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Increased in ovo cortisol content of rainbow trout oocytes from ∼3.5 to ∼5.0 ng.oocyte−1 before fertilization enhances the growth of embryos and juveniles and changes the long-term expression pattern of IGF-related genes. This study used embryos reared from oocytes enriched with cortisol and the glucocorticoid receptor (GR) antagonist, RU486, to determine whether the growth-promoting actions of cortisol involve GR protein activation and modulation of gr expression. Whole-mount in situ immunohistofluorescence studies of zygotes showed that enhanced oocyte cortisol increased the immunofluorescent GR signal and activated the relocation of GR from a general distribution throughout the cytoplasm to an accumulation in the peri-nuclear cytoplasm. In ovo cortisol treatment increased the number of embryonic cells within 48-h post-fertilization, and RU486 partially suppressed this cortisol stimulation of cell duplication. In addition, there was complex interplay between the expression of gr and igf system-related genes spatiotemporally in the different treatment groups, suggesting a role for GR in the regulation of the expression of development. Taken together, these findings indicate an essential role for GR in the regulation of epigenomic events in very early embryos that promoted the long-term growth effects of the embryos and juvenile fish. Moreover, the pretreatment of the oocyte with RU486 had a significant suppressive effect on the maternal mRNA transcript number of gr and igf system-related genes in oocytes and very early stage embryos, suggesting an action of antagonist on the stability of the maternal transcriptome.
Research Group Endocrinology and Metabolism, Department Biology, Faculty of Sciences, University of Utrecht, Padualaan 8, 3584 CH Utrecht, The Netherlands
Physiology of Growth and Reproduction in Fish, Institute of Marine Research, PO Box 1870 Nordnes, 5817 Bergen, Norway
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Research Group Endocrinology and Metabolism, Department Biology, Faculty of Sciences, University of Utrecht, Padualaan 8, 3584 CH Utrecht, The Netherlands
Physiology of Growth and Reproduction in Fish, Institute of Marine Research, PO Box 1870 Nordnes, 5817 Bergen, Norway
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Research Group Endocrinology and Metabolism, Department Biology, Faculty of Sciences, University of Utrecht, Padualaan 8, 3584 CH Utrecht, The Netherlands
Physiology of Growth and Reproduction in Fish, Institute of Marine Research, PO Box 1870 Nordnes, 5817 Bergen, Norway
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Research Group Endocrinology and Metabolism, Department Biology, Faculty of Sciences, University of Utrecht, Padualaan 8, 3584 CH Utrecht, The Netherlands
Physiology of Growth and Reproduction in Fish, Institute of Marine Research, PO Box 1870 Nordnes, 5817 Bergen, Norway
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Research Group Endocrinology and Metabolism, Department Biology, Faculty of Sciences, University of Utrecht, Padualaan 8, 3584 CH Utrecht, The Netherlands
Physiology of Growth and Reproduction in Fish, Institute of Marine Research, PO Box 1870 Nordnes, 5817 Bergen, Norway
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Due to the lack of purified, native gonadotropins (GtH) for almost all species of fish, we designed a system for the production of recombinant bioactive luteinizing hormone (LH) and follicle stimulating hormone (FSH) using the channel catfish (Ictalurus punctatus) as a model animal. The strategy was to produce the three subunits composing FSH and LH, i.e. the common α-subunit (α-glycoprotein hormone (α-GP)), β-FSH, and β-LH subunit, individually in stable recombinant insect cells (S2) with C-terminal His-tag. This expression system was also used to co-express the α-subunit without the His-tag with each of the His-tagged β-subunits. The recombinant S2 cells were capable of secreting FSH and LH heterodimers and α-GP in abundance; however, expression of the individual β-subunits was much less successful. The recombinant GtHs were partially purified from the cell medium by immobilized metal affinity chromatography to ~15% purity with a yield of 7 and 4 mg per liter of medium for FSH and LH respectively. These recombinant GtHs activated their receptors in vitro, enhanced estrogen secretion, up-regulated several steroidogenic enzyme genes in channel catfish ovarian follicles, and increased androgen secretion from African catfish testis. Interestingly, the FSH and LH dose–response curves for each of these biological activities clearly demonstrate differences in their cellular action and physiological roles. This expression system may be an important development for the production of species-specific GtHs so that FSH- and LH-specific mechanisms of actions within the reproductive endocrine processes can finally be examined with homologous, albeit recombinant, hormones.
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Tenovus Institute for Cancer Research, Welsh National School of Medicine. The Heath, Cardiff, CF4 4XX and *41 Rodney Street, Liverpool, LI 9EN
(Received 1 July 1977)
Although our knowledge of spermatogenesis is good (see Steinberger & Steinberger, 1975), we have yet to appreciate fully the integrated hormonal requirements of this process (see Courot, 1976). Infertility in men has proved an obstinate condition to treat, although gonadotrophin and androgen therapy have achieved some success. Prolactin remains something of an enigma in men although there is now considerable evidence that it can have profound action both on the testis and on the accessory sex glands of experimental animals.
It was decided to measure routinely the concentrations of testosterone and prolactin in the plasma of men attending an infertility clinic, for comparison with fertile men requesting vasectomy. The 'infertile' men (sperm count range/ml excluding azoospermic men was 5 × 103−305 × 106; median
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Tenovus Institute for Cancer Research, Welsh National School of Medicine, Heath Park, Cardiff, CF4 4XX
(Received 24 March 1977)
A technique for the analysis and measurement of C19-steroids by high-resolution selected ion monitoring has been used in this laboratory to study the level of endogenous steroids in human prostatic tissue (Millington, 1975; Millington, Buoy, Brooks, Harper & Griffiths, 1975). A similar procedure has now been used as a reference method to determine the concentration of oestradiol-17β in plasma samples from a quality control scheme for the Supra-Regional Assay Service (SAS) in the United Kingdom. Results from this combined gas chromatographic-mass spectrometric (GC-MS) method were compared with those obtained from the assay of oestradiol-17β with the routine radioimmunoassay (RIA) procedure used in this laboratory (Golder, Phillips, Fahmy, Preece, Jones, Henk & Griffiths, 1976).
All gas Chromatographie column packings and the reagent bis-(N,O)trimethylsilyl acetamide were supplied by Jones Chromatography Limited, Llanbradach, Glamorgan.
St.Vincent's Institute of Medical Research, Department of Medicine at St. Vincent's Hospital Melbourne, Department of Cancer Research and Molecular Medicine, 9 Princes St, Fitzroy, Victoria 3065, Australia
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St.Vincent's Institute of Medical Research, Department of Medicine at St. Vincent's Hospital Melbourne, Department of Cancer Research and Molecular Medicine, 9 Princes St, Fitzroy, Victoria 3065, Australia
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St.Vincent's Institute of Medical Research, Department of Medicine at St. Vincent's Hospital Melbourne, Department of Cancer Research and Molecular Medicine, 9 Princes St, Fitzroy, Victoria 3065, Australia
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Parathyroid hormone (PTH) treatment stimulates osteoblast differentiation and bone formation, and is the only currently approved anabolic therapy for osteoporosis. In cells of the osteoblast lineage, PTH also stimulates the expression of members of the interleukin 6 (IL-6) cytokine superfamily. Although the similarity of gene targets regulated by these cytokines and PTH suggest cooperative action, the dependence of PTH anabolic action on IL-6 cytokine signaling is unknown. To determine whether cytokine signaling in the osteocyte through glycoprotein 130 (gp130), the common IL-6 superfamily receptor subunit, is required for PTH anabolic action, male mice with conditional gp130 deletion in osteocytes (Dmp1Cre.gp130 f/f ) and littermate controls (Dmp1Cre.gp130 w/w ) were treated with hPTH(1–34) (30 μg/kg 5× per week for 5 weeks). PTH dramatically increased bone formation in Dmp1Cre.gp130 w/w mice, as indicated by elevated osteoblast number, osteoid surface, mineralizing surface, and increased serum N-terminal propeptide of type 1 collagen (P1NP). However, in mice with Dmp1Cre-directed deletion of gp130, PTH treatment changed none of these parameters. Impaired PTH anabolic action was associated with a 50% reduction in Pth1r mRNA levels in Dmp1Cre.gp130 f/f femora compared with Dmp1Cre.gp130 w/w . Furthermore, lentiviral-Cre infection of gp130 f/f primary osteoblasts also lowered Pth1r mRNA levels to 16% of that observed in infected C57/BL6 cells. In conclusion, osteocytic gp130 is required to maintain PTH1R expression in the osteoblast lineage, and for the stimulation of osteoblast differentiation that occurs in response to PTH.
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A reciprocal relationship between the endocrine and immune system has been demonstrated under pathophysiological conditions. However, few studies have assessed the relationship between thyroid hormones and immune function in apparently healthy individuals. Therefore, to clarify our understanding of normal physiological endocrine–immune interactions this study aimed to examine the interrelationships between thyroid hormones and immunity in healthy individuals. Total triiodothyronine (T3), total thyroxine (T4) and markers of immune status were assessed in 93 free-living and apparently healthy individuals aged 55–70 years. T3 and T4 concentrations were determined by commercially available kits. Immune status was assessed using flow cytometry and biochemical markers. Statistical analysis was performed by partial correlation, controlling for age. Thyroid hormone concentration was positively associated with markers of inflammation (P≤0.05), natural killer-like T cells (P≤0.001), expression of interleukin-6 (IL6) by activated monocytes (P≤0.05); percentage expression of memory T-lymphocytes (P≤0.01), memory T-helper lymphocytes (P≤0.05) and memory T-cytotoxic lymphocytes (P≤0.05), and higher IL2 receptor density on CD3+T-lymphocytes (P≤0.05). Thyroid hormone concentration was inversely associated with early lymphocyte apoptosis (P≤0.05) and the ratio of naïve- to memory T-cytotoxic lymphocytes (P≤0.05). The current study provides preliminary evidence of a role for T3 and T4, within normal physiological ranges, in the maintenance of lymphocyte subpopulations, and in mediating the inflammatory response. In conclusion, these findings highlight the potential implications of altered thyroid function in older individuals and the importance of future research examining thyroid–immune interactions.
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Pharmacological doses of glucocorticoids inhibit thyroid function in man and laboratory animals due to suppression of thyrotrophin (TSH) secretion (Wilber & Utiger, 1969). Administration of prednisolone or dexamethasone for 1–2 days results in a suppression of basal serum TSH levels in normal subjects and in patients with primary hypothyroidism, whilst the pituitary TSH reserve capacity, as assessed by the response to synthetic thyrotrophin releasing hormone (TRH), remains unaltered (Wilber & Utiger, 1969; Besser, Ratcliffe, Kilborn, Ormston & Hall, 1971; Haigler, Pittman & Hershman, 1971). However, impairment of serum TSH response to administered TRH does occur in patients treated with glucocorticoids for 1 or more months (Otsuki, Dakoda & Baba, 1973). These studies suggest that glucocorticoids may inhibit TSH secretion at both hypothalamic and pituitary levels but the main effect of the short-term treatment is suppression of TRH production.
Nicoloff, Fisher & Appleman (1970) found that the circadian rhythm of thyroidal
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We have previously shown that co-administration of the transient osteoclast inhibitor, salmon calcitonin (sCT), blunts the anabolic effect of parathyroid hormone (PTH) in young rats and increases osteocytic expression of the bone formation inhibitor sclerostin (Sost). To determine whether this also occurs in adult animals, we co-administered sCT with PTH to 6-month-old sham-operated (SHAM) and ovariectomised (OVX) rats. While sCT reduced the stimulatory effect of PTH on serum amino-terminal propeptide of type 1 procollagen levels, in contrast to its influence in young rats, sCT did not reduce the anabolic effect of PTH on femoral bone mineral density, tibial trabecular bone volume or bone formation rate in 6-month-old SHAM or OVX rats. Quantitative real-time PCR analysis of femoral metaphyses collected 1 and 4 h after a single PTH injection confirmed a significant increase in mRNA levels for interleukin 6 (Il6) and ephrinB2 (EfnB2), and a significant reduction in Sost and dentin matrix protein-1 (Dmp1) in response to PTH. However, in contrast to observations in young rats, these effects were not modified by co-administration of sCT, nor did sCT significantly modify Sost, Dmp1, or matrix extracellular phosphoglycoprotein (Mepe) mRNA levels. Furthermore, while CT receptor (CTR) mRNA (Calcr) was readily detected in GFP+ osteocytes isolated from young (3-week-old) DMP1–GFP mice, Calcr levels in osteocytes declined as mice aged, reaching levels that were undetectable in long bone at 49 weeks of age. These data indicate that osteocyte-mediated responses to CT are most likely to be of physiological relevance in young rodents.
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Suppression of TSH release from the hypothyroid thyrotrophs is one of the most rapid effects of 3,3′,5′-triiodothyronine (T3) or thyroxine (T4). It is initiated within an hour, precedes the decrease in TSH β mRNA inhibition and is blocked by inhibitors of mRNA or protein synthesis. TSH elevation in primary hypothyroidism requires both the loss of feedback inhibition by thyroid hormone in the thyrotrophs and the positive effects of TRH. Another event in this feedback regulation may be the thyroid hormone-mediated induction of the TRH-inactivating pyroglutamyl peptidase II (PPII) in the hypothalamic tanycytes. This study compared the chronology of the acute effects of T3 or T4 on TSH suppression, TRH mRNA in the hypothalamic paraventricular nucleus (PVN), and the induction of tanycyte PPII. In wild-type mice, T3 or T4 caused a 50% decrease in serum TSH in hypothyroid mice by 5 h. There was no change in TRH mRNA in PVN over this interval, but there was a significant increase in PPII mRNA in the tanycytes. In mice with genetic inactivation of the type 2 iodothyronine deiodinase, T3 decreased serum TSH and increased PPII mRNA levels, while T4-treatment was ineffective. We conclude that the rapid suppression of TSH in the hypothyroid mouse by T3 occurs prior to a decrease in TRH mRNA though TRH inactivation may be occurring in the median eminence through the rapid induction of tanycyte PPII. The effect of T4, but not T3, requires the type 2 iodothyronine deiodinase.
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Patients with critical illness or hepatic failure exhibit impaired cortisol responses to ACTH, a phenomenon known as ‘relative adrenal insufficiency’. A putative mechanism is that elevated bile acids inhibit inactivation of cortisol in liver by 5α-reductases type 1 and type 2 and 5β-reductase, resulting in compensatory downregulation of the hypothalamic–pituitary–adrenal axis and adrenocortical atrophy. To test the hypothesis that impaired glucocorticoid clearance can cause relative adrenal insufficiency, we investigated the consequences of 5α-reductase type 1 deficiency in mice. In adrenalectomised male mice with targeted disruption of 5α-reductase type 1, clearance of corticosterone was lower after acute or chronic (eightfold, P<0.05) administration, compared with WT control mice. In intact 5α-reductase-deficient male mice, although resting plasma corticosterone levels were maintained, corticosterone responses were impaired after ACTH administration (26% lower, P<0.05), handling stress (2.5-fold lower, P<0.05) and restraint stress (43% lower, P<0.05) compared with WT mice. mRNA levels of Nr3c1 (glucocorticoid receptor), Crh and Avp in pituitary or hypothalamus were altered, consistent with enhanced negative feedback. These findings confirm that impaired peripheral clearance of glucocorticoids can cause ‘relative adrenal insufficiency’ in mice, an observation with important implications for patients with critical illness or hepatic failure, and for patients receiving 5α-reductase inhibitors for prostatic disease.
