Adipose Tissue and Reproduction
No Reproductive Endocrinology book would be complete without
a chapter about the effects of adipose tissue on reproductive function. Both
underweight and overweight states have been recognised for a long time to have
detrimental effects on development, menstrual function, fertility potential and
pregnancy outcome. This is over and above their effects on general health in
general. The body mass index (BMI), which represents the ratio of weight in
kilograms over the height in metres squared, has been used in clinical setups
to measure the effects of adiposity.
The World Health Organisation (1)
has defined a normal BMI to cover a range between 18.5 – 24.9 kg/m2,
overweight range >25 – 29.9 kg/m2, obesity >30 kg/m2
and morbid obesity >35 kg/m2. Figures <18.5 kg/m2
were defined as underweight. However, the BMI is not a very exact reflection of
body fat, as it could be affected by age, bone density and muscles mass. More
important, it does not reflect the regional distribution of fat which proved to
be more important clinically in many respects. Furthermore, the agreed cut off
ranges might not be equally important in different ethnic groups. Nevertheless,
it is an easy formula to use with reasonable accuracy, and its efficacy could be
improved by measuring the waist circumference, and the waist: hip ratio at the
same time. Waist circumference is the most accurate clinical parameter for
estimating intra abdominal fat, but the cut off figures also vary with ethnic
origin. A value >80 cm for waist circumference, and >0.85 for
waist-to-hip ratio have been associated with increased morbidity (ASRMPractice committee 2008, 2). Measurement should
be taken with the patient standing up, with the tape at the narrowest part of
the abdomen, after expiration.
Before going into the clinical implications of obesity and
underweight, it is important to describe the structure and function of adipose tissue
which form the largest endocrine gland in the body. The adipose tissue is made
of adipocytes (fat cells), preadipocytes, endothelial cells, pericytes, macrophages,
monocytes, and fibroblasts. During infancy and early childhood, brown
adipocytes are dominant, but are rare during adult life. They are multilocular,
brown in colour, and are mainly concerned with basal heat production. On the
other hand, white adipocytes or white fat cells are unicellular, and form the
main energy stores for the body. They are 95% made of triglycerides. They could
grow in size up to a certain critical threshold, before triggering
preadipocytes differentiation into adipocytes. Once adipocytes are formed, they
would remain permanently for life. This process of lipogenesis is facilitated
by the enzyme lipoprotein lipase (LPL), and in reverse lipolysis is affected by
the hormone sensitive lipase (HSL).
Adipose tissue is essential for human survival and has many
- It is involved with energy
reserve especially during times of starvation. This could be affected
through different means, but especially so through the sympathetic nervous
system. Lipolysis to generate free fatty acids into the circulation is
achieved by stimulation of the β-adrenergic receptors, and is inhibited by
stimulation of a2A-adrenoceptors.
Insulin is also known to have an anti-lipolytic effect.
- Various metabolic functions are affected
through different chemicals produced by adipocytes. Leptin could reduce hunger and food
intake and acts as an antiobesity hormone. Together with adiponectin, and
omentin, they could promote insulin stimulated glucose uptake in the
muscles and liver. On the other hand, chemicals like tumour necrosis
factor alpha (TNF-a)
and interleukin-6 (IL-6) could disrupt insulin signalling in skeletal
muscles, leading to insulin resistance.
- It has a major endocrine
capacity though production of leptin, adiponectin and aromatisation of
androgens into oestrogens.
It has already been discussed in Chapter 2 that puberty would
not start until a critical BMI with a certain adipose tissue mass had been
attained. This effect is an important one, since failure to attain such BMI on
one hand, or accumulation of excessive body fat on the other, could affect
normal development at puberty. The hormone leptin has been identified as the
main messenger to the brain to report adequate energy reserves to facilitate
the initiation of pubertal development.
Leptin is a protein hormone produced by adipocytes. It is
made of 137 amino acids. Its main function is to decrease hunger and food
intake. Its involvement in reproduction has been highlighted by the discovery
of leptin receptors in the hypothalamus, pituitary gland, ovaries and
endometrium. It is involved in stimulation of gonadotrophins production by
stimulating GnRH production by the hypothalamus. It could also act directly at
the pituitary gland to enhance gonadotrophins production; LH more than FSH. However,
it has a paradox effect at the ovarian level. In high concentrations it could
inhibit follicular development and steroidogensis (Duggal
et al 2000 (3). On the other hand, the capacity of adipocytes to produce
leptin is enhanced by oestrogens (Jin et al 2000, 4)
and suppressed by androgens (Machinal et al 1999, 5). In this respect it could be appreciated how
adipocytes could affect pubertal development and menstrual function through
production of an extra or a reduced amount of leptin, depending on the adipose
tissue mass. Its blood level starts rising by the age of 7-8 years in girls and
reaches a peak by the age of 13-15 years. This corresponds to the time of onset
of puberty, and it is thought to facilitate, but does not trigger pubertal
development. Its level was found to shadow those of LH and oestradiol during
the later part of puberty, being lowest during the early follicular phase and
peaks during the luteal phase. Congenital absence of leptin (Faroqui et al 2002, 6) and leptin receptor mutations (Clement et al 1998, 7) have been shown to prevent
Another important endocrine function of adipocytes is their
capability to convert androgens into oestrogens. Aromatisation of
androstenedione could lead to the production of oestrone which is a weak
oestrogen. Nevertheless, it could have an important role in the function of the
hypothalamo-pituitary-ovarian axis (HPO). Excessive production of oestrone
could disrupt the HPO axis, and accordingly ovulatory function. With
anovulation, continued exposure of the endometrium to oestrone could result in
endometrial hyperplasia and abnormal uterine bleeding as well. Adipocytes also
possess the enzyme 11β hydroxysteroid dehydrogenase which is capable of
converting cortisone into cortisol. This conversion could be excessive with the
accumulation of high cortisol level in the adipose tissue, in obese patients.
Other chemicals produced by adipocytes which could affect the
endocrine system or body homoeostasis in general include:
· Adiponectin has antidiabetic properties affected
through insulin-mimetic and insulin-sensitizing properties. It also has
anti-inflammatory and anti-atherosclerotic effects. (Fang
and Sweeney, 2006, 8). The main action of adiponectin is to increase insulin
dependent glucose uptake by the muscles and liver cells. This is affected by decreasing serum free
fatty acids and triglycerides, and by suppression of hepatic glucose production
(Arner P 2005 (9) and Yamauchi
et al 2007 (10). A good review about adiponectin has been published by Haluzík et al in 2004 (11)
and would be summarised here. Fibronectin is the only adipokine which has an
inverse relationship to obesity. Normally, its plasma level is about 1000-fold
higher than leptin, but its level is decreased in diabetics and insulin
resistant patients. Few results showed an inverse relationship between
adiponectin plasma level and BMI, triglycerides, as well as fasting and
postprandial plasma glucose concentrations. Adiponectin gene expression has
been reduced by obesity, glucocorticoid, β-adrenergic agonists, TNFa,
exposure to cold and leanness. On the other hand, a positive correlation has
been shown between its plasma level and insulin stimulated glucose disposal. Animal
studies have shown promising results that adiponectin replacement might be
useful in the treatment of insulin resistance and atherosclerosis.
· Plasminogen activator inhibitor-1(PAI-1) is a
glycoprotein with a prime function of inhibiting fibrinolysis. It prevents the
conversion of plasminogen to plasmin, hence reducing the risk of thrombus
formation. Excessive increase in the level of PAI-1 is associated with venous
thrombosis, cardiovascular disease, recurrent miscarriage and other pregnancy
complications. It is produced more by visceral adipocytes than peripheral
adipose tissue. Its level is positively correlated to body fat mass, and it is
reduced by loss of weight and metformin medication.
is important for fat metabolism, as it promotes lipolysis and could increase
plasma free fatty acids. It is also involved with the development of insulin
· IL-6 could increase the production of the
inflammation markers C-reactive proteins, hence increasing the risk of thromboembolism.
It also has a negative effect on insulin signalling, which could lead to
insulin resistance as mentioned before.
Effects of adipose
In the context of this chapter adipose tissue location would
be discussed in relation to upper or lower body distribution. Upper body adipose tissue includes areas
above the waistline. This is divided into subcutaneous / extra-abdominal and
visceral / intra abdominal distribution. Measurement of the waistline has
already been alluded to for the documentation of the visceral type. Lower body
adipose tissue distribution falls below the waist line, mainly in the hips and
The significance of this distinction in adipose tissue
distribution relates to the differences in the biochemical activities of the
adipocytes in these different areas. This is reflected by the fact that upper
body obesity is more of a male trait linked to androgenic profiles, where as
women tend to have lower body obesity. Accordingly, the two types are called
android and gynaecoid obesity, respectively. This brings the issue of BMI in focus
again as it could not distinguish between the two types. Furthermore, as
visceral adiposity is more significant in relation to metabolic and reproductive
abnormalities than global fat distribution, care should be taken to ascertain
the waistline circumference as a routine procedure in all examinations.
Central obesity in women could lead to a hyperandrogenic
state through the following mechanisms:
- Central obesity could induce
insulin resistance and hyperinsulinaemia, as well as increased free fatty
- Hyperinsulinaemia could act in
two ways in creating a hyperandrogenic profile. It could act directly at
the level of the ovaries increasing testosterone production, by acting as
a co-gonadotrophin. It could also increase the level of free androgens in
circulation by reducing hepatic production of sex hormone binding
- High free fatty acids (FFA) concentration
could contribute to female hyperandrogenism by causing insulin resistance,
or by acting directly on the adrenal glands without ACTH intervention, to
stimulate androgens production (Mai et al 2006, 12).
Unfortunately, central obesity and hyperandrogenism form a
vicious circle in women as androgens also promote central obesity (Bohler H et al 2009, 13). Androgens were shown to
induce lipogenesis through augmentation of LPL activity. In fact a direct
correlation has been found between free testosterone level in obese women and
LPL activity. Oestrogens on the other hand, have an opposite effect.
Postmenopausal women who have a low oestrogen/androgen ratio tend to develop
central obesity. This pattern is reversed in women using HRT who maintained
their gynaecoid premenopausal fat distribution pattern (Haarbo et al 1991, 14).
endocrine effects of adiposity
Before describing the clinical effects of excessive or
reduced body fat on human reproduction, a short account of the effects of body
weight on endocrine glands, other than the HPO axis, would be described.
Growth hormone (GH) levels have been found to be low in obese
patients, mainly due to reduced production by the pituitary gland. This is
valid both in the basal state, and after stimulation with growth hormone
releasing hormone, growth hormone releasing peptides and arginine. This pattern
was reversed by weight loss. However, the clinical significance of this finding
is not clear, as the level of insulin like growth factor 1 (IGF-1) which is the
main mediator of GH effects, is not affected by obesity (Frystyk et al 1995 (15) and Glass et al 1981 (16). However, this last statement is not valid
with visceral obesity as the level of IGF-1 was found to be low, even in
patients with normal BMI.
Thyroid function has been scrutinised over the years in
relation to BMI. Hypothyroidism and hyperthyroidism could be associated with
weight gain and weight loss respectively. Accordingly, all obese patients and
women with excessive weight loss should have their TSH and free thyroxine
levels measured. On the other hand, no association has been found between
subclinical hypothyroidism and excessive weight gain, though an exaggerated TSH
response to TRH stimulation could be seen in some obese patients. The effect of
deranged thyroid function on the other endocrine glands has been discussed in
The relationship between the hypothalamo-pituitary-adrenal
axis and BMI has been studied intensively, because of the relationship between
Cushing’s syndrome and obesity. Nutritional obesity could be associated with
decreased level of cortisol binding globulin, increased level of urine free
cortisol, increased non ACTH dependent peripheral producton of cortisol,
increased cortisol response to ACTH stimulation test, increased ACTH pulse
amplitude and decreased cortisol suppression after 1 mg dexamethasone
suppression test. It is evident that there is increased sensitivity to stimuli
and reduced sensitivity to inhibition of the HPA axis with obesity. The direct
effect of free fatty acids on the adrenal glands has been alluded to before.
The relationship between obesity and insulin resistance is a
well known fact. This is irrespective of the cause of the obesity itself. This
is especially so for the visceral type which is characterised by reduced
peripheral glucose uptake, and increased glucose production by the liver. This
would result in increased insulin production by the pancreas which could
gradually fail with time. This might result in reduced insulin production after
a glucose load to start with, and ultimately in the basal state (Polonsky KS 2000 (17). The role of TNF-a,
IL-6 and free fatty acids in causing insulin resistance has been mentioned
It is evident from the above sections that body fat could
affect different hormones, but this is mainly so for visceral obesity. On the
other hand different hormonal dysfunctions could cause excessive deposition of
adipose tissue leading to obesity. The relationship between hypothyroidism and
obesity has already been mentioned. Cushing’s syndrome is another example
leading to central obesity. Other rare conditions include insulinomas and neuroendocrine
implications of high and low BMI
effect of BMI on the reproductive endocrine system spans from puberty to the
postmenopausal period. The effects of obesity would be addressed first in
relation to the different stages of life.
has already been mentioned that onset of puberty depends on the presence of a
critical adipose tissue mass. Underweight girls might fail to start their
pubertal development, or could have a delayed onset with incomplete
development. Increasing body weight has been shown to reverse this pattern. The
role of leptin in this context has been shown by the successful increase in
GnRH pulsatility in low weight women with hypothalamic amenorrhoea, after
administration of recombinant leptin (Welt et al, 2004,
the other hand childhood obesity could be associated with early onset of
pubertal development. However excessive teenage obesity could lead to
oligomenorrhoea or even amenorrhoea following an early menarche. This is occasionally
seen in patients with polycystic ovarian syndrome (PCOS). More seriously, adolescence
obesity has been associated with increased likelihood of lifelong nulliparity,
in comparison with women with normal adolescent BMI (Polotsky
et al 2009, 19). An earlier cohort study showed that obesity at the age
of 7 years was associated with increased risk of irregular menstruation at the
age of 33 years, stressing the importance of childhood obesity (Lake et al, 1997, 20).
obesity as well could lead to anovulation problems and dysfunctional uterine
bleeding which could be mediated through increased insulin level,
hyperandrogenaemia and deranged gonadotrophins secretion. Excessive leptin
production has also been shown to have a detrimental effect on follicular
development and steroidogensis (Duggal et al 2000, 3).
Other mechanisms which might affect the function of the HPO axis in obese
- Disturbed prolactin secretion
- Increased level of endorphins
- Increased level of dopamine and opioids
- Increased oestrone level due to increased
- Low SHBG resulting in high free androgens level.
important and may be the main reason for failed induction of ovulation with
clomiphene citrate is obesity. The higher the body mass index, the higher the
dose of clomiphene citrate needed. It is also a general observation that
overweight and obese women usually need higher doses of gonadotrophins for a
longer period of time to induce ovulation with inadequate response. Higher
chances of cycle cancellation and fewer oocytes are usually retrieved within
IVF programmes (Fedorcsák et al, 2004, 21)
the universal agreement on the detrimental effects of obesity on anovulation,
contradictory literature has been published about the risks of infertility,
recurrent miscarriages and other obstetrics complications. This might be due to
the following reasons:
- The clinical significance of the BMI ranges set
by the WHO could be different in different ethnic groups.
- The effects of central and peripheral obesity are
not usually separated during assessment of the different reproductive risk
factors related to obesity.
- The initial cause of obesity might not be taken
in consideration in different reports e.g. hypothyroidism, PCOS or adrenal
- The different effects of obesity in nulliparous
and parous women in relation to pregnancy outcome have only been
ascertained recently. Higher risks of elective preterm operative delivery,
perinatal mortality and long term disability have been shown in obese nulliparous,
but not parous women in a retrospective cohort study (Smith et al 2007, 22).
Many articles have also documented reduced fertility
potential in obese women with regular menstrual cycles, and prolonged time to
achieve a pregnancy (Gesink Law et al, 2007 (23);
Jensen et al 1999 (24) and Bolumar et al 2000, 25). This was quantified by one study which showed
4% decline in probability of natural conception per kg/m2 in women
with BMI >29 kg/m2 (van del Steeg et al
2008, 26). Furthermore, a 30% decrease in
average cycle fecundity was found for 0.1 unit increase in waist / hip ratio in
women undergoing donor insemination (Zaadstra et al
1993, 27). Some controversy exists on the effects of obesity on IVF
outcome. However, the general impression is that obese women needed larger
doses of gonadotrophins, for longer duration, with a smaller yield of oocytes.
Embryo quality is not affected by obesity with inconsistent results on clinical
The detrimental effects of obesity on pregnancy outcome have
been shown by many publications, and have been reviewed by the Practice
Committee of the ASRM Practice committee, 2008 (2).
This included early pregnancy loss, and later obstetrics complications. The
relationship between miscarriage rate and BMI has been demonstrated by a meta analysis
of 16 studies which documented 67% increased miscarriage risk in overweight
women in comparison to women with normal BMI (Metwally
et al 2008, 28). Other problems related to a BMI >30 kg/m2 included
pre eclampsia, gestational diabetes, and caesarean section (Dokras et al 2006, 29). With severe obesity and a BMI
>40 kg/m2 increased obstetrics risks also included hypertension, large for
gestational age infant, meconium aspiration, shoulder dystocia, fetal distress,
stillbirth and early neonatal death (Weiss et al 2004 (30) and Cedergren et al 2004, 31).
Furthermore, obesity had been associated with increased birth defects. Neural
tube, ventral wall and cardiac defects and multiple congenital anomalies were
found to be significantly increased (Watkins et al 2003,
32). In addition it has been reported that the usual fortification of
folic acid did not reduce the incidence of neural tube defects in obese women (Ray et al 2005, 33).
It is evident that obesity affects reproductive function
through anovulation and infertility, as well as increased miscarriage,
stillbirth and neonatal death rates. Accordingly, it has been recommended that
women with a BMI >35 kg/m2 should not be offered fertility treatment.
Ideally this figure should be reduced to 30 kg/m2, as all the complications
mentioned above were still significant beyond that level. This recommendation
is not usually heeded as most obese women are not infertile, and infertile
patients always raise this point during consultation, when asked to reduce their
weight first. The other problem with obesity is that slight reduction in weight
of 5-10% might induce ovulation and regular menstrual function, despite the
patient being still within the obese or even gross obesity range. The
difficulty here is that any pregnancy would be at risk of all the complications
mentioned before. Accordingly, a suggestion has been made that grossly obese
and obese women should use barrier methods of contraception while losing weight
till they attain an acceptable BMI (Nelson and Fleming
2007, 34). As most complications were more significant in nulliparous
than parous women, the pressure of infertility and urgency to conceive would
make this suggestion difficult to implement, though it is scientifically sound.
Change in life style, rather than dieting, would be more
appropriate means to lose weight and to prevent rapid regain of the adipose
tissue. This should be affected by regular exercise, increased every day
routine activity, and walking or cycling instead of using the car or public
transport for reasonable distances. The help of a dietician should be sought to
help with healthy eating, and to prevent consumption of high carbohydrate food.
Insulin resistant patients might find it difficult to lose weight. Metformin
could be used to control this problem and to allow better utilization of
glucose by the muscle and to reduce gluconeogenisis. It could also cause modest
weight loss when used in high doses, with an average of 5 kg over 8 months
period (Nelson and Fleming 2007, 35). Better results were documented for orlistat which
helped with 5% weight loss in 3 months, compared to 1% for metformin (Jayagopal et al 2005, 34).
The effects of obesity in older women have gained notoriety because
of its association with the development of type 1 endometrial carcinoma (Bokhman 1983, 36). Beside the sustained production of
oestrone by the adipose tissue, obesity is also associated with anovulation,
nulliparity and hyperlipidaemia, which are also considered as risk factors for
the development of endometrial carcinoma. Diabetes mellitus and hypertension
are two other risk factors closely related to obesity as well. However, no
correlation has been found between obesity or skin fold thickness and the age
of onset of the menopause. On the other hand, lean postmenopausal women are
more likely to develop osteoporosis than overweight ones. This could reflect reduced
peripheral oestrogen production which is the major source for postmenopausal
A body mass index <18.5 kg/m2 has been described
as low by the WHO (1). Many medical and
reproductive abnormalities have been associated with such low body weight. In a
reproductive function context, reduced adipose tissue mass has been associated
with absent or delayed puberty, anovulation and menstrual dysfunction,
infertility and obstetrics complications as well.
Though anorexia nervosa comes to mind first, many underweight
women do not fit that diagnosis. Excessive exercise, malnutrition and chronic
illnesses could also contribute to the spectrum of the problem. Furthermore,
the extent of the reproductive failure might rely on the extent of adipose
tissue loss, as well as the psychological predisposition of the individual
patient. With malnutrition and chronic illnesses, attainment of near normal BMI
might lead to resumption of menstrual function. However, this might not be the
case in patients with anorexia, due to the dominant psychological block of the
HPO axis. On the other hand professional women athletes might regain their
menstrual function, without putting on weight, during the closed season and
when injured and out of action. This would emphasise the predominant effect of
stress in these cases. However, the discriminating line here is very vague as
professional athletes usually have the triad of amenorrhoea, eating disorder
and psychological stress.
The major condition related to extreme weight loss and loss
of adipose tissue is anorexia nervosa. This condition might affect up to 1
percent of adolescents (Marjorie et al 2001, 37).
This diagnosis relies on demonstrating the following points:
Disturbed body image
Intense fear to gain weight
An important consequence of this condition is the loss of
bone density which could lead to osteoporosis and the risk of bone stress
fractures. As the maximum bone density is usually attained by the age of 20
years, these patients would lead a life with low bone density despite using HRT
and calcium supplements. One study suggested that using
dehydroepiandrostenedione might have a positive effect on bone turnover (Gordon et al 1999, 38).
Despite the major endocrine effects of anorexia nervosa, the
condition remains to be a psychological one and should be treated as such.
Management should aim at dietary advice, personal and family counselling, advice
modification, as well as individual and group psychotherapy. Hormone
replacement therapy (HRT) to counteract the effects of the severe hypo-oestrogenic
state, especially osteoporosis would be indicated. This could be in the form of
dedicated HRT combination drugs, or as an oral contraceptive pill. Anti
depressant treatment would be necessary in severe cases suffering from depression.
Ultimately, hospital admission could be necessary to save life with intravenous
hydration and forced feeding.
chapter was meant to deal with the inter-relationship between adipose tissue
and the reproductive function, without laying much emphasis on the metabolic
and general health issues. It is clear that fat cells have a major endocrine
role during the whole life span of women from the onset of puberty through the
reproductive years, up to the postmenopausal age. Thorough understanding of the
endocrinology of the adipose tissue and its chemical products leptin, ANF-a,
IL-6, fibronectin, free fatty acids on the HPO axis, HPA axis, insulin and
hepatic function is necessary for the reproductive endocrinologist.
Appreciating the differences in the detrimental effects of central vs.
peripheral obesity would also improve our understanding of the effects of
obesity in reproductive function, which is currently clouded by the
indiscriminate use of BMI in research projects which lead to many discordant
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