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Determinants of menarche discordance in fraternal and identical twins

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Determinants of menarche discordance in fraternal and identical twins

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Content DETERMINANTS OF MENARCHE DISCORDANCE IN
FRATERNAL AND IDENTICAL TWINS

by
Deboshree Roy

A Thesis Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(APPLIED BIOSTATISTICS AND EPIDEMIOLOGY)

December 2017

Copyright 2017 Deboshree Roy

2

TABLE OF CONTENTS

ACKNOWLEDGEMENTS 3

ABSTRACT 4

INTRODUCTION 6

METHODS 10

RESULTS 13
DISCUSSION 14
CONCLUSION 17
REFERENCES 18
TABLES 23

3

ACKNOWLEDGEMENTS
I am sincerely thankful to my advisor Dr. Thomas Mack for giving me an opportunity to join his
research and for his continuous support and guidance.
I would also like to express my utmost gratitude to the committee members Dr. Amie Hwang
and Dr. Eunjung Lee for their guidance, patience and time towards the development and
accomplishment of this thesis.

4

ABSTRACT
Background: Several published studies link earlier puberty to increased risks of breast cancer,
psychiatric disorders, personality-related disorders such as bulimia and substance abuse. While
early hormonal maturity clearly has substantial genetic determination, trends in time and space
suggest that unknown environmental factors also may determine age at menarche.

Methods: The California Twin Registry includes 3,369 pairs of MZ and 3,030 pairs of DZ
female twins. Self-responses of each twin’s age at menarche were used to determine the
difference in age at menarche. Pair-specific maternal and familial individual responses from the
same registration questionnaire were also dichotomized. When twins disagreed, we constructed
two alternative subsets, one ignoring the lower and one ignoring the higher individual estimate.
We calculated the odds ratios for the effect of each factor on the discordance for age at menarche
within each of the three data subsets. Linear regression analysis was also used to study effects of
parental education, number of biological siblings, age when moved to separate rooms, birth
order, maternal age at birth and race on difference in age at menarche.

Results: In the subset of pairs who were discordant for age at menarche (i.e. with an interval >1
year) and who agreed on the given family characteristic, age-discordant pairs were found to have
mothers who had accomplished high school or higher education (odds ratio: 1.28; 95% CI 1.03-
1.59) and, independently, had one or more biological brothers (OR 1.35; 95% CI 1.04-1.76) than
those concordant for age at menarche. The same results, with nearly identical odds ratios, were
found after the analysis of results from each data set based on paired twins who disagreed on the
family characteristic. A longer interval in age at menarche for twin pairs was associated with
5

higher birth order. No factor was found associated with discordance for age at menarche among
MZ twins and neither the number of biological sisters, the maternal age at birth, nor parity was
associated with discordance for age at menarche among DZ pairs.

Conclusions: Maternal education, birth order, and the number of biological brothers are reliably
reported by respondents, and each is clearly behaviorally and biologically meaningful. Birth
order and maternal age are known to be associated with DZ twinning. No other explanatory
hypothesis presents itself. Based on the MZ twins, no reliably non-genetic determinants of age at
menarche were found.

6

INTRODUCTION
Reproductive maturity is a significant phase in a woman’s life. Age at puberty and especially
menarche, which is the time at onset of the first menstrual cycle, marks a milestone in a female’s
biological development. Since puberty and menarche bring with it a whirlwind of complex plays
of various hormones and steroids, a shift in its time of onset has been known to cause serious
emotional and physical consequences to the individual. Over a century has been invested in
understanding the significance of early or late menarche and its association with various
disorders in both younger and older stages of life.
Studies spanning the last 20-30 years have repeatedly shown puberty and menarche
bringing in emotional and social discomfort in adolescents. School girls at grade levels 5-6, 7-8
and 11-12 were surveyed on mental health and grade 5-6 was also followed longitudinally.
1
It
was found that girls who reached menarche earlier than their peers felt confused and ambivalent
but not very traumatic. These mixed emotions have been attributed to cultural and societal
perceptions that create a negative impact on girls causing self-objectification, lack of confidence
and body-shaming.
2
The exact “menstrual attitude” among early or late maturing girls was
associated with a level of worry at menarche onset. However, premenarcheal girls were more
worried and continued to be so in comparison to their peers since they were simply not prepared
to face the changes on their own and so early in the society.
3
Multiple factors play roles in the
psychopathology at premature menarche including hormonal influences; physical, social and
psychological disparity; early transition in a disadvantaged social context and lastly, an
accentuation of adolescence related pre-existing emotional and behavioral difficulties due to
early physical and emotional demands.
4
7

Depression, eating disorder and concerns with body image have been considered of
significant consequence of early puberty. Both girls and boys who had experienced premature
puberty have self-reported depression
5
, perception of an increased risk to peer harassment
6,7
and
early intimate sexual experiences which could have disturbed a smooth adolescent passage. Not
surprisingly, other such similar studies have established links to a lack of confidence in social
life and subsequent eating disorders blaming the onset of physical transformations with puberty.
Timing of puberty has been linked to conscious self-critique of body image and self-esteem
among sixth and seventh graders from different school environments.
8
A condition termed as
“objectified body consciousness” or simply called OBC is thought to emerge during sexual
maturation where one starts self-objectifying their body for others to evaluate. OBC has been
more commonly identified in adult stages but a study improvised the testing model for early
adolescents and found the girl’s tendency toward self-surveillance which in turn led to greater
body shame.
9
Such self-consciousness has also encouraged eating disorders and bulimia in girls
with early menarche.
10
Age at menarche also has considerable effects in later adult life. Other than studies
associating early menarche with osteoporotic fracture, risk of coronary heart disease, and
conduct disorder in later life stages,
11
one of the most widely studied effects of age at menarche,
especially early menarche, is the increased risk of breast cancer. Breast cancer claims about a
million new cases worldwide every year and comprises of about 18% of all cases of female
cancer.
12
Among several causative factors studied through the years including genetics, onset of
menopause, obesity, lifestyle, parity, breastfeeding etc., age at menarche has become a major
factor of interest.
13
Since breast cancer diagnosis occur more frequently in younger, pre-
8

menopausal women, age at menarche can possibly help identify high risk groups and preventable
measures can be implemented.
Our hypothesis was primarily inspired from a study that has established a significant
association between puberty and breast cancer. The study utilized about 1800 pairs of female
twins, both discordant and concordant, for breast cancer.
15
Age at menarche was included among
other factors like age at breast development, age at menopause, family history of breast cancer,
parity etc. it was found that among disease-concordant MZ pairs, the sibling who had early
puberty had a higher risk of receiving an earlier breast cancer diagnosis compared to their
cotwin. This has put a spotlight on the associations of non-heritable factors on puberty in MZ
twins who are otherwise assumed to be strongly genetically susceptible when concordant for a
disease. Another population-based case-control study spanning around four international twin
cohorts, namely from Denmark, England & Wales, Finland and Sweden pooled their data to
study risks of breast cancer at young ages of 400 females.
14
Here, again, women who developed
breasts earlier than their twin received their diagnosis of breast cancer by 50 years of age.
The consequences of early or late menarche has prompted researchers to identify its
determinants. Although about 50% of menarche onset is known to be guided by genetics,
16
non-
genetic factors have also been in the spotlight for long. Studies have shown a strong association
between body fat and body mass index with onset of menarche,
17,18
a hypothesis originally
proposed by Rose Frisch.
19,20
Exposure to foods, endocrine disrupting chemicals like phthalates
in breast milk, pharmaceutical and consumer products containing estrogenic ingredients, to DDT
(dichlorodiphenyltrichloroethane) through fish consumption or textile industries, PCBs
(polychlorinated biphenyls), lead, plasticizers like phthalates, pollution from greenhouse gases
etc. have been linked to abnormally timed puberty and menarche.
21
Girls raised in broken or in
9

conflictual families,
22
with single or very young parents that could create unstable environments,
larger mother-daughter distance and father’s absence have been reported determinants as well.
23

Retrospective reporting of exposure to such family stressors from as young as 7 years is believed
to have led to early menarche.
24,25
Despite clear associations with aforementioned outcomes
(cancer, coronary heart disease, psychological conditions etc.), very little is known about the
underlying mechanism of menarche initiation.
To address this gap in understanding menarche, we conducted a study to identify
determinants that may affect menarche onset using twin study design. Using twins as study
subjects provides us with an opportunity to segregate genetic and environmental factors for each
twin pair, thereby allowing us to observe the inter-play between possible genetic and non-genetic
factors that may cause a discordance or concordance in menarche for each twin pair.
26
Twins can
be compared to any ordinary siblings who were born at the same time and share a nearly
identical environment. While dizygotic (DZ) twins share on average 50% of their genetic
characteristics, monozygotic (MZ) twins share their entire genome. Since twins share their age,
date of birth and even the same uterus, they are matched on multitude of early life factors more
closely than any other case-control matched pair.
27
These shared family characteristics allow for
a better utilization of various types of environmental factors or exposures which may cause a
significant disease or outcome. MZ twin pairs provide an added advantage when studying gene-
environment interactions. Since they share the same genetic traits, MZ pairs discordant for an
outcome clearly demonstrate that the exposure was environmental and not genetically
determined. In this study we examined whether familial factors can have varying effects that
may lead to a discordance in age at menarche among female twin pairs.

10

METHODS
Participants & Study Design
Our data was accessed from the California Twin Program (CTP) founded at the University of
Southern California. CTP was established in 1992 to help study relationships of genetics and
environmental factors with development of a disease. It is a population-based registry of 265,000
twins born between 1908 and 1982. To build the cohort,
28
records of live multiple births
containing the names and date of births were obtained from the California Department of Vital
Statistics with and without pertinent environmental exposures, healthy and diseased, paired and
surviving, monozygotic and dizygotic, and like-sex and unlike-sex. These were then linked with
records at the California Department of Motor Vehicles to return a current address and a new
married name wherever applicable. New or updated addresses were checked with National
Change of Address Index. Subjects were recruited in 3 waves through 1991, 1998 and 1999. The
non-respondents were looked up again for their current contact details. In case details of non-
responders were not found, a balance was attained by reducing the population of potentially
respondent-twins by the excess proportion of non-respondent twins. The 16 page questionnaire
sent to the subjects asked about basic demographics, zygosity, growth and development,
reproductive history, use of medical services, dietary preference, disease experience and lifestyle
choices. Some questions request a participant for a self-response and also a proxy-response about
the co-twin (e.g., ‘At what age did you have your first menstrual period?’ and ‘How much earlier
or later did your twin have her first menstrual period?’). Such proxy responses were utilized in
assessing the reliability of a twin’s response, especially in case the co-twin did not answer the
particular question.
11

Statistical Analysis
This is a pair-wise study where female twin pairs, in which both twins completed the baseline
questionnaire, were considered eligible participants for this study. We identified 3,369 pairs of
MZ (monozygotic or identical) and 3,030 pairs of DZ (dizygotic or fraternal) twin pairs who met
this eligibility criteria. We used proxy responses while aggregating our variables. Proxy
responses are given by a twin about her cotwin. When both siblings in a twin pair participate,
proxy responses can determine the reliability of the independent variables, even in cases where
one sibling did not respond. Proxy responses can also be used to judge the validity of both
participants claiming to be a twin pair.
39
Since our dependent variable of interest concerns “age
at menarche”, we used the respective proxy variable “How much earlier or later did your twin
have her first menstrual period”. Pairs which had a difference of 11 months or lower were
grouped as concordant and pairs who differed by one or more years were grouped as discordant.
Those pairs were selected which were, 1) fully matched on this proxy variable (e.g. one twin said
‘6 months earlier’ while cotwin said ‘6 months later’), 2) matched on magnitude and not the
ranking (e.g. one twin said ‘6 months earlier’ and cotwin also said ‘6 months earlier’), and 3)
lacked response from one of the two sisters (e.g. one twin said ‘6 months earlier’ while cotwin
gave no response). From this proxy determined subset, those pairs were chosen which showed
agreement for the independent variables. Kappa statistics determining this agreement can be seen
in the supplementary table. The final dataset used for statistical analysis comprised of 2,398 pairs
of MZ and 2,046 pairs of DZ female twins.
Eight dichotomized exposure or independent variables (as seen in Table1) were included
namely, 1) age at which the sisters moved to separate rooms: dichotomized to 14 years or
younger and 15 years or older; 2) maternal education level and 3) paternal education level: each
12

dichotomized to lower than high school and high school graduate or more; 4) number of
biological brothers and 5) number of biological sisters: each dichotomized to none and one or
more; 6) birth order of the twins: dichotomized to first pregnancy and second or later pregnancy;
7) maternal age at birth: dichotomized to younger than 25 years and 25 years or older and lastly;
8) race: dichotomized to white and other. For each exposure variable, wherever a pair’s response
conflicted, two alternative subsets were constructed, one ignoring the lowest and one ignoring
the highest individual estimate. This was done by adjusting the overestimated responses into
lower variable category or by adjusting the underestimated responses into the higher variable
category response. Therefore, in all, we had 3 different sets for each exposure variable including
the raw response set.
Our outcome or dependent variable was “difference in age at menarche” of twin pairs
which was calculated by taking an absolute numerical difference of the self-responses of each
twin for their age at first menstrual period. A linear regression analysis seemed to be the obvious
choice due to the continuous nature of the outcome variable. But since the outcome was larger in
sample size towards the lower categories, the twin pairs were also analyzed using logistic
regression. For logistic regression, the outcome was categorized dichotomously wherein a
difference of six months to a year was considered concordant while a difference of one or more
years was categorized as discordant. Unadjusted odds ratios for being discordant as opposed to
being concordant and 95% confidence intervals were computed to identify associations of the
linear and dichotomous outcome with the determinants.
Statistical analysis and modelling were carried out using SAS 9.4.

13

RESULTS
The difference in menarche age ranged from 0 to 7 years for both MZ and DZ twin pairs. About
39% of the DZ pairs were concordant for menarche while 46% of MZ pairs were found to be
concordant (as seen in Table1).
Among DZ pairs, twins of mothers with high school graduation and/or further years of
education were more likely to have their menarches one or more years apart from each other
compared to pairs whose mothers did not graduate from high school (odds ratio: 1.28; 95% CI
1.03-1.59) (Table 2). Also, independently, DZ female pairs who had one or more biological
brothers were more likely to be discordant for age at menarche (OR 1.35; 95% CI 1.04-1.76)
than DZ sisters who had no biological brothers. The results remained unchanged with nearly
identical odds ratios, after the analysis of results from each data set based on paired twins who
disagreed on the family characteristic.
When the difference in age at menarche between the twins were examined in a linear
manner (Table 3), an increase in the years of differences in age at menarche was significantly
associated with maternal education of equal or greater than high school (0.13 ± 0.06; p = 0.03)
and with the higher birth order (0.17 ± 0.08; p = 0.03). Due to the discrepancy between both
models, results obtained through the unadjusted linear regression with birth order and maternal
education was further tested for influential points. However, the outliers did not seem to be of
any concern to both models. The regression coefficients remained robust despite elimination of
the influential points.
14

Age when moved to separate rooms, paternal education, number of biological sisters,
race and maternal age at birth did not show any significant association with the outcome. And,
interestingly, significant associations were observed only in DZ pairs, none in MZ pairs.

DISCUSSION
To our knowledge, this is the first study to demonstrate the influence of maternal education and
of biological brothers on menarche age of the daughter or sister respectively. However, the
relationship between birth order and menarche age has been studied before, but sparingly.
In a large multi-cohort study carried out in twelve different sites across the United
States,
29
biology of weight gain during infancy and later in childhood was studied in about
20,000 participants from their infancy to age 7 years. Maternal education and birth order was
among other familial variables considered. An increased risk of weight gain during the first four
months of life and of being overweight at 7 years of age was associated with lower maternal
education and being first-born. This finding is of great significance, especially when trying to
understand the relationship between maternal education, birth order and age at menarche as
achieved in our study. Since body fat is known to affect timing of puberty or menarche, variables
impacting body fat and/or weight gain at childhood may explain menarche timing too. In the
longitudinal Dunedin study in New Zealand, 415 girls were followed prospectively to assess
their weight changes and age at menarche. Heavier girls were found to achieve menarche earlier
than the rest.
30
The Avon longitudinal study
31
and another study carried out in North Carolina
32

participants were followed through specific age intervals since birth till their onset of menarche
15

and found that faster rates of weight gain since birth through childhood led to earlier sexual
maturation in girls.
Other than the association with body weight, birth order has also been directly linked
with age at menarche. A large cohort of around 33,500 women with family history of breast
cancer was investigated to identify effects prenatal and infant exposures on menarche age.
33
It
was found that menarche at the early age of 11 years or younger was associated with being first
born. The Breakthrough Generations Study (BGS) in UK also found associations of birth order
with occurrence of early menarche when adjusted with sibship size.
34
These results support our
findings of the influential role of higher birth order on a significant discordance in age at
menarche.
There have been limited research on the association of biological brothers on the sister’s
sexual maturation. A retrospective study in western Australia showed that girls with exclusively
elder brothers were significantly older (by 0.9 years) at menarche than girls with no elder
siblings. This finding was supported by the hypothesis that elder brothers could deprive their
sisters of nutritional resources leading to a variance in menarche age.
35
If we similarly compare
biological brother to the father as being a male presence in the family, some results could be
drawn from previous studies that associate father’s absence with daughter’s age at menarche.
The father’s absence at home during childhood has long been studied as a factor leading to
earlier puberty in daughters who supposedly perceive this as a stressful situation. This stressful
situation can take form as family conflict, marital discord, and an overall insecurity for their
future in absence of a dependable male in the family.
24,25

16

Unlike earlier studies, we did not find any effect of presence of biological sisters and
younger or older maternal age at birth.
33,36
Race was another factor of interest when we began
designing the study,
37
however not much was found since our dataset was predominantly
(approx. 85%) White.
A notable finding in our study was our inability to find predictors of concordance in MZ
twins. While DZ pairs are genetically similar like siblings, MZ twins are genetically identical.
But MZs, like DZ twins are commonly discordant for any post-natal behavior or other non-
genetic characteristics. Thus, in this study we failed to find any non-genetic determination of
monarchic concordance. Later, we will search further for such determinants by comparing the
members of identical twin-ships discordant for age at menarche.
Summarizing the strengths and limitations of our study, the data was obtained from a
large cohort of twin pairs from the California twin program. Large sample size is advantageous
since they provide sufficient power and minimize biases related to sampling.
38
Also, data
obtained from an established registry avoids the otherwise unstable methods of participant
identification using hospital and other records. Using twins as study subjects come with its
special benefits in that they give a clear understanding of the gene-environment interaction.
Additionally, our study is the first of its kind that highlights the influence of familial variables on
discordance at menarche age in twins, especially the associations with maternal education and
biological brothers which was never found before even in singletons. Our novel hypothesis and
findings have opened up several opportunities for further study. As mentioned in the methods
section, we have used both self and proxy responses from both siblings in order to obtain well
agreed responses which will be representative to a twin pair. Chances of a differential
misclassification or recall bias may be ruled out since all data was obtained from a large
17

population-based registry and the participants were unaware of the hypothesis of this study at the
time of participation. Our results, however, are subject to a geographical sampling bias since the
dataset is only representative of twins in California. Exposure to a different weather, different
food sources, different economic status etc. in another state or country may affect the variables
used in this study and hence affect the results too.

CONCLUSION
We consider this a pilot study based on which we wish to build further research to see the
dynamics of these determinants within each pair and identify which sibling had a later or earlier
menarche that led to the discordance in the first place. Through future studies we also hope to
find answers to concordancy in menarche age in MZ pairs.

18

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Abstract (if available)

Abstract Background: Several published studies link earlier puberty to increased risks of breast cancer, psychiatric disorders, personality-related disorders such as bulimia and substance abuse. While early hormonal maturity clearly has substantial genetic determination, trends in time and space suggest that unknown environmental factors also may determine age at menarche. ❧ Methods: The California Twin Registry includes 3,369 pairs of MZ and 3,030 pairs of DZ female twins. Self-responses of each twin’s age at menarche were used to determine the difference in age at menarche. Pair-specific maternal and familial individual responses from the same registration questionnaire were also dichotomized. When twins disagreed, we constructed two alternative subsets, one ignoring the lower and one ignoring the higher individual estimate. We calculated the odds ratios for the effect of each factor on the discordance for age at menarche within each of the three data subsets. Linear regression analysis was also used to study effects of parental education, number of biological siblings, age when moved to separate rooms, birth order, maternal age at birth and race on difference in age at menarche. ❧ Results: In the subset of pairs who were discordant for age at menarche (i.e. with an interval >1 year) and who agreed on the given family characteristic, age-discordant pairs were found to have mothers who had accomplished high school or higher education (odds ratio: 1.28

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Asset Metadata

Creator Roy, Deboshree (author)

Core Title Determinants of menarche discordance in fraternal and identical twins

School Keck School of Medicine

Degree Master of Science

Degree Program Applied Biostatistics and Epidemiology

Publication Date 11/14/2017

Defense Date 11/13/2017

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag biological brothers,birth order,California Twin Registry,environmental factors,fraternal,identical,maternal education,menarche,non-genetic determinants,OAI-PMH Harvest,Twins

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Mack, Thomas (committee chair), Hwang, Amie (committee member), Lee, Eunjung (committee member)

Creator Email deboshrr@usc.edu,mshree.roy@gmail.com

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c40-453833

Unique identifier UC11265539

Identifier etd-RoyDeboshr-5903.pdf (filename),usctheses-c40-453833 (legacy record id)

Legacy Identifier etd-RoyDeboshr-5903.pdf

Dmrecord 453833

Document Type Thesis

Rights Roy, Deboshree

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Access Conditions The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the a...

Repository Name University of Southern California Digital Library

Repository Location USC Digital Library, University of Southern California, University Park Campus MC 2810, 3434 South Grand Avenue, 2nd Floor, Los Angeles, California 90089-2810, USA