Sexual frequency is associated with age of natural menopause: results from the Study of Women's Health Across the Nation

It is often observed that married women have a later age of natural menopause (ANM) than unmarried women; however, the reason for this association is unknown. We test an original hypothesis that sexual frequency acts as a bio-behavioural mediator between marital status and ANM. We hypothesize that there is a trade-off between continued ovulation and menopause based on the woman's chances of becoming pregnant. If a woman is sexually inactive, then pregnancy is impossible, and continued investment in ovulation would not be adaptive. In addition, we test an existing hypothesis that the observed relationship is because of the exposure to male pheromones. Data from 2936 women were drawn from 11 waves of the Study of Women's Health Across the Nation, which is a longitudinal study conducted in the United States. Using time-varying Cox regression, we found no evidence for the pheromone hypothesis. However, we did observe that women who reported to have sex weekly during the study period were 28% less likely to experience menopause than women who had sex less than monthly. This is an indication that ANM may be somewhat facultative in response to the likelihood of pregnancy.

driving this change? Sexual frequency could be a mediator in the association between being married and menopause onset, which could explain also the findings reported in the study.
Authors group married women and in a relationship in a single group, however there might be differences between a married couple and in a relationship. Could authors investigate the associations independently for married women and in a relationship?
I would recommend to rerun the analysis looking at the age of menopause as categorical variable: early vs. late menopause. This type of analysis would provide more meaningful results and easier to interpret.

Minor comment
The abstract in the current version is not very informative. Authors should add more information on number of women included in the study, follow-up time as well as estimates when reporting an association Decision letter (RSOS-191020.R0)

04-Oct-2019
Dear Professor Arnot, The editors assigned to your paper ("Sexual frequency is associated with age of natural menopause: results from the Study of Women's Health Across the Nation") have now received comments from reviewers. We would like you to revise your paper in accordance with the referee and Associate Editor suggestions which can be found below (not including confidential reports to the Editor). Please note this decision does not guarantee eventual acceptance.
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• Funding statement Please list the source of funding for each author. With apologies for the unusual delay in completing review (we struggled a little to find suitable reviewers), we recommend revising the paper in-line with the comments of the reviewers who have been able to comment on the paper. Please bear in mind that you may not be granted a further round of revision, so please ensure you take all the comments of the reviewers into account in the revision -it would help enormously if you could provide not only a marked-up version of the revised m/s but also a point-by-point response to the reviewers with that revision. Good luck! Comments to Author: Reviewers' Comments to Author: Reviewer: 1 Comments to the Author(s) Attached Reviewer: 2 Comments to the Author(s) Arnot et al investigated whether male-female cohabitation and sexual frequency were associated with menopause onset. The study, based on data from Women's Health Across the Nation show that male-female cohabitation was not associated with menopause onset, however women who engage in more sex enter menopause late.
Major Comments Did author have information on alcohol intake and economic status/occupation status? Alcohol and income is associated with menopause onset and should be included as covariate (Schoenaker at al; PE Teneri 2016).
Author select sexual frequency as the maximum amount of sexual activity in any of the categories: sexual touching/caressing; oral sex and sexual intercourse. It would be of interest to investigate the frequency within each strata and see whether the finding are independent of the type of sex. Also, it is not clear whether masturbation was included as sexual activity; it would be of interest to examine also whether masturbation is associated with menopause onset.
Did authors have information on frequency in orgasm since biologically these could be more relevant to menopause onset?
Being married is not associated with later onset of menopause in the univariate model, however after adjustment being married results at increased risk of early menopause. Is sexual frequency driving this change? Sexual frequency could be a mediator in the association between being married and menopause onset, which could explain also the findings reported in the study.
Authors group married women and in a relationship in a single group, however there might be differences between a married couple and in a relationship. Could authors investigate the associations independently for married women and in a relationship?
I would recommend to rerun the analysis looking at the age of menopause as categorical variable: early vs. late menopause. This type of analysis would provide more meaningful results and easier to interpret.

Minor comment
The abstract in the current version is not very informative. Authors should add more information on number of women included in the study, follow-up time as well as estimates when reporting an association Author's Response to Decision Letter for (RSOS-191020.R0) See Appendix B.

Comments to the Author(s) No further comments
Decision letter (RSOS-191020.R1)

02-Dec-2019
Dear Professor Arnot, It is a pleasure to accept your manuscript entitled "Sexual frequency is associated with age of natural menopause: results from the Study of Women's Health Across the Nation" in its current form for publication in Royal Society Open Science. The comments of the reviewer(s) who reviewed your manuscript are included at the foot of this letter.
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Kind regards, Royal Society Open Science Editorial Office Royal Society Open Science openscience@royalsociety.org on behalf of the Associate Editor, and Professor Kevin Padian (Subject Editor) openscience@royalsociety.org Sexual frequency is associated with age of natural menopause: results from the Study of Women's Health Across the Nation. This paper tests the hypothesis that sexual frequency might explain the observed association between marital status and age at natural menopause (ANM). It also tests the theory that male pheromones influence ANM. The authors use a rich US data set which includes biomarkers and is specifically designed to investigate menopause. The methods are appropriate and the write-up is clear. This study is appropriate for RS Open Science readership and would make an important contribution to the literature. My main concern is the operationalisation of sex frequency and I would like to see a few robustness checks along these lines. My specific comments are: Page 2, line 15. Please add a short explanation for why exposure to male pheromones might influence ANM. This will also help clarify the predictions made by the two hypotheses given next.
Page 3, line 16. If support is found for either hypothesis, would this not suggest that the timing of menopause is facultative? Why only for H1?
Page 3, study sample section -please state if this study is nationally representative of the US. And if not, please add something in the discussion about generalisability/biases of the findings.
Page 4, the authors state: "Sexual activity other than intercourse was used to create the sex index as the hypothesis is predicting that cues from sex will result in a trade-off, and the underlying mechanism of sexual touching, oral sex, and masturbation could all signal possible pregnancy to the body." To make an adaptive argument, it may be that only sexual intercourse influences ANM (i.e. not touching, oral, or masturbation), especially if the mechanism has something to do with sperm in the reproductive tract -are the results still the same if you use only this outcome in the sex index? Also, masturbation may signal exactly the opposite -that there is no male physical contact or likelihood of conception. Are your findings still robust if you just remove masturbation (i.e. keeping touching and oral as these include sexual partners)? It is not clear why the frequency matters so much, having sex once a month or daily might both signal the possibility to conceive. Please add something to motivate this decision.
Do your findings have implications for the Grandmother Hypothesis (GH)? It may be that ceasing reproduction becomes adaptive when daughters/children start reproducing. Are you able to you control for having grandchildren here? Even if not, please can you add a line or two in the discussion about this relationship (perhaps where you mention investment in existing kin; page 10, line 50). I realise that ceasing reproduction usually happens long before menopause but the GH is relevant to your adaptive argument.

Response to reviewers Reviewer 1.
This paper tests the hypothesis that sexual frequency might explain the observed association between marital status and age at natural menopause (ANM). It also tests the theory that male pheromones influence ANM. The authors use a rich US data set which includes biomarkers and is specifically designed to investigate menopause. The methods are appropriate and the write-up is clear. This study is appropriate for RS Open Science readership and would make an important contribution to the literature. My main concern is the operationalisation of sex frequency and I would like to see a few robustness checks along these lines.
My specific comments are: 1. Page 2, line 15. Please add a short explanation for why exposure to male pheromones might influence ANM. This will also help clarify the predictions made by the two hypotheses given next.

RESPONSE:
We have added in a short explanation into Section 1 to clarify why the authors of the pheromone hypothesis thought that it may be male cohabitation that delayed the menopause:  (Cutler et al., 1986b)." (Sievert et al., 2001:484).

Appendix B
We have clarified in text that ours is an alternative adaptive explanation, with sex signalling to the body the possibility of being pregnant, through saying: "As an alternative, we propose an adaptive explanation based on energetic trade-offs".
3. Page 3, study sample sectionplease state if this study is nationally representative of the US. And if not, please add something in the discussion about generalisability/biases of the findings. RESPONSE: Thank you for highlighting this. While SWAN is a community-based sample, existing literature has stated that SWAN is the largest, most diverse, and most representative study currently available to research aspects of the menopausal transition (Bromberger & Kravitz, 2011). We have added this information to Section 2.1.
4. Page 4, the authors state: "Sexual activity other than intercourse was used to create the sex index as the hypothesis is predicting that cues from sex will result in a tradeoff, and the underlying mechanism of sexual touching, oral sex, and masturbation could all signal possible pregnancy to the body." To make an adaptive argument, it may be that only As you can see, the hazard ratios follow the same direction, which is why we felt we were justified taking the maximum amount of sex experienced in any category as the 'sex index', as it appears that it is likely the same mechanism underlying the relationship between the individual categories and ANM. However, we are hesitant to draw too many parallels as the Grandmother Hypothesis is relevant to the evolution of the actual menopause, and very different physiological/evolutionary forces may be at play in regards to the cross-cultural variation in menopause timing.

Did author have information on alcohol intake and economic status/occupation status?
Alcohol and income is associated with menopause onset and should be included as covariate (Schoenaker at al; PE Teneri 2016).

RESPONSE: Thank you for this suggestion, and it is an important point. Yes, SWAN
does have data on these things. However, there were a number of reasons we decided not to include them when selecting covariates.
Firstly addressing economic status/occupational status: i. Occupational status is only available at the baseline wave. We could have taken this variable as "occupation at baseline", however, women have different ages at entry to the study, and also it is likely that a proportion of the women's occupations would have changed throughout the study. For these reasons, we do not think an "occupation at baseline" variable would be particularly meaningful; ii. Employment status (measured as in paid employment vs. not in paid employment) is asked at most waves, so we could have included that. However, as this is a binary variable, we thought that other variables (e.g. education, where there are more categories) were better at capturing socioeconomic position; iii. Income was also available, however, this is categorised by SWAN into very broad income categories (see below), and therefore, once again we did not think it was terribly informative.
As a result, we chose to use education as a proxy of income/economic status.
Furthermore, we show below that income and employment status are strongly associated with maximum educational attainment, and therefore we are hopefully demonstrating the effects of employment/occupation on ANM through using this variable: Relationship between income and education at age of menopause: (χ 2 = p < 0.001) we determined not to be missing at random both due to the pattern of missingness, and existing literature stating that there is likely to be a bias in non-respondents towards those who drink alcohol more often. Furthermore, as noted in Taneri et al., (2016:525):

Less than high school
"The underlying mechanisms linking alcohol consumption to the time of onset of menopause are unknown", and they go on to explain that alcohol intake may act as a proxy for lifestyle habits, such as diet and physical activity. Furthermore, alcohol consumption is associated with changes in hormones which themselves associate with menopause timing. As we already have many measures of lifestyle, such as smoking, education attainment, BMI, and self-perceived health, we do not think it would be conductive to include alcohol within the model. Furthermore, as we control for estradiol, we are also hopefully accounting for the endocrine changes related to alcohol consumption. We also observe alcohol being significantly associated with many of the lifestyle indicators, meaning that we are likely already capturing any effects the variable would bring to the final model.
2. Author select sexual frequency as the maximum amount of sexual activity in any of the categories: sexual touching/caressing; oral sex and sexual intercourse. It would be of interest to investigate the frequency within each strata and see whether the finding are independent of the type of sex. Also, it is not clear whether masturbation was included as sexual activity; it would be of interest to examine also whether masturbation is associated with menopause onset. RESPONSE: Thank you for pointing out it was unclear whether masturbation was included in the sex index. This has been clarified in text as follows: "Due to the small amount of responses in some of the categories, the aforementioned measures of sex were aggregated into three new categories".
Each measure of sex was similarly associated with menopause onset, with the results from univariate Cox regression presented below: 4. Being married is not associated with later onset of menopause in the univariate model, however after adjustment being married results at increased risk of early menopause. Is sexual frequency driving this change? Sexual frequency could be a mediator in the association between being married and menopause onset, which could explain also the findings reported in the study.
RESPONSE: Yes, this is correct. As we say in the abstract: "We test an original hypothesis that sexual frequency acts as a bio-behavioural mediation between marital status and ANM". 5. Authors group married women and in a relationship in a single group, however there might be differences between a married couple and in a relationship. Could authors investigate the associations independently for married women and in a relationship? RESPONSE: Thank you for this suggestion. We chose to group married women with women who are in a relationship as SWAN itself groups women who are married and living as married, which is already merging the boundary of in a relationship vs. married.
However, we did create two new variables to test this, which were 'relationship status' (Not in a relationship; In a relationship) and 'marital status' (Single/Never married; In a relationship 1.01 (0.92-1.11) 0.824 As can be seen, in univariate analyses, the new 'marital status' and 'relationship status' variables show that women who are married and in a relationship are more likely to enter menopause earlier (albeit to an insignificant degree), which are the results we see following adjustment in our current study.
We would like to retain the variable that we previously used in the manuscript, as in present day North America, there is a flexible marriage system, and sexual behaviour not only being confined to within a marriage, which we point out in the discussion on page 10. However, we do highlight the difference in coding decisions between studies and the influence that this can have on the results on pages 9 and 10, where we state: "Conflicting results regarding marital status' effect on ANM have been found elsewhere [e.g. 65], and one reason for this may be the way in which the researcher chooses to code the variable. In this analysis, romantic partnerships that may not have been acknowledged in previous studies due to having not been formalised by a marriage ceremony (e.g. cohabiting but unmarried) were taken into account. In addition, some prior studies have not included marital status as time-variant, and dichotomised the variable as 'ever married' or 'never married ' [e.g. 66]. Hence, the fluid way in which this study coded marital status may account for the difference in results". 6. I would recommend to rerun the analysis looking at the age of menopause as categorical variable: early vs. late menopause. This type of analysis would provide more meaningful results and easier to interpret. RESPONSE: As this is an event history analysis, and women are coded as either having experienced menopause (1) or not experienced menopause (0), this suggestion is not possible. We agree that had this been some kind of general linear model, then a binary outcome would ease the interpretation of results (although often binary variables can cause the loss of information). However, this model essentially calculates the risk (hazard ratio) or a woman experiencing the event (menopause) at any given age, and therefore a categorical version of age of menopause is not valid for this form of analysis.
7. The abstract in the current version is not very informative. Authors should add more information on number of women included in the study, follow-up time as well as estimates when reporting an association RESPONSE: Thank you for pointing this out. We have included a baseline sample size and primary effect size within the abstract.