Title: The association between reproductive history and menopausal symptoms: an evidence
from the cross-sectional survey
Version: 3 Date: 10 Feb 2022
Reviewer:  Imke Janssen
Reviewer's report:
I would like to draw the attention of the authors to a large body of literature that has been ignored.
The Study of Women’s Health across the Nation (SWAN) has published data on a cohort of
women from a diverse background of race/ethnicity. The study was designed to examine the
effects of the menopausal transition and has had ongoing assessments since 1996 with several
hundred publications, many of which were centered at the final menstrual period since 2008,
yielding particularly strong evidence for menopause-related changes. In addition, there are now
papers utilizing a pooled cohort from 6 studies. The authors may find the following 2 papers
(including references in them) of particular interest:
Matthews KA, Chang Y, Brooks MM, Crawford S, Janssen I, Joffe H, Kravitz HM, Thurston
RC, El Khoudary SR: Identifying women who share patterns of reproductive hormones,
vasomotor symptoms and sleep maintenance problems across the menopause transition: Group-
based multi-trajectory modeling in Study of Women’s Health Across the Nation; 2020
Menopause, 28(2):126-134.
Chung H-F, Zhu D, Dobson AJ, Kuh D, Gold EB, Crawford SL, Avis NE, Mitchell ES, Woods
NF, Anderson DJ, Mishra GD. Age at menarche and risk of vasomotor menopausal symptoms:
a pooled analysis of six studies. BJOG 2021; 128:603-613.
A revision of the introduction would also impact the Discussion.
Major comments:
Given the large amount of literature, what can a fairly small cross-sectional study such as this
study add? Obviously, this is a population of women from Northern Iran, but why would they
be different? A previous reviewer has asked about this, but it is not clear in the paper. The age
at menopause is fairly young compared to data from other populations, although the exclusion
criteria state that women with early and premature menopause were excluded.
Therefore, how would results from this study generalize to toher women?
A brief description of the MRS would be helpful. For example, the somatic symptoms included
hot flushes, [add 3 more]
Women using or having used hormone replacement therapy were also excluded. Why would
postmenopausal women use hormonal contraception (Tables 2 and 3)?  At 36%, this is not a
small number.
Table 1 is very busy and presents data for many variables in categorical format as well as in
continuous format. One way should be enough (the way it was used in analyses). Furthermore,
it is not clear what the p-value indicates. Is it for the categorical or the continuous format? Is it
an overall test for a difference or a test for trend? The number of children in some categories is
lower than the number of alive children. That seems very strange. Do we really need all variables
in this table, for example parity, number of children, number of alive children, number of dead
children? Some categories have extremely low numbers.
Table 2: As shown in Table 1, some categories have extremely low numbers which would
yield unstable estimates. In cases with overall significance, pairwise comparisons would be
informative. For example, in the results section, it is pointed out that postmenopausal women
had a higher mean of somatic and urogenital symptoms. Higher than what? It is also pointed
out that perimenopausal women had a higher mean of psychological symptoms. Although it is
true that they had the highest mean score, it is doubtful that this would differ significantly from
postmenopausal women.
Table 3 presents regression analyses. It is unclear how variables were defined (e.g., age at first
pregnancy for women who were never pregnant). It is also unclear how the predictors were
selected, as there are more significant results in Table 2. Lastly, in the model for total symptoms,
2 predictors (number of children and number of alive children) are highly related. Conceptually,
this model does not make sense. The adjusted R2s are all fairly low, indicating that an overall
lack of explanatory power.
Given that there were large differences in symptoms between pre-, peri- and postmenopausal
women, should menopausal status be included in the models (with premenopause as a reference)
instead of age?
Minor comments:
The term “researcher-made” questionnaire seems odd. It would be more meaningful to know
where this questionnaire included standard questions. What does gynecological surgery include?
Menopause is used in 2 different ways: menopausal transition as well as postmenopause.
An “s” should be added to “Number of abortion”.
The manuscript would benefit from input of the native English speaker.