Hypothalamo Pituitary Disconnection and Surgical Ablation

The hypothalamo-pituitary disconnection (HPD) Soay sheep model in which the pituitary gland is surgically separated from the hypothalamus has been used to further investigate the potential sites of action of melatonin in the regulation of seasonality (35). The surgical procedure involves visualising the stalk region of the pituitary gland via a paramedial, transnasal, transphenoidal approach, entering the median eminence above the pituitary portal vasculature, and evacuating the neural tissue from the tuberal cinereum (12; Figure 4). This permanently destroys the terminal fields of the median eminence and much of the arcuate nucleus region of the hypothalamus, but spares the lateral and more rostral regions of the hypothalamus and the preoptic area. It also permits the survival of the majority of the pituitary gland including the pars tuberalis which continues to express a high concentration of melatonin receptors (69). To limit reconnection of neural tissue a small piece of aluminium foil is placed in the infundibu-lum to form a barrier between the hypothalamus and the pituitary gland (Fig. 4). Following HPD surgery, sheep show clinical signs of pituitary disconnection including polyuria (loss of posterior pituitary arginine vasopressin/AVP secretion), gonadal regression (loss of gonadotrophin releasing hormone/GnRH support to gonadotrophin secretion) and gradual weight gain (loss of hypothalamic control of energy balance), but remain in good health and require no hormonal replacement therapy to maintain viability.

In HPD Soay rams PRL secretion was shown to vary in response to changes in photoperiod and the administration of melatonin despite the absence of regulation by the hypothalamus (Figure 5). The circulating PRL concentrations were slightly higher that normal presumably due to the loss of the inhibitory influence of dopamine from the hypothalamus, but treatment of HPD rams with the specific dopamine D2

Melatonin Sheep

Figure 4. Hypothalamo-pituitary disconnection (HPD) Soay sheep model used to investigate the sites of action of melatonin. The HPD operation removes the median eminence and destroys communication between the hypothalamus and pituitary gland, but maintains the viability of the pituitary gland including the cells expressing melatonin receptors in the pars tuberalis (PT). Abbreviations: AC—anterior commissure, MB mammillary body, MT—medial thalamus, OC—optic chiasma, PD—pars distalis, PI—parmtermdia, 3 V—third cerebral ventricle.

Figure 4. Hypothalamo-pituitary disconnection (HPD) Soay sheep model used to investigate the sites of action of melatonin. The HPD operation removes the median eminence and destroys communication between the hypothalamus and pituitary gland, but maintains the viability of the pituitary gland including the cells expressing melatonin receptors in the pars tuberalis (PT). Abbreviations: AC—anterior commissure, MB mammillary body, MT—medial thalamus, OC—optic chiasma, PD—pars distalis, PI—parmtermdia, 3 V—third cerebral ventricle.

Melatonin Receptor

Figure 5. Long-term cyclical changes in blood plasma concentrations of PRL in a) control and b) HPD Soay rams exposed to alternating 16-weekly periods of long (16L: 8D, LD) and short days (8L: 16D, SD), and treated with a subcutaneous implant on melatonin (horizontal bar) under long days. The sham and HPD operations occurred at week 8. Note, the persistence of normal photoperiod- and melatonin-induced PRL cycles in HPD rams (35,36).

Figure 5. Long-term cyclical changes in blood plasma concentrations of PRL in a) control and b) HPD Soay rams exposed to alternating 16-weekly periods of long (16L: 8D, LD) and short days (8L: 16D, SD), and treated with a subcutaneous implant on melatonin (horizontal bar) under long days. The sham and HPD operations occurred at week 8. Note, the persistence of normal photoperiod- and melatonin-induced PRL cycles in HPD rams (35,36).

receptor antagonist, sulpiride, failed to elicit PRL secretion under either long or short days, providing evidence that a dopaminergic system does not mediate the effect of photoperiod/melatonin on PRL secretion (36). Similar results have been obtained in foetal sheep where the more radical HPD operation still spares the ability of the foetus to modulate PRL secretion in relation to the ambient photoperiod (22). In this case the melatonin signal is generated by the mother and transferred to the foetus via the placenta.

These results provide clear support for the view that melatonin acts directly in the pituitary gland to mediate effects of photoperiod on PRL secretion. Since mela-tonin receptors are not expressed by lactotrophs in sheep (69), this effect is presumed to be relayed via the cells in the pars tuberalis which express the receptor in abundance. This is consistent with the recent observation that cultured pars tuberalis cells secrete a unidentified factor called "tuberalin" which upregulates gene expression in lactotrophs (and other cells in the pars distalis) and stimulates PRL secretion (19,56).

The pars tuberalis appears to be under inhibitory regulation by melatonin, thus short-duration exposure to melatonin daily (long day signal) may favour high tuberalin secretion thus stimulating PRL secretion, while long or continuous exposure to melatonin (short day signal) may inhibit tuberalin secretion to cause the observed decline in PRL secretion.

HPD sheep show acute changes in PRL secretion in response to manipulations of photoperiod and melatonin, but also show chronic changes indicative of the development of refractoriness. This has been observed in HPD Soay rams treated continuously with a subcutaneous implant of melatonin for 48 weeks while under long days (37). This induced an initial decline in the blood concentrations of PRL, followed by a partial recovery after 8-12weeks, with a similar profile to intact controls. The treatment with a second melatonin implant after some 20 weeks failed to inhibit PRL secretion demonstrating that the system was now unresponsive. In the studies in HPD foetal sheep, it has been observed that the PRL response varies with photoperiodic history (23). Taken together, these results support the view that the pars tuberalis-lactotroph-cellular relay within the pituitary gland has the capacity to generate temporal changes in PRL secretion and to carry a "memory" of the previous photoperiod.

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