The implications of obesity in childhood and adolescence resonate into adulthood and have implications at different levels that include psychosocial and health issues that impact beyond reproductive performance. This chapter explores the various facets and consequences on gynaecological issues of increased Body Mass Index in childhood, including the link with puberty, pubertal menorrhagia (also affecting children with complex needs) and the all too common problems surrounding hyperandrogenism, insulin resistance and the polycystic ovarian syndrome in particular which need to be seen in the specific context of the adolescent years. The wider ramifications of obesity on the psychosocial welfare of adolescents merits special attention. Finally management strategies are considered in the context of the needs of adolescents.
Introduction
The Jesuit motto “Give me a child until he is seven and I will give you the man” is allegedly based on a quote by Saint Francis Xavier but can be moulded to represent the impact of obesity in children on their future wellbeing and in particular the ramifications of childhood obesity on gynaecological and reproductive health.
Adolescents constitute some 18% of the global population and will continue to grow in numbers globally in absolute terms until around 2030 . Children who are overweight or obese are at greater risk of poor health in adolescence and adulthood including physical and psychological sequelae. The increase in children and adolescents with obesity has been particularly marked in recent years. Statistics indicate that childhood obesity has more than doubled in children and quadrupled in adolescents in the past 30 years . In the United Kingdom research by the Health & Social Care Information Centre has demonstrated sharp and substantial increases in obesity levels amongst children between 1993 and 2011 .
When asked about obesity in adolescents, respondents from the American College of Obstetrics and Gynecology considered that 20% of general gynaecological patients were obese and a further 36% overweight . In 2012 more than one third of children and adolescents were overweight or obese .
A significantly increased prevalence of obese and overweight women among adolescent gynaecological patients can therefore be anticipated. In a retrospective study Koliopoulus et al. identified that there was a strong correlation between raised Body Mass Index (BMI) in adolescents with gynaecological problems seen in a designated adolescent gynaecology clinic over a six year period, with 24% being obese (BMI >98 th centile for age) and 17% overweight (BMI>88 th -98 th centiles), representing a total of 41% of patients, as compared to the expected general population at the time of 2% and 10% for obese and overweight individuals. Figs. 1 and 2 illustrate the prevalence of childhood obesity in England and in a global context.
Prominent among the gynaecological problems linked to childhood obesity are the early onset of puberty, menstrual irregularities during adolescence and polycystic ovarian syndrome.
Obesity and the onset of puberty
The reduction in the age of the menarche over recent generations has been well recognised, with the age of menarche documented as 16.5 years in the mid to late nineteenth century as compared to as much as four years earlier in 2014, with implications for physical, mental and behavioural changes . Despite the assumption that the decrease in the age of menarche has reached a plateau, the National Health and Nutrition Examination Survey (NHANES) has demonstrated that there is an ongoing mild decline .
Overweight girls tend to mature earlier than leaner children, with attendant implications for vulnerability and precocious behaviour. Increasing evidence suggests a close association between early sexual maturation and obesity in girls and female adults. Earlier maturing girls are more likely to be obese than those not maturing early. The reverse is seen in boys. The prevalence of being overweight in girls maturing early versus the others was 34.4% as compared to 23.2%. The figures for obesity were 15.6% and 8.1%, respectively. Odd ratios and 95% confidence intervals for obesity were 2.0 (1.1, 3.5) for girls. Most significant differences in excess weight and obesity among ethnic groups disappeared after controlling for sexual maturation .
The extent of body fat has been linked to the triggering of neuroendocrine effects leading to the onset of puberty. Obese children have high leptin levels and leptin receptors have been identified in the hypothalamus, the anterior pituitary, and ovarian follicular cells. Leptin works by accelerating gonadotrophin-releasing hormone pulsatility in hypothalamic neurons, and also has a direct effect on the anterior pituitary. High levels can inhibit gonadal function, but children with obesity also have increased adrenal androgen levels, which may be involved in the accelerated growth of these children before puberty. This seems to be the relevant link in that leptin has a specific role in stimulating the activity of enzymes essential for the synthesis of adrenal androgens. Children with exogenous obesity often display an increase in height velocity with tall stature for age despite low growth hormone levels. Shalitin & Phillip have demonstrated that leptin acts by exerting a direct effect on skeletal growth in animal models, with a direct effect on skeletal growth centres. The authors concluded that elevated leptin levels might have a permissive effect on the pubertal process and pubertal growth .
The role and regulation of sex hormone binding globulin in children is poorly defined, but levels of this protein that binds androgens and estrogens are initially high in childhood (peaking at the age of five years) and then decline significantly before puberty, thereby facilitating its onset . Girls who are overweight have been identified as having low levels of sex hormone binding globulin resulting in the earlier onset of puberty. The hormones controlling appetite and body weight interact closely with those that allow fertility, thereby offering an explanation why the age of puberty has fallen over the last century and clarifying the relationship between the increasing proportion of children with obesity and the fall in the age of the menarche. The authors conclude that adiposity-related endocrine mechanisms and chronic inflammation were associated with the prepubertal decline of sex hormone binding globulin, and that lower sex hormone binding globulin levels anticipated earlier puberty. These findings may of relevance when exploring the occurrence of earlier puberty in recent decades.
Obesity and the onset of puberty
The reduction in the age of the menarche over recent generations has been well recognised, with the age of menarche documented as 16.5 years in the mid to late nineteenth century as compared to as much as four years earlier in 2014, with implications for physical, mental and behavioural changes . Despite the assumption that the decrease in the age of menarche has reached a plateau, the National Health and Nutrition Examination Survey (NHANES) has demonstrated that there is an ongoing mild decline .
Overweight girls tend to mature earlier than leaner children, with attendant implications for vulnerability and precocious behaviour. Increasing evidence suggests a close association between early sexual maturation and obesity in girls and female adults. Earlier maturing girls are more likely to be obese than those not maturing early. The reverse is seen in boys. The prevalence of being overweight in girls maturing early versus the others was 34.4% as compared to 23.2%. The figures for obesity were 15.6% and 8.1%, respectively. Odd ratios and 95% confidence intervals for obesity were 2.0 (1.1, 3.5) for girls. Most significant differences in excess weight and obesity among ethnic groups disappeared after controlling for sexual maturation .
The extent of body fat has been linked to the triggering of neuroendocrine effects leading to the onset of puberty. Obese children have high leptin levels and leptin receptors have been identified in the hypothalamus, the anterior pituitary, and ovarian follicular cells. Leptin works by accelerating gonadotrophin-releasing hormone pulsatility in hypothalamic neurons, and also has a direct effect on the anterior pituitary. High levels can inhibit gonadal function, but children with obesity also have increased adrenal androgen levels, which may be involved in the accelerated growth of these children before puberty. This seems to be the relevant link in that leptin has a specific role in stimulating the activity of enzymes essential for the synthesis of adrenal androgens. Children with exogenous obesity often display an increase in height velocity with tall stature for age despite low growth hormone levels. Shalitin & Phillip have demonstrated that leptin acts by exerting a direct effect on skeletal growth in animal models, with a direct effect on skeletal growth centres. The authors concluded that elevated leptin levels might have a permissive effect on the pubertal process and pubertal growth .
The role and regulation of sex hormone binding globulin in children is poorly defined, but levels of this protein that binds androgens and estrogens are initially high in childhood (peaking at the age of five years) and then decline significantly before puberty, thereby facilitating its onset . Girls who are overweight have been identified as having low levels of sex hormone binding globulin resulting in the earlier onset of puberty. The hormones controlling appetite and body weight interact closely with those that allow fertility, thereby offering an explanation why the age of puberty has fallen over the last century and clarifying the relationship between the increasing proportion of children with obesity and the fall in the age of the menarche. The authors conclude that adiposity-related endocrine mechanisms and chronic inflammation were associated with the prepubertal decline of sex hormone binding globulin, and that lower sex hormone binding globulin levels anticipated earlier puberty. These findings may of relevance when exploring the occurrence of earlier puberty in recent decades.
Psychosocial and sexual behaviour
Obesity in childhood is linked to psychological effects, with affected children and adolescents being the target of social discrimination with inevitable emotional and social consequences. Early recognition of the undesirability of obesity results in loss of self-esteem in adolescence, potentially leading to sequelae that include impaired social skills, anxiety, depression and a reduction in academic performance. Obesity is therefore unsurprisingly associated with a poor body image, and poor self-esteem is more likely to lead to risky sexual behaviour.
Obesity has been recognised as a factor in high risk sexual behaviour in adolescent girls. Published data in 2011 detailed high-risk behaviours of adolescent high school students in the United States with extreme obesity. With few exceptions adolescents with extreme obesity engaged in high-risk behaviours at rates comparable with healthy weight peers, sometimes in even more dangerous ways so that health care providers were encouraged to assess risk-taking behaviors in this cohort .
The Centers for Disease Control and Prevention Youth Risk Behaviors Survey which monitors health-risk behaviours including unhealthy diet and sexual behaviour identified in 2010 that obese adolescent girls were more likely to have had sexual intercourse before the age of 13 (Odds Ratio, OR, 2.6 for obese adolescents), were more likely to have more than three lifetime partners (OR 1.2, being 30% more likely) and less likely to use condoms or any form of contraception (OR 0.67, 20% less likely). The more recent results from their Survey in 2013 showed changes in obesity-related behaviours in recent years. During the past 10 years, the percentage of high school students using a computer for three or more hours per day (for non-school related work) nearly doubled from 22% in 2003 to 41% in 2013, with an accompanying reduction in those watching television for at least three hours per day on an average school day decreasing from 43% in 1999 to 32% in 2013.
An indirect association with adolescent obesity is smoking, based on a popular belief among adolescent girls trying to lose weight that smoking has a protective effect on obesity. Tobacco use is common among normal weight adolescents trying to lose weight, with a reported two-fold increase . Smoking cessation should be encouraged especially given the authors’ observation that tobacco use is also associated with a cluster of other unhealthy dietary practices in adolescents.
In a large study of 33,393 adolescents the effects of frequent dieting on negative psychosocial and health behaviour outcomes were explored. Dieting frequency was associated with a history of binge eating, poor body image, lower connectivity with others, and greater use of both alcohol and tobacco. The authors concluded that frequent dieting in adolescents should not be viewed in isolation but rather in the broader contest of health and risk-taking behaviours.
Pubertal menorrhagia
As many as 30% of adolescents experience heavy menstrual bleeding, based on objective measurements and pictorial charts. The leading cause is immaturity of the hypothalamic-pituitary-ovarian axis, anovulation and lack of progesterone. The abnormal bleeding occurs as a result of negative feed-back by higher estrogen levels on the hypothalamic-pituitary axis, causing a fall in the FSH levels and thereby of estrogen, resulting in endometrial shedding.
Obesity in childhood and early adult life increases the risk of irregular menstrual bleeding during the reproductive years. Obese women had a 29% (OR 1.29; 95% CI 1.04-1.59) increase in the probability of experiencing heavy bleeding compared to normal weight women. The possible mechanism points to high estrogen levels by way of the increased aromatization of androgens in peripheral adipose tissue together with the lack of progesterone opposing effects on the endometrial lining. The chronic estrogen-driven proliferation of endometrial tissue leads to endometrial overgrowth and irregular menstrual cycle together with heavy bleeding.
In girls with increased insulin resistance (as in polycystic ovarian syndrome), abdominal obesity is associated with an increase in circulating insulin levels, which, in turn, results in further increase of functional androgens and even higher circulating estrogen levels .
Frequent and/or heavy bleeding leads to iron deficiency and anaemia. Iron deficiency is common in adolescent girls with a prevalence of 14.2%. Although in underdeveloped countries this is partially explained by nutritional deficit, the divergence difference at puberty between girls and boys (3.6%) still implicates menstrual bleeding as the leading cause. Iron deficiency is a systemic condition which has many consequences, including decreased physical work capacity, decreased athletic performance and decreased scholastic performance. A recent study on adolescent girls from India showed that girls with low ferritin levels had lower mathematical and verbal learning scores, disrupted attention, and had lower intelligence scores. Other studies have found a positive effect of iron supplementation on verbal learning, memory and academic performance in iron deficient girls even in the absence of anaemia .
In order to prevent heavy irregular bleeding in young adolescents, hormonal intervention using cyclic progestogens or hormonal contraception may be used in addition to iron supplements.
Extreme cases with profuse bleeding might result in severe anaemia and should be treated as an inpatient with intensive high dose estrogen-progesterone oral contraception. Cases with hemodynamic instability usually require blood transfusion. Although the leading cause is immaturity of the hormonal axis, approximately 20% of those presenting with heavy periods may have an underlying blood dyscrasia such as platelet disorders, Von-Willebrand’s disease and others .
Obesity and menstrual manipulation in children with complex needs
Children with complex needs often have conditions or syndromes that are associated with obesity.
Some, mainly those with low cognitive function, also have difficulty in coping with menstrual hygiene so that there is a need for hormonal intervention to minimise the burden of menstrual flow as well as the emotional effect of endogenous hormonal changes including the premenstrual syndrome and premenstrual dysphoric disorder. Moreover these children are vulnerable and are at risk of sexual abuse, so that provision of contraceptive protection is desirable .
When considering hormonal manipulation it should be remembered that long acting reversible contraceptives not associated with weight gain should be used in preference to those where weight gain is a recognised side effect (e.g. Depot Medroxyprogesterone Acetate). There is increasing evidence of the value of the levonorgestrel intrauterine system as a tool for treating menstrual problems in adolescents . Not only is weight gain best avoided for health reasons but there are also often practical reasons given the need to lift and carry these children due to underlying mobility problems which often require resort to a wheelchair. The combined oral contraceptive is specifically contraindicated in adolescents with a Body Mass Index in excess of 40 kg/m 2 and should be used with caution in those with decreased mobility. Use of a transdermal preparation is a useful alternative in this population as long as it is not contraindicated especially if the children have difficulty with swallowing.
Polycystic ovarian syndrome (PCOS), hyperinsulinaemia and hyperandrogenism
There is a well-recognised association between obesity and certain gynaecological conditions affecting the adolescent, e.g. PCOS, which was first described by Stein and Leventhal in 1935 as the classic triad of obesity, hirsutism and oligomenorrhea .
The earliest recognised PCOS phenotype is premature pubarche with elevated levels of dehydroepiandosterone sulphate and hyperinsulinaemia . These girls are at high risk of developing the full PCOS phenotype, including ovarian hyperandrogenism and chronic anovulation.
Currently obesity is established as the major marker and promoter of PCOS, presenting in almost all (84%) affected patients. Other characteristics include hyperandrogenic appearances including hirsutism, acne (68%) and irregular menstrual cycle (∼60%). Young adolescents with PCOS are more prone to heavy menstrual bleeding and iron deficiency anaemia as a cause of higher estrogen levels and endometrial proliferation.
The estimated incidence of PCOS in adolescents is around 8%, making PCOS the most prevalent hormonal imbalance during adolescence. As the incidence of obesity increases, a higher proportion of women with polycystic ovaries develop the syndrome, so that the current epidemic of obesity is likely to make PCOS even more common .
Aetiology and pathophysiology
The pathophysiological characteristics of the PCOS are not fully understood but are known to involve complex interactions between the actions of gonadotrophins, the ovaries, androgens and insulin. There is evidence for a polygenic inheritance trait modified by environmental factors, similar to that seen with Type 2 diabetes mellitus. The basis of the pathophysiology that generates PCOS is a disorder of increased Insulin Resistance (IR) and hyperinsulinemia – seen in 75% of cases – and high androgen levels. IR has a bimodal expression. It is primarily expressed at the level of striated muscle, adipocytes and hepatocytes as opposed to the ovaries that otherwise appear to remain sensitive to insulin, or perhaps even hypersensitive to insulin. At the ovarian level even low insulin levels efficiently modulate the luteinising hormone effect on the theca cells of the ovary causing increasing androgen production. The hyperinsulinaemia associated with IR therefore means that more androgen will be produced by the ovary. As IR increases and insulin concentrations rise, ovarian androgens will increase and the PCOS will then worsen. In addition decreased sex hormone binding globulin (SHBG) production due to IR in the liver further increases the level of circulating free testosterone. High androgen levels alter folliculogenesis and prevent ovulation resulting in the disordered menstrual cycle seen in the syndrome.
In addition whereas IR is genetically determined it is modulated by the amount of fat in the tissue, with accumulation and release of free fatty acids and cytokines causing further IR and finally worsening of PCOS .
Other than for the inevitable distressing symptoms to adolescents as a result of the high androgen levels seen as clinical hyperandrogenism and anovulation, IR and hyperinsulinemia pose increased risks for long term metabolic morbidity. Young women with PCOS have increased risk of developing Type 2 diabetes mellitus (Relative risk, RR 4.1), the metabolic syndrome (RR 3.5), cardiovascular diseases (RR-3) and even malignant disease such as endometrial carcinoma (RR 2.7). There is some recent evidence examining potential mental health effects of PCOS, with affected individuals having a higher incidence of depressive disorders (RR 4.2) compared to women matched with a similar Body Mass Index but without PCOS .
Diagnosis
The Rotterdam criteria of infrequent or absent menstruation, raised androgen levels and a polycystic appearance of the ovaries on ultrasonography are well established in adults. However if the criteria as applicable to adults (with the diagnosis based on two of the three features) are applied to adolescents there is the potential for overdiagnosis with a potential prevalence of 21% instead of the more widely accepted 8% in the population. In addition there is a need to evaluate these criteria for adolescents given that normal puberty is already associated with a relatively hyperandrogenic state due to a fall in the levels of sex hormone binding globulin and increased adrenal function, hence the common findings of acne and skin eruptions in some 80% of adolescents. Moreover the anabolic state that is seen in puberty is characterised by increased insulin resistance. In addition as many as 45% of adolescents will experience anovulatory cycles for the first two years following on from the menarche and some will continue to have anovulatory cycles even after then .
Insofar as ultrasound is concerned the typical PCOS ovarian appearance is based on strict criteria that include an increased ovarian volume >10 cm 3 (4.9 ± 0.03) and a polycystic morphology containing at least 12 follicles measuring some 2-9 mm in diameter ( Fig. 3 ).
