Chapter 8

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 function

Adipose tissue is essential for human survival and has many essential functions:

  • 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 pubertal development.

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.

·   TNF-a 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 resistance

·   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 tissue location

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 thighs.

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 acids concentration.
  • 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 globulins (SHBG).
  • 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).

General 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 Chapter 3.

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 before.

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 tumours.

Clinical implications of high and low BMI

The 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.

Childhood and pubertal obesity

It 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, 18).

On 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).

Adulthood obesity

Adulthood 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 patients include:

  • Disturbed prolactin secretion
  • Increased level of endorphins
  • Increased level of dopamine and opioids
  • Increased oestrone level due to increased androgens aromatisation
  • Low SHBG resulting in high free androgens level.

An 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)

Despite 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 enzymatic deficiency.
  • 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 pregnancy rate. 

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 oestrone production.

Effects of low BMI

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:

1.    Disturbed body image

2.    Intense fear to gain weight

3.    starvation

4.    Amenorrhoea

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 on behaviour 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.


This 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 results.


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