REFERAT

THE RELATIONSHIP BETWEEN OBESITY AND

POLYCYSTIC OVARY SYNDROME IN ADOLESCENT

SUPERVISED BY:
DR. ARIE ADRIANUS POLIM, D.MAS., SP.OG-KFER

WRITTEN BY:

VINCENTIUS HENRY SUNDAH (2015 061 023)

JEMMY GUNAWAN (2015 061 026)
JENNIFER EVANGELICA DEWANTARA (2016 061 097)
EMILIANA KARTIKA (2016 061 159)

CLINICAL CLERKSHIP OF OBSTETRICS AND GYNAECOLOGY

ATMA JAYA HOSPITAL
SCHOOL OF MEDICINE ATMA JAYA CATHOLIC UNIVERSITY OF INDONESIA
APRIL 24th JULY 8th 2017
 FOREWORD

First of all, we thank God for only by His grace and His blessings we were
able to finish this paper entitled The Relationship between Obesity and Polycystic
Ovary Syndrome in Adolescent, which is one of the assignments in the clinical
clerkship of obstetrics and gynaecology, School of Medicine Atma Jaya Catholic
University of Indonesia.
The author is realize that this paper get support from many parties. Therefore,
on this occasion, the author would like to express his gratitude to all those who have
guided and provided support by all means in the process of writing until the
completion of this paper, especially to:
1. dr. Arie Adrianus Polim, D.MAS., Sp.OG-KFER, who provided insight and
expertise greatly that helped and supported us during the making of this
paper.
2. Our dear families, colleagues, and other parties that could not be mentioned
one by one for the support and encouragements completion.
We hope this paper could give useful information for the readers. We realize
this paper is far from perfect and has several limitations, therefore we apologize for
any mistakes encountered. We are hoping for future suggestions and critics to help
improve this paper in the future being.

Jakarta, May 19th, 2017

Authors

2
 TABLE OF CONTENTS

Page
TITLE PAGE ....................................................................................................... i

FOREWORD .......................................................................................................ii

TABLE OF CONTENTS .................................................................................... iii

LIST OF TABLES ............................................................................................... v

LIST OF FIGURES ............................................................................................ vi

CHAPTER I. INTRODUCTION ................................................................... 1

1.1. Background ...................................................................... 1
1.2. Problem of Analysis ........................................................ 2
1.3. Objective of Study ........................................................... 3
1.3.1. General objective ................................................. 3
1.3.2. Particular objective .............................................. 3
1.4. Benefit of Study ............................................................... 3
1.4.1. Benefit for educational institutions....................... 3
1.4.2. Benefit for public services ................................... 3
1.4.3. Benefit for research development ........................ 3
CHAPTER II. LITERATURE REVIEW ....................................................... 4
2.1. Anatomy and Physiology of Ovarium ............................. 4
2.1.1. Anatomy of Ovarium ........................................... 4
2.1.2. The follicular phase of ovarian cycle ................... 5
2.1.3. The hormonal interaction of follicular
function ................................................................ 9
2.2. Obesity ............................................................................ 12
2.2.1. Definition and classification ............................... 12
2.2.2. Regulation of obesity .......................................... 13
2.2.3. Obesity in PCOS ................................................. 16
2.3. Polycystic Ovary Syndrome (PCOS) ............................. 19
2.3.1. Definition ............................................................ 19
2.3.2. Etiopathophysiology ........................................... 19
2.3.3. Risk factor ........................................................... 26
2.3.4. Clinical manifestation ......................................... 26
2.3.5. Diagnosis ............................................................ 29
2.3.6. Management ....................................................... 29

2.4. The Relationship between Obesity and PCOS

in adolescent ................................................................... 30
2.4.1. Clinical manifestation ......................................... 31
2.4.2. Insulin resistance and PCOS ............................... 34
2.4.3. Hyperandrogenemia to hyperinsulinemia ........... 38
2.4.4. Chronic inflammation lead insulin
Resistance to PCOS ............................................ 39

3
 2.5. Researchers Related to The Relationship between
Obesity and PCOS in Adolescent ................................... 42
CHAPTER III. CONCLUSION AND SUGGESTION .................................. 52
3.1. Conclusion ...................................................................... 52
3.2. Suggestion ...................................................................... 52

REFERENCES ................................................................................................... 54

4
 LIST OF TABLES

Page
Table 2.1. Researchers Related to The Relationship between
Obesity and PCOS in Adolescent ...................................................... 42

5
 LIST OF FIGURES

Page
Figure 2.1. Internal female reproductive organs ................................................. 4
Figure 2.2. The ovarian cycle ............................................................................. 6
Figure 2.3. Production of estrogen by an ovarian follicle ................................. 12
Figure 2.4. Ferriman-Gallwey Hirsutism Scoring System ................................ 20
Figure 2.5. Interactions among insulin resistance, hyperinsulinemia, and
hyperandrogenemia in the etiopathogenesis and progression
of polycystic ovary syndrome and related comorbidities ............... 34
Figure 2.1. Insulin signalling in ovarian thecal cells and proposed
mechanisms for selective insulin resistance .................................... 38

6
 CHAPTER I

INTRODUCTION

1.1. Background
Based on current polycystic ovary syndrome (PCOS) criteria, about 4-
6% of reproductive female suffer from PCOS and in the infertility female
population with anovulatory cause is 75% caused by PCOS. Santoso and
Irawan, 2007, conducted a study in Surabaya with prevalence of PCOS in
reproductive female of 4.5%. Based on several reports in recent journals
showing an increasing trend of prevalence of PCOS, even in some journals
reported prevalence reached 8-10% PCOS. This is because the role of insulin
resistance in the pathophysiology of the emergence of PCOS, and increased
insulin resistance caused by lifestyle people with high-calorie diet but with
sedentary life style.1 The manifestations of PCOS typically begin in early
adolescence, and many investigators have hypothesized that peripubertal
obesity promotes the development of adolescent PCOS.2
The global proportion of adults with a body-mass index (BMI) of 25
kg/m or greater increased between 1980 and 2013 from 28.8% (95% UI
28.429.3) to 36.9% (36.337.4) in men, and from 29.8% (29.330.2) to
38.0% (37,538.5) in women. Prevalence has increased substantially in
children and adolescents in developed countries; 23.8% (22.924.7) of boys
and 22.6% (21.723.6) of girls were overweight or obese in 2013. The
prevalence of overweight and obesity has also increased in children and
adolescents in developing countries, from 8.1% (7.78.6) to 12.9% (12.3
13.5) in 2013 for boys and from 8.4% (8.18.8) to 13.4% (13.013.9) in
girls.3
The prevalence of obesity were highest in the WHO Regions of the
Americas (26% for obesity in both sexes) and lowest in the WHO Region for
South East Asia (3% for obesity in both sexes). Women's obesity was
significantly higher than men's, with the exception of high income countries
where it was similar. In low and lower middle income countries, obesity
among women was approximately double that among men.4
In 2011-2014, for children and adolescents aged 2-19 years The
prevalence of obesity has remained fairly stable at about 17% and affects

1
 2

about 12.7 million children and adolescents. The prevalence of obesity was
8.9% among 2- to 5-year-olds compared with 17.5% of 6- to 11-year-olds and
20.5% of 12- to 19-year-olds. 5
More than 50% of the 671 million obese individuals in the world live
in ten countries (listed in order of number of obese individuals): USA, China,
India, Russia, Brazil, Mexico, Egypt, Germany, Pakistan, and Indonesia.
Indonesia accounted the prevalence for 6% (4.87.6) of obese people
worldwide in 2013. Although age-standardised rates were lower in
developing than in developed countries overall, 62% of the worlds obese
individuals live in developing countries.3
Nationally, the prevalence of central obesity among 15 years and
above in 2013 is 26.6%, higher than the prevalence in 2007 (18.8%). The
lowest prevalence of central obesity in East Nusa Tenggara (15.2%) and the
highest in DKI Jakarta (39.7%). Childhood obesity is also more common
among certain populations, the age of 5- to 12-year-olds (8.8.%), 13- to 15-
year-olds (2,5%), and 16- to 18-year-olds (1.6%). In 2013, the prevalence of
adult female obesity (>18-year-olds) was 32.9%, increased 18.1% from 2007
(13.9%) and 17.5% from 2010 (15.5%).6
PCOS is a major cause of subfertility, and it is associated with
comorbidities such as obesity, the metabolic syndrome, and type 2 diabetes. 2
Indeed, both PCOS and obesity boast highly concerning prevalence figures. 7
For these reasons, PCOS represents a major womens health and public health
issue.2 Thus, we would like to discuss the relationship between obesity and
PCOS, especially in adolescence.

1.2. Problem of Analysis

According to the introduction, then the problem of analysis is on the
following:
What is the relationship between obesity and polycystic ovary
syndrome in adolescent?

1.3. Objective of Study

1.3.1. General objective
 3

To understand the relationship between obesity and polycystic

ovary syndrome in adolescent.
1.3.2. Particular objective
1. To understand the anatomy and physiology of ovarium.
2. To understand the general information about obesity.
3. To understand the general information about polycystic ovary
syndrome.
4. To understand the relationship between obesity and polycystic
ovary syndrome in adolescent.

1.4. Benefit of Study

1.4.1. Benefit for educational institutions
Authors hope that this study can be used as resources for
college and medical school students to deepen their knowledge.
Therefore, we could more understand the relationship of obesity and
PCOS.
1.4.2. Benefit for public services
Authors hope that this research can be a source of information
for the public to be more alarmed about obesity and PCOS in
adolescent. Therefore, they know how to manage obesity from
childhood.
1.4.3. Benefit for research development
Researchers hope that this study can be used as a source of
literature for other research, particularly regarding to break the chain
of obesity and PCOS.
 CHAPTER II

LITERATURE REVIEW

2.1. Anatomy and Physiology of Ovarium

The female internal genital organs include the ovaries, uterine tubes,
uterus, and vagina. Which, will be discussed more about the ovaries.

Figure 1. Internal female reproductive organs. This coronal section

demonstrates the internal structure of the female genital organs.8

2.1.1. Anatomy of Ovarium8

The ovaries are almond-shaped and -sized female gonads in
which the oocytes (female gametes or germ cells) develop. They are

4
 5

also endocrine glands that produce reproductive hormones. Each

ovary is suspended by a short peritoneal fold or mesentery, the
mesovarium). The mesovarium is a subdivision of a larger mesentery
of the uterus, the broad ligament.
In prepubertal females, the connective tissue capsule (tunica
albuginea of the ovary) comprising the surface of the ovary is covered
by a smooth layer of ovarian mesothelium or surface (germinal)
epithelium, a single layer of cuboidal cells that gives the surface a
dull, grayish appearance, contrasting with the shiny surface of the
adjacent peritoneal mesovarium with which it is continuous. After
puberty, the ovarian surface epithelium becomes progressively scarred
and distorted because of the repeated rupture of ovarian follicles and
discharge of oocytes during ovulation. The scarring is less in women
who have been taking oral contraceptives that inhibit ovulation.
The ovarian vessels, lymphatics, and nerves cross the pelvic
brim, passing to and from the superolateral aspect of the ovary within
a peritoneal fold, the suspensory ligament of the ovary, which
becomes continuous with the mesovarium of the broad ligament.
Medially within the mesovarium, a short ligament of ovary tethers the
ovary to the uterus. Consequently the ovaries are typically found
laterally between the uterus and the lateral pelvic wall during a
manual or ultrasonic pelvic examination. The ligament of ovary is a
remnant of the superior part of the ovarian gubernaculum of the fetus.
The ligament of the ovary connects the proximal (uterine) end of the
ovary to the lateral angle of the uterus, just inferior to the entrance of
the uterine tube. Because the ovary is suspended in the peritoneal
cavity and its surface is not covered by peritoneum, the oocyte
expelled at ovulation passes into the peritoneal cavity. However, its
intraperitoneal life is short because it is normally trapped by the
fimbriae of the infundibulum of the uterine tube and carried into the
ampulla, where it may be fertilized.
2.1.2. The follicular phase of ovarian cycle9
After the onset of puberty, the ovary constantly alternates
between two phases: the follicular phase, which is dominated by the
 6

presence of maturing follicles; and the luteal phase, which is

characterized by the presence of the corpus luteum (to be described
shortly). Normally, this cycle is interrupted only if pregnancy occurs
and is finally terminated by menopause. The average ovarian cycle
lasts 28 days, but this varies among women and among cycles in any
particular woman. The follicle operates in the first half of the cycle to
produce a mature egg ready for ovulation at midcycle. The corpus
luteum takes over during the last half of the cycle to prepare the
female reproductive tract for pregnancy in case fertilization of the
released egg occurs. The follicular phase is characterized by
development of maturing follicles.
 7

Figure 2. The ovarian cycle.9

At any given time throughout the cycle, a portion of the

primordial follicles is starting to develop under paracrine influence.
However, only those that reach a certain stage of development during
 8

the follicular phase, when the gonadotropin hormone environment is

right to promote their final maturation, continue beyond the earlier
stages of development. The others, lacking hormonal support, undergo
atresia. During follicular development, as the primary oocyte is
synthesizing and storing materials for future use if fertilized,
important changes take place in the cells surrounding the reactivated
oocyte in preparation for the eggs release from the ovary.
The first stage of follicular development is conversion of
selected primordial follicles into preantral follicles. A preantral follicle
is a follicle that has begun to grow but has not yet formed an antrum,
a fluid-filled cavity within the follicles interior. When a primordial
follicle begins to develop into a preantral follicle, the single layer of
granulosa cells thickens and then proliferates to create several layers
that surround the oocyte. The oocyte and granulosa cell secrete
glycoproteins that form a thick, gel-like rind that covers the oocyte
and separates it from the surrounding granulosa cells. This intervening
membrane is known as the zona pellucida. Gap junctions penetrate the
zona pellucida and extend between the oocyte and surrounding
granulosa cells. Glucose, amino acids, and other important molecules
are delivered to the oocyte from the granulosa cells through these
connecting tunnels, enabling the egg to stockpile these critical
nutrients. Also, signalling molecules pass through the gap junctions in
both directions, helping coordinate the changes that take place in the
oocyte and surrounding cells as both mature and prepare for
ovulation. The nurturing relationship between granulosa cells and a
developing egg is similar in many ways to the relationship between
Sertoli cells and developing sperm.
At the same time as the oocyte is enlarging and granulosa cells
are proliferating, specialized ovarian connective tissue cells in contact
with the expanding granulosa cells proliferate and differentiate to
form an outer layer of thecal cells in response to paracrines secreted
by the granulosa cells. Thecal and granulosa cells, collectively known
as follicular cells, have the ability to function as a unit to secrete
estrogen, although they do not do so at this early stage of follicular
 9

development. Preantral follicular development takes several months to

complete and occurs without gonadotropin influence.
The next stage of follicular development is gonadotropin-
dependent and involves formation of the antrum and conversion of the
preantral follicle into an antral follicle that secretes estrogen. During
this stage of follicular development, a fluid-filled cavity, or antrum,
forms in the middle of the granulosa cells. The follicular fluid
originates partially from transudation (passage through capillary
pores) of plasma and partially from follicular cell secretions. As the
follicular cells start producing estrogen, some of this hormone is
secreted into the blood for distribution throughout the body. However,
a portion of the estrogen collects in the hormone-rich antral fluid. Of
the three physiologically important estrogens in order of potency
estradiol, estrone, and estriol estradiol is the principal ovarian
estrogen.
The oocyte reaches full size during early development of the
antrum. The shift from a preantral follicle to an antral follicle initiates
a period of rapid follicular growth. Part of the follicular growth is the
result of continued proliferation of the granulosa and thecal cells, but
most results from a dramatic expansion of the antrum. As the follicle
grows, estrogen is produced in increasing quantities.
Early antral development depends on the presence of
gonadotropins, but the fluctuating levels of these hormones that occur
during the monthly reproductive cycle do not influence early antral
follicles. This early antral development takes another 45 days and, like
preantral development, is not part of the follicular phase of the
ovarian cycle. Only antral follicles that have developed to the point of
becoming extremely sensitive to FSH are recruited for further rapid
development at the beginning of the follicular phase when FSH levels
rise. Typically during each cycle, about 15 to 20 follicles are recruited.
Whereas the diameter of a preantral follicle is still less than 1 mm,
that of a recruitable antral follicle is 2 to 5 mm, and that of a recruited
mature follicle reaches 15 to 20 mm shortly before ovulation.
Of the follicles recruited, one, the dominant follicle, usually
grows more rapidly than the others, developing into a mature
 10

(preovulatory, tertiary, or Graafian) follicle within about 14 days after

being recruited. Rapid growth of recruited follicles and development
of a mature follicle is the only stage of follicular development that
takes place during the follicular phase of the ovarian cycle under the
influence of FSH. The dominant follicle that develops into a mature
follicle generally has the most FSH receptors and therefore is most
responsive to hormonal stimulation. The antrum occupies most of the
space in a mature follicle. The oocyte, surrounded by the zona
pellucida and a single layer of granulosa cells, is displaced
asymmetrically at one side of the growing follicle, in a little mound
that protrudes into the antrum.
The greatly expanded mature follicle bulges on the ovarian
surface, creating a thin area that ruptures to release the oocyte at
ovulation. Rupture of the follicle is facilitated by release from the
follicular cells of enzymes (triggered by a burst in LH secretion,
which is described later) that digest the connective tissue in the
follicular wall. The bulging wall, thus weakened, balloons out even
farther to the point that it can no longer contain the rapidly expanding
follicular contents.
Just before ovulation, the oocyte completes its first meiotic
division. The ovum (secondary oocyte), still surrounded by its tightly
adhering zona pellucida and granulosa cells (now called the corona
radiata, meaning radiating crown), is swept out of the ruptured
follicle into the abdominal cavity by the leaking antral fluid. The
released ovum is quickly drawn into the oviduct, where fertilization
may or may not take place.
2.1.3. The hormonal interaction of follicular function9
The ovary has two related endocrine units: (1) the estrogen-
secreting follicle during the first half of the cycle and (2) the corpus
luteum, which secretes both progesterone and estrogen, during the last
half of the cycle. These units are sequentially triggered by complex
cyclic hormonal relationships among the hypothalamus, anterior
pituitary, and these two ovarian endocrine units.
As in the male, gonadal function in the female is directly
controlled by the anterior pituitary gonadotropic hormones namely,
 11

follicle-stimulating hormone and luteinizing hormone. These

hormones are regulated by hypothalamic gonadotropin-releasing
hormone. The GnRH-secreting neurons, in turn, are stimulated by
kisspeptin released by higher-level hypothalamic kiss1 neurons.
Feedback actions of gonadal hormones at the anterior pituitary and
hypothalamus complete the control loop. Unlike in the male, however,
control of the female gonads is complicated by the cyclic nature of
ovarian function. For example, the effects of FSH and LH on the
ovaries depend on the stage of the ovarian cycle. Furthermore, as you
will see, estrogen exerts negative-feedback effects during part of the
cycle and positive-feedback effects during another part of the cycle,
depending on the concentration of estrogen. Also in contrast to the
male, FSH is not strictly responsible for gametogenesis, nor is LH
solely responsible for gonadal hormone secretion.
The early stages of preantral follicular growth and oocyte
maturation precede the follicular phase and do not require
gonadotropic stimulation. Hormonal support is required, however, for
further follicular development and antrum formation, and for estrogen
secretion. Estrogen, FSH, and LH are all needed. FSH induces antrum
formation. Both FSH and estrogen stimulate proliferation of the
granulosa cells. Both LH and FSH are required for synthesis and
secretion of estrogen by the follicle, but these hormones act on
different cells and at different steps in the estrogen production
pathway. Both granulosa and thecal cells participate in estrogen
production. The conversion of cholesterol into estrogen requires a
number of sequential steps, the last of which is conversion of
androgens into estrogens. Thecal cells readily produce androgens but
have limited capacity to convert them into estrogens. Granulosa cells,
in contrast, contain the enzyme aromatase, so they can readily convert
androgens into estrogens, but they cannot produce androgens in the
first place. LH acts on the thecal cells to stimulate androgen
production, whereas FSH acts on the granulosa cells to promote
conversion of thecal androgens (which diffuse into the granulosa cells
from the thecal cells) into estrogens. Because low basal levels of FSH
 12

are sufficient to promote his final conversion to estrogen, the rate of

estrogen secretion by the follicle primarily depends on the circulating
level of LH, which continues to rise during the follicular phase.
Furthermore, as the follicle continues to grow, more estrogen is
produced simply because more estrogen-producing follicular cells are
present.
Part of the estrogen produced by the growing follicle is
secreted into the blood and is responsible for the steadily increasing
plasma estrogen levels during the follicular phase. The remainder of
the estrogen remains within the follicle, contributing to the antral fluid
and stimulating further granulosa cell proliferation.
The secreted estrogen, in addition to acting on sex-specific
tissues such as the uterus, inhibits the hypothalamus and anterior
pituitary in typical negative-feedback fashion. The rising, moderate
levels of estrogen characterizing the follicular phase act directly on
the hypothalamus to inhibit the ARC nucleus kiss1 neurons, thus
indirectly inhibiting GnRH secretion and thereby suppressing GnRH-
prompted release of FSH and LH from the anterior pituitary.
However, estrogens primary effect is directly on the pituitary.
Estrogen selectively inhibits FSH secretion by the gonadotropes.
This differential secretion of FSH and LH by the gonadotropes
induced by estrogen is in part responsible for the declining plasma
FSH level, unlike the rising plasma LH concentration, during the
follicular phase as the estrogen level rises. Another contributing factor
to the fall in FSH during the follicular phase is secretion of inhibin by
the follicular cells. Inhibin preferentially inhibits FSH secretion by
acting at the anterior pituitary, just as it does in the male. The decline
in FSH secretion brings about atresia of all but the single dominant,
most mature of the developing follicles.
In contrast to FSH, LH secretion continues to rise slowly
during the follicular phase despite inhibition of GnRH (and thus,
indirectly, LH) secretion. This seeming paradox occurs because
estrogen alone cannot completely suppress tonic (low-level, ongoing)
LH secretion; to completely inhibit tonic LH secretion, both estrogen
and progesterone are required. Because progesterone does not appear
 13

until the luteal phase of the cycle, the basal level of circulating LH
slowly increases during the follicular phase under incomplete
inhibition by estrogen alone.

Figure 3. Production of estrogen by an ovarian follicle.9

2.2. Obesity
2.2.1 Definition and Classification
Althoughseveralclassificationsanddefinitionsfordegreesof
obesity are accepted, the most widely accepted classifications are
thosefromtheWorldHealthOrganization(WHO),basedonbody
massindex(BMI).TheWHOdesignationsareasfollows:
Grade1overweight(commonlyandsimplycalledoverweight)
BMIof2529.9kg/m2
Grade2overweight(commonlycalledobesity)BMIof30
39.9kg/m2
Grade 3 overweight (commonly called severe or morbid
obesity)BMI40kg/m2

Therefore, obesity is defined as BMI >30 kg/m2. While in

 14

Asian population, based on body fat equivalence and comorbid

diseaserisk,BMIsof23kg/m2 and27.5kg/m2,respectively,have
beenrecommendedasthecutoffpointsforpublichealthactionin
Asians.10
2.2.2 Regulation of Obesity
Much has been learned in the past decade regarding the
regulation of obesity as it relates to the molecular regulation of
appetite that affects energy homeostasis, particularly as positive
energy balance upsets lipid and glucose metabolism. Furthermore,
obesity affects dysregulation of cellular metabolism, which affects
insulin resistance in diabetes mellitus type 2.11 Excess adipocytes
secretenumerouscytokinesthatcontributetovasculardysfunctionin
hypertension and dyslipidemia, as manifested by
hypercholesterolemiaandtriglyceremia.Theseconditionseventually
contribute to significant atherosclerosis, and when associated with
obesityand/ordiabetesandinsulinresistance11,theymightconstitute
metabolicsyndrome.
Thereleaseofexcessivefreefattyacidsinciteslipotoxicity,as
lipids and their metabolites attributes to oxidant stress to the
endoplasmic reticulum and mitochondria. This affects adipose and
nonadiposetissue,whichisrelatedforitspathophysiologyinorgans,
including metabolic syndrome12. The free fatty acids released from
excessively stored triacylglycerol deposits inhibit lipogenesis,
preventing adequate clearance of serum triacylglycerol levels that
contribute to hypertriglyceridemia. Release of free fatty acids by
endothelial lipoprotein lipase from increased serum triglycerides
within elevated lipoproteins causes lipotoxicity that results in
insulinreceptor dysfunction. The consequent insulinresistant state
creates hyperglycemia with compensated hepatic gluconeogenesis.
Thelatterincreaseshepaticglucoseproduction,whichexplainswhy
thehyperglycemiaiscausedbyinsulinresistance.Freefattyacidsalso
decrease the usage of of insulinstimulated muscle glucose,
 15

contributing further to hyperglycemia. Lipotoxicity from excessive

freefattyacidsalsodecreasessecretionofpancreatic cellinsulin,
whicheventuallyresultsincellexhaustion13.
Adipocytes, consisting of over one billion cells, store
triacylglycerolinfatdepotsinvariousbodysitestoprovideenergy
reserves,butinaggregateconstitutethelargestendocrinetissuethat
constantly communicates with other tissues by adipocytereleased
secretagogues, such as the proteohormones lectin, adiponectin, and
visfatin.Alongwithinsulin,theseproteohormoneshelpregulatebody
fatmass.Othergenegroupsthatcontributetoadipocyteadipokines
include cytokines, growth factors, and complement proteins.These
includetheinflammatoryadipokinestumornecrosisfactor(TNF),
interleukin(IL1andIL6)thatcauselocalsteatonecrosis,butarealso
distributedbythevascularsystemandcauseinflammationelsewhere.
Visceral fat depots release inflammatory adipokines, which,
along with free fatty acids, provide the pathophysiologic basis for
comorbidconditionsassociatedwithobesitysuchasinsulinresistance
anddiabetesmellitustype2. Visceraladipokinesaretransportedby
the portal vascular system to the liver, enhancing nonalcoholic
steatohepatitis(NASH),andalsobythesystemiccirculationtoother
diversesites.Alongwithfattyacidlipotoxicity,visceraladipokines
also contribute to the adipokine inflammatory injury that leads to
pancreatic cell dysfunction, which, in turn, decreases insulin
synthesisandsecretion.14
Dyslipidemia, hypertension, and atherogenesis are comorbid
conditions,inadditiontoinsulinresistance,thatareassociatedwith
obesity and adversely influenced by the secretion of diverse
inflammatory adipokines, particularly from white adipose tissues
(WAT)invisceralfatdepots. Specificadipokinesenhanceendothelial
vasomotortone15bysecretingrenin,angiotensinogen,andangiotensin
II,whicharesimilartothosewithintherenalreninangiotensinsystem
(RAS),butwhensecretedfromadipocytes,enhancehypertensionin
 16

obesepatients.TNF secretionincreasesinproportiontoincreased
totalbodyfatmassandenhancesinflammationinfattyliversandfat
depotselsewhere,particularlyinpancreas,mesentery,andgutvisceral
sites. Adipocytesalsostimulatefatassociatedmacrophagesthatalso
secrete monocyte chemoattractant protein 1 (MCP1), macrophage
migrationinhibitingfactor(MMIF),andresistin,allofwhichdecrease
insulinsensitivity(ie,enhanceinsulinresistance).Thesemacrophages
contribute to the enhanced inflammatory state16 and, as immune
stimulators,enhancethemitogenactivatedproteinkinasefamily(C
JunNterminalKinase,inhibitorofnuclearfactorkappabeta[NFKB]
Kinase b, and phosphatidylinositol 3Kinase), inducing the
transcriptionfactorNFKBthatallowsdephosphorylationoftheIRS
1and2dockingproteins.ThelatterinhibitstheGLUT4transporter
ofglucose,resultingininsulinresistance.
The progressive proinflammatory state resulting from
increased obesity that promotes insulin resistance also perpetuates
atherogenesisthroughoutitsdevelopment,fromearlyendothelialfatty
streakstolateplaqueformation,rupture,andthrombosis.Endothelial
modulatorssuch as vasoactive endothelial growth
factor,plasminogenactivatorinhibitor1, angiotensinogen,renin,and
angiotensin IIare secreted by white fat cells, in particular by
perivascularfattissuesthatcontributetovasomotordysfunctionand
causehypertensionandendothelialinjury26.Thisprocessisfollowed
by the formation of foam cells following the enhanced endothelial
uptakeofoxidizedlowdensitylipoproteins,freefattyacids,andother
lipidmetabolitesthataccumulateasaresultoffattyacidperoxidation
all of which originate from dyslipidemic lipoproteins. Both
endothelial and adipose cell lipoprotein lipase activity are also
decreased by inflammatory cytokines such as IL6, so that by
inhibiting lipolysis they increase serum triacylglycerol levels
accentuatinghypertriglyceridemia.
Later, as atherosclerosis progresses with macrophage and
 17

smoothmusclecellinfiltration,thereisadditionalsecretionofother
cytokines,suchasMCP1,MMIF,andendothelin1,thatenhancethe
evolvinginflammatorylesions ofatheroscleroticplaqueswithinthe
vascular wall. Other adipokine procoagulants include plasminogen
activatorinhibitor1,IL6,tumorgrowthfactor,andTNF,which
causethrombosis,particularlyfromrupturedatheroscleroticplaques.
Progressionofatherosclerosiswithplaqueformationandremodeling
ofcollagenresultsfromtheactionofmatrixmetalloproteinasesalso
secretedbyadipocytes.Thisactivitycausesatheromacapthinningand
plaque rupture that precipitates release of the tissue factor, also
promoting intravascular thrombosis. Adipokines also enhance
angiogenesis and promote adipogenesis by neovascularization
enhancementofWAT.Insummary,inflammatory,insulinresistant,
hypertensive, and thromboticpromoting adipokines that are
atherogenic are counterbalanced by antiinflammatory and anti
atherogenic adipocyte hormones, such as adiponectin, visfatin, and
acylationstimulating protein, whereas certain actions of leptin and
resistinareproatherogenic.
2.2.3 Obesity in PCOS
Aside from disturbances in insulin physiology, obesity
implies thorough alterations in steroid hormone metabolism,
essentiallysummarizedas increasedconcentrationsofnearlyallof
messengers.Tothisend,hyperestrogenemiaisaparamountalteration,
stemming from extraovarian estrogen production in VAT and
subcutaneousadiposetissue(SAT),duetoexpressionofaromatasein
theseadipocytes.EstrogensstimulateLHandinhibitFSHsecretion,
contributingtoGCandTChyperplasia.Inturn,thiswouldincrease
androgensynthesis,whichnotonlycausethetypicalmanifestationsof
PCOS, but also serve as substrates for extraovarian aromatization.
Asidefromhyperinsulinemiamediatedeffects ofinsulinresistance,
increasedadiposityleadstofastercortisolmetabolism,whichresults
inhyperactivationofthehypothalamushypophysisadrenalaxis 26 and
 18

thusincreasedDHEAsynthesis.CompetitivebindingtoGCRbyGC
produced progesterone derives into diminished cortisol binding to
GCR,reinforcingHHAAactivation.
Highadiposityalsoleadstogreateraromataseexpressionin
adipocytes, which allows for increased extraovarian estrogen
synthesis27.Inturn,thiscausesanelevatedLH/FSHratio,prompting
hyperplasiaofGCandTC,whichthensynthesizesgreateramountsof
progesterone and testosterone, respectively. Hyperleptinemia and
leptin resistance result in alterations of LH secretion, as well as
downregulationofovariancollagenases,andpromotionofachronic
inflammatory state. Carbohydraterich diets may induce oxidative
stress in circulating mononuclear blood cells and thus chronic
inflammation. Lipidrich diets have been reported to increase
testosteronesynthesisanddownregulateSHBGsynthesis,resultingin
hyperandrogenemia. These diets also favor endogenous and
exogenous AGEdeposition,whichresults inoverallovarian tissue
damage.
AnothercommonfindinginwomenwithPCOSiselevated
serum concentrations of adrenal androgens, which suggest
dysregulationoftheHHAA.Paralleltotheeffectsofinsulininthis
axis, adrenal hyperandrogenemia may be reinforced by increased
amounts of VAT, which displays a high traffic and catabolism of
cortisol,triggeringacompensatoryactivationoftheHHAA,which
results in elevation of adrenal androgen levels. Additionally,
progesteronemayinteractwiththeglucocorticoidreceptor,impairing
activity of these hormones. As a consequence, hyperestrogenemia,
suchas thatfoundinPCOSandthelutealphaseofthemenstrual
cycle27,mayexacerbatethisHHAAcompensation,leadingtohigher
adrenalandrogenproduction whichcanalsobeconvertedbackto
estrone in adipose tissue and then into estradiol by 17HSD in
extraovarian tissues, restarting the hyperestrogenemia
hyperandrogenemia cycle. Moreover, glucocorticoids, which are
 19

elevatedduetoHHAAhyperactivity,induceexpressionofaromatase,
furtherfuelingthis positivefeedbackcircuit.Leptin,knownas the
prototypicaladipokine,isa167aminoacidpeptidesecretedprimarily
fromwhiteadiposetissue,althoughitispresentatseveralothersites,
includingtheovary.LeptinsecretionoccurspredominantlyinSAT
overVATinwomenandappearstobeinverselyrelatedtoadipocyte
size.Leptincanbefoundcirculatingfreelyitsmetabolicallyactive
formorboundtosolubleleptinreceptor(sOBR),acarrierprotein
derivedfromalternativesplicingofleptinreceptor(OBR)mRNAor
ectodomain shedding of OBR transmembrane structures. sOBR
modulatesleptinactivitybylengtheningclearanceandhalflife,yet
limiting its availability to membrane OBR. Leptin participates in
regulation of energy homeostasis and multiple neuroendocrine,
immune,andreproductivefunctions.
Indeed,leptinappearstoplayapermissiveroleforadequate
functioningoftheHHOA28,asobservedinsubjectswithcongenital
leptin deficiency, who are typically infertile. Leptin stimulates LH
secretion,asascertainedbycorrectionofLHpulsesfollowingleptin
administration in women with fastinginduced HHOA dysfunction.
Because hypothalamic GnRHsecreting cells do not express leptin
receptors,stimulationofLHsecretionappearstobeanindirecteffect,
possiblythroughAgRP/NPYandPOMCneurons,whichdoexpress
the receptor and are anatomically associated with GnRH neurons.
Another pathway for leptin induced GnRH secretion involves
kisspeptin29; a europeptide expressed in the arcuate and
periventricular nuclei, which binds to its receptor in hypothalamic
GnRHexpressing cells, inducing its secretion. Leptin also exerts
direct effects in all ovarian cells and seems to have a physiologic
regulatoryeffectinfolliculogenesis.InthecontextofPCOS,therole
ofleptinhasbeensubjecttoprofoundcontroversy30,withopposing
viewsregardingitstrueparticipation.Becauseleptinconcentrations
are consistently foundtobe stronglycorrelated withweight,some
 20

reports consider the hyperleptinemia seen in PCOS as only a

byproductofthiscondition.Ontheotherhand,findingslinkingleptin
levels to estradiol, testosterone, and insulin in women with PCOS
advocateforamorecomplexroleofleptininitspathophysiology.
Moreover, reports of elevated leptin in nonobese patients
further question quantitative adiposity as the sole origin of
hyperleptinemiainthisscenario.Regardlessofitsorigin,inPCOS
hyperleptinemia exerts direct effects on ovarian physiology by
arresting follicle development31. Moreover, ovarian paracrine and
autocrineleptinsignalingmayalsobedisrupted,paralleltoalterations
in the HHOA. Likewise, in vitro studies show a decrease in
collagenase expression in ovarian tissue after exposure to high
concentrationsofleptin,addingtotheovulatorydisturbancesinthis
scenario. In obese women with PCOS, the consequences of
hyperleptinemiamaybeexcacerbatedbylowerlevelsofsOBR,which
increaseleptinligandavailability.Indeed,sOBRexpressionappears
tobeinversetobothadiposityandDHEASlevels.
Finally, matters may be further complicated with the
developmentofleptinresistance,astateofdiminishedresponsetothe
neuroendocrineeffectsofthishormone,namely,regardingattenuation
of appetite. Several factors may contribute to this phenomenon,
including saturation of blood brain barrier transporters of leptin 32,
saturation and downregulation of its receptors in kisspeptin
expressingneurons,obesityinducedendoplasmicreticulumstressin
targetneurons,andanegativefeedbackloopengrainedwithinitsown
signalingcascade,whichactivatesinthefaceofleptinoveractivity. 7
InPCOS,leptinresistanceresultsnotonlyininsufficientpermissive
signalingtoachieveoptimalLHpulsesecretion,butalsoindefective
suppressionofappetite,whichmayperpetuateobesity.

2.3. Polycystic ovary syndrome (PCOS)

2.3.1. Definition
 21

Polycystic Ovarian Syndrome is defined as a disorder of

reproductiveagedwomen.PCOSisachronichyperandrogenicstate
thathasmanysignificantshorttermandlongtermimplicationsfor
patients such as oligomenorrhea, amenorrhea, infertility, diabetes
mellitus,cardiovasculardisease,increasedriskofendometrialcancer,
and excessive body hair (hirsutism). PCOS is characterized by a
menstrual cycle that ranges from > 35 days or < 8 cycles/year to
complete absence of menses (amenorrhea); evidence of androgen
excess, such as acne, hirsutism, alopecia, acanthosis nigricans, or
increasedandrogenlevelsonlaboratorytestinginwhichallother
causesofhyperandrogenismandanovulationhavebeenexcluded.
2.3.2. Etiopatophysiology
MostcausesthatelaboratesthepathophysiologyofPCOS
include:
Androgen excess. Androgen excess is considered by some
investigatorstobetheessentialaspectofPCOS.Furthermore,
sonographic detection of PCO is imperfectly predictive of
PCOS because PCO occur in 2030% of all women.
Nevertheless, visual scoring systems of hirsutism are
valuable18 because most white or black women with PCOS
demonstrate excess hair growth, although many East Asian
womenmaynot.Moreover,serumandrogenmeasurementsare
also helpful, even though detection of hyperandrogenemia27
dependsonthequalityandtypeofandrogenassaysusedand
the normative values of the control population. Circulating
totalandfreetestosteroneanddehydroepiandrosteronesulfate
(DHEAS) levels are elevated in 5075% of women with
PCOS,ifhighqualityassaysareused.
 22

Figure4.FerrimanGallweyHirsutismScoringSystem

Ovulatorydysfunctionandpolycysticovaries.Duringovarian
folliculardevelopment,primordialfolliclesarerecruitedintoa
groupofgrowingfollicles,fromwhichoneantralfollicleis
selected to ovulate. These events require coordinated
reproductive, metabolic and intraovarian interactions. In
PCOS, ovarian hyperandrogenism27, hyperinsulinemia from
insulinresistanceandalteredintraovarianparacrinesignaling
candisruptfolliclegrowth.28 Theconsequentfolliculararrest
in PCOS is accompanied by menstrual irregularity,
anovulatorysubfertilityandtheaccumulationofsmallantral
follicles within the periphery of the ovary, giving it a
 23

polycysticmorphology.29 FolliculararrestinPCOSdevelops
when granulosa cells in antral follicles normally begin to
expressaromatase22(atasizeof7mm)asexcessintraovarian
5reducedandrogensinhibitgranulosacellaromataseactivity
invitroandimpairfolliclegrowth.
Hyperinsulinemia also increases luteinizing hormone (LH)
stimulatedandinsulinlikegrowthfactor1(IGF1)stimulated
androgenproduction32,whichwillincreasethevalueofserum
freetestosteronelevelsby decreasinghepaticsexhormone
binding globulin production, and enhances serum IGF1
bioactivity through suppressed IGFbinding protein
production,whichinresultwillpromoteinhibinproduction.
Insulinexcessalsopromotes prematurefollicleluteinization
throughenhancedfolliclestimulatinghormone(FSH)induced
granulosa cell differentiation, which arrests granulosa cell
proliferation and subsequent follicle growth. Finally,
overproduction of antiMullerian hormone (AMH) by the
granulosa cells of ovarian follicles in PCOS appears to
antagonize FSH action in small PCOS follicles, as such
follicles are estrogendeficient despite sufficient FSH
bioavailability. Many women with PCOS have insulin
resistancebeyondthatpredictedbytheirBMI,with5070%
ofthesewomendemonstratinginsulinresistancebyvarious
measures.
Insulin resistance causes compensatory hyperinsulinemia,
whichdrivesmanyofthephenotypicfeaturesofPCOS33.Most
women with PCOS are young and develop compensatory
hyperinsulinemia from insulin resistance, with impaired
glucose tolerance detectable more readily by oral or
intravenousglucosetestingthanbybasalglucosemeasures.
Althoughtheprevalenceofobesityinwomenbothwithand
without PCOS has increased over the past two decades,
 24

obesity is not necessarily a defect intrinsic to PCOS. For

example,thedegreeofinsulinresistanceinPCOSisgreater
thanthatpredictedbytheBMI34,although4050%ofwomen
with PCOS are not obese. Furthermore, degree of visceral
adiposity alone does not explain differences in insulin
sensitivitybetweenwomenwithPCOSandthosewithoutthe
syndrome,althoughthisissueiscontroversial.Themolecular
mechanisms underlying insulin resistance of PCOS remain
elusive;however,primarydefectsininsulinmediatedglucose
transport, GLUT4 production35 and insulin or adrenergic
regulated lipolysis in adipocytes36 (and occasionally in
myocytes and fibroblasts), despite normal insulin binding,
havebeenreported.Thesedefectsininsulinactionseemto
representperturbedintracellularinsulinsignalingoractionby
paracrine, autocrine and endocrine factors, with abnormal
insulin receptor autophosphorylation or altered
phosphorylation of insulinreceptor substrate, glycogen
synthase kinase 3 or serine/threonineprotein kinase AKT
identified in fibroblasts, adipocytes and myocytes of some
womenwithPCOS.Inaddition,insulinresistanceinPCOS
mightpartiallyrepresentdysfunctionaladipogenesis37froman
impairedcapacityofregionaladiposetissuestorestoproperly
expandwithincreaseddietarycaloricintake.Adiposetissue
secretes approximately 100 factors that regulate metabolic
function,appetite,neuralactivity,digestionandinflammation;
this tissue is also heavily infiltrated by macrophages, and
crosstalk occurs between adipocytes, macrophages and
pluripotentcellsthatinducescomplexparacrineinteractions.
Specifically, paracrine dysregulation of adipokine (for
example, adiponectin) production by macrophagesecreted
cytokinesinPCOSfavorsdevelopmentofinsulinresistance.
Gonadotropin abnormalities. LH hypersecretion increases
 25

serumimmunoactiveandbioactiveLHlevelsinabout70%of
women with PCOS, and elevated LH pulse amplitude and
frequency induces a twofold to threefold elevation in
circulating LH versus FSH levels. Increased LH pulse
frequency in PCOS38, from enhanced hypothalamic
gonadotropin releasinghormone (GnRH) pulsatile release,
occursowingtoreducedsteroidhormonenegativefeedback
on LH secretion because of androgen excess. This
neuroendocrine abnormality occurs in adolescent girls with
PCOS which suggests that androgen excess reduces
hypothalamicfeedbackinhibitionthatcausesincreasedGnRH
pulsatilityduringpuberty39.However,notalladolescentgirls
withPCOSexhibitreducedhypothalamicfeedbackinhibition
fromandrogenexcess,whichmaybebecausethepresenceof
this defectrequires ageneticcomponentordependsonthe
duration of androgen excess. Other neuroendocrine
abnormalitiesinwomenwithPCOSincludeexaggeratedLH
responsivenesstoGnRH,40 withasexuallydimorphicpattern
of LH release that more closely resembles that of men or
women with congenital adrenal virilizing disorders than of
women without PCOS. Abnormalities in the circulating
LH:FSH ratio are primarily observed in thin women with
PCOS,asobesitylowersLHpulseamplitude41andaltersLH
pharmacokinetic structure42, which contributes to reduced
serumLHlevelswithincreasedpercentbodyadiposetissue.
Infancy to adolescence. Daughters of women with PCOS
demonstrateearlyreproductiveandmetabolicderangementsas
endocrineantecedentstoadultPCOS.Asamarkerofgrowing
ovarianfolliclenumbers,serumAMHlevelsareelevatedin
infantdaughtersofwomenwithPCOSandremainso,along
withincreasedfollicularmass,throughchildhoodandpuberty.
This phenomenon may be linked with maternal androgen
 26

production, as early follicular phase serum AMH levels in

female adolescent offspring are positively correlated with
maternaltotaltestosteronelevelsinmidgestation.Serumleptin
levels in neonates of women with PCOS are also elevated,
being positively correlated with birth weight and maternal
BMIat midgestation.Chronologically,enlargedovaries and
hyperinsulinemia exist in female children of women with
PCOS, accompanied by LH hypersecretion and androgen
excessinpuberty.Prematureadrenarcheisobservedinsome
populationsofgirlswithPCOS.Obesityfurtherinfluencesthe
adolescent PCOS phenotype by unmasking or amplifying
symptoms of hyperinsulinemia and hyperandrogenism in
susceptibleindividuals.
Genetics. PCOS is more prevalent among family members
than in the general population (prevalence 46%). A
heritabilityforPCOSof0.79amongDutchtwinssuggeststhat
genetic factors influence development of the syndrome. A
heritablecomponenttohyperandrogenemia,insulinresistance
andinsulinsecretionexistsinfamiliesofwomenwithPCOS
asevidencedbyelevatedDHEASlevelsinfirstdegreemale
relatives and an increased prevalence of insulin resistance,
endothelial dysfunction and metabolic syndrome. To date,
mostgeneticstudiesofPCOShaveemployedcandidategene
associationtechniques,inwhichvariantsinageneofinterest
aregenotypedandexaminedforcorrelationwithPCOSorits
quantitative traits. Varied diagnostic criteria, small sample
sizesinmanystudies,difficultyinassigningaphenotypeto
men or prepubertal and postmenopausal women, and
phenotypicheterogeneityhavehinderedprogressinthisfield.
PCOSappearstobeinheritedasacommoncomplexdisorder,
similar to T2DM and inflammatory bowel disease, wherein
several genetic variants are present that each contribute a
 27

moderateeffect,combinedwithriskincreasinglifestyleand
environmental factors. Discovery of genes for common
complexdisordersrequiresrobustsamplesizesandeffortsto
replicate initial associations in independent cohorts. Despite
manyassociationstudies,attemptstoreplicatepositiveresults
havebeenparticularlyinfrequent.Examplesofwellconducted
replication studies that were unable to confirm the initial
associationincludethoseforgenesencodingcytochromep450
sidechaincleavageenzyme(CYP11A),insulin,andaldoketo
reductasefamily1,memberc3(AKR1C3,alsoknownasthe
17hydroxysteroid dehydrogenase type 5 gene).103105
Genes for which association with PCOS or its component
traitshavebeenreplicatedincludefibrillin3(FBN3)and17
hydroxysteroiddehydrogenasetype6(HSD17B6).106,107A
unique study that attempted to replicate the association
betweenPCOSandvariantsin26genesfoundgoodevidence
ofreplicationwithFBN3andproopiomelanocortin(POMC),
and nominal replication of variants in activin A receptor
typeIIA(ACVR2A),fem1homologB(FEM1B),andsmall
glutaminerich tetratricopeptidecontaining protein alpha
(SGTA).Thus,progressinPCOSgeneticshasbeenlimited
comparedwiththatinothercommondisorderssuchasT2DM,
where genomewide association studies have discovered
numerous risk alleles that have been robustly replicated.
Genomewideassociationstudies,whichinvolvegenotyping
300,000to 1 million single nucleotide polymorphisms, take
advantageoflinkagedisequilibriumtocapturemostvariation
in the entire genome. This unbiased, discoverydriven
approachidentifiesnovelgenesthatwouldnototherwisebe
chosen as candidate genes and will probably advance the
understandingofthegeneticsofPCOS.
Environmental factors. Lifestyle profoundly affects the
 28

phenotypic expression of PCOS. Weight gain worsens

metabolic and reproductive abnormalities of PCOS, as
evidencedbyincreasedtotalandabdominalobesityaswellas
insulin resistance, menstrual irregularity and
hyperandrogenism in women with the most severe PCOS
phenotype.WomenwithPCOSintheUSAhavemoresevere
metabolic dysfunction than their counterparts in other
countries,partiallybecauseoftheirgreaterbodyweightand
dietarysaturatedfatintake.Conversely,weightlossinwomen
with PCOS lowers circulating androgen and insulin levels,
while improving hirsutism, menstrual and ovulatory
dysfunction as well as dyslipidemia. A sedentary lifestyle
alone also contributes to metabolic dysfunction in PCOS
because moderateintensity exercise without weight loss
improvesinsulinresistanceanddecreasesbodyadiposetissue.
Environmental endocrine disrupting chemicals also might
disrupt ovarian and metabolic function, causing PCOSlike
abnormalities.BisphenolA(BPA),awidelyusedestrogenic
industrial plasticizer, is one such endocrine disrupting
chemicalthatisdetectableinmostindividuals.
2.3.3. Risk factor
Family history. PCOS tends to run in families. Social/cultural
history. Ethnic factors must be considered in the evaluation of
women who are hirsute for example Mediterranean white women.
Asian women usually have small amounts of hair on their face,
torso, and extremities.
2.3.4. Clinical Manifestations
Major clinical manifestations which could be found by the
history taking and assessment include:
Oligomenorrhoea, or amenorrhoea. Polycystic ovarian
syndrome (PCOS) is defined as ovarian dysfunction associated
with hyperandrogenism and polycystic ovarian morphology.
PCOS is the commonest endocrinopathy among women of the
reproductive age group and is characterized by metabolic
 29

derangement: hyperinsulinemia, hyperandrogenism and excess

LH. The excess luteinizing hormone and insulin cause
increased ovarian androgen production. These hormonal
changes lead to anovulation and bleeding irregularities.
Symptoms onset is usually in the late second and third
decades.
Infertility. PCOS is major cause of infertility especially in the
developed countries. About 75% of patients with PCOS may
complain of difficulty in conceiving. Anovulatory cycles lead
to inadequate oocyte formation.
Recurrent miscarriage. PCOS is associated with 3-fold
increase in the rate of spontaneous pregnancy loss. PCOS is
also considered an important cause for recurrent miscarriage.
The specific aetiology for miscarriage is not known. Factors
implicated with pregnancy loss include obesity, insulin
resistance, hyperandrogenism, polycystic ovaries and placental
thrombosis.
Weight gain. The excess fat mass in obese patients increase
insulin resistance. The resulting hyperinsulinaemia contributes
to weight gain which turn further worsens insulin resistance.
This results in a vicious cycle.
A history of headaches or blurred vision (indicating pituitary
tumor).
Any signs or symptoms of thyroid dysfunction (as a
differential diagnosis of amenorrhea).

Major clinical manifestations which could be found by the

physical examination may include:
Acne/ Excess hair growth / male pattern baldness
Due to hyperandrogenism. Excess hair growth (hirsutism)
mainly occurring in the face, chest and lower abdomen is a
common symptom of PCOS and may in fact be the only
symptom. Androgen secretion from the ovary is stimulated by
LH and hyperinsulinaemia.
Weight gain, or high BMI, or high waist-to-hip ratio.
 30

The excess fat mass in obese patients increase insulin

resistance. The resulting hyperinsulinaemia contributes to
weight gain which turn further worsens insulin resistance. This
results in a vicious cycle.
A history of acne, hirsutism, deepening of the voice, and
increase in muscle mass (without exercise).
Acanthosis nigricans
A black discoloration and roughening usually observed at the
back of the neck, axillae and other flexures. Acanthosis
nigricans is associated with hyperinsulinaemia. This may
appear before the onset of diabetes mellitus.

Major findings found by laboratory test that confirmed the

diagnosis are:
Pelvic ultrasound scan transvaginal scan.
Polycystic ovaries are defined as 12 or more subcapsular
follicles of <10mm diameter in an ovary or ovarian volume >
10ml.
LH and FSH level. The normal 1:1 ratio between
concentrations of LH and FSH is lost in PCOS. In PCOS the
LH concentration is usually elevated with a ratio of LH to FSH
of 2:1 or 3:1. Assessment LH, FSH ratio is not essential for
diagnosis.
Testosterone, androstenedione, Sex hormone binding globulin
(SHBG).
The concentration of androgens is usually elevated. The level
of SHBG will be reduced.
Thyroid function test. Rule out thyroid dysfunction which may
present with menstrual irregularities and hyperandrogenism.
The endocrinological abnormality of PCOS begins soon after
menarche. Chronically elevated luteinizing hormone (LH) and
insulin resistance are 2 of the most common endocrine
aberrations seen in PCOS. High LH and hyperinsulinemia
work synergistically, causing ovarian growth, androgen
production, and ovarian cyst formation.
Obesity, which is seen in 50% to 65% of PCOS patients, may
increase the insulin resistance and hyperinsulinemia. Need to be noted
 31

that hyperandrogenism and insulin resistance has been recognized in

both obese and nonobese anovulatory women. Thus, it is important to
realize that a nonobese patient may also have insulin resistance
though the insulin levels in obese women are higher. Clinically,
though, both groups will have evidence of hyperandrogenism and
oligoovulation or anovulation.
Insulin resistance can be characterized as impaired action of
insulin in the uptake and metabolism of glucose. Impaired insulin
action leads to elevated insulin levels, which causes a decrease in the
synthesis of 2 important binding proteins: insulin-like growth factor
binding protein (IGFBP-I) and sex hormone binding globulin
(SHBG). IGFBP-I binds to IGFBP-II and SHBG binds to sex steroids,
especially androgens. The triad of hyperandrogenism, insulin
resistance, and acanthosis nigricans syndrome appears in a subgroup
of patients with PCOS. Acanthosis nigricans, a dark and
hyperpigmented hyperplasia of the skin typically found at the nape of
the neck and axilla, is a marker for insulin resistance. Acanthosis
nigricans is usually found in about 30% of hyperandrogenic women.
2.3.5. Diagnosis
Rotterdam criteria is used for diagnosis of PCOS. Two or more
out of the following three criteria is required to diagnose PCOS.
A history of irregular bleeding due to anovulation
oligomenorrhoea, amenorrhoea,
Clinical or biochemical evidence of hyperandrogenism,
Ultrasonogram results shown features of polycystic ovaries.
2.3.6. Management
Weight reduction. Weight reduction is associated with
significant improvement in menstrual symptoms) Life style
modifications, dietary changes and regular exercise help reduce
weight.
Managing menstrual dysfunction. Combined oral
contraceptive pill and cyclical progesterone is used to regulate
menstruation. Contraceptive pills with anti-androgen effects
(cyproterone acetate/co-cyprindiol- dianette) are used to control both
menstrual irregularities and features of hyperandrogenism. Weight
loss also improves regularity of menstruation.
 32

Treatment for hyperinsulinaemia and lifestyle modification.

Lifestyle modification with dietary changes and regular exercise is the
most effective measure to control the effects of hyperinsulinaemia.
Metformin is increasingly being used for management of PCOS
patients with metabolic syndrome. Metformin has beneficial effects
on regularizing the menstruation. Even though widely used, the
evidence on the benefits of metformin is limited and controversial.
Management of subfertility. Weight loss alone may improve
spontaneous ovulation. Ovulation induction can be carried out with
clomiphene. Use of gonadotrophins is another management option if
anti-estrogens fail. Metformin is currently not recommended for
management of subfertility. In vitro fertilization may be required in
patients who fail to conceive after medical therapy.
Management of hyperandrogenic features. Hirsutism can be
managed with topical therapy with Eflornithine cream or with oral
therapy with Cyproterone acetate and metformin. GnRH analogues
with low dose HRT, Finasteride and Spironolactone can be used in
patients with severe symptoms. Cosmetic hair removal by shaving,
depilatory cream, laser or electrolysis can also be carried out.

2.4. The relationship between obesity and PCOS in adolescent

Obesity is defined as a body mass index (BMI) which is 30 kg/m 2 in
adults and a BMI for age percentile 95% in children and it is widely
believed to contribute to the pathophysiology of Polycystic Ovarian
Syndrome (PCOS).2 The mechanisms which obesity influences the
pathophysiology and clinical expression of PCOS are not completely
understood. But obesity is an independent factor that associated with insulin
resistance and also sex steroid disturbances, which may lead to the increased
risk of menstrual irregularities and hyperandrogenemia.42 So it is negatively
influence its clinical expression. The manifestations of PCOS typically begin
in early adolescence, and many investigators have hypothesized that
peripubertal obesity promotes the development of adolescent PCOS.2
2.4.1. Clinical manifestation
Polycystic Ovarian Syndrome (PCOS) presentation is
heterogeneous, with a broad clinical manifestation spectrum. The
 33

presence of oligomenorrhea indicates ovulatory dysfunction. Obese

oligomenorrheic women have higher plasma testosterone than non-
obese women. That might be due to excessive peripheral conversion
of androstenedione to testosterone or increased adrenal androgen
production.43
In women with PCOS, obesity is a very prevalent condition,
along with insulin resistance. Increased adiposity is associated with
higher androgen concentrations and greater menstrual dysfunction in
women and adolescents with PCOS and it is associated with higher
androgen concentrations among those without PCOS.2 The clinical
manifestations that might be presence in this syndrome are menstrual
dysfunction and hyperandrogenic. Skin is the major target of
androgen activity, so that several hyperandrogenemia-triggered
dermatologic alterations can be seen in PCOS, such as hirsutism as
the most common clinical manifestation to be shown, androgenic
alopecia, acne, seborrhea, onycholysis, and onychorrhexis.44 Signs of
ancanthosis nigricans were more significantly manifested in obese
PCOS women. Mean levels of the metabolic and sex hormones that
have been studied were significantly higher in obese PCOS women.45
Hirsutism defined as the presence of excessive terminal hair in
areas of the body that are androgen-dependent which usually appear
in the hairless area or in the area with limited hair growth, such as the
face, chest, areolas, abdomen, and upper thighs.46 It is a hair
development that is affected by hyperandrogenemia. Normally, in
females past pubarche the major androgenic molecules are
dehydroepiandrosterone sulfate (DHEAS), androstenedione,
dehydroepiandrostenedione, testosterone, and dihydrotestosterone
(DHT), in descending order of serum concentration. Only the latter
two can bind to the androgen receptor and promote hair follicle
changes.7 Terminal hair is different from vellus hair. The latter of
terminal hair is a longer version of lanugo and it covers all body
surfaces such as pubic and axillary areas, scalp, eyelashes, eyebrows,
and male body and facial hair, but not the lips, palms, and soles. The
hairs are more pigmented, longer and coarser. The development of
 34

terminal hair requires androgen stimulation as seen in pubarche,

where androgens trigger vellus to mature into terminal hair. Thus,
hirsutism can be seen as the result of the interaction
hyperandrogenemia and its influence in the hair follicle unit.47
The modified Ferriman-Gallwey Score is used to assesed
hirsutism, it is a qualitative tool for evaluating and quantifying hair
growth in nine androgen-dependent areas in women. It evaluates the
presence of terminal hair in nine different body parts (upper lip, chin,
chest, upper back, lower back, upper abdomen, lower abdomen, arm,
and thigh), with scores ranging from zero (no excessive terminal hair
growth visible) to four (visible extensive hair growth) for each body
part evaluated.46 A score of 1 to 4 is given for nine areas of the body.
A total score less than 8 is considered normal, a score of 8 to 15
indicates mild hirsutism, and a score greater than 15 indicates
moderate or severe hirsutism.48 A score of 0 indicates absence of
terminal hair. This scoring system has limitations because of the
somewhat subjective nature of the assessments and the difficulty of
evaluating women who have cosmetically removed their hair.46
Another androgen-dependent structures are sebaceous glands.
The sebocytes have being highly sensitive to androgen signaling that
is exacerbated in PCOS and leading to the development of acne and
seborrhea.49 Androgens stimulate sebocyte proliferation especially in
the mid-back, forehead, and chin and secretion of sebum, a mixture of
lipids including glycerides, squalene, free fatty acids (FFA), and
cholesterol. Local bacteria further complicate the process by secreting
lipolytic enzymes which break down triglycerides produced in the
sebocyte. The resulting FFA that are released into sebaceous ducts by
apocrine glands are responsible for the characteristic odour observed
in these patients.7
A study by Cela et al. reported that 67% of the women with
PCOS also have androgenic alopecia and elevated levels of
testosterone and androstenedione. The alopecia pattern is dominated
by the frontal and parietal scalp. The occipital area has greater hair
density, as the crown area has thinner and scarcer hair. This disorder
 35

features neither bald spots nor hair loss, only shortening in its length
and width, manifesting as wispy distal ends. Androgenic alopecia is a
disorder in which hair is miniaturized, due to an increase of telogen :
anagen ratio. Anagen hair being mitotically active while telogen hair
being at mitotical rest. It is also associated to the increased 5-
reductase activity in the hair follicle. The enzymatic activity that
increased would make a local conversion of testosterone into DHT.50
Menstrual irregularities and anovulation appear to be more
prevalent and severe in obese women with PCOS than in their
nonobese counterparts, and weight loss of at least 5% tends to be
associated with improvement of these conditions. Furthermore, obese
women with PCOS have greater long term difficulty for conception. 7
Menstrual cycle pattern might serve as a marker of insulin resistance
in patients with PCOS, as insulin resistance can induce
oligomenorrhea or anovulation. Menstrual cycle irregularity caused
by exacerbating hyperandrogenemia and by disrupting follicular
growth. The severity of menstrual abnormality also reflects the degree
of hyperandrogenemia. Indeed, ovarian hyperandrogenism is
associated with anovulation in PCOS by inducing ovarian follicular
arrest.51
Premature pubarche might be an early marker of future PCOS.
It refers to the appearance of pubic hair and/or axillary hair before 8
years of age in girls, without any other signs of puberty. The precise
etiology of premature pubarche is still not known, but it has been
attributed to the early maturation of reticularis zone which leads to an
increase of adrenal androgens that levels usually seen in early puberty.
This early activation could be mediated through marked weight gain
and resultant hyperinsulinemia. It is also proposed that the increase in
androgen biosynthesis might be due to the preferential
hyperphosphorylation of the enzyme P450c17 due to an activating
mutation of the kinase that is responsible for the serine/theonine
phosphorylation of the enzyme.52
Obesity and PCOS is also partly related to the reduction of the
concentration of Sex Hormone Binding Globulin (SHBG) which
 36

resulted on increasing the testosterone bioavailability and leading to

anovulation. It is also associated with increased total testosterone
concentrations which implies on increased androgen production. Low-
fibre diets would lower SHBG synthesis.53 Moreover,
hyperandrogenemia appears to inhibit glyoxalase-I activity, which is
an important enzymatic scavenging system for 2-oxoaldehydes,
including major precursors of AGE. Thus, in PCOS, the deleterious
effects of AGE deposition may be exacerbated.7
2.4.2. Insulin resistance and PCOS7

Figure 5. Interactions among insulin resistance, hyperinsulinemia, and

hyperandrogenemia in the etiopathogenesis and progression of polycystic
ovary syndrome and related comorbidities.7

Insulin resistance defined as a metabolic state characterized by

a decrease in cellular ability to respond to insulin signalling. It
appears to be essential pathophysiologic mechanism in the
development of all metabolic complications of PCOS. It will lead to
compensatory hyperinsulinemia that mediate many deleterious effects.
This phenomenon follows as a response of pancreatic cells in order
to preserve lipid and carbohydrate homeostasis because of diminished
 37

insulin sensitivity. It might lead to diabetes mellitus type 2 or other

hyperglycaemic complication.
It is generally accepted that insulin resistance play an
important role in the molecular mechanisms implicated in the
androgenic hypersecretion. This has been evidenced by the decrease
in fasting insulin levels observed in women with PCOS that undergo
insulin-sensitizing pharmacotherapy, which appears to concurrently
lower androgenemia and improve ovarian functionalism.
Insulin may play a part in the development of the typical
increased amplitude and frequency of GnRH and LH pulse secretion
seen in PCOS. Elevation of LH and GnRH secretion in response to
insulin infusion has been observed in vitro, both in dose dependent
and time dependent. This effect may be mediated by insulin in GnRH-
secreting cells of the hypothalamus, by potentiating GnRH gene
transcription through the MAPK pathway. As a result, increased
GnRH synthesis and secretion lead to a subsequent elevation of LH
levels. This continuous stimulation would translate into augmented
synthesis of ovarian steroid hormones, particularly androgens.
Insulin also reinforces adrenal glands as an alternate androgen
source parallel to ovaries, by potentiating hypothalamus-hypothesis-
adrenal axis (HHAA) activity at several key sites. The hippocampus is
an important mediator of HHAA negative feedback, by inhibiting
hippocampal activity; insulin indirectly enhances hypothalamic CRH
secretion although it may also play a direct role in both the
hypothalamus and the hypothesis. Lastly, although the mechanisms
remain unclear, insulin appears to augment adrenal cortex sensitivity
to ACTH stimulation, with increased androgen secretion.
Elevated insulin concentrations have been associated with
lower levels of SHBG, leading to enhanced bioavailability of
androgens. Although insulin and the insulin-like growth factor 1 (IGF-
1) unable to directly repress SHBG, they may be key indirect
mediators, as they have been associated with decreased total protein
secretion in human hepatic cells. Inhibition of SHBG by elevated
concentrations of glucose and fructose is also an important
 38

component, mediated by downregulation of hepatocytenuclear factor

4- (HNF-4) activity. Nonetheless, in the context of IR, this is yet
another indirect effect, as it relies on high concentrations of these
monosaccharides due to dysfunctional insulin signalling and not on
insulin activity. On the other hand, insulin has been shown to repress
insulin-like growth factor-1 binding protein (IGFBP-1) synthesis in a
direct, rapid, and complete way in both the liver and the ovaries,
allowing for greater IGF-1 availability, which in turn boosts insulin
activity not only in the liver, but also in the ovaries, reinforcing PCOS
pathophysiology. This suppression is mediated by intranuclear
thymine-rich insulin response elements (TIRE). Although not all
components of the signalling cascade linking the insulinreceptor
(INSR) with TIRE are currently known, inhibition of GSK-3 through
the PI3K pathway appears to be essential in this process.
Pleiotropy is a distinguishing feature of insulin signalling,
being involved in a wide catalogue of physiologic and
pathophysiologic roles through distinct, yet interconnected, second-
messenger pathways. For example, phosphorylation of IRS allows it
to act as a docking site for other signaling proteins, such as Grb2,
NcK, and PI3K, which are crucial for translocation of GLUT-4.
Likewise, further downstream in the PI3K pathway is Akt, which
mediates activation of GSK, essential for glycogenesis, as well as
mTOR, an important step for insulin-induced protein synthesis. A
mitogenic pathway is also activated by insulin, through the binding of
phosphorylated IRS or Shc with Grb-2/SOS complexes, leading to
MAPK activation through p21Ras and Raf-1.
The presence of INSR and IGF-1 receptors in TC, GC, and
stromal cells of ovarian tissue unequivocally identifies this organ as a
target of insulin activity, confirmed by observations of decreased
steroidogenesis in TC and GC from both healthy and polycystic
ovaries, following in vitro administration of both anti-IGF1R and
anti-INSR antibodies. One of the key links in this activity is the acute
steroidogenic regulatory protein (StAR), a molecule implicated in
transportation of cholesterol to the internal mitochondrial membrane,
 39

where the cholesterol side-chain cleavage enzyme (CYP11A1) is

anchored, the rate-limiting enzyme in steroid hormone synthesis.
Insulin appears to augment not only StAR expression, but also
CYP11A1, 17--hydroxylase/17,20-lyase (CYP17A1), 3--
hydroxysteroid dehydrogenase (3--HSD), and aromatase (CYP19A1)
expression, contributing to an excess in the production of
progesterone, 17--hydroxyprogesterone, and testosterone in
polycystic ovaries in comparison to healthy ovaries.
The central paradox in the pathophysiologic association
between hyperinsulinemia and hyperandrogenemia in PCOS is that
the ovary remains sensitive to insulin activity and subsequent
androgen production, despite a systemic state of IR, setting the stage
for the selective insulin resistance theory. Several mechanisms have
been proposed to explain this phenomenon, albeit the true chain of
events remains elusive.
Insulin appears to act in synergy with LH to elevate
intracellular concentration of cAMP, which activates StAR,
potentiating steroidogenic activity. Although this effect may be direct
through the PI3K pathway, the requirement of cAMP for this activity
suggests divergence from the usual insulin cascade, yet the differential
molecular interactions are unknown. Similarly, insulin and LH may
also act in synergy to increase transcription of LDL-C receptors in GC
through the PKA, PI3K, and MAPK pathways. On the other hand,
insulin may also augment steroid synthesis through aromatase up
regulation in GC, which would serve as substrates for TC for further
conversion into androgens.
This unifying proposalfor hyperinsulinemia-
hyperandrogenemia in PCOS stems from observations of Dunaif et
al., who ascertained a significant decrease in tyrosine-kinase activity,
accompanied by considerably higher serine-kinase activity, in
fibroblasts of women with PCOS. This differential behaviour resulted
in attenuated metabolic effects of insulin with normal mitogenesis.
Furthermore, in TC, increased serine phosphorylation results in
activation of CYP17A1, reflecting into augmented androgen
 40

production. Nonetheless, no specific kinase has been evidenced to

display these dual effects. However, a key link in the activity of this
hypothetical serine-kinase may be the PI3K/Akt pathway, which
would explain the coexistence of elevated steroidogenesis with fully
functional mitogenic signalling.
Lastly, this pathway stands apart from previous mechanisms as
it appears to be independent of all insulin signalling-related molecules
except INSR itself. Although the full succession of this cascade is
largely unknown, inositolphosphoglycans seem to be able to
potentiate steroidogenic activity by stimulating CYP11A1, CYP17A1,
and CYP19A1 activity in TC. These observations are noteworthy, as
this transduction system may remain intact in the context of IR, in
terms of defective tyrosinekinase activity of INSR substrates and
dysfunctional glucose metabolism, warranting ovarian androgen
synthesis despite these abnormalities.

Figure 6. Insulin signalling in ovarian thecal cells and proposed mechanisms

for selective insulin resistance.7
2.4.3. Hyperandrogenemia to hyperinsulinemia7
The relationship between IR and PCOS was considered to be a
unidirectional pathway toward ovarian disturbances. Nonetheless,
recent evidence stated a complex reciprocal interaction between these
 41

phenomena. In the context of PCOS, hyperandrogenemia may affect

insulin sensitivity. This may be mediated by upregulation of -3
adrenergic receptors and hormone-sensitive lipase expression in
visceral adipose tissue (VAT) through testosterone or DHEAS
signaling, modifying lipolytic activity and favoring release of FFA
into circulation. This increase in FFA availability causes functional
and structural changes in hepatocytes and skeletal myocytes, with the
accumulation of metabolites from the long-chain FFA reesterification
pathway, including Acyl-CoA and diacylglycerol. In turn, these
molecules can activate PKC, a serine/threonine kinase which is
widely accepted as pivotal for the mechanisms underlying IR,
particularly through serine phosphorylation of IRS-1.
In PCOS, androgens also appear to modify metabolic
architecture and functionality in skeletal muscle, by decreasing the
amount of type I muscle fibres, which are highly oxidative and
insulin-sensitive, and increasing type II fibres, which are glycolytic
and less sensitive, as well as decreasing expression of glycogen
synthase.
Further mechanisms remain poorly characterized, including
androgen-driven proinflammatory cytokine secretion from VAT and
androgen-induced interference of insulin signalling. In adipocytes,
testosterone appears to induce serine phosphorylation of IRS-1, which
reflects on inhibition of the metabolic effects of insulin accompanied
by normal mitogenic signalling, suggesting that, in PCOS, selective
insulin resistance may not only be limited to ovarian tissue, but also
be present in adipocytes.
2.4.4. Chronic inflammation lead insulin resistance to PCOS7
Recent evidence describes a central role for certain
proinflammatory mediators in the pathophysiology of PCOS, posing a
new focus on the etiological considerations for PCOS, which is
currently considered a chronic, low-grade inflammatory disorder,
independently of the presence of obesity, although these phenomena
are indeed exacerbated by adiposity. Reports show that women with
PCOS, both with obesity and normal weight, exhibit elevated serum
 42

TNF, C-reactive protein (CRP), monocyte and lymphocyte circulating

levels, and inflammatory infiltration in ovarian tissue.
Several mechanisms have been proposed to explain these
features. Among these, the existence of proinflammatory genotypes
has been suggested, including polymorphisms of sequences codifying
TNF, TNF receptor, IL-6, and IL-10. Remarkably, greater expression
of the CD11c gene is associated with greater proinflammatory
macrophage infiltration is SAT and VAT, favouring a transition to
decreased secretion of adiponectin and increased TNF and leptin
secretion from adipocytes.
The role of TNF is especially important in the setting of IR
and PCOS. In addition to the diminishing effect it bears over insulin
sensitivity, through serine phosphorylation of IRS-1 by PKC. This
cytokine also stimulates steroidogenesis and proliferation in TC, as
well as follicular atresia, contributing to hyperandrogenemia, posing
yet another level of complexity and self-perpetuation for PCOS.
Furthermore, hyperglycaemia may contribute to inflammation
in PCOS, possibly explaining the greater magnitude of manifestations
in PCOS. Circulating mononuclear cells utilize glucose as their main
redox substrate, with part of its metabolites going into the pentose-
phosphate pathway to yield NADPH. Oxidation of this molecule leads
to the production of reactive oxygen species (ROS), which induce
oxidative stress, with the subsequent activation of NF-kB, a
transcription factor involved in the expression of proinflammatory
mediators such as TNF and IL-6. Hyperglycaemia may result in
increased ROS production.
Additionally, oxidative stress appears to also induce key
steroidogenic molecules in TC, namely, CYP11A1, CYP17A1, 3--
HSD, and StAR, favouring hyperandrogenemia. Additionally,
hyperleptinemia boosts its effects in immune function regulation,
including production of proinflammatory cytokines, such as TNF, IL-
6, and IL-12, stimulation of polymorphonuclear cell chemotaxis,
inhibition of lymphocyte apoptosis by suppression of Fas-mediated
 43

signalling, and induction ofTh1 differentiation, both in obese and

nonobese females with PCOS.
Beyond these implications in PCOS, the reinforcing cross-talk
between IR and chronic inflammation generates a welcoming
environment for the development of further cardiometabolic
disturbances. Oxidative stress caused by ROS production in immune
cells plays a fundamental role in the genesis and progression of
endothelial dysfunction, which leads to the development of arterial
hypertension, and cardiovascular disease. Furthermore, chronic
inflammation and IR are two essential elements in the
etiopathogenesis of MS and DM2, which in turn open the door for
further complications for the overall health of women with PCOS.
2.5. Researchers related to the relationship between obesity and PCOS in adolescent

No Title Objectives Methods Result and Conclusion

1. Polycystic Ovary Unravel the intricate Review Article Insulin resistance lead to compensatory
Syndrome, Insulin pathophysiologic hyperinsulinemia induce hyperandrogen with some
Resistance, and cross-talk among mechanisms, such as increase production of LH by
Obesity: Polycystic Ovary stimulating GnRH gene, direct mechanism by
Navigating the Syndrome, Insulin mitogenic pathway in ovarian cell, or reducing sex
Pathophysiologic Resistance, and hormone binding globulin.
Labyrinth7 obesity Hyperandrogen itself also play role to further enhance
the insulin resistance by triggering lipolysis.
Obesity as magnifying factor increase androgen
production not only from ovaries, but from
subcutaneous tissue and adrenal glands.
2. Reproductive and To compare Cohort study of 180 women Obese women reported higher age of menarche,
biochemical changes reproductive, with PCOS who attended abortion and menstrual disturbance with statistically
in obese and non- clinical and outpatient clinic at Taibah significant difference signs of hyperandrogenism and
obese polycystic laboratory data University. Period : January acanthosis nigricans were significantly more
ovary syndrome between obese and to September 2012 manifested in obese PCOS women.
women45 non-obese Mean levels of studied metabolic and sex hormones

women with PCOS. were significantly higher in obese PCOS women.

44
3. Overweight, obesity To describe the MEDLINE EMBASE, Women with PCOS had increased prevalence of
and central obesity in prevalence of CINAHL, Cochrane Central overweight, obesity and central obesity compared with
women with overweight, obesity Register of Controlled Trials women without PCOS
polycystic ovary and central obesity (CENTRAL) and The Caucasian women with PCOS had a greater

syndrome: a in women with and PSYCINFO were searched increase in obesity prevalence than the Asian women

systematic review without PCOS and for studies reporting the with PCOS compared with women without PCOS
Conclusion : women with PCOS had a greater risk of
and meta-analysis54 to assess the prevalence of overweight,
overweight, obesity and central obesity.
confounding effect obesity or central obesity in
of ethnicity, women with or without
geographic regions PCOS. Data were presented
and the diagnostic as prevalence (%) and risk
criteria of PCOS on ratio. CI 95%. Random-
the prevalence. effect models were used to
calculate pooled RR.
4. The effect of obesity The objective of the 270 women with PCOS Significantly more obese women had
on the outcome of study is to attending the infertility oligomenorrhoea (p<0.01) and anovulation (p<0.01)
infertility investigate the clinic were evaluated than women with normal weight.
management in incidence of obesity clinically, biochemically, Obesity adversely affected the outcome of ovulation

women with among patients with and laparoscopically. They induction with clomiphene citrate and

polycystic ovary polycystic ovarian were stratified according gonadotrophins; 79% of women with BMI 1824
45 to
 syndrome55 syndrome attending their BMI as follows:
infertility clinic and normal weight: 1824;
the effect on overweight: 2529,
treatment outcome. obese:3034, and grossly
obese: 35. Therapy
included induction of
ovulation with clomiphene
citrate and gonadotrophins.
The patients were followed
up through during induction
of ovulation and pregnancy.
5. Randomized To compare Design: Randomized
controlled trial of the metformin and controlled study.
effects of metformin combined oral Setting: Alexandria ICSI
versus combined oral contraceptive pill centre. Patients: 117
ovulated at 6 months compared to 15.3% in those
with BMI 3034 (p<0.001) and 11.8% in women
with BMI 35 (p<0.001). The pregnancy rate and
outcome were also adversely affected by obesity.
Conclusion : Obesity has a negative impact on the
outcome of treatment of infertility. Weight reduction
programme should be an essential component of
infertility management.
In group B a significant decline in serum testosterone
reached the lowest value by the end of the second year
(0.7 0.2 versus 1.3 0.5 lg/ml).
Group A showed a significant decline in fasting

contraceptives in (COC) effects over adolescent girls with (18.63.0 10.0 3.0 lIU/ml) and after-load insulin

adolescent PCOS 24 months in PCOS, were randomized levels (126 4364 15 lIU/ml) with a significant

women through a 24 adolescent PCOS to: group A (n = 40): rise in glucose/insulin ratio (GIR) from 4.1 0.3 to

month follow up met- formin, group B (n 4.6 0.5.

Group B showed a significant rise in fasting and after-
period56 = 40): COC, and group
46
 C (n = 39): control.
Interventions: Group A:
received metformin,
group B: received
combined oral
contraceptives.
Main outcome measures:
Improvement in cycle
rhythm and hirsutism.
6. Serum leptin level in To evaluate the Cohort study that women
women with relation between diagnosed with either tubal
polycystic ovary serum leptin level block/male factor infertility
syndrome: correlation with body mass and with PCOS, enrolled for
with adiposity, index, insulin and in vitro fertilization and
insulin, and with circulating embryo transfer (IVF-ET)
circulating testosterone in were recruited for this study.
testosterone22 PCOS women. All were reviewed for47body
load insulin (from 15.0 3.0 lIU/ml and 103.0 91.0
lIU/ml to 19.0 4.0 and 187.0 22.0 lIU/ml,
respectively) and GIR dropped significantly from 4.4
0.2 to 3.1 0.3.
Metformin was associated with a significant loss of
weight from 87.0 6.0 to 72.0 0.5 kg while COC
was associated with a non-significant gain in weight
(from 84.0 6.0 to 91.0 9.0 kg).
Metformin and COC have comparable therapeutic
effectiveness on cycle regularity and hirsutism.
Metformin was associated with a significant
improvement in metabolic syndrome, while COC was
associated with a deterioration of metabolic syndrome.
Positive correlation was observed between serum leptin,
BMI, and insulin in both the groups. Mean BMI, LH, and
LH:FSH ratios were found elevated in the PCOS
population. PCOS women also had significantly elevated
androgens and fasting levels of insulin. In conclusion,
hyperleptinemia in PCOS women appears to be due to the
positive correlation between serum leptin, BMI, and
insulin.
 mass index (BMI),
endocrine milieu (including
pituitary gonadotropins,
TSH, prolactin, gonadal
steroids, and insulin) and for
circulating serum leptin.
Interpretation of data was
done using PRISM
Statistical Software
Package.

7. An evidence based To understand the
approach for pathophysiologic
diagnosis of connections
adolescent polycystic underlying PCOS,
ovarian syndrome31 specifically several
hormonal
disturbances,
including
hyperandrogenemia,
Review Article Insulin appears to disrupt all components of the
hypothalamus-hypophysis-ovary axis, and ovarian tissue
insulin resistance results in impaired metabolic
signaling,which favors hyperandrogenemia, that appears
to be the main cause of the clinical picture in PCOS. In
turn, androgens may lead back to insulin resistance (IR)
by increasing levels of free fatty acids and modifying
muscle tissue composition and functionality, perpetuating
48 the IR-hyperinsulinemia-hyperandrogenemia cycle.
 insulin resistance Nonobese women with PCOS showcase several
(IR), and differential features with unique biochemical and
hyperinsulinemia, in hormonal profiles. Both lean and obese patients have
order to provide chronic inflammation mediating the long term
superior therapeutic cardiometabolic complications and comorbidities
strategies and observed in women with PCOS, including dyslipidemia,
warrant improved metabolic syndrome, type 2 diabetes mellitus, and
quality of life to cardiovascular disease.
women with this
syndrome.
8. Insulin resistance in Determining Insulin-stimulated glucose Women with polycystic ovary syndrome (PCOS) have
polycystic ovary whether impaired transport and GLUT-4 decreased sensitivity and responsiveness to insulin.
syndrome: decreased insulin abundance were measured GLUT-4 content was also significantly decreased in
expression of responsiveness was in abdominal adipocytes PCOS (by 36%, P < or = 0.01), independent of obesity.
GLUT-4 glucose associated with from obese (n = 9) and lean
transporters in diminished GLUT-4 (n = 7) PCOS as well as
adipocytes35 glucose transporter obese (n = 8) and lean (n =
content in 8) control women matched
adipocytes for age and weight.
The maximal insulin-49
 stimulated increment in
adipocyte glucose transport
was independently
decreased by obesity and by
PCOS.
9. In PCOS patients the Investigated whether Fifty-six PCOS patients After therapy regular menses were restored in
addition of low-dose therapy with were randomized in two approximately 82% of group A patients (P < 0.001)
spironolactone metformin plus low- groups: group A (28 and in 68% of group B patients (P < 0.001).
induces a more dose spironolactone Circulating testosterone, D-4-androstenedione and
patients) was treated
marked reduction of is more effective Hirsutism Score (HS) significantly decreased in both
with metformin (1700
clinical and than metformin groups.
mg/day) and group B
Dehydro-epiandrosterone sulphate significantly
biochemical alone in PCOS (28 patients) was treated
decreased only in group B, and HS underwent a
hyperandrogenism patients. with metformin (1700
stronger reduction in group B (P < 0.001).
than metformin mg/day) plus low-dose Conclusion: Metformin together with the adjunct of
alone57 spironolactone (25 low-dose spironolactone may be of further benefit for
mg/day). PCOS-associated hyperandrogenism
Anthropometric,
hormonal and metabolic
parameters were
evaluated at baseline and
50
 after six months of
treatment.
10. Prevalence of To compare the Design: Cross-sectional Prevalence of PCOS and its components did not differ
polycystic ovary prevalence of clinical study. between MUO and BMI-matched MHO groups
syndrome in Chinese polycystic ovary Setting: Tertiary hospital. (67.89% and 66.96%, respectively). In logistic
obese women of syndrome (PCOS) Patient(s): We studied 299 regression analysis, MetS did not predict the presence
reproductive age with and related clinical MUO and 122 MHO of PCOS after adjusting for confounding factors. The
or without metabolic characteristics Chinese women matched on MHO group had lower visceral adipose tissue,
58
syndrome between body mass index. relatively higher insulin sensitivity, and better b-cell
metabolically Metabolically healthy obese function, compared with those in the MUO group; but
unhealthy obese was defined as obesity with there were no significant differences in sex hormones
(MUO) and no more than one metabolic (except for free T and sex hormone-binding globulin)
metabolically abnormality. Diagnosis of and ultrasound manifestations between MHO and
healthy obese PCOS was based on the MUO women.
(MHO) women of revised Rotterdam criteria. Conclusion: For the first time, our findings suggest

reproductive age. Intervention(s): Each subject that MetS does not add additional risk for PCOS. In

underwent physical addition, we found that both MUO and MHO are

examination, laboratory associated with insulin resistance to some extent.

evaluation, and gynecologic

ultrasound for a diagnosis
51 of
PCOS or metabolic
syndrome (MetS).
Main Outcome Measure(s):
Prevalence of PCOS was
calculated in both groups.
Insulin resistance was
determined by homeostasis
model assessment of insulin
resistance or by the insulin
sensitivity index derived
from Bergman's minimal
model. Fat distribution was
measured with computerized
tomography scan.

52
 CHAPTER III

CONCLUSION AND SUGGESTION

3.1. Conclusion
The polycystic ovary syndrome among in adolescent is better to be
understand when know the anatomy and physiology especially of ovarium.
The female internal genital organs include the ovaries, uterine tubes, uterus,
and vagina. The regulation of physiological changes in ovarium are complex
that involve hormonal and anatomical changes. So that, the physiological
changes will make a cycle continuously and regularly. Some part of hormonal
changes that impaired, will be the cause of PCOS.
Obesity is defined as BMI >30 kg/m2. While in Asian population,
based on body fat equivalence and comorbid disease risk, BMIs of 23 kg/m 2
and 27.5 kg/m2, respectively, have been recommended as the cut-off points
for public health action in Asians. Obesity itself is metabolic disease that
affect to lead the PCOS itself because of the effect to the hormonal changes,
especially the estrogen.
PCOS is a disorder of female reproductive, especially the ovary,
chronic hyperandrogenic state that has many significant short-term and long-
term implications for patients such as oligomenorrhea, amenorrhea, infertility,
diabetes mellitus, cardiovascular disease, increased risk of endometrial
cancer, and excessive body hair (hirsutism).
The relationship between obesity and polycystic ovary syndrome in
adolescent is very complicated that affect one to another or multifactorial.
The PCOS itself is caused by the lifestyle changes nowadays. Many of
studies were found that there is a connection between both of them.

3.2. Suggestion
We must aware to our daughter especially from the obesity in
childhood. We should not be happy because of their cuteness when become
fat or something like that. Hence, we should consider that they might be
suffer from future diseases like PCOS itself. This disease, as we know that
developing from the young age and manifest on the future age especially in
reproductive ages. Therefore, it will be wise when we take care of them,
especially about their nutrition ideally for their bright future.

53
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