CHAPTER I

INTRODUCTION
1.1 Background
The global health community has had great success in improving maternal and
child health in the past decade, partly through a focus on reproductive health. Infertility is
a critical component of reproductive health, and has often been neglected in these efforts.
The inability to have children affects men and women across the globe. Infertility is a
common condition that happened on couple and caused by male or female factors, or both
of them. Infertility problem has a great impact for the husband and wife. Beside of the
medical issue, infertility also causes economic, psychologic, and social problem. They
will have a long term of evaluation and treatment, which this process can make some
physical and psychological load for the patient. Infertility can lead to distress and
depression, as well as discrimination and ostracism.1,2
Infertility is inability to become pregnant or having a child despite actively trying
for a year or more, or what is usually called by primary infertility. Then, the secondary
infertility is inability to become pregnant or having a child again despite actively trying
after had been pregnant or had a child in past. 3 In 2010, an estimated 48.5 million couples
worldwide were infertile. Between 1990 and 2010, levels of primary and secondary
infertility changed little in most world regions. The exceptions were Sub-Saharan Africa
and South Asia where infertility prevalence decreased during the 20-y period. However,
the absolute number of infertile couples worldwide increased due to population growth.1
World Health Organization (WHO) conclude that 36% of infertile couples caused
by male factors, and 64% by female factors. This data is collected by 17% couples that
already married for two years but not having sign of being pregnant. WHO also state that
50-80 million couples which means 1 from 7 couples around the world are having
infertility problems, and 2 million of new infertility couple arise every year.4
Many factors can cause infertility, and actually the easiest factor that can be
manipulated is life style factors such as alcohol consuming, smoking, stress, exercise,
cafein consuming, and excess body weight. Along with lifestyle changes these days, as
well as excessive fast food consuming, and increasing motor vehicles which make less
activity to the population affect to obesity and overweight growth level. Obesity is
considered now as an epidemic disease that rapidly progressing in developed and

underdeveloped world. Many researches already reveal the association between excess
body weight and infertility.2 According to Markku Sallmen et al, the percentage of
infertility is increasing among the obesity men and women. The percentage of obesity and
infertility women were 41% and men were 37%. While the percentage of normal body
weight and infertility women were 27% and men 25%. From this data, researcher
conclude that excess body weight affect infertility of both gender.5
The mount prevalence of obesity has had an impact on female reproductive health.
Increased body mass index (BMI) is associated with ovulatory subfertility and
anovulatory infertility. Fertilization rates are poorer and the embryo quality is impaired in
younger women who are obese. Pregnancy rate in some studies is lower and there is an
increased risk of early pregnancy loss.6 On the same side, obesity in male is also
associated with infertility in numerous studies. Poor semen quality and lower sperm count
has been found on obese men.7
According data above, author decide to investigate further about the association
between obesity and infertility among men and women and the way to manage this
situation.
1.2 Problem Statement
What is the correlation between obesity and infertility?
1.3 Objectives
1
2
3

To discover the association between obesity and infertility among women and men
To discover the management of infertility caused by obesity among women and men
Affect people for more aware about their reproductive health, associate with their

body weight
Affect people for having a healthy life style

CHAPTER II

LITERATURE
2.1 Definition of Obesity
Obesity is often defined simply as a condition of abnormal or excessive fat
accumulation in adipose tissue, to the extent that health may be impaired. Obesity is also
known as a condition that happens if the quantity of the body fat tissue compared with
total body weight is more than normal. Obesity occur because of instability between
energy from the intake is more than energy that used. Obesity is measured by various
methods such as body mass index (BMI), waist circumference, waist-hip ratio, skinfold,
and percent body fat measurements. The majority of countries used BMI, with a few
using waist circumference to measure obesity. Skinfold anthropometry is not commonly
used. Obesity is classified with BMI > 25 for the Asian population.
Table 2.1 Body Mass Index Classification for the Asian Population 8
BMI
< 18,5

Nutrition State
Underweight

18,5 22,9

Normal

23,0 24,9

Overweight

25,0 29,9

Obesity type 1

>30

Obesity type 2

Obesity has become an epidemic in many parts of the world. The World Health
Organization has warned of the escalating epidemic of obesity that could put the
population in many countries at risk of developing non-communicable diseases (NCD).8,9
2.2 Definition of Infertility
Infertility is defined as the inability to conceive after 1 year of unprotected
intercourse of reasonable frequency. It can be classified to primary and secondary
infertility. Primary infertility occurs when there is no prior pregnancies so the woman is
unable to ever bear a child, either due to the inability to become pregnant or the inability
to carry a pregnancy to a live birth. Furthermore, secondary infertility defines inability to
conceive following at least one prior conception.10
Most couples are more correctly considered to be subfertile, rather than infertile,
as they will ultimately conceive if given enough time. This concept of subfertility can be

reassuring to couples. However, there are obvious exceptions, such as the woman with
bilaterally obstructed fallopian tubes or the azoospermic male.10
2.3 The Hormonal Regulation of Reproductive System
2.3.1 Hormonal Regulation of Male Reproductive System
Gonadotropin Releasing Hormone (GnRH) is mainly made in the preoptic area of
the hypothalamus from where it travels to the pituitary gland where it stimulates the
synthesis and secretion of the follicle-stimulating hormone and luteinizing hormone.
Follicle Stimulating Hormone (FSH) is released by the anterior pituitary gland. Its
presence in males is necessary for the maturation of spermatozoa. Luteinizing Hormone
(LH) is released by the anterior pituitary gland. In the testes, LH binds to receptors on
Leydig cells, which stimulates the synthesis and secretion of testosterone. It also
stimulates the testes to produce the Androgen Binding Protein (ABP). Testosterone is
made in the interstitial cells. It stimulates the sex drive, and is the hormone that is
hormone will increase the production of spermatozoa by preventing the apoptosis of type
A spermatogonia. The associated with aggression. Inhibin is made by the Sertoli cells
when they are low in nutrients in order to feed developing sperm cells. It acts as a
negative feedback, going to the brain to slow the release of FSH and GnRH.
Hormonal control of spermatogenesis varies among species. In humans the
mechanisms are not completely understood. However, it is known that initiation of
spermatogenesis occurs at puberty due to the interaction of the hypothalamus, pituitary
gland, and Leydig cells. If the pituitary gland is removed, spermatogenesis can still be
initiated by follicle-stimulating hormone and testosterone.
Follicle-stimulating hormone stimulates both the production of androgen-binding
protein by Sertoli cells, and the formation of the blood-testis barrier . Androgen-binding
protein is essential to concentrating testosterone in levels high enough to initiate and
maintain spermatogenesis, which can be 20-50 times higher than the concentration found
in blood. Follicle-stimulating hormone may initiate the sequestering of testosterone in the
testes, but once developed, only testosterone is required to maintain spermatogenesis.
However, increasing the levels of follicle-stimulating hormone inhibin acts to decrease
the levels of follicle-stimulating hormone. Studies from rodent models suggest that

gonadotropin hormones (both LH and FSH) support the process of spermatogenesis by

suppressing the proapoptotic signals and, therefore, promote spermatogenic cell survival.
The Sertoli cells themselves mediate parts of spermatogenesis through hormone
production. They are capable of producing the hormones estradiol and inhibin. The
Leydig cells are also capable of producing estradiol in addition to their main product
testosterone.11
2.3.2 Hormonal Regulation of Female Reproductive System (Menstrual Cycle)
The menstrual cycle is the physiological change that occur under the control of
the endocrine system in fertile women for the purposes of sexual reproduction and
fertilization. It is divided into three stages: follicular phase, ovulation, and the luteal
phase.
The follicular phase (or proliferative phase) is the phase of the menstrual cycle during
which follicles in the ovary mature. It is under control of estradiol.
Follicle-stimulating hormone (FSH) is secreted by the anterior pituitary gland.
It begins to rise in the last few days of the previous menstrual cycle. It is highest and most
important during the first week of the follicular phase. The rise in FSH levels
recruitstertiary-stage ovarian follicles (aka antral follicles) for entry into the menstrual
cycle.
Follicle-stimulating hormone induces the proliferation of granulosa cells in the
developing follicles and the expression of luteinizing hormone (LH) receptors on these
cells. Under the influence of FSH, granulosa cells begin estrogen secretion. This
increased level of estrogen stimulates production of gonadotropin-releasing hormone
(GnRH), which increases production of LH. LH induces androgen synthesis by thecal
cells, stimulates proliferation, differentiation, and secretion of follicular thecal cells, and
increases LH receptor expression on granulosa cells.
Throughout the entire follicular phase, rising estrogen levels in the blood
stimulates growth of the endometrium and myometrium of the uterus. It also causes
endometrial cells to produce receptors for progesterone, which helps prime the
endometrium to the late proliferative phase and the luteal phase.

Two or three days before LH levels begin to increase, one (or occasionally
two) of the recruited follicles has emerged as dominant. Many endocrinologists believe
that the estrogen secretion of the dominant follicle lowers the levels of LH and FSH,
leading to the atresia (death) of most of the other recruited follicles. Estrogen levels will
continue to increase for several days.
High estrogen levels initiate the formation of a new layer of endometrium in the
uterus, the proliferative endometrium. Crypts in the cervix are also stimulated to produce
fertile cervical mucus. This mucus reduces the acidity of the vagina, creating a more
hospitable environment for sperm. In addition, basal body temperature may lower slightly
under the influence of high estrogen levels.
Estrogen levels are highest right before theluteinizing hormone surge begins.
The short-term drop in steroid hormones between the beginning of the LH surge and the
event of ovulation may cause mid-cycle spotting or bleeding. Under the influence of the
preovulatory LH surge, the first meiotic division of the oocytes is completed. The surge
also initiates luteinization of thecal and granulosa cells. Ovulation normally occurs 30 (
2) hours after the beginning of the LH surge.
Ovulation is the process in a female's menstrual cycle by which a mature
ovarian follicle ruptures and discharges an ovum (aka oocyte). The time immediately
surrounding ovulation is referred to as the ovulatory phase or the periovulatory period.In
the pre-ovulatory phase of the menstrual cycle, the ovarian follicle will undergo cumulus
expansion, which is stimulated by FSH. Then, ovum will leave the follicle through the
formed stigma. Ovulation is triggered by a spike in the amount of FSH and LH released
from the pituitary gland.
The luteal phase begins with the formation of the corpus luteum stimulated by
FSH and LH and ends in either pregnancy or luteolysis. The main hormone associated
with this stage is progesterone, which is produced by growing corpus luteum and is
significantly higher during the luteal phase than other phases of the cycle. Progesterone
plays a vital role in making the endometrium receptive to implantation of the blastocyst
and supportive of the early pregnancy; it also raises the woman's basal body temperature.

Several days after ovulation, the increasing amount of estrogen produced by the
corpus luteum may cause one or two days of fertile cervical mucus, lower basal body
temperatures, or both. This is known as a "secondary estrogen surge. " The hormones
produced by the corpus luteum also suppress production of the FSH and LH, which leads
to its atrophy. The death of the corpus luteum results in falling levels of progesterone and
estrogen, which triggers the end of the luteal phase. Increased levels of FSH start
recruiting follicles for the next cycle.12
2.4 The Relation of Obesity and Infertility in Male
2.4.1 Hypoandrogenism in Obese Males
The origin of hypoandrogenism in obese males is multifactorial. It is primarily
attributable to an increase in circulating estrogens that appear to result in relative
hypogonadotropism, although the diminished levels of sex hormone-binding globulin
(SHBG) in obese individuals will by itself result in reduced total testosterone levels. In
fact, weight correlates negatively with blood testosterone levels and testosterone/estradiol
ratio.13
2.4.1.1 Hyperestrogenemia
The origin of hypoandrogenism in obese males is multifactorial. It is primarily
attributable to an increase in circulating estrogens that appear to result in relative
hypogonadotropism. In fact, weight correlates negatively with blood testosterone levels
and testosterone/estradiol ratio. Both estrone and estradiol are increased in obese males
compared with controls. The aromatization of C19 androgens such as testosterone and
androstenedione is a key step in estrogen biosynthesis and is catalyzed by the aromatase
enzyme, a product of the CYP19 gene. It is believed that the increase in estrogens in
obese males is due to increased conversion of adrenal and testicular androgens owing to
the increase in available aromatase enzyme in the fatty tissue. Estrogen production by
adipose tissue is dependent on the availability of androgenic precursors in the circulation.
In severe obesity, pituitary gonadotropin secretion appears suppressed with normal or
decreased levels of luteinizing hormone (LH) in the presence of decreased levels of
testosterone.13 A significant decrease in total and free testosterone levels and increase in
estradiol was described in obese men.14

Some of the testosterone is converted to estrogens by aromatase (ARO). On the

other hand, another study discovered that ARO was present in the stromal cells of
adipocytes in humans, indicating that adipose tissue was involved in the metabolism of
sex hormones. Within fat tissue, enzymes such as aromatase are responsible for
metabolizing testosterone into estrogen. So, increased ARO activity in obese males led to
more androgens converting to estrogens, resulting in a higher level of estrogen and a
decline of androgen in the plasma.15
It is well established that obesity has an impact on the hypothalamus-pituitarytesticular axis, a study on obese males showed that the Body Mass Index had a negative
correlation with the concentration of testosterone and a positive correlation with estradiol.
The same study indicated that the LH pulse frequency was similar in both normal and
obese groups, while the mean diurnal LH levels, mean diurnal LH pulse amplitude, and
the sum of all diurnal LH pulse amplitudes and secretory masses were noticeably lower in
the obese group. Furthermore, an increase in pro-inflammatory cytokines such as TNF
from adipose tissue influences the secretion of gonadotropin in the pituitary.15
It is known that in obese men both estrone and estradiol are increased due to
increased peripheral aromatization of androgens. Estrogens have a negative effect on
hypothalamus that alters the gonadotropin-releasing hormone (GnRH) pulses and
suppresses FSH and LH secretion.16
2.4.1.2 Insulin Resistance
The second suggested cause of hypoandrogenemia is insulin resistance. Insulin
resistance, a predisposition of obesity, has also been reported to be associated with low
testosterone levels. Age-adjusted fasting insulin and C-peptide were shown to be
inversely correlated to total and free testosterone in men. This association is confounded
by the independent relation between SHBG and insulin resistance. After adjusting for
SHBG levels, however, low testosterone levels remain correlated with insulin resistance.13
Moreover, hyperinsulinemia, frequently found in obese men, has an inhibitory
effect on SHBG synthesis. Thus, the decrease in plasma insulin levels occurring after
weight loss may lead to increased SHBG levels and consequently, to higher serum
concentrations of Total Testosterone. The results of this study confirm that, in obese men,

total serum testosterone levels are significantly decreased as compared to those in normal
men of similar age. A previous study has indicated an inverse linear correlation of serum
SHBG concentration with BMI and a direct linear correlation of plasma insulin with BMI.
An inhibitory effect of insulin on SHBG synthesis has been demonstrated in vitro in
human hepatoma cells and the inhibitory effect maybe involved in vivo. The reduced
serum Total Testosterone in men is linked with a decrease in SHBG levels and this may
be connected to the inhibitory effect induced by high plasma insulin concentrations.17
SHBG has been previously shown to be inversely related to components related to
insulin resistance. Low SHBG concentrations have also predicted development of
diabetes. Inhibition of insulin secretion by diazoxide leads to increased SHBG levels,
suggesting that SHBG production in the liver is regulated by insulin.18
The Endocrine Society now recommends that men with type 2 diabetes be
screened for low testosterone levels. Obese men and men with type 2 diabetes can have
secondary hypogonadism because of the peripheral and central insulin resistance and the
effect of proinflammatory cytokines (TNF and IL-6) on the hypothalamic-pituitarygonadal axis. Sex hormone- binding globulin (SHBG) levels are reduced in obese men as
a result of increased circulating insulin levels associated with the insulin resistance of
obesity. However, after adjusting for SHBG levels, low testosterone levels have been
shown to be correlated with insulin resistance and obesity, denoting an independent effect
of insulin resistance on testosterone production.16 When insulin resistance happened, the
body produces insulin but doesn't use it properly. As a result, glucose builds up in blood
rather than being absorbed by cells.
A study published in 2013 in the journal BioMed Research International found
that low testosterone levels may help predict if a man will develop insulin resistance or
type 2 diabetes in the future. According to the researchers, in a group of more than 300
obese and non-obese men, 44 percent had both type 2 diabetes and low testosterone,
compared with 33 percent who had low testosterone but did not have diabetes. The
researchers also noted that 25 percent of those with type 2 diabetes and low testosterone
were not obese, concluding that low testosterone is linked to insulin resistance regardless
of body weight.

A 2010 study published in the journal Diabetes Care found an inverse relationship
between body mass index (BMI) and testosterone levels in men with type 2 diabetes. That
means that as a man's BMI increases, his testosterone level falls. Obesity may also be a
reversible risk factor for low testosterone levels.
Research also suggests that low testosterone could be a complication of type 2
diabetes involving the pituitary gland. A 2004 study published in The Journal of Clinical
Endocrinology & Metabolism found that one-third of 103 men with type 2 diabetes had
low levels of whats called free testosterone, or testosterone circulating in the blood that is
not bound to a protein called sex hormone binding globulin. 19 About 50% of testosterone
in adult males is bound to albumin, 44% is bound to SHBG, and only 2-3% says freeform. In fact, SHBG is known to decrease the metabolic clearance rate of testosterone.15
2.4.1.3 Sleep Apnea
The third suggested cause of hypoandrogenism in obese males is sleep apnea.
Patients with sleep apnea, which more common among the obese, often have fragmented
sleep course due to repetitive episodes of upper airway obstructions and hypoxia followed
by arousal. It has been demonstrated that patients with fragmented sleep have a blunted
nocturnal rise of testosterone. Patients with obstructive sleep apnea (OSA) have lower
mean testosterone and LH values compared with both young and middleaged controls.
Morning testosterone levels were also found to be lower in patients with OSA. Further, in
patients with OSA, weight loss increased testosterone levels. These alterations in
testosterone levels are likely to contribute to hypogonadism in a number of obese males.
This observation is confounded by obesity, such that an independent effect on testosterone
levels of sleep apnea separate from obesity requires further confirmation.13
In a recently published study found that the adjusted means (corrected for age and
BMI) of total testosterone is reduced proportionally to the severity of the sleep apnea.
Sleep apnea can affect both testosterone levels as well as independently erectile function.
The combination of both factors may result in compounding effect of male infertility.16
Mens bodies produce testosterone during the night. Insufficient sleep, such as that
caused by sleep apnea, can reduce testosterone levels, resulting in poor erection and
decrease libido, though their exact role is not clear. Its also possible that men with sleep

10

apnea arent getting enough oxygen while they sleep. Oxygen is important for healthy
erection, so any defeiciency can cause problem. Oxygen rich blood is one of the most
important components for erectile health. Oxygens level may vary widely from reduced
levels in the flaccid state to very high in erect state. During sleep, a man can normally
have three to five erections per night, bringing oxygen-rich blood to the penis.20,21
Researchers in Spain have recently investigated the relationship between OSA and
male fertility. They found that the intermittent disruptions to breathing that are the
hallmark of sleep apnea may lead to a decrease in fertility among men. Researchers
conducted the study using male mice. Scientists induced in the mice brief, repeated
periods of hypoxia, or oxygen deprivation. Their intent was to stimulate in mice the
episodes of interrupted breathing that people experience when they suffer from
obstructive sleep apnea. The mice were exposed to short episodes of oxygen deprivation
followed by re-oxygenation for six hours a day over a period of 60 days. Scientists then
assessed the fertility by allowing the mice to mate, and measuring the number of
pregnancies resulting from the hypoxia mice compared to a control group of mice that
had not experienced daily episodes of oxygen deprivation. The results were striking. Male
mice that experienced a daily pattern of hypoxia episodes demonstrated significantly
lower rates of fertility than the normal mice in the control group.
CPAP (continuous positive airway pressure) is the most common and effective
treatment for obstructive sleep apnea. Often, people have concerns about wearing the
apparatus necessary to receive CPAP therapy. When using CPAP, a mouthpiece worn by
the sleeper is connected to a machine that supplies a continuous stream of air that helps to
keep the airway open and unobstructed during sleep. Often patients have concerns about
discomfort, but they also sometimes harbor self-consciousness and concern about the
CPAP device interfering with their sex lives and intimacy with partners. When used
consistently as directed, CPAP is highly effective at improving sleep apnea. When CPAP
is used regularly, it also leads to improvements in erectile dysfunction.22
2.4.1.4 Inability to Synthesize Leptin or Malfunctioning of Leptin Receptors
Leptin was observed that the concentration increased in the bloodstream as the
quantity of body fat increased. Another experiment on ob/ob mice with the inbility to
synthesize leptin and db/db mice with malfunctioning of leptin receptors indicated that

11

both groups of mice showed less movement, less energy expenditure, and increased food
intake, leading to obesity and infertility, known to be caused, in this case, by
malfunctioning of spermatogenesis in the testes. When leptin was injected into these
mice, only the ob/ob group recovered from infertility. These findings imply that obesity is
not the sole cause of infertility, but rather, leptin plays a critical role in normal
reproduction.
Spermatic cells and Leydig cells in the testes express receptors for leptin. This
indicates that leptin may play a role in secretion of testosterone and in reproduction.
Several lines of evidence have shown that leptin was involved in gonadotropin-stimulated
testicular steroidogenesis. Leptin also participates in spermatogenesis of the testis.
According to research on the distribution of leptin receptors in the testes of the mouse,
leptin had an effect on proliferation and differentiation of germ cells through
phosphorylation of signal transducer and activator of transcription-3. Another study that
compared a group of normal mice with a group of leptin-deficient ob/ob mice showed that
impaired spermatogenesis, increased germ cell apoptosis, and up-regulated expression of
proapoptotic genes were associated with leptin deficiency.15
2.4.2 Direct Effect on Testicular Function
2.4.2.1 Scrotal Temperature
Sedentary life, prolonged sitting, and fat deposition in the lower abdomen can
reduce male fertility, likely through increased testicular temperature to the level of body
core temperature.16 Another hypothesis is the increase of scrotal temperature caused by
hip and abdominal fat tissue accumulation, or even scrotal fat deposition, which would
involve spermatogenesis disturbance.14
Researchers have found that the reason why a man's testicles rest outside the body
in the scrotum rather than in the abdomen like the ovaries is because the ideal
temperature for sperm production is three to four degrees below normal body
temperature. Any warmer will affect sperm count, slashing it by about 40 percent per
one-degree rise. Temporary overheating of the testicles can result from exposure to
things such as saunas, hot tubs, heating blankets, even waterbeds.

12

Research has shown that men who sleep in waterbeds are up to four times more
likely to suffer fertility problems than those who prefer a traditional mattress. Frequent
bike riding and wearing tight clothing can temporarily trap heat as well, although tight
underwear has not been shown scientifically to cause any increase in testicular heat.
Nevertheless, a change to looser clothing couldn't hurt when fertility is a concern.
One study found that semen specimens obtained in New Orleans during the
summer had significantly lower sperm concentration, total sperm per ejaculate, percent
motile sperm and motile sperm concentration than samples provided at other times of
year, suggesting that men may be more fertile in cooler climates and during cooler
months of the year. Sperm counts are about 30 percent lower in summer and, while heat
may play a role, the seasonal rise and fall may be a legacy of our ancestors who bred
seasonally.
In addition, exposure to heat over an extended period of time, such as in
occupations which involve long hours of sitting, may result in permanently impaired
fertility. One experiment showed that scrotal temperature rises by up to 2.2 degrees
within two hours of driving a vehicle, putting truckers and taxi drivers at risk for a low
sperm count. As for those who work with computers, another recent study warned young
men to limit the time they use laptops on their laps after tests showed the heat from the
battery might impair sperm production.
As far as damage from other factors, such as saunas, hot tubs and heating
blankets, it is believed that sperm generally recover quickly from heat exposure, so a
man's sperm count should return to normal within about a week.23
2.5 The Relation of Obesity and Infertility in Female
Most obese women are not infertile, however, obesity and its negative impact
upon fecundity and fertility are well documented. Obese women are three times more
likely to suffer infertility than women with a normal body mass index. Obesity in women
has been shown to increase time of conception. 24 A study by Sudha G and Reddy K shows
when infertility period increases, BMI also increases. 25

13

Reproductive organs and tissues affected by obesity include the hypothalamus, the
ovary and ovarian follicle, the oocyte, the embryo, and the uterine endometrium.26
Table 2.2 Reproductive organs and tissues affected by obesity26

2.5.1 Obesity and Hormonal Abnormality

Obesity has been known to be associated with several abnormalities of
sex steroid balance. It alters important homeostatic factors such as pancreatic
secretion of insulin. Hyperinsulinemia and insulin resistance are widely accepted to be
involved in the underlying mechanisms linking obesity to alterations in androgens
and estrogens and their carrier protein, sex-hormone-binding-globulin (SHBG).
Women with central obesity and with higher proportion of visceral fat usually
have high insulin resistance leading to lower SHBG concentrations. In insulin
resistance syndrome, excess insulin is capable

of

stimulating

steroidogenesis,

excessive androgen production from the theca cells and excessive estrogen
production from the granulosa cells of the ovaries.27 Thus, state of high body fat or
obesity causes increase in estrogen production which the body interprets as birth
control, limiting the chances of getting pregnant. 25 In addition, by directly inhibiting
SHBG synthesis, excess insulin may further increase

the

delivery

of

free

androgens to target tissues. The excess in local ovarian steroidogenesis induced by

excess circulating of insulin may cause premature follicular atresia and then favour
anovulation. Thus anovulation may lead to menstrual disturbance in obese women.27

14

High BMI is associated with an increase in serum and follicular fluid leptin
concentration and decrease in adiponectin levels. Leptin then acts at the receptors on
theca and granulosa cell which leads to alteration of ovarian steroidogenesis. Lower
adiponectin levels are associated with increased circulating insulin which can cause
hyperandrogenemia partly by inhibiting the hepatic sex hormone binding globulin
production.28
Normal ovarian function resulting in normal puberty and reproductive
competence is controlled primarily by the gonadotrophins LH and FSH from the
pituitary gland, the secretion of which is regulated by the brain hormone, GnRH. In
the majority of physiologic conditions, the gonadal steroids feedback at the
hypothalamus and pituitary to decrease GnRH and gonadotropin secretion. So the
excessive amount of estrogen that was found in obese women as discussed before will
act as negative feedback to GnRH production by pituitary gland with subsequent
anovulation and menstrual disorder.27

Picture 2.1 Hormonal change in obesity which effect infertility29

15

Accumulating data conclude that insulin resistance and hyperinsulinemia

resulting in hyperandrogenemia are the hormonal abnormalities, which disturb
ovarian function in women with excess adipose tissue.27
Fertility processes involve a complex of factors and mechanisms of both
ovarian

and

extra

ovarian origin. Obesity

may

interfere

with many

neuroendocrine and ovarian functions, thereby reducing both ovulatory and

fertility rates in otherwise healthy wo-men. Oligoovulation, anovulation and sub
fertility are present in obese females with a relative risk of anovulatory
infertility of 3.1 for women with a BMI >27 compared with women of BMI 2025.27
2.5.2 Obesity and PCOS
Obesity is also associated with PCOS which is characterized by oligo or
anovulation, hyperandrogenism, menstrual irregularities and subfertility. Affected
women show a high-waist to hip ratio, enlarged adipocytes, reduce serum adiponectin
level, and lower lipoprotein lipase activity. Thus, obesity can have synergistic effect
on PCOS and can worsen ovulatory dysfunction and hyperandrogenism.23,28
In overweight women and/or those with polycystic ovary syndrome (PCOS),
an increase in the number of fat cells results in a cascade of changes involving
increased leptin and insulin levels and a preferential increase in LH, but not FSH
levels. The insulin stimulates the theca cells of follicles to secrete high levels of
androgen, but which rarely ovulate (hence low progesterone). These changes are
exacerbated by insulin-induced reduction in SHBG which amplifies increasing serum
androgen levels in obese women. In addition, there is a genetic predisposition to
PCOS. In women with PCOS, weight loss decreases the androgen levels and improves
insulin resistance. Hyperinsulinaemia and hyperandrogenaemia changes the ovarian
function in both obese and non-obese women. 27,29

16

Table 2.3 Effect obesity upon PCOS

2.5.3 Obesity and Oocyte

Oocyte number were also affected in obesity. Overweight women have
significantly fewer oocytes retrieved.28 A large cohort study has shown that in
comparison with women of normal weight, overweight women (25< BMI <30 kg/m 2)
have significantly fewer oocytes retrieved (12.98 6.91 vs . 14.497.96, P<0.001). 30
These findings were supported by a systematic review where the weighted mean
difference (WMD) of the number of oocytes recovered in women with BMI >25
kg/m2 was 0.58 (95% CI: 0.22, 0.94) in comparison with women with BMI <25
kg/m2.28
Compared with normal BMI patients, severe obesity was associated with a
greater prevalence of spindle anomalies and non-aligned chromosomes in failed
fertilized oocytes. Observations indicate a high prevalence of cytoskeletal
abnormalities in failed fertilized oocytes from severely obese patients compared with
those from normal BMI patients. Among oocytes with a single spindle, those from
severely obese patients showed a significantly higher prevalence of disarranged
spindles with non-aligned chromosomes compared with those from normal BMI
patients (28.6 versus 8.6%; OR 4.58, CI 1.05 19.86,P-value 0.04).31
2.5.4 Obesity and Ovarium
Obesity also affects ovarian stimulation, which gonadotropin requirements are
higher in overweight and obese women who have an increased incidence of poor

17

ovarian response. A systematic review of IVF outcomes among overweight and obese
women demonstrated that the dose of gonadotrophins required was higher in women
with BMI of>25 kg/m2 [weighted mean difference (WMD) 210.08, 95% CI: 149.12,
271.05] in comparison with those with BMI of <25 kg/m2. Gonadotrophin
requirements were higher (WMD 361.94, 95% CI: 156.47, 567.40) in obese women
(BMI>30 kg/m2) when compared to non obese women.28
Obesity also has impact on fertility treatment such as ovulation induction
because obese women response poorly to ovulation induction using clomiphene
citrate.31 A systematic review of 13 studies suggests that obesity and insulin resistance
are predictors of suboptimal outcomes

following ovulation induction using

gonadotrophins. Women with high BMI need higher total doses of FSH to achieve
ovulation. These women also face a higher risk of cycle cancellation [and are less
likely to ovulate.28
2.5.5 Obesity and Endometrium
Obesity

Cytokines proinflammatory

hyperinsulinem

hyperestrogene

glycodelin

IGFBP1

Alters
endometrial

Alters
adhesion

Detrimental effect upon endometrial receptivity

Pregnancy
loss

Picture 2.2 Effect obesity to endometrium receptivity

18

Several studies have attempted to define the effect of obesity on the

endometrium. It has been suggested that the state of relative hyperestrogenaemia seen
in the obese women may have a detrimental effect upon endometrial receptivity.
Visceral obesity has been observed to alter insulin resistance, inflammatory mediators,
coagulation and fibrinolysis. Obesity is associated with insulin resistance and
hyperinsulinaemia, and elevated insulin levels have been associated with a reduction
in glycodelin and a reduction in IGFBP1. Low levels of glycodelin have been
associated with recurrent pregnancy loss. IGFBP1 has been observed to facilitate
adhesion at the maternalfetal interface. Therefore, perturbation of such molecules
may contribute to reduced fertility at an endometrial level. Obese women have been
observed to have elevated levels of acute phase proteins and pro-inflammatory
cytokines (including IL6, PAI1 and TNF); these inflammatory markers are thought to
exert a negative effect upon implantation and early embryonic development.
Therefore, one could speculate that the higher levels seen in the obese women might
impart a negative influence upon implantation and subsequent pregnancy. This may
reflect insulin resistance at an endometrial level in obese PCOS women. Since insulin
has also been implicated in the regulation of endometrial development, metabolism
and receptivity, one could envisage that the development of endometrial insulin
resistance would affect fertility. The effect of obesity upon implantation rate has been
inconsistently reported. Some authors have identified a reduction in implantation rates
among the obese women, whereas others have not demonstrated a weight related
reduction; however, the evidence is inconsistent and obese women tend to suffer nonrecurrent spontaneous pregnancy loss. This suggests that whilst the endometrium may
play a part, oocyte quality is likely to be the more influential factor.24
2.5.6 Obesity and Embryo
Since early embryonic development is largely driven by the oocyte, one might
expect that if obesity affects oocyte development, then it would affect embryonic
development also. Inconsistent findings have been reported with respect to the effect
of obesity upon embryo quality. In a prospective study of 247 women undergoing
IVF, it was observed that obese (BMI >30 kg/m2) women had significantly poorer
quality embryos compared with women with BMI 2030 kg/m2. However, other
researchers were unable to demonstrate significant differences in quality of the

19

transferred embryos between the BMI strata. Whilst the quality of the transferred
embryos may not be significantly different in obese women, some authors have
reported a reduction in the overall quality of the embryos created in an IVF cycle. In
contrast, a retrospective analysis of 6500 IVF cycles failed to demonstrate a difference
in embryo quality and embryo cryopreservation across the BMI strata despite
observing poorer outcomes in the obese women. However, the hypothesis which
relates obesity and embryo is a relative gonadotrophin resistance which is seen in
obese women, as such obese women require a higher total dose of gonadotrophin
when undergoing ovarian stimulation. It has been suggested that the higher doses of
gonadotrophin may lead to impaired oocyte quality and embryo quality, leading to
impaired embryonic development and implantation potential.24
2.6 Complications
2.6.1 Obesity and Spontaneous Abortion
Obesity increases risk of miscarriage after spontaneous conception. It has been
suggested that this is due to impaired folliculogenesis and poor oocyte quality in
obese women. Other hypothesis is that endometrial receptivity is impaired in the
overweight and obese women.28 Patients with a body mass index of > 25 kg/m2 had
significantly higher odds of miscarriage, regardless of the method of conception.32
The association between obesity and higher miscarriage rates is possibly
because of the alteration of embryo or the endometrium or both. One of the proposed
mechanisms is the endometrial damage induced by obesity that affects the
implantation process more than fertilization and early pregnancy development. In
conclusion, alterations in endocrine milieu, embryo quality, or uterine receptivity may
contribute to the increased miscarriages.24
A study analyzing all pregnancies, and compared to women with a normal
body mass index, obese and underweight patients had a significantly higher odds of
miscarriage in the subsequent pregnancy, whereas there was no significantly increased
odds of miscarriage in overweight women. Logistic regression analysis showed that
the most important factor predicting the occurrence of miscarriage was advanced
maternal age followed by an increased body mass index. In women with recurrent
miscarriage, a mild increase in the body mass index does not increase the risk of

20

miscarriage, whereas obese and underweight patients have a small but significant
increased risk of miscarriage in the subsequent pregnancy.33
2.6.2 Obesity and Assisted Conception
Because of the obesity epidemic worldwide and its association with infertility,
a large number of overweight and obese women are treated using ART. However, poor
reproductive outcomes are encountered in ART, such as natural conception, and this is
particularly related with central adiposity and PCOS. Rittenberg et al. found that
women who are overweight or obese have a poorer outcome following in vitro
fertilization (IVF) treatment than women within normal weight ranges. Metwally et
al. demonstrated that there is an association between obesity and poor embryo quality
in women below 35 years of age, and young obese women have a less chance of
cryopreserved embryos and need a higher dose of gonadotropins to stimulate ovarian
in ART. In high concentrations such as obesity, leptin acts as an inhibitory
gonadotropin Another difficulties during the treatment in obese women is that the
ovarian response to controlled ovarian stimulation in obese women undergoing IVF is
low. Some of these studies demonstrated that beside elevated gonadotropin
requirements, obesity is also related with lack of follicular development, and
reduction in the number of oocytes. In conclusion, recent studies and meta-analyses
have shown that the obesity has adverse effects on assisted reproductive technology,
including ovulation induction and IVF treatments. Obesity reduces the pregnancy
rates, live birth rates, and increases the miscarriage rates in treatment cycles.28,29,30
2.7 Management of Obesity in Infertility
Treatment of obesity itself should be the initial aim in obese infertile male and
female. Obesity and overweight can be treated by a variety of strategies including
dietary management, physical activity, behaviour modification, pharmacotherapeutic
treatment and surgery. Dietary management with lifestyle modification as an objective
should be adopted initially with pharmacological and other interventions reserved for
use when weight-loss regimes have proved unsuccessful. Since the overall emphasis
is to achieve and maintain a reduced weight, attempts should be made to establish
sensible eating patterns and a healthy lifestyle. 34

21

Table 2.4 Management of Obesity in Adult Patients 35

A weight loss and maintenance strategy for individual patients is outlined in

Table 2.4. The weight-loss phase involves establishing a negative energy balance by
reducing energy intake and increasing physical activity. Most motivated patients can
succeed in this phase, but different strategies suit different individuals. The next
phase, weight maintenance, is more difficult and requires more emphasis. Lifestyle
modification plus pharmacotherapy, if required, offer the best chance of success. For
those who have failed in weight maintenance, bariatric surgery currently produces the
best results and should be considered. 35

22

Table 2.5 Investigations for Subfertility in Primary / Secondary Care 36

23

Table 2.6 Criteria for Early Referral to Specialist Infertility Clinic 37

2.7.1 Evaluation of the Infertile Obese Male 16

The evaluation of the infertile obese man includes a basic evaluation of male
infertility with an special focus on potential obesity-related risk factors. The history
should ensure that other etiologies for male infertility are not overlooked. Relevant
history includes prior fertility, childhood illnesses such as viral orchitis or
cryptorchidism, genital trauma or prior pelvic or inguinal surgery, infections such as
epididymitis or urethritis, gonadotoxin exposures such as prior radiation
therapy/chemotherapy, recent fever or heat exposure, current medications, family
history of birth defects, mental retardation, reproductive failure or cystic fibrosis,
prior medical problems, history of smoking, use of alcohol, illegal drug use, and
anabolic steroids. The clinician should look for symptoms of hypogonadism including
sexual dysfunction such as reduced libido, erectile dysfunction, diminished penile
sensation, difficulty in attaining orgasm as well as reduced ejaculate with orgasm,
reduced energy, depressed mood or diminished sense of well-being, increased
irritability, difficulty concentrating, and other cognitive problems. An important part
of the evaluation is the assessment of comorbidities such as cardiovascular diseases

24

including coronary artery disease and stroke, sleep apnea, and diabetes. Such
comorbidities may aggravate infertility or affect treatment options.
Physical examination should note the blood pressure, weight, and height for
BMI calculation. The examination should also assess the stage of virilization (Tanner
stages of pubic hair) and volume (using an orchidometer) and consistency of testis,
consistency of the epididymis, presence of a varicocele, and signs of hypogonadism
that include anemia, muscle wasting, absence or regression of secondary sex
characteristics including body habitus, hair distribution, and gynecomastia. Of note,
the prevalence of varicocele is thought to be lower in obese men. This was attributed
in part to a more difficult diagnosis because of the adipose tissue.
A hormonal profile consisting of serum estradiol, total and free testosterone,
FSH, LH, prolactin, thyroid-stimulating hormone, and SHBG should be obtained. In
the absence of adequate techniques to measure free testosterone, free testosterone
calculation based on measures of total testosterone and SHBG remains an adequate
assessment of the free testosterone levels. This evaluation should also include
screening for diabetes (fasting glucose, glycosylated hemoglobin or 2-hour 75-g oral
glucose tolerance test) and lipid abnormalities (lipid panel) in men with severe obesity
and signs of metabolic syndrome. Furthermore, all obese infertile men would benefit
from screening for sleep apnea.
The semen analysis is the cornerstone of the laboratory evaluation of infertile
men. At least two properly performed semen analyses after 2 to 7 days of abstinence
are necessary to confirm the diagnosis. A semen analysis not only evaluates the
number and quality of the sperm ejaculated but the function of the accessory glands as
well. Semen analysis includes testing of semen volume, sperm concentration, sperm
motility, and sperm morphology. These composite parameters thought to correlate
with fertility can be calculated:
Total sperm count per ejaculate = semen volume x sperm concentration
Total motile sperm count = semen volume x sperm concentration x percentage
motile sperm
Total progressive motile sperm count = semen volume x sperm concentration x
percentage progressive motile sperm
25

Although debatable, DNA fragmentation can be evaluated in the presence of

unexplained infertility or otherwise unexplained poor embryo quality in IVF.
Table 2.7 Evaluation of The Infertile Obese Male 16

2.7.2 Evaluation of the Infertile Obese Female

Ideally, the initial consultation should be scheduled to allow sufficient time to
obtain a comprehensive medical, reproductive, and family history and to perform a
thorough physical examination. This is also an opportune time to counsel patients
regarding preconception care and screening for relevant genetic conditions. Relevant
history should include duration of infertility and results of any previous evaluation and
treatment, menstrual history (age at menarche, cycle length and characteristics, presence
of molimina, and onset/ severity of dysmenorrhea), pregnancy history (gravidity, parity,
pregnancy outcome, and associated complications), previous methods of contraception,
coital frequency and sexual dysfunction, past surgery (procedures, indications, and
outcomes), previous hospitalizations, serious illnesses or injuries, pelvic inflammatory
disease, or exposure to sexually transmitted infections, thyroid disease, galactorrhea,
hirsutism, pelvic or abdominal pain, and dyspareunia, previous abnormal pap smears and
any subsequent treatment, current medications and allergies, family history of birth

26

defects, developmental delay, early menopause, or reproductive problems, occupation and

exposure to known environmental hazards, use of tobacco, alcohol, and recreational or
illicit drugs 38
Physical examination should document weight, body mass index (BMI), blood
pressure, and pulse, thyroid enlargement and presence of any nodules or tenderness,
breast characteristics and evaluation for secretions, signs of androgen excess, vaginal or
cervical abnormality, secretions, or discharge, pelvic or abdominal tenderness, organ
enlargement, or masses, uterine size, shape, position, and mobility, adnexal masses or
tenderness, cul-de-sac masses, tenderness, or nodularity 38
Table 2.8 Evaluation of The Infertile Obese Female 38

Treatment of obesity itself should be the initial aim in obese infertile women
before embarking on ovulation-induction drugs or ART. Reduction of fat and abdominal
fat should result in improved menstrual function and fertility and a reduction of
metabolic risks. A reduction of 25% in body weight was associated with restoration of
ovulation, an 11% reduction in abdominal fat, and a 71% increase in insulin sensitivity.
Weight loss results in an increase in SHBG, reduction in testosterone, improved
menstrual function, improvement in conception rate and reduction in miscarriage rate. As
27

central adiposity is associated with menstrual disorders and infertility, abdominal fat loss
is critical in restoring ovulation. Various strategies have been suggested to overcome the
problem of obesity. Amongst these are dietary management, physical activity, behavior
modification, pharmacologic treatment and surgery. The issues are the long-term
compliance to these strategies and maintaining the weight loss. The NIH recommends a
multifaceted approach to treating obesity. It emphasizes the importance of achievable and
sustainable goals, notably a combination of diet, physical activity and behavior therapy
39-40

2.7.3 Dietary Management

A number of alternative dietary approaches to the conventional low fat-high
carbohydrate regime such as partly modified diets or moderately lower carbohydrate
diets which are consistent with a healthy eating plan may assist in maintaining an energy
restricted diet.34 Individuals consulting about weight management should be advised to
reduce intake of energy-dense foods (including foods containing animal fats, other high
fat foods, confectionery and sugary drinks) by selecting low energy-dense foods instead
(for example wholegrains, cereals, fruits, vegetables and salads) consumption of fast
foods and alcohol intake. Obese men showed increases in sex hormone binding globulin
and testosterone (free and total) after a very low-energy diet. 41
A reduction of 2500 kJ (600 calories) from the stable prior intake is generally
advised, which should lead to weight loss of 0.6 kg per week. Both low carbohydrate
(<30 g/day) and low-fat (<30% of total daily energy) diets are associated with modest
weight loss at 12 months. 35
Bates and Whitworth were the first to show a reduction in plasma androgens with
dieting, and associated return of menstrual cycle. Subsequently other studies
investigating dietary manipulation in subjects with obesity and PCOS, demonstrated that
strict calorie restriction with 5% or greater weight loss led to changes in insulin, insulinlike growth factor, SHBG and menstruation. The key component of diet should be calorie
restriction rather than the composition of the diet itself. Dietary intervention in managing
obesity should aim for gradual weight loss via reduced calorie consumption and
increased physical activity, with the overall aim of energy expenditure exceeding energy
intake. Sensible eating plans, tailoring to individual weight and current dietary and

28

exercise pattern, increase the chance of sustained weight loss. Diets based on healthy
eating principles have a better long-term outcome, which is important because weight
loss maintenance requires that changes in eating habits be sustained for life 42
2.7.4 Physical Activity
Exercise should be an integral component in any weight loss program. Exercise
increases insulin sensitivity both by acting directly on muscle metabolism and indirectly
by assisting in weight management.42 Increased physical activity is an important
component of lifestyle modification. The increase must be substantial as 80 minutes of
moderate-intensity activity per day, but cannot usually be achieved immediately. A more
modest initial target can be set (eg, 30 minutes of walking 35 days per week) and
increased. The recommended kind of exercise: walking, cycling and programmed aerobic
exercise promote weight loss in the initial phase, lifestyle exercise continued for long
term. Overweight and obese individuals should be prescribed a volume of physical
activity equal to approximately 1,800-2,500 kcal/week. This corresponds to
approximately 225-300 min/week of moderate intensity physical activity (which may be
achieved through five sessions of 45-60 minutes per week, or lesser amounts of vigorous
physical activity) 35, 41

Hakonsen et al described the effect of a weight loss program of 14 weeks on the

hormonal profile and semen parameters of obese men (BMI: 33 to 61 kg/m2). The
median weight loss was 22 kg. After subanalyses of <10 patients presenting the largest
weight loss, an increase in total sperm count, semen volume, testosterone, SHBG, and
anti-Mllerian hormone were found. In another randomized study, obese men who
received detailed advice about how to achieve a loss of > 10% in their total body weight
by reducing caloric intake and increasing their level of physical activity had a higher rate
of weight loss and improvement in erectile dysfunctions than controls. 16
2.7.5 Behaviour Medication
Other lifestyle issues that need to be addressed are smoking, alcohol consumption
and stress-related environment. Smoking is a major risk factor for reduced fertility in
women, with consequences including extended time to pregnancy, preterm birth and low
birth weight. High levels of alcohol intake have been associated with reduced fertility
29

and increased risk of spontaneous abortion. Therefore, cessation of smoking, cessation or

reduction of alcohol and reduction of psychosocial stressors are important issue that need
to be addressed. 16-17
Women who are exposed to smoking take longer to conceive. Chemicals (such as
nicotine, cyanide, and carbon monoxide) in cigarette smoke speed up the loss rate and
defect of ovum; more likely to conceive a chromosomally unhealthy pregnancy. Maternal
smoking increases the risk of low birth weight and birth defects, women who smoke
reach menopause earlier than non-smoker. Male smokers can suffer decreased sperm
quality with lower counts (numbers of sperm) and motility (sperms ability to move) and
increased numbers of abnormally-shaped sperm. These could cause decrease the sperms
ability to fertilize eggs and also damage sperm DNA 43
Several studies showed multiple fertility problems in those alcohol consumption
women including, ammenorrhea (delayed/absent menstrual cycle), reduced ovarian
weight, lowered hormone concentrations, inhibited ovulation, and interference with
sperm cell transportation through the fallopian tube. In men it can cause impotence,
reduce libido, affect sperm quality. One prospective study of couples undergoing ART
reviewed male and female alcohol consumption in the year prior to treatment as well as
during treatment. Both male and female alcohol consumption decreased the chance of a
live birth and increased the risk of miscarriage 43
Caffeine may affect ovulation and corpus luteum functioning through alterations
to hormone levels. Klonoff-Cohen et al conducted a prospective study over five years on
couples undertaking assisted reproductive technology (ART) treatment. Increased
caffeine consumption was found to be a risk factor for not achieving a live birth (either
by not becoming pregnant or by having a miscarriage. Willcox et al conducted a
prospective study of 104 women attempting pregnancy. Women who consumed < 1 cup
of coffee were twice as likely to become pregnant, per cycle, as moderate coffee drinkers
and the risk of not becoming pregnant increased with higher consumption. 43
A group environment can provide support for weight loss and maintenance of
weight loss. At the same time, it is necessary to tailor intervention to an individual's
weight and current dietary and exercise patterns. The use of a dietician is warranted to

30

aid in the evaluation of dietary intake and eating patterns and in individualizing an
appropriate dietary approach.34
Clark et al. conducted a study involving lifestyle modification through behavioral
changes in relation to diet, exercise and stress management. They noted that menstrual
regularity can be restored and pregnancy achieved by lifestyle modification without so
much emphasis on calorie restriction. In their follow-up study of 67 women, 60 resumed
ovulation after weight reduction through 6 months of lifestyle modification and 18
became pregnant spontaneously. Huber-Buchholz et al. used a lifestyle modification
approach that resulted in very modest weight reduction. In the 18 subjects with PCOS
and anovulation, nine became regularly ovulatory with weight loss ranging from 2 to 5%.
Moran et al. demonstrated improvements in ovulation and menstrual status in 11 out of
25 women treated with dietary intervention resulting in weight loss. Overall, the weight
of evidence supports the role of lifestyle modification in weight reduction with a
corresponding improvement in reproductive function. A group environment provides
support and could make it easier for patients to implement these lifestyle changes. 16-17
2.7.6 Pharmacotherapy
2.7.6.1 Male 16
2.7.6.1.1 Aromatase Inhibitors
The finding of increased estradiol and reduced testosterone-to-estradiol ratio in
obese men suggests that aromatase inhibitors may be a potential therapy for infertility in
this group. In the context of obese men, aromatase inhibitors were found to improve
hypogonadism. Treatment with aromatase inhibitors, such as testolactone 1 g daily for 6
weeks, letrozole 2.5 mg daily or 2.5 mg every other day for 6 weeks, and Arimidex 1 mg
for 6 months, resulted in an increased LH and total testosterone and reduced estradiol
levels in obese men. These studies included a small number of participants (<10) with
severe obesity (average BMI = 40 kg/m2) and did not evaluate fertility, except the study
by Roth et al that was a case report of a 29-year-oldman with infertility who was able to
father a child 6 months after anastrozole therapy.

31

Two studies investigating the effect of this class of medication on infertile men
with reduced testosterone-to-estrogen ratio are worth mentioning because of the
similarity of hormonal profile to that found in obese men. Pavlovich et al treated 45 men
(11 obese) with severe male factor infertility and reduced testosterone-to-estradiol values
with testolactone 50 to 100 mg twice daily for 5 months. After treatment, there was
improvement in the hormonal profile with increased serum testosterone and testosteroneto-estradiol ratio. Semen parameters were tested in a subgroup of 12 oligospermic and 12
azoospermic men before and after testolactone treatment. Sperm concentration, motility,
and total sperm count improved in the oligospermic but not in the azoospermic men with
a low testosterone-to-estradiol ratio. Raman and Shlegel evaluated the effect of
anastrozole 1 mg on the hormonal and semen profiles of infertile men with decreased
baseline testosterone-to-estradiol ratio (testosterone (ng/dL)/estradiol (pg/mL) <10).
After an average of 4.7 months of therapy, there was improvement in the serum
testosterone and a reduction in the serum estradiol, resulting in an increase in the
testosterone-to-estradiol ratio; these results were also confirmed in the subgroup of obese
men (defined as BMI >35 kg/m2). A total of 25 oligospermic and 14 azoospermic men
had their semen tested before and after at least 3 months of therapy. In the oligospermic
men, there was an increase in semen volume, sperm concentration, and motility index
after treatment in correlation to a decrease in estradiol concentration and an increase in
the testosterone- to-estradiol ratio. There was no change in the azoospermic men.
Unfortunately the analysis of semen data was not reported in the obese subgroup, likely
because of the small number.
2.7.6.1.2 Gonadotropin Therapy
In obese men, hypogonadism can be independent of increased estradiol. When
this picture occurs in the presence of low or normal levels of gonadotropins, such central
hypogonadism expected to be responsive to gonadotropin stimulation. The efficacy of
FSH in the treatment of idiopathic male infertility, and FSH-human chorionic
gonadotropin (hCG) treatment for idiopathic hypothalamic hypogonadism is suggested
by multiple studies. Little is known about the efficacy of hCG or FSH/hCG in the
treatment of the secondary hypogonadotropic hypogonadism related to obesity.

32

2.7.6.1.3 Phosphodiesterase Inhibitors and Androgen Therapy

Phosphodiesterase (PDE) inhibitors are considered the first line medical treatment
of erectile dysfunction after lifestyle modification. The major contraindications are
concomitant treatment with nitrates or nitric oxidedonating drugs (including amyl nitrite
poppers), patients in whom sexual activity is inadvisable (those with unstable angina,
severe heart failure, recent infarction), and patients who are allergic or intolerant to the
drug. For patients with erectile dysfunction, sildenafil was the first oral PDE inhibitor to
become commercially available. Tadalafil and vardenafil are two newer oral agents used.
PDE inhibitors do not improve libido.
In hypogonadal men who have low testosterone levels, androgen therapy is
typically indicated to treat sexual dysfunction resistant to PDE inhibitors, particularly the
decreased libido. However, testosterone treatment in infertile men can have a deleterious
effect on spermatogenesis and fertility. Testosterone can block gonadotropin secretion
through a negative feedback at the hypothalamic-pituitary level. The resulting decrease
in gonadotropins results in decreased testicular production of testosterone and presumed
lower intratesticular testosterone levels. In fact, androgens are often used in male
contraception.
2.7.6.1.4 Metformin
With the finding of an independent contribution of insulin resistance to
hypogonadism, studies explored the effect of metformin on the hormonal profile and
semen parameters of obese men. Ozata et al studied the effect of a low-calorie diet (1200
to 1400 Kcal/day) and metformin (850 mg twice daily) for 3 months on the hormonal
profile of obese men with and without type 2 diabetes. After intervention, there was a
reduction in total and free testosterone in obese men when compared with diabetic men
who had a reduction in their total but not their free testosterone. In obese men without
diabetes, the reduction in free testosterone can be explained by the increase in sex
hormone-binding protein.
In a more recent article, Casulari showed improvement in free and total
testosterone in men with metabolic syndrome who were normogonadal or hypogonadal
after 4 months of therapy with metformin 850 mg twice daily. Morgante et al described

33

the effect of metformin (850 mg three times daily for 6 months) in 45 overweight and
obese men with metabolic syndrome. There was a significant improvement in total and
free testosterone, a decrease in estradiol, and an increase in sperm concentration,
motility, and normal morphology after treatment, despite an absence of change in BMI
and waist circumference. More research focusing on the impact of metformin on male
fertility is needed.
2.7.6.2 Female 40, 44
Pharmacotherapy for the management of obesity is primarily aimed at weight
loss, weight-loss maintenance and risk reduction, and has included thyroid hormone,
phenylpropanolamine, mazindol, fenfluramines and, more recently, sibutramine and
orlistat. These agents decrease appetite, reduce absorption of fat or increase energy
expenditure. However, studies evaluating the long-term efficacy of anti-obesity agents
are limited. Longer and more methodologically rigorous studies of anti-obesity drugs that
are powered to examine the long-term effect and end points such as cardiovascular
morbidities are awaited. Despite rapid strides toward an ideal anti-obesity agent, the role
of diet, exercise and behavior modification must be considered the cornerstone for any
potential future pharmacotherapy.
Given

the

importance

of

hyperinsulinemia

in

the

development

of

hyperandrogenism and disrupted folliculogenesis in obesity and PCOS, the use of

insulin-sensitizing drugs seems reasonable in order to facilitate spontaneous ovulation
and restore fertility. The most extensively studied insulin-lowering agent in the treatment
of PCOS is metformin. Metformin is a biguanide oral antihyperglycemic agent that has
been extensively used in the treatment of Type 2 diabetes mellitus. It lowers blood
glucose mainly by inhibiting hepatic glucose production and increase in the peripheral
glucose uptake. Several other actions may contribute to this effect, such as increased
intestinal use of glucose and decreased fatty acid oxidation. Therefore, metformin can
reduce peripheral insulin concentrations and improve glucose tolerance and metabolism.
There are also preliminary in vitro data indicating that metformin may directly decrease
ovarian androgen production. Tang et al. in a study on the effect of metformin compared
with a combination of metformin and lifestyle modification, concluded that metformin
alone does not improve weight loss or menstrual frequency in obese patients with PCOS.
Weight loss alone through lifestyle changes improves menstrual frequency.
34

A meta-analysis of 13 randomized trials comparing metformin with placebo or

metformin plus clomiphene with clomiphene alone in women with PCOS concluded that
metformin increased the ovulation rate by a factor of approximately four. It was
discovered that pregnancy rate did not differ significantly between metformin and
placebo, but pregnancy rates for metformin plus clomiphene were significantly higher
than for clomiphene alone. However, in a multicenter, randomized trial involving 20
Dutch hospital and 228 patients, Moll concluded that metformin is not an effective
addition to clomiphene citrate as the primary method of inducing ovulation in women
with PCOS. The ovulation rate in the metformin/clomiphene group was 64% compared
with 72% in the clomiphene/placebo group, a nonsignificant difference. In a larger study,
which involved 626 infertile women with PCOS assigned to either clomiphene,
metformin or combination therapy, Legro et al. noted that although ovulation rate in the
combination- therapy group was significantly higher than that in the other groups, the
increase did not translate into a higher live birth rate. He concluded that clomiphene is
superior to metformin in achieving live birth in infertile women with PCOS, although
multiple pregnancies are a complication.
2.7.7 Surgery
Bariatric surgical procedures cause weight loss by restricting the amount of food
the stomach can hold, causing malabsorption of nutrients, or by a combination of both
gastric restriction and malabsorption. Bariatric procedures also often cause hormonal
changes. Most weight loss surgeries today are performed using minimally invasive
techniques (laparoscopic surgery). The most common bariatric surgery procedures are
gastric bypass, sleeve gastrectomy, adjustable gastric band, and biliopancreatic diversion
with duodenal switch. Each surgery has its own advantages and disadvantages. 45-46

35

Picture 2.3 Types of Bariatric Surgery Procedure 46

A. Gastric Bypass
The Roux-en-Y Gastric Bypass often called gastric bypass is considered the
gold standard of weight loss surgery and is the most commonly performed bariatric
procedure worldwide. There are two components to the procedure. First, a small stomach
pouch, approximately one ounce or 30 milliliters in volume, is created by dividing the top
of the stomach from the rest of the stomach. Next, the first portion of the small intestine is
divided, and the bottom end of the divided small intestine is brought up and connected to
the newly created small stomach pouch. The procedure is completed by connecting the
top portion of the divided small intestine to the small intestine further down so that the
stomach acids and digestive enzymes from the bypassed stomach and first portion of
small intestine will eventually mix with the food.
The gastric bypass works by several mechanisms. First, similar to most bariatric
procedures, the newly created stomach pouch is considerably smaller and facilitates
36

significantly smaller meals, which translates into less calories consumed. Additionally,
because there is less digestion of food by the smaller stomach pouch, and there is a
segment of small intestine that would normally absorb calories as well as nutrients that no
longer has food going through it, there is probably to some degree less absorption of
calories and nutrients. Most importantly, the rerouting of the food stream produces
changes in gut hormones that promote satiety, suppress hunger, and reverse one of the
primary mechanisms by which obesity induces type 2 diabetes.
The advantages of this surgery are
1. Produces significant long-term weight loss (60 to 80 percent excess weight loss)
2. Restricts the amount of food that can be consumed
3. May lead to conditions that increase energy expenditure
4. Produces favorable changes in gut hormones that reduce appetite and enhance satiety
5. Typical maintenance of >50% excess weight loss
The disadvantages of this surgery are
1. Is technically a more complex operation than the AGB or LSG and potentially could
result in greater complication rates
2. Can lead to long-term vitamin/mineral deficiencies particularly deficits in vitamin
B12, iron, calcium, and folate
3. Generally has a longer hospital stay than the AGB
4. Requires

adherence

to

dietary

recommendations,

life-long

vitamin/mineral

supplementation, and follow-up compliance

B. Sleeve Gastrectomy
The Laparoscopic Sleeve Gastrectomy often called the sleeve is performed by
removing approximately 80 percent of the stomach. The remaining stomach is a tubular
pouch that resembles a banana. This procedure works by several mechanisms. First, the
37

new stomach pouch holds a considerably smaller volume than the normal stomach and
helps to significantly reduce the amount of food (and thus calories) that can be consumed.
The greater impact, however, seems to be the effect the surgery has on gut hormones that
impact a number of factors including hunger, satiety, and blood sugar control.
Short term studies show that the sleeve is as effective as the roux-en-Y gastric
bypass in terms of weight loss and improvement or remission of diabetes. There is also
evidence that suggest the sleeve, similar to the gastric bypass, is effective in improving
type 2 diabetes independent of the weight loss. The complication rates of the sleeve fall
between those of the adjustable gastric band and the roux-en-y gastric bypass.
The advantages of this surgery are
1. Restricts the amount of food the stomach can hold
2. Induces rapid and significant weight loss that comparative studies find similar to that
of the Roux-en-Y gastric bypass. Weight loss of >50% for 3-5+ year data, and weight
loss comparable to that of the bypass with maintenance of >50%
3. Requires no foreign objects (AGB), and no bypass or re-routing of the food stream
(RYGB)
4. Involves a relatively short hospital stay of approximately 2 days
5. Causes favorable changes in gut hormones that suppress hunger, reduce appetite and
improve satiety
The disadvantages of this surgery are
1. Is a non-reversible procedure
2. Has the potential for long-term vitamin deficiencies
3. Has a higher early complication rate than the AGB

38

C. Adjustable Gastric Band

The Adjustable Gastric Band often called the band involves an inflatable band
that is placed around the upper portion of the stomach, creating a small stomach pouch
above the band, and the rest of the stomach below the band. The common explanation of
how this device works is that with the smaller stomach pouch, eating just a small amount
of food will satisfy hunger and promote the feeling of fullness. The feeling of fullness
depends upon the size of the opening between the pouch and the remainder of the
stomach created by the gastric band. The size of the stomach opening can be adjusted by
filling the band with sterile saline, which is injected through a port placed under the skin.
Reducing the size of the opening is done gradually over time with repeated
adjustments or fills. The notion that the band is a restrictive procedure (works by
restricting how much food can be consumed per meal and by restricting the emptying of
the food through the band) has been challenged by studies that show the food passes
rather quickly through the band, and that absence of hunger or feeling of being satisfied
was not related to food remaining in the pouch above the band. What is known is that
there is no malabsorption; the food is digested and absorbed as it would be normally. The
clinical impact of the band seems to be that it reduces hunger, which helps the patients to
decrease the amount of calories that are consumed.
The advantages of this surgery are
1. Reduces the amount of food the stomach can hold
2. Induces excess weight loss of approximately 40 50 percent
3. Involves no cutting of the stomach or rerouting of the intestines
4. Requires a shorter hospital stay, usually less than 24 hours, with some centers
discharging the patient the same day as surgery
5. Is reversible and adjustable
6. Has the lowest rate of early postoperative complications and mortality among the
approved bariatric procedures

39

7. Has the lowest risk for vitamin/mineral deficiencies

The disadvantages of this surgery are
1. Slower and less early weight loss than other surgical procedures
2. Greater percentage of patients failing to lose at least 50 percent of excess body weight
compared to the other surgeries commonly performed
3. Requires a foreign device to remain in the body
4. Can result in possible band slippage or band erosion into the stomach in a small
percentage of patients
5. Can have mechanical problems with the band, tube or port in a small percentage of
patients
6. Can result in dilation of the esophagus if the patient overeats
7. Requires strict adherence to the postoperative diet and to postoperative follow-up
visits
8. Highest rate of re-operation
D. Biliopancreatic Diversion with Duodenal Switch (BPD/DS) Gastric Bypass
The Biliopancreatic Diversion with Duodenal Switch abbreviated as BPD/DS
is a procedure with two components. First, a smaller, tubular stomach pouch is created by
removing a portion of the stomach, very similar to the sleeve gastrectomy. Next, a large
portion of the small intestine is bypassed. The duodenum, or the first portion of the small
intestine, is divided just past the outlet of the stomach. A segment of the distal (last
portion) small intestine is then brought up and connected to the outlet of the newly
created stomach, so that when the patient eats, the food goes through a newly created
tubular stomach pouch and empties directly into the last segment of the small intestine.
Roughly three-fourths of the small intestine is bypassed by the food stream.

40

The bypassed small intestine, which carries the bile and pancreatic enzymes that
are necessary for the breakdown and absorption of protein and fat, is reconnected to the
last portion of the small intestine so that they can eventually mix with the food stream.
Similar to the other surgeries described above, the BPD/DS initially helps to reduce the
amount of food that is consumed; however, over time this effect lessens and patients are
able to eventually consume near normal amounts of food. Unlike the other procedures,
there is a significant amount of small bowel that is bypassed by the food stream.
Additionally, the food does not mix with the bile and pancreatic enzymes until
very far down the small intestine. This results in a significant decrease in the absorption
of calories and nutrients (particularly protein and fat) as well as nutrients and vitamins
dependent on fat for absorption (fat soluble vitamins and nutrients). Lastly, the BPD/DS,
similar to the gastric bypass and sleeve gastrectomy, affects guts hormones in a manner
that impacts hunger and satiety as well as blood sugar control. The BPD/DS is considered
to be the most effective surgery for the treatment of diabetes among those that are
described here.
The advantages of this surgery are
1. Results in greater weight loss than RYGB, LSG, or AGB, i.e. 60 70% percent excess
weight loss or greater, at 5 year follow up
2. Allows patients to eventually eat near normal meals
3. Reduces the absorption of fat by 70 percent or more
4. Causes favorable changes in gut hormones to reduce appetite and improve satiety
5. Is the most effective against diabetes compared to RYGB, LSG, and AGB
The disadvantages of this surgery are
1. Has higher complication rates and risk for mortality than the AGB, LSG, and RYGB
2. Requires a longer hospital stay than the AGB or LSG

41

3. Has a greater potential to cause protein deficiencies and long-term deficiencies in a

number of vitamin and minerals, i.e. iron, calcium, zinc, fat-soluble vitamins such as
vitamin D
4. Compliance with follow-up visits and care and strict adherence to dietary and vitamin
supplementation guidelines are critical to avoiding serious complications from protein
and certain vitamin deficiencies
Studies showed that weight loss through bariatric surgery was associated with
correction of the abnormal hormonal profile in obese men with an increase in SHBG
and total testosterone levels and reduction in estradiol levels. 16
In women with morbid obesity failing other interventions, weight loss may be
induced with surgical intervention. Bariatric surgery today is the only effective
therapy for morbid obesity. Bariatric operations are either restrictive, limiting the
amount of food ingested; malabsorptive limiting the amount of nutrient absorbed; or
a combination of both. Bariatric surgery dates back to the 1950s when jejunoileal
bypass was introduced. Since then, numerous improvements have been made in
procedures and techniques. Currently, the two most common bariatric procedures
performed are laparoscopic adjustable gastric banding and laparoscopic Roux-en-Y
gastric bypass. Both of these operations provide excellent results, with the majority of
patients losing more than 50% of their excess weight and with most obesity related
comorbidities, such as diabetes and hypertension, reversed or prevented. Morbidly
obese patients considering such operations have to meet a strict criteria and must be
evaluated by a multidisciplinary team. However, they would still need to commit to
longterm dietary changes, behavioral modifications and medical supervision. 40
Eid et al. evaluated the outcomes of 24 women diagnosed with PCOS who had
undergone weight loss surgery between July 1997 and November 2001. All of the
women studied resumed normal menstrual cycles after a mean of 3.4 2.1 months
postoperatively. Five women had spontaneous conception after the surgery without
the use of clomiphene. Tietelman et al. noted the effect of bariatric surgery on 98
patients who were anovulatory preoperatively. A total of 70 patients (71.4%) regained
normal menstrual cycles after surgery. Those patients who regained ovulation had
greater weight loss than those who remained anovulatory (61.4 kg vs 49.9 kg, p =

42

0.02). Anovulation resulting in abnormal menses is a common problem in morbidly

obese premenopausal women. The menstrual cycle disorders may completely resolve
after bariatric surgery. Gastric bypass surgery and its consequent weight loss results in
a significant improvement of menstrual problems and PCOS-related fertility. Thus,
infertility owing to anovulation among morbidly obese women could potentially be
viewed as an additional indication for bariatric surgery if other simple measures
failed. 40

43

CHAPTER III
CONCLUSION
Inability to have a child affects men and women across the globe. Infertility is
defined as the inability to conceive after 1 year of unprotected intercourse of reasonable
frequency. This is a common condition that happened, caused by male or female factors,
or both of them. Infertility problem has a great impact for couple because beside of the
medical issue, infertility also causes economic, psychologic, and social problem. It is
known that life style can be one of the factor leading to infertility, and the one which has
a strong association with infertility is excessive weight or obesity.
The condition between obesity and sperm count suggest a potential link between
obesity and male fertility. Obesity is associated with altered spermatogenesis and erectile
dysfunction. The altered spermatogenesis is mainly due to hypoandrogenism and the
deleterious effect of increased levels of estrogens. Beside of that, direct effect to the
testicular function also play a role. All of these factors can affect the ability of a male to
participate in the conception of a child.
Obesity in women has been shown to increase time of conception. Reproductive
organs and tissues affected by obesity include the hypothalamus by alternating sex steroid
balance, the ovary and ovarian follicle, the oocyte, the embryo, and the uterine
endometrium. Obesity may interfere with neuroendocrine such as hyperinsulinemia and
also ovarian functions, thereby reducing both ovulatory and fertility rates in otherwise
healthy women. The primary mechanism how obesity affect sex hormone imbalance is by
hyperinsulinemia which leads to alterations in androgens and estrogens and SHBG. Other
mechanism is by increasing leptin hormon that is found in obesity which also cause
alteration of ovarian steroidogenesis. Oocyte number and ovarian stimulation were also
affected in obesity which overweight women have significantly fewer oocytes retrieved
and gonadotropin requirements are higher in overweight and obese women. Obesity
increases risk of miscarriage after spontaneous conception, and affecting upon
endometrial receptivity for implantation of the embryo and the embryo quality itself.
Obesity is not only affecting natural conception but also has adverse effects on assisted
reproductive technology, including ovulation induction and IVF treatments.

44

Diet and lifestyle modifications remain the cornerstone in achieving and

maintaining weight loss. Several studies show that weight reduction induced by exercise
and low calorie diets improves hyperandrogenism, insulin resistance, and menstrual
dysfunction. Dietary management with lifestyle modification as an objective should be
adopted initially, with pharmacological and other surgical/medical interventions reserved
for use when weight loss regimes have proved unsuccessful.

45

REFERENCES
1. Mascarenhas MN, Flaxman SR, Boerma T, Vanderpoel S, Stevens GA (2012)
National, Regional, and Global Trends in Infertility Prevalence Since 1990: A
Systematic Analysis of 277 Health Surveys. PLoS Med 9(12): e1001356.
doi:10.1371/journal.pmed.1001356
2. Konsensus Penanganan Infertilitas. Jakarta: Himpunan Endokrinologi Reproduksi
dan Fertilitas Indonesia, 2013.
3. Vanderpoel, Sheryl. Prevalence of Infertility. World Health Organization, 2012.
4. WHO | Infertility [Internet]. WHO. [cited 2015]. Available from:
http://www.who.int/gho/en/
5. Sallmen, Markku, Dale Sandler, Jane Hoppin, Aaron Blair, and Donna Baird.
Reduced Fertility Among Overweight and Obese Men. Epidemiology, April 21,
2006.
6. Pandey, Shilpi, Suruchi Pandey, Abha Maheswari, and Siladitya Battacharya. The
Impact of Female Obesity on the Outcome of Fertility Treatment. J Hum Reprod Sci,
August 2010.
7. Katib A. Mechanisms linking obesity to male infertility. Cent European J Urol. 2015;
68: 79-85
8. Musaiger, Abdulrahman. Overweight and Obesity in Eastern Mediterranean Region:
Prevalence and Possible Causes. Hindawi Publishing Corporation 2011 (June 30,
2011).
9. WHO

Obesity

[Internet].

WHO.

[cited

2015].

Available

from:

http://www.euro.who.int/en/health-topics/noncommunicable-diseases/obesity/dataand-statistic
10. Hoffman BL, Schorge JO, Schaffer JI, Halvorson LM, Bradshaw KD, Cunningham
FG, et al. Williams gynecology. 2nd ed. New York: The McGraw-Hill
Companies;2012.
11. Boundless. Hormonal Regulation of the Male Reproductive System. Boundless
Anatomy and Physiology. Boundless, 21 Jul. 2015. Retrieved 11 Oct. 2015 from
https://www.boundless.com/physiology/textbooks/boundless-anatomy-andphysiology-textbook/the-reproductive-system-27/physiology-of-the-malereproductive-system-253/hormonal-regulation-of-the-male-reproductive-system1236-9349/
12. Boundless. Hormonal Regulation of the Female Reproductive Cycle. Boundless
Anatomy and Physiology. Boundless, 21 Jul. 2015. Retrieved 14 Oct. 2015 from
https://www.boundless.com/physiology/textbooks/boundless-anatomy-and46

physiology-textbook/the-reproductive-system-27/physiology-of-the-femalereproductive-system-256/hormonal-regulation-of-the-female-reproductive-cycle1250-7196/
13. Hammoud, Ahmad, Mark Gibson, Matthew Peterson, Wayne Meikle, and Douglas
Carrell. Obesity a Significant Factor in Male Infertility. Review of Endocrinology,
May 2008.
14. Sermondade, N. BMI in Relation to Sperm Count: An Updated Systematic Review
and Collaborative Meta-analysis. Human Reproductive Update Advance, December
12, 2012.
15. Ki Lee, Hyun, Kyung Lee, and Belong Cho. The Role of Androgen in the Adipose
Tissue of Males. Korean Society for Sexual Medicine and Andrology, August 31,
2013.
16. Hammoud, Abdolrahman. Obesity and Male Infertility: A Practical Approach.
Reproductive Health Problem and Obesity, 2012.
17. Lima, N, H Cavaliere, M Knobel, A Halpbern, and G Medeiros-Neto. Decreased
Androgen Levels in Massively Obese Men May Be Associated with Impaired
Function of the Gonadostat. International Journal of Obesity, 2000.
18. Laaksonen, David et al. Testosterone and Sex Hormone Binding Globulin Predict the
Metabolic Syndrome and Diabetes in Middle Aged Men. American Diabetes
Association, 2004.
19. Dallas, Mary. The Link Between Low Testosterone and Diabetes. Low Testosterone,
January 16, 2014. http://www.everydayhealth.com/hs/low-testosterone-guide/lowtestosterone-diabetes/.
20. Impotence
In-Depth

Report.

The

New

York

Times,

2010.

http://www.nytimes.com/health/guides/symptoms/erection-problems/print.html.
21. Can Obstructive Sleep Apnea Lead to Erectile Dysfunction (ED)?, 2015.
http://www.issm.info/education-for-all/sexual-health-qa/can-obstructive-sleep-apnealead-to-erectile-dysfunction-ed.
22. Breus, Michael. Is Sleep Apnea Related to Sperm Crisis?, December 13, 2014.
http://www.huffingtonpost.com/dr-michael-j-breus/is-sleep-apnea-relatedto_b_6297262.html.
23. How Heat May

Affect

Male

Infertility.

Preconception

Weekly,

2015.

http://www.parentingweekly.com/preconception/preconception_information/heat_and
_male_infertility.htm.
24. Brewer CJ , Balen AH. The adverse effects of obesity on conception and implantation.
Reproduction. 2010 Sep;140(3):347-64

47

25. Sudha G, Reddy KSN. Causes of female infertility: a cross-sectional study.

International Journal of Latest Research in Science and Technology. 2013: 2(6):119123
26. Jungheim ES, Travieso JL, Hopeman MM. Weighing the impact of obesity on female
reproductive function and fertility. Nutrition Reviews. 2013:71(Suppl. 1):S3S8
27. Queen Chidinma Ogbuji. Obesity and Reproductive Performance in Women. African
Journal of Reproductive Health Sept. 2010 (Regular Issue); 14(3):143-52
28. Pandey S, Maheshwari A, Bhattacharya S. The Impact of female obesity on the
outcome of fertility treatment. J Hum Reprod Sci. 2010:3(2).
29. Da ZO, Dilbaz B. Impact of obesity on infertility in women. J Turk Ger Gynecol
Assoc 2015; 16: 111-7
30. Zhang D, Zhu Y, Gao H, Zhou B, Zhang R, Wang T, et al. Overweight and obesity
negatively affect the outcomes of ovarian stimulation and invitro fertilisation: A
cohort study of 2628 Chinese women. Gynecological Endocrinology. 2010;26:325-32.
31. Machtinger R, Combelles CMH, Missmer SA, Correia KF, Fox JH, Racowsky C. The
association between severe Obesity and characteristics of failed Fertilized oocytes.
Hum Reprod. 2012 Nov;27(11):3198-207
32. M Mostafa et al. Does high body mass index increase the risk of miscarriage after
spontaneous and assisted conception? A meta-analysis of the evidence. Fertility and
Sterility Vol. 90, No. 3, September 2008.
33. M Mostafa et al. Body mass index and risk of miscarriage in women with recurrent
miscarriage. Fertility and Sterility Vol. 94, No. 1, June 2010
34. NJ Robert, N Manny, W Ruijin, DJ Michael, M Lisa, WX Jim. Improving
reproductive performance in overweight/obese women with effective weight
management. Human Reproduction Update Vol. 10 No. 3. 2004
35. Proietto J, Baur LA. Management of obesity. MJA 2004; 180: 474480
36. D J Cahill, P G Wardle. Management of infertility. BMJ 2002;325:2832
37. Kamel RM. Management of the infertile couple: an evidence based protocol. Kamel
Reproductive Biology and Endocrinology 2010, 8:21
38. Practice Committee of the American Society for Reproductive Medicine. Diagnostic
evaluation of the infertile female: a committee opinion. Fertility and Sterility Vol. 103,
No. 6, June 2015 0015-0282
39. Kaur KK, Allahbadia G, Singh M. Current Management of Obesity in an Infertile
Female-Recent Advances and Future Prospective Drugs. Journal of Pharmacy and
Nutrition Sciences, 2013;3,03.
40. Zain MZ, Norman RJ. Impact of obesity on female fertility and fertility treatment.
Women's Health (2008) 4(2), 183194
41. Scottish Intercollegiate Guidelines Network. Management of obesity. A national
clinical guideline. February 2010.

48

42. M Sucheta, A Lovely, BK Mrinal, R Debilina. Role of Weight Reduction and its
significance in Restoring Fertility - in Obese and Overweight Women. Journal of
Evolution of Medical and Dental Sciences 2014; Vol. 3, Issue 05, February 03;1245-9
13
43. The Fertility Society of Australia. Effects of caffeine, alcohol and smoking on fertility.
44. Legro RS et al. Clomiphene, Metformin, or Both for Infertility in the Polycystic
Ovary Syndrome. N Engl J Med 2007;356:551-66.
45. Bariatric Surgery Procedures American Society for Metabolic and Bariatric
Surgery. https://asmbs.org/patients/bariatric-surgery-procedures
46. Summary of Positives & Negatives of Established Weight Loss Surgery Procedures.
Gregg H. Josart, MD, FACS. 2008. http://www.bariatric-surgery-source.com/types-ofbariatric-surgery.html

49