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R P Stolk
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S W J Lamberts
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F H de Jong
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H A P Pols
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D E Grobbee
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Abstract

To investigate the role of cortisol in the etiology of insulin resistance in men and women, we examined 218 healthy non-hospitalized elderly, selected from the Rotterdam Study. Free cortisol was assessed by the ratio of fasting serum cortisol over corticosteroid-binding globulin (CBG), and insulin resistance was estimated by the fasting insulin level. CBG was higher in women and decreased with age. In both men and women, the early morning free cortisol level showed no association with age or waist/hip ratio. In men, an inverse association between cortisol and body mass index was observed. In women, higher cortisol levels were associated with increased insulin levels; an increase of 9·7 mU/l insulin per unit cortisol/CBG (s.e. 3·9, P=0·01). The association did not change after adjustment for age, body mass index or waist/hip ratio. The results of this study in elderly subjects suggest that in women cortisol may be implicated in the age-associated insulin resistance.

Journal of Endocrinology (1996) 149, 313–318

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I A Klaij
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M A Timmerman
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P Kramer
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H M A Meijs-Roelofs
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F H de Jong
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Abstract

Age-related short-term effects of hemicastration on testicular weight, serum FSH, immunoreactive inhibin, LH and testosterone, testicular levels of inhibin subunit mRNA expression, and bioactive and immunoreactive inhibin were studied in rats of 8, 15 and 22 days of age. Hemicastration led to an increased weight of the remaining testis after 24 h in 8- and 15-day-old rats, but not in 22-day-old rats. Serum FSH levels were elevated in all hemicastrated rats after 8 h. However, serum immunoreactive inhibin levels were decreased only after 72 h in 8-day-old rats and after 24 h in 15- and 22-day-old rats. Inhibin α-subunit mRNA expression was increased in the testes of hemicastrated rats of 8 and 15 days of age, whereas inhibin βB-subunit mRNA expression was elevated in the testes of 15-day-old rats but not in those of 8- and 22-day-old rats. The increase in α-subunit mRNA content per testis was caused by an increased concentration and increased testicular weight, whereas the increase in βB-subunit mRNA in the remaining testis parallelled the increased testicular weight, indicating that different mechanisms play a role in the regulation of these mRNAs. In 22-day-old rats, a transiently decreased expression of inhibin βB-subunit mRNA was observed 8 h after hemicastration. The increased inhibin α- and βB-subunit mRNA expression in 8- and 15-day-old rats did not result in increased testicular bioactive and immunoreactive inhibin content of the remaining testis, whereas in 22-dayold rats an increased immunoreactive inhibin content of the remaining testis was observed. These data indicate that efficiency of translation, post-translational modifications or transport from the testis play an important role in determining the final testicular content of inhibin.

In conclusion, the response of the remaining testis and the role of inhibin in the regulation of the pituitary-testis axis after unilateral castration depend on the age at which the animals are hemiorchidectomized.

Journal of Endocrinology (1994) 141, 143–151

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W. P. HERMANS
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M. H. M. DEBETS
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E. C. M. VAN LEEUWEN
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F. H. DE JONG
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A single injection of steroid-free bovine follicular fluid (bFF), which contains inhibin-like activity, was given to adult female rats at 09.00 h on dioestrus-2 (the day after metoestrus), dioestrus-3, pro-oestrus or oestrus. Peripheral concentrations of gonadotrophins were measured at 2-h intervals after injection. Compared with values in control animals treated with bovine plasma, injection of bFF did not influence concentrations of LH. In contrast, at all days studied injection of bFF resulted in suppressed concentrations of FSH, during a period which started between 4 and 10 h after injection and lasted 4–12 h, depending on the day of the cycle. With the exception of pro-oestrus, the period of suppression was followed by one in which fluctuating levels of FSH were found; in general, resulting levels were higher though not significantly increased. This latter effect was most pronounced on dioestrus-2 and dioestrus-3, when levels of FSH, which were already low in control animals, were first suppressed during the 6 h after injection of bFF.

These data, in conjunction with results from an earlier study in rats at dioestrus-1, showed that administration of bFF induces a fast and selective suppression of FSH secretion on all days of the cycle. This period of suppression was followed by one with fluctuating levels of FSH which showed a tendency to be higher, indicating that disturbances in FSH secretion, such as are caused by bFF, can be compensated for quickly. In this way the process of follicular maturation might be protected.

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A. J. Grootenhuis
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J. Steenbergen
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M. A. Timmerman
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A. N. R. D. Dorsman
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W. M. M. Schaaper
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R. H. Meloen
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F. H. de Jong
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ABSTRACT

The existence of various molecular weight forms of inhibin in ovarian follicular fluid has been reported earlier, while there is no information on the form of inhibin in testicular tissue. Inhibin bioactivity was therefore estimated in eluates of slices, obtained after SDS-PAGE of rat testicular and ovarian homogenates, rat Sertoli cell-conditioned medium (rSCCM) and bovine ovarian follicular fluid (bFF).

The only form of inhibin detected in testes from 22-day-old rats and in rSCCM was a 30 kDa protein. In rat ovarian extracts, larger forms of inhibin were also found as well as the predominant 30 kDa form. An activin-like activity was found in the 25 kDa SDS-PAGE eluates of both rSCCM and ovarian homogenates, which caused a dose-dependent increase of FSH release from cultured pituitary cells.

Activin-like activity and several forms of inhibin were found in bFF after SDS-PAGE. After purification of inhibin from bFF using dye affinity, anion-exchange, lentil lectin affinity chromatography and a subsequent reversed phase chromatography step, two pools of inhibin activity were obtained. These were separated by SDS-PAGE revealing 30 and 58 kDa inhibin forms. The immunoactivity of these forms of inhibin was then estimated using antibodies against the 22 N-terminal amino acids of the α subunit of 30 kDa bovine inhibin. It appeared that the two molecular weight forms of inhibin had bioactivity/immunoactivity ratios which differed more than five-fold. This indicates that results of radioimmunoassays of inhibin of ovarian origin, using peptide antisera, should be interpreted with caution.

Journal of Endocrinology (1989) 122, 293–301

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W. P. HERMANS
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M. H. M. DEBETS
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E. C. M. VAN LEEUWEN
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F. H. DE JONG
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The time-related changes in gonadotrophin concentrations after a single injection of steroid-free bovine follicular fluid (bFF), which contains material with inhibin-like activity, were studied in 25-day-old and adult female rats which either were intact or had been ovariectomized 2 days before. In ovariectomized and intact rats administration of bFF caused a selective suppression of FSH after 4–8 h in 25-day-old rats and after 3–4 h in adult rats. No systematic changes in concentrations of LH after bFF injection were observed. Relative suppression of FSH levels in adult rats was more pronounced and of longer duration than in 25-day-old rats. Moreover, the total period of suppression lasted longer in ovariectomized than in intact rats (12 and 8 h for 25-day-old and 24 and 15 h for adult rats respectively). Hypersecretion of FSH was found in intact rats after the initial suppression; this phenomenon was more pronounced and of longer duration in adult than in 25-day-old rats. No clear change in the numbers of healthy growing follicles was observed after injection of bFF into intact rats. These results indicate that the pituitary secretion of FSH responds quickly and selectively after administration of bFF to intact and ovariectomized, 25-day-old and adult female rats. The hypersecretion of FSH in intact rats might compensate for the initial suppression of this gonadotrophin, and may thus ensure the maturation of a normal number of follicles.

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W. P. HERMANS
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E. C. M. VAN LEEUWEN
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M. H. M. DEBETS
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F. H. DE JONG
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Administration of steroid-free bovine follicular fluid (bFF), containing inhibin-like activity, depressed levels of FSH measured 4 h after injection in intact adult and 35-day-old female rats, but not in younger females. Suppression of FSH was also observed in intact male rats, aged 55 days, but not in older and younger male rats. Eight hours after injection of bFF, FSH levels were depressed in 15-day-old and older immature and adult rats of both sexes. Male and female rats, gonadectomized 2 days earlier, responded similarly to bFF treatment as did the intact animals.

In a second experiment it was found that the rise of FSH levels, occurring within 8 h of gonadectomy, decreased with age in male and increased with age in female rats. Steroid treatment was found to prevent the rise in FSH levels partially in 15-day-old male and completely in 25-day-old female rats, whereas treatment with bFF was fully effective in blocking the FSH rise in both immature and adult rats of both sexes.

It is concluded that inhibin might be a major physiological factor in a fast-acting control of FSH concentrations from at least the age of 25 days onwards in female rats. In male rats its physiological significance might be limited to the prepubertal period, despite the fact that pituitary secretion of FSH is suppressed by exogenous inhibin-like activity at all ages studied.

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G A C van Haasteren
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H van Toor
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W Klootwijk
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B Handler
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E Linkels
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P van der Schoot
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J van Ophemert
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F H de Jong
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T J Visser
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W J de Greef
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Abstract

This study describes the effects of litter size and acute suckling on the synthesis and release of hypothalamic TRH, as indirectly estimated by determination of hypothalamic prothyrotrophin-releasing hormone (proTRH) mRNA and median eminence TRH content. The effects of litter size (five or ten pups) were studied throughout lactation, while suckling-induced acute changes were analyzed on day 13 of lactation in dams with ten pups. In view of the enhanced adrenal activity during lactation and recent evidence that corticosteroids have negative effects on hypothalamic TRH, we also studied adrenalectomized (ADX) dams treated with corticosterone to maintain basal plasma corticosterone levels.

In addition to an increased plasma level of prolactin (PRL), adrenal weight and plasma corticosterone increased, while plasma TSH, tri-iodothyronine (T3), thyroxine (T4) and free T4 (FT4) levels decreased during lactation. Litter size correlated positively with plasma PRL, adrenal weight and plasma corticosterone. No effect of litter size was observed on plasma T3, but rats with ten pups had lower plasma TSH, T4 and FT4 than rats with a five-pup litter. Compared with dioestrous rats, lactating rats showed an increased hypothalamic proTRH mRNA content on day 2, but not on days 8 and 15 of lactation. Median eminence TRH in lactating rats gradually increased until day 15 and decreased thereafter. Acute suckling, after a 6-h separation of mother and pups, rapidly increased plasma PRL and corticosterone in the mothers, but had no effects on plasma TSH and thyroid hormone levels. Hypothalamic proTRH mRNA increased twofold after 0·5 h of suckling, and then gradually returned to presuckling values after 6 h. Compared with sham-operated rats, corticosterone-substituted ADX rats with ten pups had increased plasma PRL and TSH, hypothalamic proTRH mRNA and pituitary TSH β mRNA on day 15 of lactation. Moreover, while acute suckling did not enhance TSH release in sham-operated rats, it provoked not only PRL but also TSH release in corticosterone-substituted ADX dams.

It is concluded that suckling exerts a rapid, positive effect on hypothalamic proTRH mRNA content. However, the concurrent enhanced adrenal activity has negative effects on hypothalamic proTRH gene expression resulting in a suppressed hypophysial-thyroid axis during lactation. While TRH appears to play a role in PRL release during the first days of lactation and during acute suckling, TRH seems not important in maintaining PRL secretion during continued suckling.

Journal of Endocrinology (1996) 148, 325–336

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G A C van Haasteren
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E Linkels
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H van Toor
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W Klootwijk
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E Kaptein
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F H de Jong
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M J Reymond
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T J Visser
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W J de Greef
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Abstract

The reduced thyroid activity during short-term starvation is associated with a lowered hypothalamic synthesis and secretion of TRH. However, little is known about the cause of the reduced thyroid function during prolonged malnutrition. We have therefore studied the effects of food reduction to one-third of normal (FR33) on the hypothalamus-pituitary-thyroid axis of male and female Wistar rats. After 3 weeks body weights of FR33 rats were almost 50% lower than those of controls. In both sexes, FR33 caused marked increases in serum corticosterone, and decreases in serum TSH, thyroxine (T4), free T4, tri-iodothyronine (T3) and free T3. While the free T3 fraction (FFT3) in serum decreased, the free T4 fraction (FFT4) tended to increase. Electrophoretic analysis indicated that decreased FFT3 was correlated with an increased thyroxine-binding globulin, while the increase in FFT4 seemed due to a decreased thyroxine-binding prealbumin binding capacity. Total RNA and proTRH mRNA in the hypothalamus were not affected by FR33. Median eminence and posterior pituitary TRH content tended to increase in FR33 rats, suggesting that hypothalamic TRH release is reduced in FR33 rats. Anterior pituitary TSH content was decreased by FR33 in both sexes, but pituitary TSHβ mRNA and TRH receptor status were not affected except for increased pituitary TSHβ mRNA in female FR33 rats. Although FR33 had no effect on pituitary weight, pituitary RNA and membrane protein content in FR33 rats were 50–70% lower than values in controls.

In conclusion, prolonged food reduction suppresses the pituitary-thyroid axis in rats. In contrast to short-term food deprivation, the mechanism whereby serum TSH is suppressed does not appear to involve decreases in proTRH gene expression, but may include effects on pituitary mRNA translation. Our results further support the hypothesis that TSH release may be lowered by increased corticosterone secretion, although the mechanism of this effect may differ between acute starvation and prolonged food reduction.

Journal of Endocrinology (1996) 150, 169–178

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A. M. W. Toebosch
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D. M. Robertson
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I. A. Klaij
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F. H. de Jong
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J. A. Grootegoed
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ABSTRACT

The effects of FSH and testosterone on inhibin mRNA expression and inhibin production by highly purified Sertoli cell preparations were examined. Sertoli cells were isolated from testes of 22-day-old rats by sequential trypsin, collagenase and hyaluronidase treatments, with subsequent osmotic shock treatment on day 3 of culture. Contamination by peritubular and germ cells was <0·5 and 1–3% respectively. Intracellular and secreted inhibin levels were measured by radioimmunoassay, using Sertoli cells which were incubated for 24 h in the absence or presence of FSH and testosterone from days 4 to 5 of culture. FSH stimulated the cellular inhibin content and the secreted inhibin level by four- and sevenfold respectively, with a half-maximal effective dose of 5–50 ng/ml. Under the present incubation conditions, testosterone (1 μmol/l) had no effect on immunoreactive inhibin levels in either the presence or absence of FSH. Similarly, the expression of inhibin α-subunit mRNA was increased following FSH stimulation, whereas testosterone had no effect. The expression of inhibin βB-subunit mRNAs was not influenced by FSH or testosterone.

It is concluded that highly purified Sertoli cell preparations, with a very low number of peritubular or germ cells, are fully responsive to FSH with respect to inhibin mRNA expression and inhibin production.

Journal of Endocrinology (1989) 122, 757–762

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R van der Pas
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L J Hofland
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J Hofland
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A E Taylor Division of Endocrinology, School of Clinical and Experimental Medicine, Department of Internal Medicine, Erasmus Medical Center, room Ee 569, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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W Arlt Division of Endocrinology, School of Clinical and Experimental Medicine, Department of Internal Medicine, Erasmus Medical Center, room Ee 569, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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J Steenbergen
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P M van Koetsveld
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W W de Herder
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F H de Jong
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R A Feelders
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The antifungal agent ketoconazole is often used to suppress cortisol production in patients with Cushing's syndrome (CS). However, ketoconazole has serious side effects and is hepatotoxic. Here, the in vitro effects of ketoconazole and fluconazole, which might be less toxic, on human adrenocortical steroidogenesis were compared. The effects on steroidogenesis were examined in primary cultures of nine human adrenocortical tissues and two human adrenocortical carcinoma cell lines. Moreover, the effects on mRNA expression levels of steroidogenic enzymes and cell growth were assessed. Ketoconazole significantly inhibited 11-deoxycortisol (H295R cells; maximum inhibition 99%; EC50 0.73 μM) and cortisol production (HAC15 cells; 81%; EC50 0.26 μM and primary cultures (mean EC50 0.75 μM)). In cultures of normal adrenal cells, ketoconazole increased pregnenolone, progesterone, and deoxycorticosterone levels, while concentrations of 17-hydroxypregnenolone, 17-hydroxyprogesterone, 11-deoxycortisol, DHEA, and androstenedione decreased. Fluconazole also inhibited 11-deoxycortisol production in H295R cells (47%; only at 1 mM) and cortisol production in HAC15 cells (maximum inhibition 55%; EC50 35 μM) and primary cultures (mean EC50 67.7 μM). In the cultures of normal adrenals, fluconazole suppressed corticosterone, 17-hydroxypregnenolone, and androstenedione levels, whereas concentrations of progesterone, deoxycorticosterone, and 11-deoxycortisol increased. Fluconazole (1 mM) slightly increased STAR mRNA expression in both cell lines. Neither compound affected mRNA levels of other steroidogenic enzymes or cell number. In conclusion, by inhibiting 11β-hydroxylase and 17-hydroxylase activity, pharmacological concentrations of fluconazole dose dependently inhibit cortisol production in human adrenocortical cells in vitro. Although fluconazole seems less potent than ketoconazole, it might become an alternative for ketoconazole to control hypercortisolism in CS. Furthermore, patients receiving fluconazole because of mycosis might be at risk for developing adrenocortical insufficiency.

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