Reviewer's report 
 Melatonin effects on luteinizing hormone in postmenopausal women: A clinical trial Title: 
NCT00288262 
 1  21 February 2006 Version: Date: 
 Josephine Arendt Reviewer: 
Reviewer's report: 
General 
This study is one of the rare studies to investigate the effects of melatonin in humans, based on its known functional role in photoperiodic animals and as such is important. The amount of melatonin used gives close to physiological concentrations in some but not all people. The design- evening 
melatonin to advance and extend the profile, and morning melatonin to delay and extend the profile 
is commonly used for phase shifting studies without regard to photoperiodic effects (a study simultaneously advancing and delaying the profile, also with 0.5 mg melatonin has been presented and published in abstract form only (Haimov et al., Sleep Online, abstracts of the WFSRS Dresden, 
1999)). 
There were evident problems with the study, recruitment, funding etc so that it is understandable that 
the authors wish to publish these data as preliminary observations. 
The major problem is that in order to achieve significance for the suppression of LH they had to 
combine both the evening and the morning melatonin groups. I do not think that these two groups can be justifiably combined. The advance of the evening rise and the increased duration of high 
levels will have been consistent from one individual to another after evening melatonin, however the 
morning decline after morning melatonin will have been very variable from one individual to another, 
and also the duration of high levels. This is due to large individual variability in pharmacokinetics of 
exogenous melatonin. Thus, even if the data are not significant I would keep the groups separate, 
but add a statement that combined they were significant, and temper the conclusions accordingly. A 
further consideration is the different circadian phase shift that theoretically will have been produced by evening and morning melatonon. 
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Major Compulsory Revisions (that the author must respond to before a decision on publication can be reached) 
1) The title should reflect the preliminary nature of the work. 
2) Separate the evening and morning melatonin groups in the analysis 3) Provide a Figure to show the LH data. 
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Minor Essential Revisions (such as missing labels on figures, or the wrong use of a term, which the author can be trusted to correct) 
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Discretionary Revisions (which the author can choose to ignore) Minor point- introduction: acute exogenous melatonin elevates prolactin (Waldhauser et al) but 
chronic long duration melatonin (in animals) signals short days and a decline in prolactin. This could 
be mentioned in the introduction. Is there a good reason why chronic short days (or chronic long 
duration melatonin) should increase prolactin in humans when it does the opposite in animals? 
 Unable to decide on acceptance or rejection until the authors have responded to the What next?: 
major compulsory revisions 
 An article of importance in its field Level of interest: 
 Acceptable Quality of written English: 
 No Statistical review: 
Declaration of competing interests: 
I am a memeber of the Sleep advisory Board of Alliance Pharmaceuticals, who are developing 
melatonin for use in circadiann rhythm related sleep disorders