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Letters to the Editor |
Department of Physiology University of Pittsburgh Medical School Pittsburgh, Pennsylvania 15261
To the editor:
I should like to comment on the recent study published in the February 2000 issue of The Journal of Clinical Endocrinology & Metabolism by Suter et al., (1) and entitled "Circulating concentrations of nocturnal leptin, growth hormone, and insulin-like growth factor-I increase before the onset of puberty in agonadal male monkeys: potential signals for the initiation of puberty."
As described in the paper, this study employed plasma samples that had been previously collected for an earlier investigation of the pattern and tempo of the pubertal increase in pulsatile GnRH release in the male monkey (2). This earlier study, which was conducted in my laboratory and published in 1998, was aimed at tracking hypothalamic GnRH pulse generator activity during the peripubertal phase of development using LH secretion from a GnRH- sensitized pituitary as an indirect index of GnRH discharges. Series of sequential blood samples taken between 1900 and 0200 h were collected from the monkeys every 10 days, and pulses of LH secretion were identified by "Pulsar" (3). To analyze changes in LH pulsatility across this critical phase of development, an algorithm for identifying the age at which increased LH pulsatility first occurred was generated and applied to data from individual monkeys. This algorithm was purely arbitrary, although it was applied objectively to provide a developmental reference point, designated day 0, on which LH data for individual monkeys was aligned. In this manner, a composite timecourse of the developmental changes in LH pulse frequency was derived (see Fig. 4 from Ref. 2). As may be seen from this figure, there was an indication that LH pulse frequency increased before day 0, and in the discussion of this paper we remarked on the probable need to refine the algorithm for future studies (2).
Suter et al. (1) later analyzed for GH and leptin in selected single evening samples collected at the same 10-day intervals used for the earlier assessment of GnRH pulse generator activity, and, as in the 1998 paper, day 0 was again used for data alignment in order to obtain composite timecourses of developmental changes in mean nocturnal leptin and GH concentrations (see Figs. 1 and 3 from Ref. 1). Suter et al. (1) also combined bins of data for leptin and GH collected before day 0 into two developmental periods that they refer to as an early and late prepubertal phase, and demonstrated that levels of leptin and GH in the early prepubertal phase were significantly lower that those for the late prepubertal phase (see Figs. 1 and 3 from Ref. 1). In addition to using day 0 as a reference for data alignment, Suter et al (1) also use this arbitrary parameter as the time of the onset of "puberty" and are therefore, able to reach the conclusion that leptin and GH increase prior to the onset of this critical developmental phase. To use day 0 in this manner, however, may well be inappropriate since the precise relationship of this parameter to the age at which the hypothalamic events leading to increased pubertal GnRH release are set in motion in primates is simply not known. With the extant data available from the two studies, the closest that we can get to this issue is to relate changes in LH pulse frequency (a robust index of GnRH pulse generator activity in the agonadal situation) with the concomitant changes in circulating leptin and GH levels, and then to formally examine whether the increases in leptin and GH levels precede that of the index of GnRH activity. I have attempted to correlate these hormonal changes in Fig. A by "guestimating" means and SEMs from Figs. 1 and 3 from Suter et al. (1) and superimposing them on the original LH frequency data (2). Certainly, visual inspection of the hormonal timecourses shown in Fig. A fails to provide any optimism for the view that either the leptin or GH changes precede those in GnRH pulse generator activity and, therefore, the initiation of the onset of puberty. A more parsimonious conclusion is that the pubertal initiation of GnRH pulse generator activity may coincide with increases in circulating leptin and GH concentrations, which in turn indicates that the same developmental signal, be it neurobiologic or somatic, triggers these hormonal changes concomitantly.
The foregoing criticism of the analytical approach taken by Suter et al. (1) to identify the temporal relationship between developmental patterns in leptin and GH and the onset of puberty does not detract from the potential importance of their empiric observation that suggests nocturnal leptin and GH levels may increase in agonadal primates at an age that is associated with the pubertal re-augmentation of GnRH pulse generator activity. As pointed out in the editorial to this paper (4), the findings of Suter et al. (1) reinforce the need to establish whether "sampling paradigms" are appropriate for the questions being addressed. At the same time, investigators, reviewers, and editors should appreciate that experimental paradigms, in general, and particularly those addressing the initiation of the onset of puberty, are not perfect and, therefore, their application demands that attention to cautious interpretations of all available data is not overlooked.
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