Endocrine Abstracts

Development of the fetal hypothalamic-pituitary-adrenal (HPA) axis is important for normal maturation of the fetus and the timing of parturition. In hypothyroid fetuses, gestational length may be prolonged and maturational processes delayed, although the role of the HPA axis is unknown. This study investigated the effects of hypothyroidism before birth on the structure and function of the anterior pituitary and adrenal glands in fetal sheep near term.

All procedures were performed under the UK Animals (Scientific Procedures) Act 1986. In 15 twin-bearing pregnant ewes at 102–110 days of gestation (d; term ~145 d), one fetus was thyroidectomised (TX) while the other was sham-operated under general anaesthesia. At 143d, umbilical blood and fetal pituitary and adrenal glands were collected after euthanasia. Fractional volume and mass of adrenocorticotrophin (ACTH)-containing corticotrophs in the anterior pituitary gland were determined by immunohistochemistry and stereology. Adrenal zone composition, and adrenocortical and medullary mRNA abundances of key steroidogenic enzymes and growth factors, were determined by stereology and RT-qPCR, respectively. Data were assessed by Student’s t-test (P < 0.05). Plasma concentrations of thyroxine, triiodothyronine, ACTH and cortisol were lower in TX than sham fetuses. Fetal hypothyroidism increased absolute and relative (to fetal body weight) masses of the anterior pituitary gland (sham 22.0 ± 1.5, TX 41.8 ± 3.1 mg/kg) and corticotroph population (sham 6.8 ± 0.4, TX 10.6 ± 0.5 mg/kg).In the adrenal gland, absolute mass of the zona fasciculata was decreased (sham 117 ± 12, TX 86 ± 7 mg) and relative mass of the medulla was increased (sham 17.2 ± 1.4, TX 22.4 ± 0.8 mg/kg) by thyroid hormone deficiency, without any change in total adrenal mass. In TX fetuses, adrenocortical mRNA abundance was reduced by 42–63% for cholesterol transport protein StAR, steroidogenic enzymes CYP11A1, CYP17, 3β-hydroxysteroid dehydrogenase, CYP21 and CYP11B1, and for insulin-like growth factor-I (IGFI) and IGF type 1 receptor. Fetalhypothyroidism had no effect on adrenocortical ACTH receptor, IGFII or IGF type 2 receptor, or adrenomedullary phenylethanolamine-N-methyltransferase, IGFI, IGFII or IGF receptor mRNA abundance. Thyroid hormones are important regulators of the structure and secretory capacity of the pituitary-adrenal axis before birth. In hypothyroid fetuses, low plasma cortisol may result from impaired adrenocortical growth and steroidogenic enzyme expression, secondary to low circulating ACTH concentration. Greater pituitary corticotroph population during fetal hypothyroidism indicates compensatory cell proliferation and abnormal corticotroph capacity for ACTH synthesis and/or impaired hypothalamic input. Suppression of normal development of the fetal pituitary-adrenal axis by thyroid hormone deficiency may contribute to the delay in fetal maturation and delivery observed in hypothyroid offspring.