Sometimes new scientific ideas and discoveries simply erupt. Others emerge more slowly, requiring pieces of a complex jig-saw to be fitted together before a concept heads towards reality. And so it has been for the emerging concept of a gonadotrophin surge inhibiting or attenuating factor. A non-steroidal factor, distinct from inhibin and ovarian steroids, which reduces the luteinizing hormone (LH) response of the pituitary gland to gonadotrophin-releasing hormone (GnRH) and so blocks or attenuates the preovulatory surge of LH secretion. To date its existence has only been implicated by experimental observations. However, if such a factor is identified it could explain how a timely LH surge is stimulated and why the hypothalamic-pituitary axis is suddenly released from the negative feedback action of oestrogen. Or alternatively, why oestrogen can suddenly exert a positive feedback action to induce the preovulatory surge of LH secretion.
S. A. Whitehead
D. A. CARTER and S. A. WHITEHEAD
The effect of hyperprolactinaemia on the progesterone-induced LH surge which occurs in oestrogen-primed, ovariectomized rats has been investigated. Hyperprolactinaemia was produced by implanting pituitary glands under the kidney capsule and levels of LH and prolactin in the circulation were measured at appropriate times during the steroid treatment. Twenty-four hours after oestrogen administration plasma LH levels were significantly reduced in both hyperprolactinaemic and sham-operated control rats. Progesterone induced a surge of LH which peaked 5 h after injection in both groups of rats. However, the peak LH level in the hyperprolactinaemic rats was less than 50% of that observed in the controls. Differences were also found in the effect of oestrogen on prolactin release in the hyperprolactinaemic rats. It is suggested that prolactin reduces the sensitivity to progesterone by a direct action on the hypothalamic–pituitary axis.
D. A. CARTER and S. A. WHITEHEAD
The effect of hyperprolactinaemia induced by dopamine-antagonist drugs on pituitary responsiveness to gonadotrophin releasing hormone (Gn-RH) and on plasma LH levels has been investigated in intact and ovariectomized rats. The animals were pretreated with haloperidol, pimozide or domperidone and the sensitivity of isolated pituitary glands to pulses of Gn-RH were tested using a perifusion system. Trunk blood, collected at the time of killing, was assayed for plasma LH and prolactin. In addition, a direct effect of the drugs on pituitary responsiveness to Gn-RH was investigated by perifusing pituitary glands taken from untreated, pro-oestrous rats in medium containing the dopamine antagonists.
The pituitary responsiveness was significantly impaired in intact rats after treatment with each of the drugs whereas no effect was observed in pretreated ovariectomized rats. None of the drug treatments altered levels of circulating LH. High concentrations of the drugs present in the perifusion medium also inhibited pituitary responsiveness although it is not known whether the concentrations of the drugs present in the pretreated animals would exert a similar effect.
The results suggest that short-term hyperprolactinaemia impairs pituitary responsiveness through a modulation of ovarian steroid secretion and that Gn-RH release is not altered. Treatment with domperidone exhibited similar effects on the parameters measured here to those caused by the two neuroleptics, indicating that this novel anti-dopaminergic drug is acting in a similar manner.
J F Laycock and S A Whitehead
Everyone accepts that the principal physiological action of the neurohypophysial hormone vasopressin is to stimulate the osmotic reabsorption of water by binding to V2 receptors on collecting duct cells. Activation of these G-protein coupled receptors induces the intracellular generation of cyclic AMP and, ultimately, the movement of water across the renal epithelium through water channels inserted into the apical membranes (see Brown 1989). These water channels, called aquaporins, have now been cloned for collecting duct apical membranes in various mammalian species (Fushima et al. 1993).
However, the first observed effect of this antidiuretic hormone was not concerned with the renal action on water transport. In 1895, Oliver and Schäfer showed that extracts of the hypophysis had powerful pressor activity, hence the name given to the active ingredient – vasopressin. Ironically, many people today do not believe that vasopressin has a physiological role in cardiovascular regulation even though it was
J. M. Hall and S. A. Whitehead
The rise in gonadotrophin release which occurs after ovariectomy is caused by steroid withdrawal resulting in an enhanced pituitary responsiveness to LH releasing hormone (LHRH) associated with increased LHRH release and pituitary LHRH binding. The effects of oestrogen replacement after ovariectomy and chronic treatment of intact rats with an oestrogen antagonist, tamoxifen, on LH release and in-vitro pituitary responses to LHRH have been investigated. Capsules containing crystalline oestradiol, implanted at the time of ovariectomy, completely inhibited the rise in LH release although pituitary responsiveness was greater after 10 days in the oestrogen-treated rats than in untreated ovariectomized controls. On day 4 after ovariectomy pituitary responses to LHRH were comparable in both treated and untreated groups although in both groups the responses were greater than those measured in intact dioestrous rats. Treatment with tamoxifen over a 4-day period also augmented pituitary responsiveness but only at the lowest dose (0·5 mg/kg); no effect on serum LH concentrations was observed. Higher doses of the antagonist (1 and 2 mg/kg) did not affect pituitary responses, although the highest dose did cause a significant rise in serum LH. Treatment with a daily dose of 50 ng [d-Ser(But)6]LHRH(1–9)nonapeptide-ethylamide, starting on the day of ovariectomy, markedly attenuated the LH responses to LHRH ex vivo at days 2, 4 and 10 after ovariectomy. In contrast, the analogue treatment did not abolish the rise in LH release but this was proportionately less than in controls.
G. M. Spencer and S. A. Whitehead
The effects of the opiate antagonist naloxone on serum LH concentrations was investigated in gonadectomized rats given different regimes of steroid pretreatment. Two injections of testosterone given 48 and 24 h before naloxone treatment failed to reinstate LH responses to this drug in castrated rats while subcutaneous testosterone-filled silicone elastomer capsules implanted for a week were effective in this respect. Injections of oestrogen, oestrogen plus progesterone or progesterone alone all restored LH responses to naloxone in ovariectomized rats when given 48 and/or 24 h before drug treatment, although the magnitude of these responses varied according to the precise steroid treatments. The hypothalamic-pituitary axis was also responsive to naloxone just before the progesterone-induced LH surge in oestrogen-primed ovariectomized rats. Results show that gonadal steroids are permissive to the effects of opiate drugs, but they suggest that endogenous opioid systems do not necessarily mediate the negative feedback effects of steroids. Some other factor(s), as yet unidentified in the rat, may control the opioid modulation of gonadotrophin secretion or exert an independent inhibitory effect on gonadotrophin release.
J. Endocr. (1986) 110, 327–334
J. D. Heather and S. A. Whitehead
The acute in-vivo effects of a potent LH-releasing hormone (LHRH) agonist, buserelin, on LH secretion and pituitary responsiveness to LHRH have been investigated in oestrous rats. Doses of 50, 100 and 250 ng buserelin stimulated LH release in a dose-dependent manner, the peak serum LH concentrations being measured 1 h after the treatment. Thereafter LH levels fell rapidly between 1 and 6 h and by 18 h serum LH concentrations were similar in all groups of animals. Pituitary responsiveness to a challenge with 100 ng LHRH was potentiated by 50 or 100 ng buserelin injected 1 or 2 h before the LHRH challenge. In contrast, 250 ng buserelin completely abolished the LH response to LHRH when tested 1, 2 and 4 h after treatment, but by 6 h a small but attenuated response was observed. Four hours after treatment there was no significant difference in the responses when compared with the saline-treated controls.
J. Endocr. (1985) 106, 27–30
S. E. Inkster, R. N. Clayton and S. A. Whitehead
The effects of neonatal monosodium l-glutamate (MSG) treatment on pituitary responsiveness to LH-releasing hormone (LHRH) and on pituitary LHRH receptors have been investigated in the intact adult female rat. Three- to four-month-old rats treated with MSG (4 mg/g body wt) on days 2, 4, 6, 8 and 10 after birth had significantly reduced ovarian and pituitary weights, showed an absence or disruption of ovarian cyclicity after puberty, and had significantly higher concentrations of serum prolactin despite normal levels of LH. In-vitro pituitary LH responses to LHRH were in the normal range for one group of treated animals whilst in a second group the LH responses were markedly enhanced. In contrast, the total number of pituitary LHRH receptors were significantly reduced in all MSG-treated animals showing that the increased pituitary responsiveness of MSG-treated animals is not attributable to an increase in pituitary LHRH receptors.
J. Endocr. (1985) 107, 9–13
J. H. BOTTING, E. A. LINTON and S. A. WHITEHEAD
Department of Pharmacology, Chelsea College, Manresa Road, London, SW3 6LX, and *Department of Physiology, St George's Hospital Medical School, Tooting, London, SW17 OQT
(Received 12 May 1977)
There is evidence accumulating to suggest that prostaglandins (PG) have a hypothalamic action in mediating the preovulatory surge of luteinizing hormone from the pituitary gland. Intraventricular injection of inhibitors of PG synthesis has been shown to block ovulation (Behrman, Orczyk & Greep, 1972; Orczyk & Behrman, 1972) and this effect can be overcome by subsequent administration of PG or luteinizing hormone releasing hormone. Similarly, PGE2, administered intraventricularly, can overcome the ovulatory blockade induced by the α-adrenoceptor antagonist phentolamine (Linton, Perkins & Whitehead, 1977). In this study, we have investigated the action of the prostaglandin antagonist N-0164 (Eakins, Rajadhyaksha & Schroer, 1976) on ovulation in the rat.
Female Wistar rats weighing between 230 and 280 g were maintained under a controlled lighting schedule (12
S. A. Whitehead, J. M. Pennington and D. A. Carter
Changes in pituitary responses to pulses of LH releasing hormone (LH-RH) after ovariectomy in the rat have been investigated with an in-vitro perifusion system. On the third day after ovariectomy there was a large increase in the responsiveness of the pituitary gland to LH-RH compared with days 1 and 2 and this preceded the first significant rise in circulating concentrations of LH. Exaggerated responses were observed on all subsequent days tested (days 4, 6, 10, 18 and 28) although the size of the response on day 10 was significantly lower compared with days 6, 18 or 28. It is suggested that the early phase of increased pituitary responsiveness to LH-RH results from a rise in pituitary LH-RH receptors, which increases both the synthesis of LH and the response to exogenous LH-RH. The reduced LH response, measured on day 10, may correlate with an increase in the endogenous secretion of LH-RH and an imbalance between LH synthesis and secretion at this time.