Secondary Causes of Obesity

REVIEW

Secondary causes of obesity

Jocelyne G Karam & While the rising epidemic of obesity is primarily attributed to sedentary lifestyle, poor Samy I McFarlane† dietary habits and the aging of the population, secondary causes of obesity generally go †Author for correspondence undetected and untreated. These include endocrinological disorders, such as Cushing’s State University of New York, Division of Endocrinology, syndrome, polycystic ovary syndrome, hypogonadism and hypothyroidism, as well as Diabetes and Hypertension, genetic, syndromic and drug-related obesity. We present an overview of the major Department of Medicine, disorders associated with obesity, highlighting the pathophysiologic mechanisms and Box 50 Health Science Center at Brooklyn Kings County discussing diagnostic and treatment strategies that are most helpful to practicing Hospital Center, physicians in recognizing and treating these generally underdetected and 450 Clarkson Avenue, undertreated disorders. Brooklyn, NY 11203, USA Tel.: +1 718 270 3711; Fax: +1 718 270 6358; During the past few decades, prevalence of obes- recognized by physicians and specific therapeutic Email: smcfarlane@ downstate.edu ity has dramatically increased in the Western strategies should be planned in conjunction with world, including the USA where obesity has cur- diet and exercise. rently reached epidemic proportions. A compar- In this review, we provide the readers with a ison of data from two National Health and general overview of the secondary causes of obesity, Nutrition Examination Surveys (NHANES) has highlighting the pathophysiology, the clinical diag- shown that among US adults, the prevalence of nosis and the therapeutic options of each disorder. obesity increased from 15% (in the 1976–1980 Obesity is a state of excessive body weight asso- survey) to 32.9% (in the 2003–2004 survey) [1]. ciated with adverse health risks such as diabetes, Data from the 2003–2004 survey estimate that hypertension, hyperlipidemia and coronary approximately 66% of US adults are overweight artery disease. In 1997 and 1998, The WHO and or obese and 17.1% of US children and adoles- the National Heart Lung and Blood Institute of cents are also overweight [1]. This sharp increase the National Institute of Health advocated the in the prevalence of obesity correlates with a pro- use of a specific BMI threshold of 30 to diagnose portional increase in obesity-associated comor- obesity and 25 to diagnose overweight [5,6]. The bidities, such as Type 2 diabetes, hypertension BMI is calculated by dividing a person’s weight in and cardiovascular disease (CVD) [2], and a sig- kg by height in m2. nificant rise in healthcare costs related to Furthermore, it appears that fat distribution obesity [3]. The economic burden of obesity in plays a key role in determining the associated the USA was estimated to be US$117 billion in health risks. Central or android obesity is associ- 1998, with obesity accounting for approximately ated with greater risk of adverse health effects 5.7% of the US National Health expenditure [3]. than lower-body or gynecoid obesity [7]. There- The relatively rapid and dramatic increase in fore, waist circumference measurement has been the prevalence of obesity has been largely attrib- a useful clinical tool in risk stratification of over- uted to a changing lifestyle that promotes weight in moderately obese patients increased caloric intake and reduced physical (BMI 25–35). A waist circumference greater than activity. A high-fat diet, excessive consumption 40 inches (102 cm) in men and 35 inches (88 cm) of sugar-sweetened beverages and increased fast in women is linked to higher CVD risks and food intake might all contribute to the continuing should lead to more aggressive weight reduction increase in prevalence of obesity [4]. strategies in overweight patients. Although most cases of weight gain are indeed Interpretation of BMI values may also change Keywords: endocrinologic related to increased caloric intake and sedentary with ethnicities. For example, android obesity obesity, genetic obesity, lifestyle, obesity can also be secondary to known leading to increased cardiovascular risk is clearly obesity, overweight, secondary obesity, syndromic obesity and possibly treatable neuroendocrine or genetic present in Asian individuals with lower BMI disorders that affect appetite, metabolism, (not in overweight and obesity categories), sug- part of energy balance and fat distribution (Box 1). gesting a lower BMI cut-off for definition of Although rare, these conditions should be obesity in this population [8].

Box 1. Endocrine and genetic causes At a physiological level, the principal gluco- of obesity. corticoid, cortisol, contributes significantly to the regulation of protein, carbohydrate, lipid and Endocrine causes nucleic acid, enhancing the production of blood • Hypothyroidism glucose by antagonizing the secretion and action • Cushing disease of insulin, increasing peripheral protein break- • Polycystic ovaries down and enhancing the activation of lipo- • Growth hormone deficiency protein lipase in adipocytes, which in turn • Hypothalamic obesity increases fat accumulation [9]. Glucocorticoids • Hypogonadism are also required for the differentiation of adi- • Insulinoma pose stromal cells to mature adipocytes. The • Pseudohypoparathyroidism action of cortisol on adipose tissue varies in dif- Genetic causes ferent parts of the body, decreasing peripheral Monogenic obesity: adipose tissue mass and expanding abdominal and interscapular fat. • Leptin and leptin receptor deficiency Furthermore, the highly expressed • POMC deficiency β • Melanocortin Receptor 4 deficiency 11 -hydroxysteroid-dehydrogenase-1 in omen- • Prohormone convertase deficiency tal adipose tissue is believed to enhance the local • BDNF and TrkB insufficiency effect of cortisol on adipose tissue by converting • SIM 1 insufficiency inactive cortisone to active cortisol [10]. Hypercortisolism in Cushing’s syndrome Syndromic obesity: results in central obesity, with fat accumulation • Prader–Willi syndrome in the face (moon face), neck, dorsocervical area • Bardet–Biedl syndromes (buffalo hump), supraclavicular area (fat pads), • Beckwith–Wiedemann syndrome retroorbital space (exophthalmos), trunk and • Alstrom–Hallgren syndrome abdomen, with sparing or wasting of the • Carpenter syndrome extremities, characterizing the typical central fat • Cohen syndrome distribution of the syndrome [11]. In addition to the gradual obesity that develops in 80–90% of Pathophysiology of obesity individuals, patients with Cushing’s syndrome The development of obesity requires a period of may present with hypertension, impaired glu- positive energy balance where energy intake cose tolerance, proximal muscle weakness, thin- exceeds energy expenditure, manifesting clearly in ning of the skin, increased tendency to bruise, obese individuals with high caloric intake and sed- red or violacious striae, hypokalemia, oste- entary lifestyle. Energy expenditure is divided into oporosis with vertebral compression fracture or basal metabolic rate, energy expended in activity aseptic necrosis and menstrual irregularities and thermic effect of food. Moreover, to maintain with signs of androgen excess in women. energy balance, the organism should be able to Hyperpigmentation in this context reflects sig- assess its own energy stores, the caloric content of nificantly elevated ACTH levels, favoring the the diet and the current balance status of the body, etiologic diagnosis of ectopic ACTH secretion, and be able to adjust hormone levels, energy and to a lesser degree Cushing’s disease. Chil- expenditure and consumption behaviors accord- dren with Cushing’s syndrome characteristically ingly. A defect at any energy balance level may present with abnormal weight gain and poor result in positive balance and obesity, as seen in linear growth [12]. most cases of secondary obesity (Figure 1). A widely used screening test for Cushing’s syndrome is the overnight 1 mg low-dose dexameth- Endocrine causes of obesity asone suppression test where at 8 am the cortisol Cushing’s syndrome value is expected to be lower than 2 µg/dl Cushing’s syndrome results from prolonged (55 nmol/l) in normal subjects who had received exposure to glucocorticoid excess deriving from dexamethasone 1 mg at 11 pm. However, owing four potential sources: pituitary tumors (Cush- to relatively high rates of false-negative and false- ing’s disease), adrenal tumors, ectopic adreno- positive results, a 24 h urine-free cortisol test is corticotropic hormone (ACTH) secretion and, considered a more accurate diagnostic approach, most commonly, exogenous glucocorticoids, followed if necessary, by late-evening plasma or including oral, topical or inhaled steroids. salivary cortisol level [13,14]. Acute or chronic

642 Therapy (2007) 4(5) futurefuture sciencescience groupgroup Secondary causes of obesity – REVIEW

Figure 1. Endocrinologic etiologies of obesity and related pathophysiology.

Hypothyroidism

Growth hormone Cushing Energy expenditure Glycosaminoglycans deficiency Fat tissue modulation Fat deposition

Polycystic ovary Hypogonadism syndrome Fat redistribution

Energy balance disruption polyphagia Lipolysis GH Hypothalamic Energy intake PHP obesity

Insulinoma

PHP: Pseudohypopparathryoidism.

illnesses, depression and alcohol abuse can result expenditure [18]. Thyroid hormone deficiency in hypercortisolism or pseudo-Cushing’s syn- slows metabolism, resulting in a decrease of drome, sometimes making the distinction more resting energy expenditure, oxygen consumption difficult and challenging. and utilization of substrates. Reduced thermo- The treatment of Cushing’s syndrome should act genesis is reflected in the classical cold intoler- to target the etiology of excessive glucocorticoids in ance of hypothyroid patients. The effect of specific patients. thyroid hormone deficiency on appetite and energy intake is not well known, however the Hypothyroidism decrease in energy expenditure explains the slight Primary hypothyroidism is a very common net gain in energy stores and adipose tissue disease worldwide. In the UK, the Whikham observed in these patients. Another mechanism survey revealed an incidence of hypothyroidism contributing to weight gain in hypothyroidism is of 4.1/1000/year in women and 0.6/1000/year the accumulation of fluid rich in gly- in men [15,16]. Similarly, in the NHANES III in cosaminoglycans. However, marked obesity is the USA, hypothyroidism was found in 4.6% of not characteristic of hypothyroidism. the 13,344 people screened without known In addition to modest weight gain, hypothyroid disease [17]. Marked female pre- thyroidism is clinically characterized by fatigue, ponderance and autoimmunity were uniformly cold intolerance, joint aches, constipation, depres- noted in these populations [15–17]. The preva- sion, dry skin, hair loss and menstrual irregulari- lence of hypothyroidism can be more common ties. Physical examination may reveal firm goiter, in iodine-deficiency regions. Other common hypertension, bradycardia, periorbital swelling, etiologies of hypothyroidism include iatrogenic coarse hair, dry skin, and delayed relaxation of the causes such as postthyroidectomy and deep tendon reflexes. Laboratory clues to postradioiodine hypothyroidism. hypothyroidism include normocytic anemia, In adults, thyroid hormone plays a major role hypercholesterolemia, hyponatremia and elevated in metabolism by increasing food intake and creatinine phosphokinase. subsequently, the thermic effect of food, acceler- The measurement of serum thyroid-stimulat- ating metabolic rates and enhancing thermo- ing hormone (TSH) level is currently the most genesis, leading to a net increase in energy sensitive test for screening for hypothyroidism. futurefuture sciencescience groupgroup www.futuremedicine.com 643 REVIEW – Karam & McFarlane

In view of the high prevalence of the disease and either a subnormal serum insulin-like and the simplicity of the screening tool, it is growth factor-1 concentration or a subnormal recommended that obese patients should be serum GH response to a potent stimulus such as screened for hypothyroidism. Most symptoms insulin-induced hypoglycemia or the combina- reverse shortly after administration of synthetic tion of arginine and growth hormone-releasing thyroid hormone replacement. hormone (GHRH). Therapy with GH replacement has demon- Polycystic ovaries syndrome strated efficacy in restoring normal body fat dis- Polycystic ovaries syndrome (PCOS) is one of tribution and increasing resting energy the most common female reproductive dis- expenditure, along with variable improvements orders, affecting 5–10% of premenopausal in other cardiovascular and metabolic women [19]. The key clinical features of PCOS are parameters [27,28]. menstrual irregularities (due to oligomenorrhea or amenorrhea and hyperandrogenism), causing Hypothalamic obesity hirsutism, acne and male-pattern hair loss with Obesity is commonly observed in patients with elevated serum androgen levels [20]. Polycystic hypothalamic tumors, trauma, inflammation, or ovaries, infertility, insulin resistance and obesity after hypothalamic surgery or radiotherapy. are other classic associated manifestations of the Weight gain is thought to result from the injury of syndrome. Studies have shown that approxi- the ventromedial hypothalamic nucleus. Its major mately 50% of women with PCOS are obese [21]. role is to integrate metabolic information regard- The pathophysiologic link between PCOS, insu- ing nutrient stores and food availability. Damage lin resitance and obesity is not clearly under- to these areas leads to hyperphagia, decreased met- stood. Hyperinsulinemia, especially in the abolic rate, autonomic imbalance and GH defi- presence of obesity, increases androgen levels by ciency, all of which result in progressive obesity stimulating androgen biosynthesis in the ovarian [29,30]. An associated alteration in corticosteroid theca cell and by suppressing sex hormone bind- metabolism may also contribute to weight gain in ing globulin (SHBG) production by the liver. hypothalamic obesity, by enhancing endogenous On the other hand, obesity by itself may favor or exogenous glucocorticoids effect. ovarian hyperandrogenism in a subset of PCOS Clinically, patients with hypothalamic women [22,23]. obesity might present with headache, vomit- Weight loss and insulin-sensitizing agents, ing, visual disturbances, diabetes insipidus, such as metformin and thiazolidinediones, have hypogonadism, hypothyroidism, adrenal been associated with improvement of hyperan- insufficiency hypothermia, hyperthermia or drogenism and metabolic parameters of PCOS, neurologic symptoms. including restoration of menses [24]. Obesity occurs in approximately 50% of children treated surgically for cranio- Growth hormone deficiency pharyngeoma [31]. Growth hormone (GH) deficiency is the most Patients at high risk of hypothalamic obesity common hormonal deficits observed in pituitary should be indentified and counseled regarding disease, almost constantly in the setting of hypo- life therapeutic changes to prevent weight gain pituitarism. GH plays significant roles in regulat- together with specific hormone replacement ing energy expenditure, body composition, bone as indicated. mineral density, lipid metabolism and cardiovascular function. Notably, GH inhibits lipoprotein Hypogonadism lipase, increases hormone-sensitive lipase, and Gonadal steroids play a determinant role in body stimulates adipocytes lipolysis. [25]. GH enhances fat distribution, as reflected by the typical gen- protein synthesis and increases muscle and bone der-related body fat changes that occur at the mass. GH deficiency in adults is associated with onset of puberty. decreased muscle mass, increased truncal fat dep- Androgens contribute significantly to fat osition and reduction of total body water, with a metabolism and body fat composition [32]. net weight increase of 3.6–7.5 kg of body weight Testosterone inhibits uptake of triglycerides and compared with normal subjects [26]. promotes lipid mobilization from visceral fat [33]. The diagnosis of GH deficiency in adults is In addition, testosterone levels are inversely asso- usually established with the history of pituitary or ciated with visceral fat mass, which may explain hypothalamic disease with panhypopituitarism, the increased visceral obesity with age in men.

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Androgen deficiency has been classically asso- of obesity: reduced lipolytic response to epine- ciated with obesity and metabolic syndrome [34], phrine (secondary to decreased intracellular whereas testosterone therapy has showed cAMP levels), accelerated differentiation of decreases in visceral adiposity and improvements fibroblasts to adipocytes and GH in glycemic control, insulin resistance and deficiency [44–47]. Patients have a classical presen- cholesterol [35–37]. tation, known as Albright hereditary osteodys- Of note, obesity may decrease the serum con- trophy (AHO), characterized by round faces, centration of SHBG, thereby decreasing the short stature, short fourth metacarpal bones, serum total testosterone concentration without obesity, subcutaneous ossifications and develop- normally lowering the free testosterone concen- mental delay, in addition to the hyperphos- tration. The binding abnormality is proportion- phatemia and hypocalcemia owing to PTH ate to the degree of obesity and is corrected by resistance at the renal tubule, along with second- weight loss [38]. ary hyperparathyroidism and hyperparathyroid Similarly, menopause is often associated with bone disease (osteitis fibrosa). decreased lean body mass with increased visceral Paternal inheritance of the mutation, which fat and visceral fat–subcutaneous fat ratio, with usually leads to the AHO alone without PTH or without weight gain [39–41]. The fat redistribu- abnormalities (pseudopseudohypoparathyroidism), tion in postmenopausal women is thought to be might not be as strongly associated with obesity the result of the loss of estrogen and progester- as PHP1a [48]. one and the relatively rapid decline in GH. Pre- disposition to central obesity in postmenopausal Genetic causes of obesity women is associated with metabolic abnormali- Genetic susceptibility to obesity ties such as increased cholesterol levels and Body weight appears to be determined through plasma glucose [39,40], and may therefore directly an interaction of genetic, environmental and affect the cardiovascular risk. psychosocial factors. The genetic contribution to Despite the lack of change in body weight body weight is thought to work through suscep- with the use of hormonal replacement therapy, tibility genes and heritability estimates of estrogen replacement has been linked to the 40–70% have been constantly reported in family reversal of abdominal obesity in postmenopausal studies and investigations of twins and adopted women as well as improvement of lean body children [49–51]. If both parents are obese, mass [42]. approximately 80% of their offspring will also be obese. If only one parent is obese, the likeli- Insulinoma hood of obese offspring falls to 10%. Human Insulinoma is an extremely rare disease charac- obesity appears to be polygenic in the majority terized by tumoral excessive insulin secretion, of cases. manifesting clinically by frequent hypoglyc- emias, inconstantly associated with neuroglyco- Single-genes causes of obesity penic and autonomic symptoms. Insulinomas During the past few decades, intensive research are associated with obesity in 18–39% of indi- led to the identification of several genes involved viduals [43]. Weight gain in these patients is in signaling between peripheral sites and the believed to be related to excessive caloric intake hypothalamic center of satiety and hunger, such in order to avoid hypoglycemia and is usually as leptin, pro-opiomelanocortin (POMC), pro- reversible after surgical treatment. hormone convertase 1 and melanocortin 4 receptor (MC4R) genes. In most cases, these Pseudohypoparathyroidism gene mutations lead to abnormal eating behav- Pseudohypoparathyroidism type 1a (PHP1a) is iors followed by the development of severe early- an autosomal dominant disease due to maternal onset obesity, which is usually not associated transmission of a mutation of the GNAS1 gene, with other abnormal features. Obesity based on a leading to an inability to activate adenyl cyclase mutation of one gene product is called and therefore causing target-organ unresponsive- monogenic obesity. ness to multiple hormones, including parathy- roid hormone (PTH), TSH, luteinizing Leptin & leptin receptor deficiency hormone, follicle-stimulating hormone and Produced mostly by adipose tissue, leptin is a GHRH. Multiple pathways affected by GNAS1 hormone that plays a determinant role in signal- mutation might contribute to the development ing the brain regarding the quantity of stored fat futurefuture sciencescience groupgroup www.futuremedicine.com 645 REVIEW – Karam & McFarlane

and, with respect to food intake, acting in the mutations do not specifically present with binge- hypothalamus to reduce the production of neu- eating disorder or a history of early-onset ropeptide Y2, one of the most potent stimulators obesity [62]. The onset and severity of the obesity of appetite [52,53]. in the carriers is related to the functional severity While leptin levels were found to be elevated of the MC4R mutations. Although there is no in most obese individuals, suggesting possible specific therapy at this time for MC4R defi- leptin resistance, congenital leptin and leptin- ciency, research is open to potential development receptor deficiencies due to mutations in the lep- of MC4R agonists in heterozygote forms of the tin or leptin-receptor genes have been described disease [64]. in few families, mostly from Pakistan, Turkey and Algeria [54–56]. Clinically, these patients Syndromic obesity present with profound hyperphagia and early- Severe obesity is a characterisitic feature of onset obesity, as well as hyperinsulinemia, many congenital and genetic disorders, such as hypothalamic hypothyroidism and hypogonado- AHO, Alstrom–Hallgren syndrome, Bar- tropic hypogonadism. Therapy with physiologic det–Biedl syndrome, Beckwith–Wiedeman syn- doses of leptin resulted in a dramatically drome, Carpenter syndrome, Cohen syndrome decreased food intake and substantial reduction and Prader–Willi syndrome (PWS), the latter in weight and fat mass [57,58]. being one of the most common syndromic forms of obesity in children [65]. In addition to POMC deficiency being overweight, children with genetic syn- POMC is the precursor of ACTH, lipotropin, dromes associated with obesity typically have α-melanocyte-stimulating hormone (α-MSH), characteristic physical findings, including dys- β-MSH and endorphin. Bioactive peptides morphic features, developmental delay and derived from this prohormone are generated in mental retardation. neurons of the hypothalamus and act as endogenous ligands for the MC4R, a key molecule in Prader–Willi syndrome appetite control and energy homeostasis. Con- PWS is a congenital neurodegenerative disorder genital POMC deficiency has been described in caused by genetic abnormalities of the long arm families, with clinical characteristics of isolated of chromosome 15(q11–13), usually secondary ACTH deficiency (MC2R signaling deficiency), to the deletion of paternal DNA, leading to the hyperphagia with severe early-onset obesity lack of the SNRP gene, which occurs sporadi- (MC3R and MC4R signaling deficiency) and cally [66]. Clinically, PWS results in hypotonic altered skin and hair pigmentation (MC1R sign- infants and later in insatiable obese, mildly aling deficiency), manifesting with red hair in retarded, behaviorally disturbed adolescents and patients of Caucasian origin [59]. Heterozygous adults [67]. Most patients have reduced GH parents are asymptomatic, suggesting an secretion and hypogonadotropic hypo- autosomal recessive mode of inheritance. gonadism, suggesting hypothalamic–pituitary dysfunction [68,69]. Genetic testing usually con- MCR4 deficiency firms the clinical diagnosis. There is no effective Of the five known melanocortin receptors, treatment for most of the problems associated MC4R has been particularly linked to energy with PWS. Nevertheless, encouraging results balance control in rodents and is thought to have been observed with the early admin- mediate most of the anorectic effects of istration of GH, resulting in accelerated growth leptin [60,61]. Mutations of this receptor in and decreased body fat; sex hormone replace- humans represent the most common cause of ment may also be beneficial [69,70]. Obesity monogenic obesity because they are detected in management is crucial in the care of the 1–2.5% of obese patients and almost 6% of patients with PWS; limiting access to food adults with early-onset severe obesity [62,63]. More through close supervision and physical barriers than 30 different mutations of MC4R have been is usually recommended. identified. Homozygous forms are associated with more pronounced obesity. Iatrogenic causes of obesity Clinical spectrum of MC4R includes early Drugs hyperphagia leading to obesity, along with A review of medications is essential in the assess- increase in bone mass. Nonetheless, obese adult ment of obese patients as several drugs are carriers of functionally relevant MC4R known to be associated with weight gain.

646 Therapy (2007) 4(5) futurefuture sciencescience groupgroup Secondary causes of obesity – REVIEW

Anti-diabetic medications Smoking cessation In the UK Prospective Diabetes Study (UKPDS), Smoking cessation has been traditionally linked treatment of diabetic patients with insulin and to a 3–5 kg average weight gain, which is thought sulfonylureas, and not metfomrin, resulted in an to be at least in part due to nicotine average weight gain of 4.8 kg in 3 years [71]. The withdrawal [77]. The potential mechanisms of effect of insulin is usually associated with weight gain include increased caloric intake, increased hunger and appears to be dose-depend- decreased resting metabolic rate, decreased physi- ent [72]. A potential explanation of the weight cal activity and increased lipoprotein lipase activ- gain with insulin is the improved utilization of ity. Therefore, close monitoring of body weight calories through a decrease in glycosuria. and promoting lifestyle changes should be part of Thiazolidinediones use is also classically asso- smoking cessation programs. The use of bupro- ciated with modest weight gain, with preferential pion and nicotine replacement, particularly nico- distribution of fat in the subcutaneous areas and tine gum, might be helpful in preventing weight around the hips [73]. gain in this vulnerable population [77]. Diabetic patients treated with insulin or sulfonylureas or thizolidinediones should be counseled Expert commentary regarding lifestyle changes necessary to avoid In addition to assessing the degree of obesity and weight gain. screening for the associated comorbidities and cardiovascular risk factors, the evaluation of Centrally acting medications obese patients should include screening for Antipsychotics, antidepressants and antiepilep- potentially treatable endocrine, neurologic or tics can increase body weight, probably through genetic conditions. their effect on the monoamines in the CNS. Symptoms of hypothyroidism, hypogonadism, Among newer neuroleptic medications, clozap- glucocorticoid excess, PCOS or hypothalamic ine and olanzapine have been associated with an and pituitary deficits should direct physicians average weight gain ranging between 3–4.4 kg towards a possible underlying endocrine or and an increased risk of diabetes and dyslipi- hypothalamic disorder. The presence of hyper- demia [74,75]. Moreover, schizophrenia has been phagia and early severe obesity, along with a posi- associated with an increased risk of metabolic tive family history of early-onset obesity, supports disturbances and diabetes; this link is poorly a genetic diagnosis. The presence of dysmorphic understood, with a low attribution to the role of features with massive obesity in young patients antipsychotic medication [76]. suggest syndromic obesity. Medications should The antidepressants amiryptilin and paroxet- always be reviewed and alternatives to weight ine have specifically been implicated in weight gain-associated drugs should be offered. gain. Carbamazepine, gababpentin and val- Nonetheless, secondary obesity is rare and proates are anticonvulsants that can cause weight environmental factors on a genetic predisposi- gain as well. Weight-reducing or weight-neutral tion background represent the most common alternatives should always be considered when etiology of obesity. Therefore, lifestyle changes possible in overweight or obese subjects. including dietary modification and increased

Executive summary

• Secondary causes of obesity are rare and can be divided into endocrinological, genetic and iatrogenic etiologies.

• Endocrinologic diseases leading to obesity include hypothyroidism, Cushing’s syndrome, polycystic ovaries syndrome, hypogonadism, growth hormone deficiency, hypothalamic diseases and pseudohypoparathyroidism.

• Early-onset obesity with abnormal eating behavior are suggestive of monogenic obesity, such as leptin deficiency, MCR4 deficiency and pro-opiomelanocortin deficiency.

• Prader–Willi syndrome is characterized by severe obesity in early age with insatiability, mild mental retardation and hypogonadism.

• Several centrally acting medications and antidiabetic agents can be associated with obesity.

• Physicians should recognize potentially treatable secondary causes of obesity.

futurefuture sciencescience groupgroup www.futuremedicine.com 647 REVIEW – Karam & McFarlane

physical activity remain the cornerstone of man- focus of intensive research at different phases of agement of obesity, even in several of the second- development. Identifying the genetic basis of ary causes of obesity such as drug-induced obesity will certainly open the door to novel ther- obesity, postmenopause, PCOS, hypothalamic apeutic agents that could potentially curb the obesity and syndromic obesity. escalating epidemic of obesity.

Future perspective Financial disclosure Although endocrinologic diseases and syndromes The authors have no relevant financial interests, including associated with obesity are well established and employment, consultancies, honoraria, stock ownership or described entities, genetic causes of overweight and options, expert testimony, grants or patents received or obesity remain poorly known and are currently the pending, or royalties related to this manuscript.

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