THE INFLUENCE OF EXOGENOUS MELATONIN ON THE SEASONAL PATTERNS OF OVULATION AND ESTRUS IN SHEEP

A novel dose form of melatonin (Regulin(R)) is described which maintains plasma melatonin levels of sheep continuously elevated to near physiological night-time values of 300-1000 pmol l-1. The melatonin (18 mg) was compressed into a subcutaneous implantable dose-form coated with a rate-limiting diffusion membrane to provide a near zero-order release over a period of approximately 10 weeks. The implants, (Regulin(R)) were administered to ewes of different breeds and at different times of the year and ovarian function was assessed by serial endoscopic observation of the number of corpora lutea present on both ovaries at 3- to 6-week intervals for up to 1 year following treatment. In a series of studies it was shown that the administration of a single implant resulted in an advancement of the normal peak seasonal reproductive activity by up to 100 days with an observed lag phase from start of treatment to peak response of approximately 50-70 days. The pharmaceutical 'short-day' treatment was effective in Merino, Corriedale and more-seasonal British breeds such as the Romney Marsh, but only if the treatment was given at the time of receptivity to the short-day stimulus ('the effective treatment window'). The effective treatment window in spring and summer was wider for the less-seasonal breeds than for breeds of British origin. The initial inductive phase of the response to melatonin was characterised by more ewes ovulating and by a higher ovulation rate compared with contemporaneous untreated controls. No superovulatory activity was induced. This inductive phase was followed by an early partial reversion to reproductive quiescence and, in one study, was followed by a second peak of reproductive activity at the end of the normal period. Short-term treatments, with durations of less than 40 days were either without effect or caused suppressed reproductive function, and highlighted the need for implant integrity for proper function. Although these studies do not provide a definitive answer to the way in which sheep interpret a continuous presence of melatonin, the data are more consistent with a 'short-day' rather than a 'non-day' mode of action. Analysis of the dynamic pattern of the ovarian response, in both the presence and absence of rams, permitted the development of a standardised treatment strategy for the use of melatonin implants to achieve a practical improvement in the early breeding performance of ewes under farm conditions.