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SUMMARY

The metabolism of [³H]pregnenolone and [³H]dehydroepiandrosterone ([³H]DHA) by tissue from the separated zones and whole adrenal glands from newborn anencephalic infants was investigated.

Pregnenolone was metabolized by the whole gland homogenates mainly to pregnenolone sulphate and unconjugated 17α-hydroxypregnenolone and also to small amounts of DHA and dehydroepiandrosterone sulphate (DHAS). DHA was metabolized by the whole gland homogenates mainly to androstenedione and DHAS and small amounts of 11β-hydroxyandrostenedione.

Adrenal gland tissue from a 42-week-old anencephalic infant containing three histologically distinct zones in the adult cortex in addition to residual foetal zone had sulphokinase, 17α-hydroxylase, 17–20 lyase and 3β-hydroxy-steroid dehydrogenase/Δ^4,5 unsaturated isomerase activity in each of these zones. These enzymes were also present in the adrenal adult zone of another anencephalic infant.

Omission of ATP from the incubation medium greatly reduced the conversion of DHA to DHAS in the homogenates and separated zones.

These results are discussed in relation to oestrogen biosynthesis in anencephaly and to foetal 4-en-3-oxosteroid synthesis in utero.

SUMMARY

Dehydroepiandrosterone sulphate (DHAS) was injected intravenously or intra-amniotically into eight volunteers carrying live anencephalic foetuses (including one microcephalic foetus). Urinary and unconjugated serum oestrone, oestradiol and oestriol were measured before and after DHAS administration. In seven pregnant women with live anencephalic foetuses the urinary excretion of oestriol was very low, and the ratio of oestriol to oestrone+ oestradiol was much less than that during normal pregnancy. Increases of urinary oestrone and oestradiol but no significant change in the ratio of oestriol to oestrone + oestradiol were observed 24 h after i.v. administration of DHAS to five patients. In three patients, between 1 and 12 h after i.v. administration of DHAS (100–200 mg), the concentrations of serum oestrone, oestradiol and oestriol increased to 13·5, 6·8 and 3·1 times the control values, respectively. After injection of DHAS (200 mg) intra-amniotically into two patients, the urinary excretion of all three oestrogens increased much more on day 2 than on day 1, and the ratio of urinary oestriol to oestrone + oestradiol rose greatly. On the other hand, the concentrations of unconjugated serum oestrogens in these patients increased progressively between 1 and 12 h or more after DHAS administration, and the maximal level of serum oestriol was 9·8 times the control value while those of oestrone and oestradiol were 4·6 times and 5·0 times the control values, respectively. These results suggest that in late human pregnancy DHAS in the circulation of the mother is converted to oestriol largely via the phenolic pathway (DHAS → oestrone → oestriol), whereas DHAS circulating within the foeto-placental compartment is converted to oestriol via both the phenolic and the neutral intermediates.

Universitätsfrauenklinik, 74 Tübingen, and *II. Medizinische Universitätsklinik, Düsseldorf, Germany

(Received 9 May 1975)

We have reported previously changes of plasma dehydroepiandrosterone (DHA) and plasma dehydroepiandrosterone sulphate (DHAS) before and during pregnancy (Nieschlag, Walk & Schindler, 1974). There are strong indications that labour represents a stressful stimulus to the endocrine system. This is reflected in a rise of maternal plasma corticotrophin (ACTH), corticosteroids, free fatty acids, insulin, androgens and oestrogens (Migneon, Kenny & Taylor, 1968; Rivarola, Forest & Migneon, 1968; Lefebvre, Chapedelaine & Bolté, 1970; Nieschlag, Wombacher, Kremer & Martin, 1970; Kuwabara, Kihara, Arai & Sakamoto, 1971; Kauppila, Tuimala & Haapalahti, 1974). Steroid changes in cord blood during labour have also been noticed (Arai, Kuwabara, Kihara, Okinaga & Sakamoto, 1972). Determinations of DHA and DHAS concentrations in maternal blood during the course of labour are rare and do show a variety of results (Lefebvre et al. 1970; Gandy, 1971). Therefore, we

SUMMARY

Plasma levels of testosterone, androst-4-ene-3,17-dione, dehydroepiandrosterone (DHA) and dehydroepiandrosterone sulphate (DHAS) were estimated both before and after administration of clomiphene citrate to endocrinologically normal boys aged from 2–16 yr and to boys with adrenocortical hypofunction or hypogonadism. A divided daily dose of 200 mg/1·7 m² of surface area was maintained for 15 days. The unconjugated steroids were measured by means of a double isotope derivative technique and the sulphates by gas-liquid chromatography.

The boys without testicular anomaly who were well established in puberty responded with a rise in plasma testosterone. In contrast, prepubertal boys showed a statistically significant decrease in plasma testosterone levels.

A concomitant finding was a significant rise in the plasma levels of androstenedione, DHA and DHAS. It is concluded that clomiphene does not liberate luteinizing hormone before puberty but it may well diminish its secretion. A secondary effect of clomiphene is the stimulation of adrenal C₁₉-steroid production.

Since Baulieu (1962) suggested that dehydroepiandrosterone sulphate (DHAS) was a natural adrenal secretory product, several endocrine tissues have been shown to form steroid sulphates. These can be metabolized and still preserve their conjugated form (Calvin & Lieberman, 1964). This report presents evidence for such transformations by polycystic ovarian tissue.

Homogenized tissue, in 3 ml. Krebs—Ringer improved bicarbonate buffer, was incubated with 25 μc [7α-³H]DHAS (Radiochemical Centre, Amersham, 605 mc/m-mole) for 2 hr. at 37°, in 95%O₂5%CO₂. Neutral, phenolic and conjugate fractions were obtained after adding carrier steroids to the incubation mixture (Fahmy, Griffiths, Turnbull & Symington, 1968). Complete extraction of free steroids was made before conjugate extraction.

The neutral fraction (45% of recovered radioactivity) was chromatographed on

SUMMARY

Infusion into the mother of adrenocorticotrophin during late normal pregnancy was accompanied by rises or falls in the urinary excretion of oestrone, oestradiol and oestriol. A similar variable pattern was found when the subjects infused were receiving regular pharmacological doses of glucocorticosteroid (i.e. when maternal adrenal function was reduced) or were carrying anencephalic foetuses (i.e. when foetal adrenal function was reduced). Similar infusion of a substantial quantity of androst-5-en-17-on-3β-yl sulphate (DHAS) was accompanied by rises in oestrogen excretion by normal subjects. The rises were large compared with basal levels, but small (a few per cent) compared with the amount of DHAS infused. The changes in a pregnancy with anencephaly were within the range of the normal subjects. It is concluded that maternal DHAS plays little part in placental oestrogen synthesis, and that some control of oestrogen synthesis from DHAS occurs by the placenta itself.

SUMMARY

A pool of 500 ml. normal equine follicular fluid was examined for the presence of Δ⁵ 3β-hydroxy steroids. Neither pregnenolone nor 17α-hydroxypregnenolone could be detected (< 1 μg./l.), but there appeared to be a small amount of dehydroepiandrosterone (DHA) present (8 μg./l.). These findings suggest that in the Graafian follicle of the mare the conversion of pregnenolone to progesterone normally proceeds fairly rapidly, and the pregnenolone → 17α-hydroxypregnenolone → DHA → androstenedione pathway is probably of minor importance.

ABSTRACT

Total sulphoconjugated and unconjugated dehydroepiandrosterone (DHA) and total oestrone were measured in plasma of intact sheep fetuses, fetuses hypophysectomized at 104–112 days and fetuses bilaterally adrenalectomized at 98–101 days. At 120–127 days, the mean concentrations of total DHA and oestrone in intact fetuses (n = 13) were 29·7 ± 4·2 (s.e.m.) nmol/l and 14·3 ± 2·8 nmol/l respectively. At term, the values for total DHA and oestrone in hypophysectomized fetuses (n = 13) of 18·0 ± 1·9 nmol/l and 9·1 ±2·0 nmol/l were significantly (P <0·05) lower than the intact group whereas in the adrenalectomized fetuses (n = 8) total DHA (80·8±13·0 nmol/l) was higher (P < 0·05) and total oestrone values were similar to the intact animals. Intrafetal infusion of cortisol at term (1 mg/h for 84 h) raised levels of total oestrone in intact (n = 6; 12·3 ± 2·9 vs 31·6± 8·5 nmol/l) and adrenalectomized (n = 4; 14·2 ± 2·6 vs 190·6 ± 53·0 nmol/l) fetuses and of total DHA in hypophysectomized fetuses (n = 7; 16·0±1·9 vs 31·6 ± 8·5 nmol/l) while infusion of ACTH(1–24) (5 μg/h) was without significant effect in any group. It is concluded that the ovine fetal adrenal in late pregnancy makes no significant contribution either to the high circulating concentrations of DHA sulphate or to the substrates for placental oestrogen synthesis.

J. Endocr. (1985) 104, 279–283

In 12 anaesthetized boars the concentrations of oestrone sulphate and dehydroepiandrosterone sulphate (DHAS) were 15- to 35-fold higher in lymph collected from a vessel in the spermatic cord than in testicular venous blood plasma from a vein in the spermatic cord. The concentrations of testosterone, total unconjugated oestrogens and dehydroepiandrosterone (DHA) were about twofold higher in lymph. The concentrations of all steroids studied were higher in testicular venous blood plasma than in arterial blood plasma (testosterone about sixfold; total unconjugated oestrogens about fourfold; oestrone sulphate about threefold; DHA and DHAS about twofold), but the concentrations of testosterone, total unconjugated oestrogens and oestrone sulphate in rete testis fluid were comparable to those in arterial blood plasma.

Lymph flow from the pig testis was about 7% of plasma flow so that about 80% of the oestrone sulphate and DHAS produced by the testis leaves the organ in the lymph; the comparable values for testosterone, total unconjugated oestrogen and DHA were about 20%.

In the 90-min period following an injection of human chorionic gonadotrophin there were substantial increases in the concentration of testosterone and smaller increases in the other steroids in arterial and spermatic venous blood plasma and in testicular lymph, but not in rete testis fluid; there were also small increases in lymph flow, but no change in blood flow.

SUMMARY

Human adrenal tissue was sliced and incubated with 25 μc [7α-³H]-pregnenolone. The percentage conversion of radioactive precursor to dehydroepiandrosterone (DHA), DHA sulphate, androstenedione, 11β-hydroxyandrostenedione, cortisol and 11-deoxycortisol was estimated by the reverse isotope dilution technique. Incubations of both adult and foetal adrenal slices gave reproducible results. The duration of the incubation period was an important factor affecting the pattern of radioactive steroids synthesized, the adult adrenal pattern being dissimilar to that of the foetal adrenal. A direct proportional relationship between the weight of the incubated tissue and the biosynthesis of cortisol from exogenous [7α-³H]-pregnenolone was not established.

The production of DHA sulphate relative to free DHA increased markedly from 12 to 27 weeks gestation. When incubated for 2 hr. the combined production of DHA and DHA sulphate relative to cortisol and androstenedione decreased with gestational age. There was evidence for considerable 3β-hydroxysteroid dehydrogenase activity in foetal adrenals at 12 to 27 weeks gestation.