Impact Objectives• Investigate the hypothesis that diet interference with circadian rhythm has a negative
effect on reproductive function• Explore how dieting during puberty may contribute to the development of gynaecologicaldisorders after reproductive function is restored

Unknown mechanisms toboost reproductive health
Dr Tomoko Fujiwara’s important studies on the links between dietary habits and menstrual problems
will elucidate valuable knowledge with the potential to alleviate reproductive issues
Firstly, can you
explain what isthe context of yourresearch?
Currently,
the increasein gynaecological diseases such as
endometriosis, which causes dysmenorrhea,
has become a major problem, in parallelwith the spread of food skipping, dietingfor cosmetic purposes, etc., among young
women. Although the relationship between
menstrual pain and eating habits has notbeen fully investigated, menstrual painis also a sign of organic gynaecologicaldiseases, and menstrual pain in students
is extremely important information from a
medical point of view.
In a world first, we reported that breakfast
skipping is associated with menstrual painin female students and that menstrual pain
worsens after dieting. From these findings,
we proposed the hypothesis that dietinterference with circadian rhythm has anegative effect on reproductive function, andthat dieting during puberty may contribute to
the development of gynaecological disorders
after reproductive function is restored.
How did you become involved in this field?
For many years, I have been teaching at a
women’s college in a field related to foodscience and nutrition. I have had many
opportunities to learn about the dietary
habits of young women aged 18 to 24, and atthe same time, I have come into contact with28 www.impact.pub

their physical problems, especially menstrualproblems. Although there have already been
many reports on the effects of breakfast
skipping on daily performance and dietingon the menstrual cycle, there have been nostudies examining the effects of breakfast
skipping and dieting from the perspective ofmenstrual pain. Since dysmenorrhea is oneof important clinical signs for gynaecologicaldiseases, and menstrual pain in students
is considered to be extremely important
information from a medical point of view,
I have been working on the analysis of therelationship between dietary habits andmenstrual pain in young women.
Can you tell us more about theseinvestigations?
In addition to breakfast skipping, anotherdietary issue for adolescent females toconsider is excessive dieting. An importantfirst finding regarding dieting was thatcollege women who had previously dietedsuffered more menstrual cramps, eventhough they were not currently dieting.
This finding alerts us to the possibility that
abnormal hunger stress during adolescencemay lead to abnormal uterine function in thefuture.

reproductive functions, and if abnormalities
in reproductive organ functions areprogrammed, it may lead to problems suchas decreased fertility. This new disease
concept is ADHOGD (Adolescent Dietary
Habit-induced Obstetric and GynecologicDisease), and we believe it is necessary toelucidate these mechanisms and provide
comprehensive guidelines for prevention
based on this knowledge.
Can you describe the expected influence
from this work?
The ultimate impact of this study is toprovide a programme for young dieterswith exacerbated hunger stress that can beconverted to favourable hunger stress andachieve weight loss goals without inducing
abnormalities in hypothalamic, reproductive,
muscular and metabolic function. Those
who will benefit from the results of thestudy will be young women and men ingeneral and athletes who require weight
management. l

Why is this an important area ofinvestigation?
The links between breakfast skipping, dieting
and abnormal hunger stresses are extremely
important, especially in young women.
This is because young women are in theperiod of development and maturation ofRegular dietary habits

Concept of ADHOGD - Adverse dietary habits from adolescence to young adulthood impair reproductive function (1), which induces the latent progression of obstetric andgynecologic disorders (2). Although apparent recovery is achieved after correcting adverse eating habits (3), the reproductive function is precociously declined (4), later leading
to the onset of ADHOGD (5)Reproductive health forgenerations to comeAt the Department of Human Life Environments, Kyoto Notre Dame University, interrelated studies areunravelling the links between dietary habits and menstrual problems, ultimately establishing educational
strategies for promoting reproductive health and preventing issues

Dieting can be both mentally and physically
detrimental, with the potential to lead todisordered eating behaviours and cause
unhealthy changes in body composition, as
well as hormonal changes and menstrual
disturbances. These are just a few of thepotential issues known to be associated with
dieting and it can be particularly nefarious
for adolescents who are still developing
both mentally and physically. They cansuffer growth deceleration and permanent
damage to bones and organs caused bynutritional deficiencies, including poor brain
development and even malnutrition, which
can be fatal.
Another important area to consider isreproductive health. Diet is inextricably
linked to reproductive health and dieting inadolescence can have long-term impacts
on this, including infertility. This is a
research area of interest for Dr Tomoko
Fujiwara. In the context of rising incidenceof gynaecological diseases in parallel withfood skipping and dieting in young women,
Fujiwara is establishing unknown links,including the relationship between menstrual
pain and eating habits, which is one that is
yet to be fully investigated.

Fujiwara is focusing on female students
due to their still-developing status andthe potential long-term issues dieting maycause. ‘When abnormal hunger stresses
occur during adolescence, when the bodyand organs are developing, the basis for
future life activities, such as appetite andmetabolic efficiency, may be programmedin accordance with the living environment
during this period,’ she articulates. The teamis interested in the concept of hunger stressand the implications of negative hungerstress. ‘We assume the existence of two typesof hunger stress: good stress, which resets
the physical body cycle and makes it morebalanced, and bad stress, which conversely
disrupts the cycle, i.e., disrupts the clockfunction of central and peripheral organs,’outlines Fujiwara. The researchers are using
animal models to explore hunger stress andinterrelated concepts in more detail, with afocus on future disease development causedby habits in adolescence.
In a world first, Fujiwara and her team whoare based in the Department of Human
Life Environments, Kyoto Notre DameUniversity, Japan reported that breakfast
skipping is associated with menstrual painand menstrual pain worsens after dieting.
‘We conducted a large-scale health survey offemale students and confirmed that breakfast
skipping is associated with menstrual
cramps and that students with a history ofdieting have a higher frequency of menstrual
problems,’ explains Fujiwara.
THE IMPORTANCE OF
BREAKING THE FAST
Building on this important finding, theteam conducted research to establish
further links between dietary habits andmenstrual disorders, as well as explore
whether breakfast skipping can be aneffective predictor for the management
and prevention of menstrual disorders. In
this work, they surveyed more than 3,000
female students on health and lifestyle andanalysed the relationship between dietary
habits and menstrual disorders. It was foundthat troubles or worries with menstruation
were significantly higher in those with ahistory of dieting and breakfast skipping
and also that the female students who
skip breakfast have a significantly higher
incidence of period pain (also known asdysmenorrhea) which suggests that skipping
breakfast can negatively impact ovarian andwww.impact.pub 29

uterine functions. The researchers believe
that, as meal skipping can be corrected witheducation, these findings have the potential
to help manage and even prevent menstrualissues.
In another line of investigation, expandingon their previous research, Fujiwara andthe team unearthed findings that support
the existence of a new hypothesis called
Adolescent Dietary Habit-induced Obstetricand Gynecologic Disease (ADHOGD). ‘In
this research, we posited that the circadianrhythm and reproductive rhythm are closely
linked and that the peripheral clock system inthe uterus plays a critical role in reproductive
diseases and proposed naming the concept
ADHOGD,’ describes Fujiwara. The
researchers are currently summarising thesefindings in a paper and expect to elucidate
further detailed mechanisms leading topreventative methods in the future. With
more testing of the hypothesis, they hopethat the ADHOGD concept will contribute tofurthering understanding of, and developing
treatments for, reproductive diseases,including polycystic ovary syndrome,hypothalamic amenorrhea, endometriosis,infertility, and preterm labour. Fujiwara points
out that there are important educational
impacts from this work. ‘The results obtained
from the analysis of this study may not only
open up a new academic field, but also
provide a theoretical basis for proposing a‘nutrition education programme to reduce
the adverse effects of dieting based on themechanism of circadian rhythm regulationof reproductive function by diet’ for dietconscious young women,’ she comments.

TIMING IS EVERYTHING
In a further study, using nocturnal rodents,
Fujiwara and her collaborators explored theeffects of meal timing during the circadiancycle on ovarian function. This involved
dividing young female rats into three different
groups, each of which was fed at a different
time and different amounts of calories
and nutrients. The researchers evaluatedchanges in body weight and ovulation,
ultimately discovering that ovarian function
was impaired by daytime feeding, which
confirmed that the timing of food intake
during the circadian cycle is a key factor
influencing reproductive function. ‘We havecreated an animal model of the disease inwhich breakfast deprivation is regarded as anabnormality in the hunger rhythm, thereby
inducing clock gene dysfunction,’ explainsFujiwara. It was pleasing for the team that
their results support this hypothesis.
Collaborations are an important part of thisresearch, and help advance the learnings.
‘We are currently collaborating with experts
in clock genes, genetically engineered mice,obstetrics and gynaecology, and metabolism,’highlights Fujiwara. ‘We believe this isimportant for elucidating the mechanisms
by which excessive hunger stress duringadolescence induces abnormalities inhypothalamic, reproductive, muscular andmetabolic functions, and for developing
diagnostic, therapeutic and preventative
methods,’ she says. Looking ahead, theresearchers will continue to build on theirimportant findings so far and will seek toclarify a particular point. ‘We plan to continue
our analysis of the effects of abnormal
eating rhythms during adolescence on future
quality of life and its gender differences,’

observes Fujiwara. ‘In particular, it has beensuggested that excessive hunger stressduring adolescence may be a cause of eating
disorders, and we hope to clarify this point
as well.’
Fujiwara’s work is paving the way topromoting improved reproductive andmenstrual health. She is investigating key
areas and unearthing crucial findings that
could help establish healthier eating habits
and prevent long-term reproductive issues. lProject Insights
FUNDING
This work was supported in part by
Grant-in-Aids for Scientific Research(19500707, 21500813, 24501022, 15K00903,
19H01617 and 21K18297), Japan Scienceand Technology Agency (192166890) andJapan Agency for Medical Research andDevelopment (20gk0210016h0003)
COLLABORATORS
Kanazawa University – Professor Michihiro
Mieda (Department of Integrative
Neurophysiology), Professor Hiroaki
Yoshikawa (Health Service Center),
Professor Takiko Daikoku (Division ofAnimal Disease Model, Research Center forExperimental Modeling of Human Disease),
Professor Hitoshi Ando (Department ofCellular and Molecular Function Analysis),
Professor Hiroshi Fujiwara (Department ofObstetrics and Gynecology)
Tokyo Medical University - Associate
Professor Masanori Ono (Department ofObstetrics and Gynecology)
Nara Women’s University - Associate
Professor Rieko Nakata (Department ofFood Science and Nutrition)
CONTACT DETAILSDr Tomoko Fujiwara
T: +81 75 706 3688
E: fujiwara@notredame.ac.jp
W: https://notredame-db.net/detail.
php?id=108
BIO
Dr Tomoko Fujiwara graduated from NaraWomen’s University in 1984 and obtained
her Doctor of Philosophy in 2009. From2015, she has been a Professor at the Kyoto
Notre Dame University, Kyoto.

Clock systems in ADHOGD - Desynchronisation between central and peripheral clocks from adolescence to young
adulthood by adverse dietary habits (1) is memorised in the hypothalamic-pituitary-ovarian axis and the uterus
from the developing to mature stages (2), leading to ADHOGD (3)30 www.impact.pub