannot simply be explained by blood contamination or cell damage. These results are interpreted as indirect evidence for an exocrine as well as an endocrine secretion of PAPP‐A by the endometrium which might be influenced by hormones.

Early Ultrastructural Changes in RU-486-Exposed Decidua

An antiprogesterone (RU-486) was administered to women undergoing voluntary interruption of pregnancy. Five patients received 100 mg 12 h before surgical interruption, 5 others received 100 mg twice, 24 and 12 h before interruption, respectively, and another 5 received no drug at all and served as controls. Placentas and deciduae were examined morphologically with the light microscope and by electron microscopy. No specific lesions were detected in placental tissue. With conventional histology, the deciduae showed various degrees of interstitial edema and necrosis, changes which did not enable a distinction between treated cases and controls, although stromal disintegration tended to be more marked in RU-486-treated patients. At the ultrastructural level, the endothelium of decidual capillaries showed striking hyperplasia of the endoplasmic reticulum. Morphometric evaluation showed a statistically significant difference between RU-486-treated patients (2 X 100 mg) and controls. A possible link between these morphological changes and the induction of prostaglandin synthesis by the antiprogesterone is suggested. However, the full significance of the observed lesions remains uncertain and does not allow definite conclusions concerning the abortifacient effect of RU-486.

Measles giant cell pneumonia without rash in a case of lymphocytic lymphosarcoma

A case of measles pneumonia with no rash is reported in an adult woman with lymphocytic lymphosarcoma. It was characterized by the presence of inclusion-bearing giant cells lining the alveoli. Electron microscopic studies of the lung showed that the giant cells were formed by fusion of type II alveolar epithelial cells. Inclusion bodies were filled with tubular and rod-shaped filaments similar to those observed in cell cultures infected with measles virus. The progression of the giant cell pneumonia may have been facilitated by depressed cell-mediated immunity secondary to lymphocytic lymphosarcoma.

Progesterone dependence and extratrophoblastic origin of pregnancy-associated plasma protein-A (PAPP-A) in early pregnancy

SummaryPregnancy-associated plasma protein-A (PAPP-A) is a macromolecular glycoprotein produced in increasing concentration as pregnancy advances. PAPP-A is not specific to pregnancy since measurable levels have been found in non-pregnant females and in males. In non-pregnant females, PAPP-A is probabely produced by the endometrium. The origin of PAPP-A in pregnant women is still controversial. In-vitro trophoblast and decidual explants both produce PAPP-A. So far, it is not known if the same applies to the in-vivo situation and to what extent these two tissues contribute to the circulating levels of PAPP-A.This study compares the circulating concentrations of PAPP-A and β-hCG and progesterone in different pathological situations. In hydatidiform moles, β-hCG levels are very high demonstrating an intense trophoblastic activity, whereas PAPP-A levels remain in the normal range. With spontaneous abortions, β-hCG levels decline to very low values whereas PAPP-A continues to increase. These observations furnish indirect evidence for a major contribution to circulating PAPP-A levels by extratrophoblastic sites. Furthermore, PAPP-A levels decrease after administration of an antiprogesterone (RU486) either in-vivo or in-vitro. This is considered as a proof that PAPP-A levels in early pregnancy are progesterone dependent.

Follicle-stimulating hormone. IV. Study of the histology of pubertal cryptorchid and scrotal testes in relation to the secretion of gonadotropins**Supported in part by a grant from the Swiss National Science Foundation (3.845.0.79).

The morphologic characteristics of 85 cryptorchid and 63 contralateral (scrotal) testes showing histologic changes of puberty were studied. Spermatogenesis was not only delayed on the cryptorchid side but also hypocellular in all cases. The scrotal testes appeared hypocellular in 82.5% of the cases. Repetitive biopsies, performed in 12 patients, showed no improvement of cellularity after orchidopexy but progress in pubertal maturation. In the 22 boys submitted to luteinizing hormone-releasing hormone (LH-RH) stimulation, luteinizing hormone (LH) baseline values did not change significantly whereas follicle-stimulating hormone (FSH) baseline levels increased with advancing age and histologic stage of maturation. LH responses increased with the stage of maturation (without statistical significance); however, LH responses were significantly higher in the group without germ cells. FSH responses to LH-RH stimulation were consistently and significantly higher with advancing stages of maturation and in the group without cells.