Reviewer's report
Title:Hormone replacement therapy use and plasma levels of sex hormones in
The Norwegian Women and Cancer Postgenome Cohort
Version: 1Date:21 August 2007
Reviewer: Henrik Toft Sorensen
Reviewer's report:
This paper uses data on women included in the NOWAC study. It examines
plasma hormone levels according to self-reported HRT use, menopausal status,
and BMI. Furthermore, it aims to validate two self-administered questionnaires –
an 8-page questionnaire collected 6 months before blood draw and the other (a
2-page questionnaire) collected at the time of blood draw. These questionnaires
included data on HRT use, height, weight, menopausal status, oral contraceptive
use, etc. The current study selects out HRT use, BMI and menopausal status
and validates these by comparing the data to plasma hormone levels.
Studies such as this can be important to illustrate the validity of questionnaire
data and to enable future work utilizing these data for investigations on disease
etiology, etc. The NOWAC study is a well-designed, prospective study, with a
very good study population and which has been and will be utilized for many
studies on breast cancer etiology, among others, both as a stand alone study
and with other studies such as the EPIC cohort.
The current paper, therefore, has the potential to be a very useful reference
study in future papers. However, the paper has numerous limitations and in its
current form, is unacceptable for publication.
Major comments:
Overall, the paper lacks clarity and is confusing to read. There does not appear
to be any chronological order to the text, particularly in the results section. There
are a number of spelling and grammar mistakes, which need to be corrected.
A condition for this study is that you can determine menopausal status for the
blood samples, independent of the use of HRT. The validity of the menopausal
data is potentially interesting on condition that the gold standard really is a gold
standard.
There are a number of issues that the discussion section fails to address. For
example, compliance with HRT use is an important determinant for accurate
measurement of HRT use and is a source of bias which is not mentioned in the
discussion. Furthermore, the cross-sectional nature of the study means that the
study has several limitations when it comes to the ability to talk about causal
association.
The NOWAC study focuses on cancer in women. It is not clear why the authors
have not included information on other risk factors for breast cancer such as
alcohol intake, parity, socioeconomic status, use of oral contraception, etc.
Couldn’t these additional risk factors modify the plasma hormone levels in
addition to HRT, BMI and menopausal status??? As the methods section
outlines, these data were definitely available on the 8-page questionnaire, and
some of these data were available on the 2-page questionnaire. This would
enable future studies to examine whether or not HRT impacts on hormones
mediating cancer risk independent of other breast cancer risk factors.
As the paper stands, the aim of the current study was not to look at all breast
cancer risk factors, but to specifically examine HRT, BMI and menstrual status in
relation to blood hormone levels. I’m not certain why the authors didn’t include
information on contraceptive use – it may be that the majority of these women
(aged 48-62 years) no longer used contraception, but if they didn’t then the
authors should say this. Perhaps looking at the additional risk factors is the
subject of another paper, but failure of the authors to mention anything to do with
these additional breast cancer risk factors in the current study and their reasons
for focusing solely on HRT, BMI and menstrual status, is a major limitation and
leaves the reader wondering.
In table 3 and in the abstract, the authors should report 95% confidence intervals
for the specificity and sensitivity.
Specific comments:
The validity of the reported data is not included in the title.
Methods:
The methods section is far too long and needs to be substantially reduced. The
statistical analyses are not clear. Why was McNemar’s test used?
It is not clear from the text who and what proportion of women were asked to fast
before their blood draw. This needs to be inserted in the methods section.
Results:
The results section is very confusing and needs substantial revision. There is no
clear order to the text. The results would benefit by beginning with general
descriptive data on the study population as is done, but then dealing specifically
with the menopausal status, followed by BMI, etc. Paragraph 2 of the results
section deals with the classification of post-menopausal women. This is very
difficult to follow. The text could benefit and could be clarified by inserting a
flow-chart diagram outlining how these post-menopausal women came to be
classified as such. I think 9 + 325 = 334 and not 333!!
In paragraph 3 of the results section, the authors focus on BMI of
post-menopausal women. The results section seems to jump from dealing with
BMI in paragraph 1 and then back again to BMI in paragraph 3. Why not have
these in the same section???
The order of the text and tables does not correspond. Why are the findings
relating to Table 4 presented before Table 3?
Discussion:
The information on BMI was calculated from self-reported weight and height.
Although this information may be accurate given that FSH levels were lower
among women with a high BMI, have there been any studies correlating
self-reported with actual BMI on the NOWAC study, or a similar study?
The authors mention that reports show a decrease in FSH levels with long-term
use of oral and transdermal E2. Although they had information on use of HRT at
the time of blood draw and six months before blood draw, it would be interesting
to see if these FSH levels correlate with increased length of time on HRT –
perhaps by expanding the “years since menopause” variable, or if available,
mentioning how these FSH levels correlated with length of time on oral and
transdermal E2.