Early development of the human placenta and pregnancy complications.

An adequately sized placenta at a suitable site with appropriate depth and centripetal progression of implantation are the major factors for optimal fetal development. The cytotrophoblasts surround the blastocyst fuses at the site of the uterine attachment. This forms a second layer of multinucleated syncytiotrophoblasts that constitutes the inner epithelial boundary of the chorionic villous against the intervillous space. In a normal pregnancy, extravillous cytotrophoblasts (EVT) invade and obstruct the spiral arteries and remodel them. Vacuoles in the syncytial cell layer fuse and develop the intervillous space. The inner cell mass (embryoblast) gives rise to the umbilical cord and the mesenchyme in the chorionic villi. Vasculogenesis starts with the formation of hemangioblastic cords in this mesenchyme. The trophoblastic cell columns anchor the placenta. A variety of molecular pathways participate in the placentation process. Placental morphogenesis occurs mainly through complex cellular interactions between the chorionic villous and the extravillous cytotrophoblasts. The formation of the normal structure of the chorionic villi, syncytiotrophoblast layer and vasculature is essential for placental function, hormone production, and regulation of fetal growth. At each stage of placental development, genetic variants, exposure to infection, poor vascular function, oxidative stress, or failure of normal development can all lead to abnormal formation resulting in the clinical complications of pregnancy such as fetal growth disorders, neonatal neurologic abnormalities, placental adhesions, and inflammatory problems as well as maternal disease such as preeclampsia.

The Role of Oxidative Stress, Adhesion Molecules and Antioxidants in Preeclampsia.

Oxidative stress is a consequence of reduction in the antioxidant capacity and excessive production of reactive oxygen and nitrogen species (ROS). Oxidative agents, which are overproduced due to ischemic-reperfusion injury in the placenta, may overwhelm the normal antioxidant activity. This imbalance is a key feature in the pathogenesis of preeclampsia. A decrease in glutathione peroxidase (GPX) activity is associated with the synthesis of vasoconstrictive eicosanoids such as F2-isoprostanes and thromboxane, which are known to be upregulated in preeclampsia. Biochemical markers of lipid peroxidation, such as malondialdehyde and F2-isoprostane in the placenta, are also increased. Adhesion molecules participate in the pathophysiology of preeclampsia by contributing to a reduced invasion by the trophoblast and increased vascular endothelial damage. Superoxide dismutase (SOD), catalase (CAT) and GPX play important roles counteracting oxidative stress. Other antioxidant factors participate in the etiology of preeclampsia. Levels of antioxidants such as Lycopene, Coenzyme 10, as well as some vitamins, are reduced in preeclamptic gestations.

Medical abortion in the first trimester: the use of serum hCG and endometrial thickness as markers of completeness.

OBJECTIVE: The combination of mifepristone and misoprostol is an established method for induction of early first trimester abortion, but there is no consensus about the best evaluation of treatment outcome. We assessed endometrial thickness, determined by ultrasound and serum-human chorionic gonadotropin (s-hCG) as markers of successful management. METHODS: Prospective trial involving 255 women, with a gestation of 62 days or less, who were to undergo medical abortion. In addition to our established routines of performing clinical and ultrasound examinations, we also determined the s-hCG level prior to treatment and at follow-up. RESULTS: Of the 255 subjects treated during the study, 20 (7.8%) were lost to follow-up. The overall complete abortion rate was 94.0%. Fourteen subjects required vacuum aspiration, nine of them prior to the scheduled follow-up and five thereafter. None of the pregnancies were ongoing. A decrease of 99% in s-hCG levels was noted in 99% of the women, when levels determined prior to mifepristone intake and those measured 15-71 days post-abortion were compared. CONCLUSION: This study confirms that s-hCG levels drop sharply after medical abortion. To assess the completeness of medical abortion, we recommend that clinical examination to be combined with determination of s-hCG. Ultrasonography should be carried out only when indicated.

Retarded bone growth in thyroid hormone resistance. A clinical study of a large family with a novel thyroid hormone receptor mutation.

OBJECTIVE: Thyroid hormone resistance (RTH) is characterised by variable tissue hyporesponsiveness to thyroid hormone. The disorder is usually caused by mutations in the thyroid hormone receptor beta (TR beta). We describe a large family with this disorder. SUBJECTS AND MEASUREMENT: We identified 36 family members with RTH in four generations by screening relatives of patients with the diagnosis. The diagnosis was verified by identification of a mutation in the thyroid hormone receptor beta (TR beta) gene. Symptoms, clinical findings and laboratory tests of 29 affected individuals were compared with those of 16 first-degree relatives. RESULTS: Bone maturation in children with RTH was delayed. The height was lower both in children and in adults with RTH than in the controls. Children with RTH had lower birth weight than the controls, particularly when the condition was inherited from the father. We did not observe increased prevalence of neuropsychological symptoms associated with RTH in this family. Palpitations and increased pulse rate indicated mild cardiac hyperthyroidism. Direct sequence analysis of the TR beta gene revealed a novel point mutation, a heterozygous transition c.1031G>C in exon 9 theoretically substituting Gly344Ala. CONCLUSIONS: We found evidence of skeletal tissue hypothyroidism that resulted in permanent growth retardation from prenatal to adult life. We found substantial variations in thyroid hormone levels and clinical presentation, but most individuals were without symptoms of thyroid disorder.

Human chorionic gonadotropin in maternal serum in relation to fetal gender and utero-placental blood flow.

BACKGROUND: To investigate whether fetal gender differences in human chorionic gonadotropin (hCG) in maternal serum and the presence of hCG receptors in the wall of the uterine arteries influence the utero-placental blood flow. METHOD AND MATERIAL: Sixty-six healthy women with singleton uncomplicated pregnancies were examined at 8-10, 16-19 and 31-37 weeks of gestation. The pulsatility index (PI) was measured in the uterine arteries, simultaneously with sampling of peripheral maternal blood for hCG determination. Volume flow in the uterine arteries was determined in the second and third trimesters only. RESULTS: In the first and second trimesters no gender differences in the hCG levels were observed. From the second to the third trimester the hCG levels increased significantly in pregnancies with female fetuses (P < 0.05), while in pregnancies with male fetuses the hCG levels tended to decline. The PI declined significantly from the first to the third trimester in both genders (P < 0.001). In the first and third trimesters no gender differences were seen. In the second trimester the PI values were significantly higher in pregnancies with male fetuses than in those with female fetuses (P < 0.02). The flow volume increased significantly in both genders from the second to the third trimester (P < 0.001). In the third trimester the flow volume was higher in pregnancies with female fetuses than in those with male fetuses (P = 0.05). CONCLUSION: The gender differences in uterine artery PI and flow volume were not correlated to maternal serum hCG levels.

Effects of the endothelin-1 receptor antagonist tezosentan on renal blood flow and diuresis during prolonged increased intra-abdominal pressure.

BACKGROUND: It has earlier been shown that increased intra-abdominal pressure (IAP) reduces renal blood circulation and urine output both clinically and experimentally. The aim of this study was to investigate the effect of endothelin-1 inhibition by the endothelin-1 receptor antagonist tezosentan on renal blood circulation and diuresis in pigs subjected to prolonged increased intra-abdominal pressure. MATERIAL AND METHODS: The IAP in domestic pigs was maintained at 30 mmHg for 3 h. One group of 10 animals was pre-treated with the endothelin-1 receptor antagonist tezosentan, and then received continuous infusion of tezosentan throughout the experiment. Another group of 10 animals served as control. We measured renal cortex blood flow, plasma renin activity, blood concentrations of endothelin-1 and aldosterone, and diuresis. RESULTS: The administration of tezosentan to pigs with an IAP of 30 mmHg was followed by reduced arterial pressure, reduced renal cortex blood flow, and reduced diuresis. The plasma renin activity increased markedly, but neither renal vascular resistance nor blood concentration of aldosterone did change significantly. CONCLUSION: Tezosentan reduced the arterial blood pressure, which resulted in decreased renal cortex blood flow, and aggravation of the oliguria usually observed under increased IAP. The plasma renin activity increased, but this was not followed by changes in renal vascular resistance, or blood concentration of aldosterone. The results indicate that drugs, which reduce the arterial pressure, may be harmful to the kidneys under increased IAP.

Replacement of dehydroepiandrosterone in adrenal failure: no benefit for subjective health status and sexuality in a 9-month, randomized, parallel group clinical trial.

The physiological role of dehydroepiandrosterone (DHEA) is not well understood, but studies suggest positive effects on subjective health and bone metabolism. We have conducted a clinical trial with DHEA replacement in adrenal failure with the primary aim of evaluating effects on subjective health status and sexuality. Thirty-nine women with adrenal failure were randomized to 9 months of treatment with 25 mg DHEA (n = 19) or placebo (n = 20). Treatment effects were assessed by validated questionnaires of subjective health and sexuality. DHEA replacement yielded a wide variation of effects on the subjective health scales, which were not different from the effects of placebo. Almost all patients receiving DHEA obtained normal androgen levels. Eighty-nine percent of the patients receiving DHEA experienced side-effects, in particular increased sweat odor and scalp itching. DHEA replacement did not significantly change the levels of blood lipids, IGF-I, and markers of bone metabolism. In conclusion, we do not find evidence of beneficial effects of DHEA on subjective health status and sexuality in adrenal failure. However, DHEA may be beneficial for subgroups of patients with adrenal failure, but these remain to be identified. Premenopausal androgen levels can be restored with 25 mg DHEA daily in most female patients, but side-effects are frequent.

Human chorionic gonadotropin and testosterone in normal and preeclamptic pregnancies in relation to fetal sex.

OBJECTIVE: The aim of the present study was to evaluate the effects of fetal gender on serum human chorionic gonadotropin (hCG) and testosterone in normotensive and preeclamptic pregnancies. METHODS: The study consisted of 137 women with singleton pregnancies in the third trimester. Seventy-three pregnancies were uncomplicated; among those were 35 male and 38 female fetuses. Sixty-four pregnancies were complicated by preeclampsia; among those were 33 male and 31 female fetuses. Human chorionic gonadotropin and total testosterone were measured in maternal peripheral blood. RESULTS: In male-bearing pregnancies, maternal hCG and testosterone serum levels were significantly higher in preeclamptic than normotensive mothers (P <.001). In female-bearing pregnancies, testosterone levels were significantly higher in preeclamptic than normotensive mothers (P <.001), whereas the hCG levels were not significantly different. Male-bearing preeclamptic women had significantly higher testosterone levels than female-bearing preeclamptic women (P <.02), whereas the hCG levels were not significantly different. In uncomplicated pregnancies the hCG levels were significantly higher in female-bearing than in male-bearing mothers (P <.005), whereas the testosterone levels were not significantly different. CONCLUSION: In preeclamptic pregnancies with male fetuses, the maternal serum hCG levels were significantly higher than in uncomplicated pregnancies. Total testosterone levels were significantly higher in pregnancies with either gender and significantly higher in male-bearing than in female-bearing pregnancies. This may indicate an androgen influence on the pathophysiologic mechanism of preeclampsia.

Hormonal changes related to reduced renal blood flow and low urine output under prolonged increased intra-abdominal pressure in pigs.

OBJECTIVE: To investigate effects of prolonged increased intra-abdominal pressure (IAP) on diuresis, renal blood flow, and hormones that influence renal function, in particular endothelin. DESIGN: Experimental study. SETTING: Haukeland University Hospital, Norway. ANIMALS: 21 domestic pigs. METHODS: The TAP was maintained at normal (n = 7) or at 20 mmHg (n = 7) or 30 mmHg (n = 7) for three hours. MAIN OUTCOME MEASURES: Urine output, renal venous pressure, renal artery blood flow (transit-time flowmetry), renal cortex blood flow (microspheres), and renin, aldosterone, atrial natriuretic factor (ANF), adrenaline, noradrenaline, cortisol, and endothelin-1 (ET-1) in renal venous blood. RESULTS: An IAP of 20 mmHg was followed by no significant changes in the variables studied. An IAP of 30mmHg was associated with anuria, considerably reduced renal blood flow and increased renal vascular resistance. The renin activity and the blood concentrations of ET-1, aldosterone, noradrenaline, adrenaline, and cortisol increased during the three hours that IAP was at 30 mmHg. CONCLUSION: An IAP of 20 mmHg did not influence renal haemodynamics or diuresis. The low renal blood flow observed at an IAP of 30 mmHg probably results from reduced arteriovenous pressure difference and vasoconstriction. Increased concentrations of endothelin, angiotensin II, and noradrenaline may account for the vasoconstriction. The anuria can be explained by low renal blood flow and increased reabsorption of sodium in renal tubules caused by aldosterone.

Neurohormonal activation rapidly decreases after intravenous therapy with diuretics and vasodilators for class IV heart failure.

OBJECTIVES: This study was designed to determine whether therapy with vasodilators and diuretics, designed to normalize loading conditions in decompensated heart failure (HF), reduces neurohormonal activation in the short term. BACKGROUND; Elevated vasoactive neurohormone levels in chronic HF have adverse prognostic impact and may be targeted by specific therapies. METHODS: Endothelin-1, catecholamines, renin, aldosterone, angiotensin and atrial natriuretic peptides (ANP, N-ANP and BNP) were measured in 34 patients with advanced HF before and after hemodynamically guided therapy with vasodilators and diuretics. The therapy was designed to reduce filling pressures and systemic vascular resistance (SVR) without inotropic therapy. Blood was drawn before therapy (A), after initial diuretic and nitroprusside therapy to optimize hemodynamics (B, mean 1.4 days) and after transition to an oral regimen designed to maintain improved hemodynamics (C, mean 3.4 days). RESULTS: Mean pulmonary wedge pressure fell from 31 to 18 mm Hg, right atrial pressure from 15 to 8 mm Hg, and SVR from 1,780 to 1,109 dynes/s/cm(-5). Cardiac index increased from 1.7 to 2.6 l/min/m(2) without intravenous inotropic agents (all p < or = 0.05). Average endothelin levels declined by 30%, from 7.7 to 5.5 pg/ml, and remained low at time point C, 5.2 pg/ml (p < 0.01). Norepinephrine was 858 at time A, 817 at time B, and fell by time C to 608 pg/ml (p < or = 0.05). The mean plasma BNP level fell by 26% after only 1.4 days and by 53% at time C (p < 0.001). CONCLUSIONS: Neurohormonal activation rapidly decreases after short-term therapy tailored to decrease severely elevated filling pressures and SVR without inotropic agents. Therapy designed to address neurohormonal activation should include therapy to improve severe resting hemodynamic compromise.

Disappearance of human chorionic gonadotropin after cesarean section with regard to fetal sex.

BACKGROUND: To evaluate the influence of gender on the disappearance of human chorionic gonadotropin by cesarean section after fullterm pregnancies. MATERIALS AND METHODS: Forty-nine uncomplicated pregnancies: 26 had male (male group) and 23 had female (female group) fetuses. RESULTS: Before the cesarean section the serum human chorionic gonadotropin levels were higher in the female than in the male bearing pregnancies. After cesarean section the human chorionic gonadotropin levels fell rapidly. The decrease in the human chorionic gonadotropin values was significantly faster in the male than in the female group during the first hours after delivery (2P < 0.02), while no significant difference was seen after 24 and 72 h. CONCLUSION: This study shows a significantly faster human chorionic gonadotropin disappearance rate in pregnancies with male compared with female fetuses during the first hours after a cesarean section. This indicates a gender difference, which could be related to different human chorionic gonadotropin molecular structures or to more specific metabolic events.