Beverley E. Pearson Murphy

Does the human fetal adrenal play a role in parturition

Abstract Cortisol and cortisone were determined in umbilical cord serum by competitive binding radioassay following extraction and column chromatography. Cortisol levels in early gestation (12 to 18 weeks) were very low (7.0 ± 1.2 ng. per milliliter) but had risen to 23.3 ± 3.4 ng. per milliliter by late pregnancy (36 to 41 weeks). Levels were unchanged by induced labor (24.0 ± 4.5 ng. per milliliter) but were considerably elevated (P

CORTISOL AND CORTISONE IN HUMAN FETAL DEVELOPMENT

Abstract Although in adult life cortisone (E) circulates at only about 1 5 the concentration of cortisol (F), the situation is reversed in fetal life where the amount of E exceeds that of F. This is due to the high rate of metabolism of F to E by the placenta and other fetal tissues and the relative inability of the fetus to reduce E to F. Thus although the fetal adrenal produces F as early as 8 weeks of life, much of it is converted to E and secreted as such. This state appears to continue until late in pregnancy. An exception is the chorionic membrane which, like the maternal uterus, reduces E to F during the second half of gestation, thereby increasing amniotic fluid F. At about 35 weeks gestation, there is an alteration in fetal adrenal function as reflected by a 5-fold rise in amniotic fluid cortisol sulfate which parallels rising surfactant concentration and lung maturation. This change may be brought about at least in part by a dialyzable, heat-stable 11β-dehydrogenase inhibitor which is present in umbilical cord serum at delivery. It seems likely that conversion of F to E serves to maintain a low cortisol level throughout gestation until cortisol is required for maturational events to occur close to term.

Neuroendocrine responses to inhibitors of steroid biosynthesis in patients with major depression resistant to antidepressant therapy

Objective: Patients with major depression frequently have high Cortisol levels and resistance to dexamethasone. We sought to determine to what extent major depression might be influenced by inhibitors of steroid biosynthesis and to study the endocrine changes produced. Method: After drug washout, 20 treatment-resistant patients with major depression were given aminoglutethimide, metyrapone, and/or ketoconazole, along with a small dose of cortisol for 8 weeks. Hamilton Depression Rating Scale (HDRS) ratings, 8:00 AM Cortisol, dehydroepiandrosterone sulfate (DHAS), adrenocorticotropin (ACTH), and testosterone levels were followed weekly or offener. A dexamethasone suppression test (DST) was conducted before and after treatment. Results: Seventeen patients (85%) completed the course of treatment, and a significant mean drop (P ≤ 0.0001) of 50% in the HDRS score occurred by 7 weeks of treatment. Cortisol levels fluctuated widely and were often still high after the patient had improved clinically. Dehydroepiandrosterone sulfate levels fell more uniformly and were found to be a useful indicator of compliance and, to some extent, efficacy with aminoglutethimide and ketoconazole therapy. The correlation between DHAS and HDRS (r = 0.94) was significant (P = 0.02). Testosterone levels in men fell with ketoconazole but returned promptly to normal at the end of treatment. Adrenocorticotropin levels were normal or elevated, depending on the assay used, and rose (P = 0.07; n = 13) in most subjects during therapy. Of the 6 responders who had nonsuppressor DSTs before starting therapy, 5 had reverted to normal 1 to 2 weeks following cessation of therapy (P = 0.0006). Conclusions: Abnormal metabolism of adrenocortical steroids may perpetuate depression, and alterations of synthesis or metabolism of these steroids may lead to a remission.

Demonstration of novel compounds in human fetal tissues and a consideration of their possible role in parturition

A study of a new group of compounds and their possible relevance to human parturition is presented. These compounds behave chemically and chromatographically like steroids and have been tentatively identified as analogues of 11-hydroxypregnenolone. Determined by radioenzymatic assay, highest levels were found in the fetal zone of the fetal adrenal and were about 100 times those of fetal serum. Umbilical cord levels were higher after spontaneous labor than after elective cesarean section or induced labor in premature as well as mature infants. It is hypothesized that a fetal factor distinct from adrenocorticotropic hormone acts on the adrenal cortex, particularly the fetal zone, to stimulate 11 beta-hydroxylation of nonglucocorticoid corticosteroids and that these steroids and their metabolites are excreted via the urine into the amniotic fluid. Thus they would reach the membranes and decidua where they might complete with progesterone for receptor sites, decreasing lysosomal stability with the resultant production of prostaglandins and the onset of labor.

Relative binding of certain steroids of low polarity to human sex hormone—Binding globulin: Strong binding of 2-methoxyestrone, a steroid lacking the 17β-oh group

The cross-reactivities for binding sites on human sex hormone-binding globulin (SHBG) of a number of steroids of low polarity, including progesterone and estrogen metabolites, were studied. Binding relative to testosterone (100%) was low (less than or equal to 3%) except for 2-methoxyestrone (81%), 3-acetoxyestradiol (16%), 4-methoxyestradiol (6%), 3 beta-hydroxy-5 beta-pregnan-3-one (5.8%), 5 alpha-dihydrodeoxycorticosterone (4.5%), deoxycorticosterone (4%), 20 alpha-hydroxy-5 alpha-pregnan -3-one (4%), 4-methoxyestrone (4%) and 5 alpha-dihydroprogesterone (3.5%). 2-Methoxyestrone is the only steroid lacking a 17 beta-hydroxyl group which binds to SHBG with strong affinity.

Pitfalls in the assay of cortisol.

Many currently used cortisol assays, including commercially available kits, are validated only for adult serum and may give misleading results when applied to urine, fetal or neonatal serum or amniotic fluid. Evidence for such errors is presented to illustrate the danger and confusion which may result.

Does sex hormone-binding globulin play a role in the transport of estradiol in vivo?

The distribution of estradiol and testosterone into sex hormone-binding globulin (SHBG)-bound, albumin-bound, and unbound fractions in whole serum under equilibrium conditions at 37 degrees C is described in women with normal menstrual cycles, pregnant women, and newborn infants. The percentage of estradiol bound to SHBG was determined by equilibrium dialysis at 37 degrees C. Whole serum, 0.1 ml, was dialyzed against 0.1 ml of the same serum heated at 60 degrees C for 1 hour (a procedure shown to denature SHBG but not to affect albumin). The percentage of unbound estradiol in whole serum was measured by dialyzing native serum against an isosmotic dextran solution. Testosterone binding was studied similarly. Our findings show that SHBG is an important binder of estradiol in both pregnant and nonpregnant women. However, estradiol binding by SHBG is undetectable in the newborn infant. Testosterone is significantly bound to SHBG under all circumstances. We conclude that SHBG does play a role in the transport of estradiol in women, particularly in pregnancy.

Radioenzymaticassay for some substrates and inhibitors of human placental 11-hydroxysteroid dehydrogenase.

A radioenzymaticassay (REA) is described, using labelled cortisol and a homogenate of human placenta. Steroids which are able to compete with the tracer for conversion to the 11-keto form can be measured. Of these, 11 beta and 11 alpha-hydroxyprogesterone (11 beta-hydroxypregn-4-ene-3, 20-dione), 3 beta, 11 beta-dihydroxypregn-5-ene-20-one, 11 beta, 20 alpha-dihydroxypregn-4-ene-3-one and corticosterone are the most active, while cortisol and prednisolone are moderately active. All other steroids tested competed less than 10% as effectively as 11 beta-hydroxyprogesterone at 50% conversion with no added substrate. The sensitivity was 0.8 ng of 11 beta-hydroxyprogesterone and 5 ng cortisol. Using this REA, preliminary studies were carried out to investigate the endogenous substrates and inhibitors of 11-hydroxysteroid dehydrogenase in human fetal tissues.