European Journal of Endocrinology

Changes occur in the infant ovary which develop the structurally simple organ at birth to a highly complex one in the maturing animal. The ovary in the immature mouse is not a dormant organ but one that is characterized by a continuous growth and development and a concurrent continuous degeneration of oocytes and follicles. The stroma cells which are present in the ovary at birth are apparently a pool of cells with multiple potentialities, which contribute to the development of the earliest granulosa and theca cells. The interfollicular stroma of the juvenile ovary, however, originates from collapsing and contracting follicles. The quantitative changes in the oocyte and follicle population during the immature period lead to a marked reduction in the total number of oocytes and a simultaneous numerical increase in follicles at different stages of development. Factors influencing oocyte atresia and follicle development in the immature mouse are discussed.

Using a variety of experimental techniques, including perfusion of placentas in situ, injection into the intact foeto-placental unit via the umbilical vein, as well as long-term administration into the amniotic sac or antecubital vein of the mother, very little if any oestrone, 17β-oestradiol- or oestriol-like radioactive material could be detected in the placenta, foetal tissues and urine of the mother following the administration of labelled progesterone.

The results are interpreted as supporting the concept that progesterone is not a significant precursor of placental oestrogens.

Anti-oestrogenic substances have been studied systematically in order to get some guides about structure - activity relationships. The substances were tested in the mouse a) for uterotrophic and anti-uterotrophic activities and b) for their capacity to inhibit the uptake of 17β-oestradiol by the uterus and vagina in vitro. A few such in vitro experiments were also carried out in the rat.

Only MER-25 was completely devoid of any oestrogenic activity and was able to suppress oestrogenic stimulation completely. U-11,100A and CN-55,945 were partial agonists producing less than total oestrogen antagonism. MRL-37, DMS, meso-butoestrol, oestriol and ent-17β-oestradiol were impeded oestrogens, i. e., produced dose-response curves with shallow slopes. These compounds, except oestriol which was inactive, were weakly anti-uterotrophic. Cis- and trans-clomiphene, ICI-47,699 and ICI-46,474 which are also cis/trans isomers, WSM-4613 and U-11,555A showed no sign of anti-oestrogenic activity.

All the tested substances suppressed the binding of 17β-oestradiol to the mouse uterus and vagina. The impeded oestrogens were generally very potent. However, their inhibitory action was of short duration since they were easily washed out. The remaining compounds (dialkylamino-alkyl-ether derivatives) were generally very firmly bound to the target tissues, the binding being even firmer than that of the oestrogens 17β-oestradiol or meso-hexoestrol.

Possible mechanisms of actions of the two kinds of anti-oestrogens are presented. A model explaining the impeded uterotrophic response is also given.

Background and aim: The aim of this study was to illustrate the present role of transsphenoidal surgery as primary therapy in GH-secreting adenomas, and to compare the results concerning control of disease with previous series using older criteria of cure.

Method: We report on a consecutive series of 688 acromegalic patients treated over a time period of 19 years. Biochemical cure was defined as normalisation of basal GH level, suppression of GH levels to below 1 ng/ml during an oral glucose load and normalisation of IGF-I levels. Of the 506 patients undergoing primary transsphenoidal surgery, a total of 57.3% postoperatively fulfilled the criteria used.

Results: The rate of biochemical ‘cure’ correlated with the magnitude of the initial GH levels, the tumour size and invasion. The overall complication rate was below 2%. Mortality in this series was 0.1% (1 of 688). During a follow-up period of 10.7 years only two recurrences (0.4%) occurred. However, in the patients treated by transcranial surgery and by repeat surgery the cure rate was found to be relatively low (5.2 and 21.3% respectively).

Conclusions: These data suggest that surgery remains with very few exceptions the primary treatment of acromegaly for (i) a high cure rate, (ii) low morbidity, (iii) low recurrence rate and (iv) immediate decline of GH. Based on current criteria of cure, recurrences are uncommon. However, cure by surgery alone is improbable in patients harbouring extended, invasive tumours with high secretory activity, in whom further adjuvant treatment is mandatory.

IGF-I and -II share specific serum carrier proteins which elute on neutral Sephadex G-200 gel permeation chromatography at apparent molecular masses of 50 and 200 kD. The half-lives of free and carrier protein-bound ¹²⁵I-IGF-I and -II were determined after bolus injections of the tracers into two normal adults. Labelled IGF-I and -II migrated first with the 50-kD and later with the 200-kD complex. In these complexes their apparent half-lives were 20–30 min and 12–15 h, respectively. The apparent half-life of free ¹²⁵I-IGF-I and -II was 10–12 min. In a second set of experiments, recombinant human insulin-like growth factor I was infused during 6 days in two healthy adults at a dose of 20 μg · kg⁻¹ · h⁻¹ (corresponding to around 30 mg/day). Serum obtained before and during the infusion was subjected to neutral Sephadex G-200 gel permeation chromatography and fractions were pooled according to the apparent molecular masses at which the carrier protein complexes elute. IGF-I and -II in these pools were determined by RIA. Before the IGF-I infusion, 92 and 272 μg/l of IGF-I and -II were found in the 200-kD complex, 45 and 91 μg/l in the 50-kD complex, and 15 and 5 μg/l were present in the free form. Corresponding figures during the IGF-I infusion were 389 and 18 μg/l for the 200-Kd complex, 201 and 54 μg/l for the 50-kD complex, and 80 and < 1 μg/l for free IGF-I and -II. Using the half-lives of the tracer studies and the levels of the different molecular weight forms of IGF in serum, the production rates for IGF-I and -II were calculated to be 10 mg and 13 mg per day.

Objective: In the past years the interaction of GH and 11βhydroxysteroid dehydrogenase (11βHSD) in the pathogenesis of central obesity has been suggested.

Design: We studied the effects of 9 months of GH treatment on 11βHSD activity and its relationship with body composition and insulin sensitivity in 30 men with abdominal obesity, aged 48–66 years, in a randomised, double-blind, placebo-controlled trial.

Methods: Urinary steroid profile was used to estimate 11βHSD type 1 and 2 (11βHSD1 and 11βHSD2) activities. Abdominal s.c. and visceral adipose tissues were measured using computed tomography. Glucose disposal rate (GDR) obtained during a euglycaemic–hyperinsulinaemic glucose clamp was used to assess insulin sensitivity.

Results: In the GH-treated group the 11βHSD1 activity decreased transiently after 6 weeks (P< 0.01) whereas 11βHSD2 increased after 9 months of treatment (P< 0.05). Between 6 weeks and 9 months, GDR increased and visceral fat mass decreased. Changes in 11βHSD1 correlated with changes in visceral fat mass between baseline and 6 weeks. There were no significant correlations between 11βHSD1 and 11βHSD 2 and changes in GDR.

Discussion: The study demonstrates that short- and long-term GH treatment has different effects on 11βHSD1 and 11βHSD2 activity. Moreover, the data do not support that long-term metabolic effects of GH are mediated through its action on 11βHSD.

The present study investigates the diurnal variations of free plasma oestradiol levels in late human pregnancy. The oestradiol levels are correlated to the maternal adrenal function as reflected by the plasma levels of cortisol.

According to the half life time of oestradiol, blood samples were collected at short time intervals of 30 and 60 min, respectively. Three pregnant women volunteered in the study.

Free oestradiol was measured by radioimmunoassay and cortisol was quantitated by a protein binding method.

All patients exhibited a circadian rhythm for free oestradiol with significantly higher values in the early morning (28.3 ± 7.2 ng/ml) than in the afternoon and early night (21.2 ± 3.6 ng/ml, P < 0.001). The course of oestradiol followed in a moderate but significant correlation plasma cortisol (r = 0.34, P < 0.001). During the period of increasing cortisol the oestradiol levels demonstrated the phenomenon of episodic secretion.

The results obtained suggest that the maternal adrenals predominantly regulate the diurnal rhythm of free oestradiol in late human pregnancy.