Controlled-release melatonin implants delay puberty in rats without altering melatonin rhythmicity

Abstract

There is increasing evidence that continuous availability of melatonin via implants can produce the same physiological changes in animals as timed administration of the hormone. The mechanisms underlying this apparent contradiction are not known. In an attempt to gain further understanding of the way continuous melatonin administration affects reproductive activity, the effects of melatonin implants on gonadal development and melatonin production were investigated in rats treated neonatally with testosterone. Five-day-old male rats maintained on a 12L:12D photoperiod were injected with 1 mg testosterone propionate to induce photo-responsiveness and implanted at 21 days of age with novel melatonin implants designed to raise the daytime blood melatonin concentration into the nighttime range, i.e., from less than 60 pM in the controls during the day to 380 +/- 33 pM in the implanted rats. Following 21 days treatment, seminal vesicle and ventral prostate weights of implanted rats were significantly less than the controls (27.0 +/- 1.9 vs. 18.5 +/- 1.5 mg/ 100 g BW (P = 0.003) and 33.8 +/- 2.1 vs. 26.7 +/- 2.2 mg/100 g BW (P = 0.02), respectively). To determine the effect of the implants upon melatonin production, urine was collected at hourly intervals during the last four days of the experiment and the hourly 6-sulphatoxymelatonin (aMT.6S) excretion rate was determined. Rats bearing melatonin implants maintained a rhythm of aMT.6S excretion in 12L:12D, which was indistinguishable from that in the control animals except for a raised daytime excretion of the metabolite. Following one cycle of urinary aMT.6S measurements in the light/dark cycle, the animals were released into constant darkness, with the implants still in place or after their removal four hours before darkness to evaluate the characteristics of the melatonin rhythm in the absence of masking effects of the light/dark cycle. The melatonin rhythm persisted in both control and implanted rats and no differences in the onset, offset, or amplitude could be determined. The results of this study indicate that, like many other mammals, for laboratory rats controlled continuous release of melatonin can mimic the effects of short daylength or timed melatonin administration. Despite the reproductive consequences of continuous melatonin delivery, the timing of endogenous melatonin production is unaffected.