hypothesis that the adrenal medulla is involved in this suppression of LH pulses ... and the adrenal medulla in the stress-induced suppression of LH pulsatility is ...
Journal of Neuroendocrinology, 1997, Vol. 9, 867–872
Hypoglycaemia-Induced Inhibition of Pulsatile Luteinizing Hormone Secretion in Female Rats: Role of Oestradiol, Endogenous Opioids and the Adrenal Medulla Felino Ramon A. Cagampang, Philippa S. Cates, Satwinder Sandhu, Paul H. Strutton, Cliona McGarvey, Clive W. Coen and Kevin T. O’Byrne Anatomy and Human Biology, Biomedical Sciences Division, King’s College London, Strand, London WC2R 2LS, UK Key words: luteinizing hormone, hypoglycaemia, oestrogen, opioids, female rats, adrenal medulla.
Abstract Oestradiol (E ) has been shown to exacerbate the inhibitory effect of hypoglycaemic stress on gonadotrophin-releasing hormone pulse 2 generator (GnRH) activity in primates. The mechanism by which this is mediated is not yet known. We therefore aimed to establish whether there is a sensitizing influence of E on the suppression of LH pulsatility in response to hypoglycaemia in the female rat, thus 2 providing a more amenable model in which to study this phenomenon. In ovariectomized Wistar rats with E replacement, insulin-induced 2 hypoglycaemia (0.5 U/kg iv) resulted in an interruption of pulsatile LH secretion. Induction of the same degree of hypoglycaemia in ovariectomized rats without E replacement was without effect on LH pulsatility. Naloxone administration prevented the hypoglycaemia2 induced inhibition of LH pulses. Because hypoglycaemia is a potent activator of the sympathetic nervous system, we also tested the hypothesis that the adrenal medulla is involved in this suppression of LH pulses in the rat. Adrenomedullectomy completely prevented this inhibitory response to hypoglycaemic stress. These data are consistent with the hypothesis that E sensitizes the GnRH pulse 2 generator to the inhibitory influences of hypoglycaemic stress in the rat. Furthermore, a clear role for both endogenous opioid peptides and the adrenal medulla in the stress-induced suppression of LH pulsatility is identified.
The gonadal steroid oestradiol ( E ) has been shown to potentiate 2 the suppression of luteinizing hormone ( LH ) pulses in response to a number of perturbations in a variety of species. The disruption of LH pulses in response to fasting in the rat ( 1) and to insulininduced hypoglycaemic stress in the rhesus monkey (2 ) is more severe in ovariectomized animals that have received E replace2 ment than in those without such treatment. The mechanism by which E exerts this sensitizing influence on stress-induced sup2 pression of LH pulses has yet to be elucidated; it is likely that it acts by modulating the activity of central neurotransmitter systems involved in regulating GnRH pulse generator activity. Although the sensitizing influence of E has already been clearly established 2 in the rhesus monkey using insulin-induced hypoglycaemia (2 ), whether this action of E extends to the effect of hypoglycaemic 2 stress on LH pulses in the rat, a widely used species for studying the neural control of gonadotrophin secretion, has yet to be determined. The use of insulin is convenient since it provides a well established stressor that is easily reproducible and quantifiable. The first aim of our study was therefore to demonstrate whether there is a sensitizing influence of E on the suppression 2 of LH pulses in response to hypoglycaemia in the female rat. Central neurotransmitter systems involved in the hypothalamopituitary-adrenocortical axis have been clearly implicated in the
hypoglycaemia-induced suppression of pulsatile LH secretion in monkeys; these neurotransmitters include corticotrophin releasing hormone (CRH) (3, 4) and vasopressin (AVP) (3, 5). Endogenous opioid peptides are also involved in hypoglycaemic stress-induced suppression of LH secretion in the ewe ( 6) and the male rat (7 ), but not in the rhesus monkey (2). In addition to the central neurotransmitter systems, adrenomedullary products have been implicated in stress-induced suppression of LH release. Thus, adrenomedullectomy prevents the inhibitory effect of chronic restraint stress on mean plasma concentrations of LH in the rat (8 ) and peripherally administered adrenaline inhibits LH secretion in this species ( 9). Hypoglycaemia is a potent activator of the adrenal medulla, inducing c-fos expression in medullary cells ( 10) and increasing adrenaline secretion (11 ). These issues led us to test whether endogenous opioid peptides and/or adrenomedullary products are involved in the hypoglycaemic stress-induced suppression of LH pulsatility in the female rat.
Results Administration of 0.5 U insulin/kg intravenously (iv) to ovariectomized rats either with or without E replacement resulted in a 2
Correspondence to: Kevin T. O’Byrne, Department of Anatomy and Human Biology, Biomedical Sciences Division, King’s College London, London WC2R 2LS, UK. © 1997 Blackwell Science Ltd
80 60 40 20
OVX (n=7)
OVX+E2 (n=7)
OVX + E2
B
Naloxone (n=7)
100
Insulin 80 60 40 20 0
8 6 LH (ng/ml)
6 LH (ng/ml)
0
F. 2. The effects of insulin-induced hypoglycaemic stress ( 0.5 U insulin/kg iv) on pulsatile LH secretion in ovariectomized rats (stippled bar, OVX ), ovariectomized rats with oestradiol ( E ) replacement (solid 2 bar, OVX+E ) and OVX, E -treated rats administered with naloxone 2 2 (1 mg/kg iv) 10 min prior to insulin administration ( hatched bar, Naloxone). Control animals, either with or without E replacement, were 2 administered with saline instead of insulin (open bar, Saline). Inhibition of pulsatile LH secretion, expressed on the ordinate as a prolongation of the first interpulse interval after insulin administration is presented as percentage of pretreatment control (mean±SEM ). The first LH pulse interval after insulin was only significantly prolonged in OVX+E 2 animals. *P
