Expression of androgen receptors in upper human fetal reproductive tract.

BACKGROUND: Androgens play a key role in human fetal development. All androgens act through a single intracellular androgen receptor (AR), which is encoded by a single copy gene on the X chromosome. ARs are expressed as early as 9 weeks in the epithelium and mesenchyme of the urogenital sinus, paramesonephric (Müllerian) and mesonephric (Wolffian) ducts. METHODS: Using immunohistochemistry, we investigated the distribution of ARs in the gonads and lower genital tracts of 54 human fetuses at 8-11 weeks of gestation. Gender was determined by PCR. RESULTS: The AR was expressed in a similar pattern in both male and female fetuses. There appears to be no difference in expression in the mesonephros or the mesonephric ducts when male and female pelvises were compared. Expression in the female paramesonephric duct was within the epithelium, whereas, in the male pelvises, expression was in the mesenchyme of the paramesonephric duct. When AR expression was compared in the ovary and testes, both gonads seem to express AR at 9 weeks, but this expression was extended into the 10th week of gestation in the male. CONCLUSION: The specific pattern of AR expression implies a key role in gonadal development. However, the pattern of staining was similar in the gonads at 8 and 9 weeks in both sexes, although staining persisted longer in the testis until the 10th week. AR expression, therefore, is not a key determinant of human gonadal differentiation.

Prospective observational study of bone mineral density during pregnancy: low molecular weight heparin versus control.

BACKGROUND: The aim of this study was to assess the effect of long-term low molecular weight heparin (LMWH) on bone mineral density (BMD) during pregnancy. METHODS: Fifty-five patients with recurrent miscarriage and known thrombophilia (antiphospholipid syndrome) were followed through pregnancy in an ethically approved prospective observational study. All women had dual energy X-ray absorptiometry (DEXA) scans at the lumbar spine (L1-L4) performed within 6 months prior to conception and in the immediate post-natal period, within 6 weeks of delivery. LMWH (5000 U/day) plus low-dose aspirin was commenced after a positive urine pregnancy test and continued throughout pregnancy and after delivery until 6 weeks post-partum. A group of 20 volunteers with recurrent miscarriage, not requiring any treatment intervention, acted as controls and were monitored in an identical fashion. RESULTS: Characteristics were not significantly different between treated patients and controls. Both groups showed a similar loss in lumbar spine (L1-L4) BMD by the end of the pregnancy [LMWH 4.17% or 0.045 g/cm(3), 95% confidence interval (CI) 0.036-0.062 versus control 3.56% or 0.043 g/cm(3), 95% CI 0.027-0.059]. However, the difference in bone loss between the groups was not statistically significant (0.002 g/cm(3), CI -0.0124 to 0.00865; P = 0.88). No patient suffered vertebral fracture. CONCLUSIONS: Bone loss associated with the use of long-term LMWH is not significantly different from physiological losses during pregnancy.

A longitudinal study of maternal dose response to low molecular weight heparin in pregnancy.

OBJECTIVE: To assess the maternal response to low molecular weight heparin during pregnancy, by estimation of plasma anti-Xa activity, at three specified gestation points and in the nonpregnant state. METHODS: A longitudinal, prospective, observational study was set in a tertiary referral recurrent miscarriage clinic. Twenty-four women, attending consecutively, were invited to participate and gave informed consent. Each woman had a history of recurring pregnancy loss and positive preconception screening for antiphospholipid syndrome. After confirmation of a viable pregnancy all subjects began taking 5000 IU of dalteparin once daily subcutaneously. Serial measurement of plasma anti-Xa activity after administration of dalteparin was performed at three standard gestation points (12, 24, and 36 weeks) and in the nonpregnant state (6 weeks postpartum). RESULTS: Peak anti-Xa levels occurred at 4 hours postbolus in pregnancy, as compared with 2 hours in the nonpregnant state. The mean anti-Xa levels at 12, 24, and 36 weeks' gestation were significantly reduced, at 2 hours postinjection, as compared with the nonpregnant state (P <.001, P <.01, P <.001, respectively). The lowest dose-response curve was at 36 weeks' gestation. A repeated-measures analysis of variance found a significant difference (P <.05) between the 36-week group and the postterm group but not between any of the other groups. CONCLUSION: During pregnancy, differences in the pharmacokinetics of low molecular weight heparin were observed, with an overall reduction in anti-Xa activity. On the basis of this study it is questionable to extrapolate dosing and lack of dose monitoring, in pregnant women, using data derived from a nonpregnant population.

The use of whole rat embryo culture as a technique for investigating potential serum toxicity in recurrent miscarriage patients.

Previously, the rat embryo model has been used as an experimental technique in investigations of the aetiology of idiopathic recurrent miscarriage. The aim of the present study was to validate it as a tool in the investigation of the aetiology of this condition. Subjects (n = 36) with a history of recurrent miscarriage were recruited from two dedicated recurrent miscarriage clinics and compared with control women with at least one previous pregnancy resulting in a live birth (n = 23). Serum from each woman was used as culture medium in the rat embryo model. Cultured embryos were scored for growth and differentiation. No statistical difference was found in any parameter between the two groups. Furthermore, patients from the recurrent miscarriage group whose serum demonstrated a trend towards lower scores, subsequently conceived and underwent uncomplicated pregnancies.

Intra-uterine death due to umbilical cord thrombosis secondary to antiphospholipid syndrome.

This is a case of intra-uterine death due to a thrombotic event on the fetal side of circulation in a woman who was subsequently diagnosed with Antiphospholipid Syndrome.

Oncogenes and tumour suppressor genes in first trimester human fetal gonadal development.

Tumour suppressor genes and oncogenes that control proliferation and apoptosis are known to play an important role in embryogenesis, second trimester fetal oocyte loss, adult ovulation, and in adult male testicular degeneration. We have examined tumour suppressor genes, oncogenes and oestrogen receptors during first trimester human gonadal differentiation to investigate their role at this crucial phase in development. Immunohistochemistry was used to localize the gene products of Bcl-2, c-erB-2, c-myc, p53, nm23 and oestrogen receptor. As gonadal development occurred at 6-12 weeks gestation, a changing pattern of expression was observed that varied in different cell types. The oestrogen receptor was not present in oogonia, spermatogonia and supporting cells during the first trimester. This study highlights the importance of oncogenes and tumour suppressor genes in first trimester gonadal development.

Predicting recurring miscarriage: what is important?

OBJECTIVE: To audit the Miscarriage Clinic in Liverpool and to categorize women into those at low and high risk of a subsequent pregnancy loss. METHODS: Over 4 years (1989-1992), 203 consecutive couples attended the Miscarriage Clinic in Liverpool. A data base was designed and a mathematical model formulated that described the data base. RESULTS: A successful pregnancy outcome was most likely in the presence of the following features: menstrual regularity, fewer than four previous miscarriages, maternal age of less than 30 years, absence of antiphospholipid antibodies, and a previous live birth. Oligomenorrhea was a considerably more significant feature than any other in predicting a subsequent miscarriage. These high-risk oligomenorrheic women were found to have low luteal phase estradiol levels, but normal luteal phase progesterone profiles and normal LH profiles throughout the menstrual cycle. CONCLUSIONS: Women suffering from recurring miscarriage can be placed into differing risk categories. Women with a good prognosis require counseling alone. Women at high risk of a subsequent miscarriage had oligomenorrhea and an isolated deficiency of estradiol in the luteal phase of the menstrual cycle.