Reviewer’s report
Title: 
RISK FACTORS FOR NATURAL MENOPAUSE BEFORE THE AGE
OF 45: EVIDENCE FROM TWO BRITISH POPULATION-BASED BIRTH
COHORT STUDIES
Version: 
0 
Date: 
31 Dec 2021
Reviewer's report:
These are important data from population-based birth cohorts followed over
many years. The uniqueness of these data deserves emphasis. That you also have
data from pre-birth, childhood, adulthood, perimenopause and into menopause
makes this study very important. However, insufficient information is currently
provided to accurately understand what these data mean, how accurate they may
be, how they may be interpreted and sufficient data that they could be repeated.
We need a consort figure, to know exactly how many women (as babies) began
the study, how many were excluded for hysterectomy/bilateral ovariectomy
(hyx/ovx), starting hormone therapy before menopause, clear identification of
missing data points in each cohort, what "gynecological problems" mean
(described in detail by what women report) and at what ages1 2 4. In the same
request for more physiology, considering menopause "estrogen deficiency" is
incorrect5 and calling of hormonal treatment in menopause "hormone
replacement therapy" is inaccurate and outmoded6. 
Specific Necessary Changes
1. The title should be more specific (such as "factors related to natural
menopause before age 45") and identify that these are population-based
prospective data over a median of ____ years.
2. The abstract needs to include the numbers enrolled in both birth cohorts,
participation rate, the number excluded for hyst/ovx, the number whose data
contributed the final age at menopause.
3. The introduction waxes dramatic about "early menopause" and its apparent
negative health consequences. But if 50 or 52 are the average age, then 45 years
may be within the SD for natural menopause; most of the negative
"consequences" are related to pre/perimenopausal bilateral ovariectomy. To
frame their study appropriately they need to show what is now known about non-
surgery related menopause before 45, and if it is from population-based rather
than with convenience or worse yet, clinical samples. 
4. The framing of ovarian ageing needs to include understanding that the
hypothalamic pituitary responses also change 7 8.
5. Line 164 inaccurately implies that every cycle is ovulatory; epidemiologic
data do not support that erroneous assumption9 10.
6. Suggest Methods include a subsection on participants that includes the
consenting process. (That I am assuming was quite complete but it needs stating
in this independent research publication).
7. The three objectives do not include assessments of potential variables after
ages 30 and 33 (respectively). 
Why? 
Lines 218-9 say assessments were obtained
at ages 38 and 42—these deserve a separate objective and need more clarity. 
If
you intend to analyze them later (or have already published on them, please says
so/provide the references).
8. Methods needs to define "gynecological problems" lines 231-33 since
conditions 
like PCOS and hypothalamic amenorrhea differ in their ages at
menopause, heavy flow occurs for almost a third of midlife/perimenopausal
women11, and it is important to know if endometriosis is related to a different
age at menopause.
9. Please provide scientific publications for the assembly and baseline data from
each of two birth cohorts on lines 213 and 214, not just the website links that are
difficult to navigate and at least superficially contain no data. 
10. Thank you for defining menopause appropriately (and avoiding the
"postmenopause" inaccurate terminology). However, your physiological framing
of this normal life phase as "oestrogen deficiency" is just plain wrong. Why?
Because low oestradiol and progesterone are normal in this normal phase of life
and progesterone decreases numerically more than oestrogen between
premenopause and menopause. 
11. When discussing hormone therapy for treatment of perimenopausal or
menopausal symptoms please describe it rather than using the inaccurate and
outmoded "hormone replacement therapy6" or "HRT" language 
which just
perpetuate non-physiological approaches to women's reproduction. 
12. Please provide a consort figure—it needs to start with the parents signing
informed consent for each birth cohort, and include drop-outs at each age
assessment for both groups. It further needs to show the missing data now
appropriately replaced by imputation and finally the number of menopausal
women from whom the age at menopause was derived.
13. Because the age at menopause may show temporal change, please specify the
age by birth cohort (if possible).
14. If you are able to, please include as part of perimenopause, data from at least
the two years before your current definition of "perimenopause". The way you've
defined it now is inaccurate and inappropriately limited. Defining it as those
who've skipped 3-12 cycles includes only women in the Stages of Reproductive
Aging Workshop 10+ "Late Menopause Transition"1 and what most call "Late
Perimenopause" (the year after the final menstrual flow). 
15. 
Tables 1A and 2A in the Supplemental data need to be added to the body of
the paper.
16. In providing results, please provide the mean and 95% CI of the percentage
of early menopause in each different cohort and specify whether or not these
percentages differ. 
17. 
Lines 317-8 you use 2.2 times once and 24% higher another time. Please use
the same language for describing all of the data. 
18. 
Please provide the mean age and 95% confidence intervals on younger
women's age at birth and also the statistics on its association with early
menopause (even if the 95%CI include 1).
19. 
What are the units of standardized birthweight (include in the table)
20. 
Line 337 is unclear—what does "suffered periods" mean. Are you talking
about severe cramps or endometriosis? 
Clarify.
21. 
Line 344 "economically active" as in playing the stock market or having a
part-time or full-time out-of-the-home job? It is not adequately descriptive to
understand. 
22. 
It is not possible to understand stats as in Table 3 without, for example,
knowing what percentage of all women in each cohort used hormone
contraceptives. Ideally would differentiate combined hormonal contraceptives
(with high dose oestrogen/normal dose progestins) from progestin-only or IUD
methods.
23. 
What does "other" under social class in Table 3 mean?
24. 
The language at 385-6 needs clarifying.
25. 
Line 390—there is a lot of direct and indirect evidence that physical activity
influences women's reproductive hormones. Consistent older literature shows
lower risks of breast cancer with young adult physical activity12. A recent
review documents the adaptive changes that commonly occur13. 
The cited
reference, by itself, is inadequate to cover a complex topic. 
26. 
It needs to be listed as a limitation (and also a strength) in discussion that
almost half of the potential cohort was excluded related to surgical menopause,
hysterectomy, unclear data, use of hormone therapy before menopause etc.
27. 
Another limitation is that variables in perimenopause (assessed at ages 38
and 44) were not included in this careful life cycle analysis.
28. 
A further limitation is lack of information about race/ethnicity. 
29. 
There are some complex relationships here that the current statistical analysis
can't parse. For example, heavy menstrual bleeding is commonly ascribed to
fibroids in perimenopause (although it is associated with high estrogen levels
and less consistent ovulation14) and few fibroids are anatomically likely to
cause it15. Fibroids are often "treated" by hysterectomy leading to those women
being excluded from this analysis of age at menopause. 
30. 
Rewrite the conclusions to clearly specify the integrated percentage of these
population-based cohorts with natural menopause before age 45 and the main
infancy, childhood, young adulthood that are related to this.
Reference List
1. Harlow SD, Gass M, Hall JE, et al. Executive summary of the Stages of
Reproductive Aging Workshop +10: addressing the unfinished agenda of staging
reproductive aging. Climacteric 2012;15(2):105-14.
2. Gracia CR, Freeman EW. Onset of the Menopause Transition: The Earliest
Signs and Symptoms. Obstet Gynecol Clin North Am 2018;45(4):585-97. doi:
10.1016/j.ogc.2018.07.002 [published Online First: 2018/11/08]
3. Prior JC. Clearing confusion about perimenopause. B C Med J
2005;47(10):534-38.
4. Coslov N, Richardson M, Mitchell ES, et al. Symptom experience during the
late reproductive stage and the menopausal transition: observations from the
Women Living Better survey. Menopause 2020;28(9):1012-25. doi:
https://www.menopause.org/annual-meetings/2020-meeting/meeting-abstracts 
5. Prior JC. Women's Reproductive System as Balanced Estradiol and
Progesterone Actions—a revolutionary, paradigm-shifting concept in women's
health. Drug Discovery Today: Disease Models 2020;32:31-40. doi:
https://doi.org/10.1016/j.ddmod.2020.11.005
6. Speroff L. It's time to stop using the word 'replacement'. Maturitas 2000;34:1-
3.
7. Weiss G, Skurnick JH, Goldsmith LT, et al. Menopause and hypothalamic-
pituitary sensitivity to estrogen. JAMA 2004;292(24):2991-96.
8. Prior JC. Perimenopause: The complex endocrinology of the menopausal
transition. Endocrine Reviews 1998;19:397-428.
9. Vitzthum VJ, Bentley GR, Spielvogel H, et al. Salivary progesterone levels
and rate of ovulation are significantly lower in poorer than in better-off urban-
dwelling Bolivian women. Hum Reprod 2002;17(7):1906-13.
10. Prior JC, Naess M, Langhammer A, et al. Ovulation Prevalence in Women
with Spontaneous Normal-Length Menstrual Cycles - A Population-Based
Cohort from HUNT3, Norway. PLOS One 2015;10(8):e0134473. doi:
10.1371/journal.pone.0134473
11. Kaufert PA. The perimenopausal woman and her use of health services.
Maturitas 1980;2:191-205.
12. Wyshak G, Frisch RE. Breast cancer among former college athletes
compared to non-athletes: a 15-year follow-up. BrJ Cancer 2000;82(3):726-30.
13. Liu AY, Petit MA, Prior JC. Exercise and the Hypothalamus: Ovulatory
Adaptations. In: Hackney AC, Constantini NW, eds. Endocrinology of Physical
Activity and Sport, 3rd Edition. Switzerland: Humana Press 2020:123-51.
14. Moen MH, Kahn H, Bjerve KS, et al. Menometrorrhagia in the
perimenopause is associated with increased serum estradiol. Maturitas
2004;47(2):151-55.
15. Seltzer VI, Benjamin F, Deutsch S. Perimenopausal bleeding patterns and
pathological findings. Journal American Medical Women's Association
1990;45:132-34.
Publons Reviewer Recognition
. Springer Nature can send verification of this
review directly to Publons (a subsidiary of Clarivate Analytics). If you would
like to take advantage of this service, please click on the “Yes” option below.
Your name, email address, title of the reviewed manuscript, name of the journal,
and date of your review submission (the “Review Data”) will then be transmitted
to Publons after the final decision on the manuscript has been made. If you have
already registered at Publons, they will notify you of the receipt of this review
and update your profile 
as per your settings and their policy. If you are not
registered with Publons, you will receive an email from them asking you to
register in order for them to be able to recognize your review on your new
profile page. Publons may use the Review Data to generate derivative metadata
for the benefit of Publons and you as a reviewer, carefully considering the
sensitivity of such information. For example, Publons may verify your record as
a reviewer by updating your profile published on its webservice if you have
registered for such service or help editors to identify candidate reviewers. Please
find the details of processing in Publons’ privacy policy
https://publons.com/about/terms
Yes
Declaration of competing interests
Please complete a declaration of competing
interests, considering the following questions:
1
. 
Have you in the past five years received reimbursements, fees, funding, or
salary from an organisation that may in any way gain or lose financially
from the publication of this manuscript, either now or in the future?
2
. 
Do you hold any stocks or shares in an organisation that may in any way
gain or lose financially from the publication of this manuscript, either now
or in the future?
3
. 
Do you hold or are you currently applying for any patents relating to the
content of the manuscript?
4
. 
Have you received reimbursements, fees, funding, or salary from an
organization that holds or has applied for patents relating to the content of
the manuscript?
5
. 
Do you have any other financial competing interests?
6
. 
Do you have any non-financial competing interests in relation to this
paper?
If you can answer no to all of the above, write 'I declare that I have no competing
interests' below. If your reply is yes to any, please give details below.
I declare that I have no competing interests.
Reviewer Publication Consent.
 I agree for my report to be made available
under an Open Access Creative Commons CC-BY License (
http://creativecommons.org/licenses/by/4.0
) if this manuscript is accepted for
publication. Any comments that I do not wish to be included in the published
report have been included as confidential comments to the editor, which will not
be published.
If you are not happy for us to publish this report, please contact the
editorial office before completing the review.
If you wish, you can include your
name in your published report. Please note you must decide whether to include
your name at the start of the process and confirm this decision whenever
prompted. If you change your decision later, we will not be able to publish your
name.
I agree to the terms of the CC-BY 4.0 license; please publish my name with my
report.
Is the study design appropriate to answer the research question (including the use
of appropriate controls), and are the conclusions supported by the evidence
presented?
Yes
Are the methods sufficiently described to allow the study to be repeated?
No
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
No
Are the images in this manuscript (including electrophoretic gels and blots) free
from apparent manipulation?
Yes