Ask The Experts

Would You Recognize and Know How to Treat Hypothalamic Obesity?

Hypothalamic obesity is a treatment-resistant subtype of obesity, requiring early diagnosis and progressive therapeutic management.

with Eugenie A. Hsu, PhD, and Shana McCormack, MD

How did I become an expert in hypothalamic obesity? The simple answer....my child developed it. I had been counseling clients on weight management for 11 years when my three-year old son was diagnosed with a craniopharyngioma and then experienced rapid weight gain, leading to obesity, shortly after surgical resection of the tumor.

I spent the next six years fighting a losing battle to this aggressive condition that caused my previously healthy child to gain over 100 pounds, develop nonalcoholic fatty liver disease, hyperlipidemia, hypertension, sleep apnea​, ​and joint​ ​pain; and if that wasn’t bad enough, this constellation of avoidable, obesity-driven conditions severely reduced his quality of life. 

Following treatment for a benign brain tumor, patients may develop an aggressive form of obesity.f

How Does Hypothalamic Obesity Differ from Generalized Obesity?

Craniopharyngiomas are nonglial, intracranial tumors affecting the hypothalamus. Albeit rare, the incidence of craniopharyngiomas is 0.5–2.0 cases per million individuals annually with approximately half of all cases diagnosed in childhood and adolescence​​.

​Rapid weight gain in individuals with a history of a craniopharyngioma is a likely sign of ​hypothalamic obesity—​a form of obesity that arises following damage to the posterior hypothalamus​; some definitions require one pituitary hormonal deficit as additional evidence of hypothalamic damage.2

​​Some individuals with hypothalamic obesity may exhibit hyperphagia, a form of disordered eating that is characterized by abnormal food-seeking behavior such as sneaking or stealing food while others will develop obesity without the obvious excessive hunger and overeating.

Another sign that the unexplained rapid weight gain is not attributable to generalized obesity is that it ​doesn’t respond to conventional treatment such as caloric restriction and lifestyle modification.3​  

Other common symptoms to watch for:

Craniopharyngiomas account for half of the reported cases of hypothalamic obesity, with lesser occurrences arising from other posterior fossa tumors (such as astrocytoma and medulloblastoma).

The syndrome has also been reported in instances of pseudotumor cerebri, trauma, and infiltrative or inflammatory diseases of the hypothalamus,3​as well as in patients with genetic disorders such as Prader-Willi and Bardet-Biedl Syndromes.4​

Implications of Delayed Diagnosis of Hypothalamic Obesity

Any delay in making a diagnosis of a craniopharyngioma is likely to increase the development of hypothalamic obesity, challenging the long-term prognosis of these patients. ​Furthermore, hypopituitarism is prevalent in anyone who has had a craniopharyngioma given the likelihood that the tumor will invade and destroy some or all of the pituitary gland.

The precipitous development of obesity not only produces a significant adverse impact on quality of life and increases the risk of earlier onset of cardiovascular comorbidities, hypothalamic obesity may also lead to an acceleration in comorbidities, and hastened mortality, if effective treatment is not initiated.4

Regardless of the timing ​of ​disease onset, the repercussions of obesity will manifest throughout adulthood. ​It’s important to note that an extremely high rate of hypothalamic obesity (30-70%) has been documented after craniopharyngioma treatment.5

Some investigators have proposed that hyperinsulinemia ​may be an important driver of weight gain in patients with hypothalamic obesity in response to increases in parasympathetic and decreased sympathetic activity​.3 In fact, one possible mechanism leading to appetite stimulation in individuals with hypothalamic obesity may be the dysregulation of insulin, which remains under study.4 ​​

This dynamic promotes lipogenesis and stimulates the sensation of hunger, complicating any efforts toward slowing weight gain. This differs from the hyperinsulinemia seen in a person with nonhypothalamic-related obesity, which may be caused by insulin resistance. Although insulin resistance may arise in patients with hypothalamic obesity, it may not  be the initial driving force behind the hyperinsulinemia.

Hypothalamic Obesity, A Complication of Craniopharyngiomas 

According to Nathan C. Bingham, MD, PhD, assistant professor of pediatrics at the Monroe Carell Jr. Children's Hospital at Vanderbilt University Medical Center, in Nashville, Tennessee:5 “As a primary result of  the tumor, the majority of patients present with one or more hypothalamic-pituitary deficits including:  growth hormone, gonadotropins, adrenocorticotrophic hormone (ACTH), TSH, and or antidiuretic hormone.”  

In addition to sudden, excessive weight gain in an estimated 58% of patients observed in the first six months following surgery, primary symptoms arising from a craniopharyngioma include visual impairment and endocrine deficits as well as an adverse impact on quality of life.5

Damage to the hypothalamus appears to disrupt the ability of the neuroendocrine system to maintain appetite control, satiety, and energy balance. When normal hunger/fullness signaling is disrupted, the necessary feedback loop is disturbed, which in turn, seems to produce a perpetual state of perceived starvation. The result is a physiological decrease in energy expenditure, which is the most common and consistent feature of hypothalamic obesity in both adults and children.5

The most common complaints raised by patients with hypothalamic obesity are persistent fatigue, and lack of ability to do any physical activity.3​ Another hallmark of individuals with a history of childhood craniopharyngioma is a disruption in the circadian rhythm, which manifests as greater daytime sleepiness leading to diminished physical activity in comparison to BMI-matched healthy controls.1

This constellation of factors is what drives the accelerated weight gain, which requires early and aggressive intervention to slow, if not inhibit, the onset of obesity.

Treatment Approach for Craniopharyngioma Impacts HO Outcome

It is quite clear that treatment strategies aimed to preserve hypothalamic integrity are mandatory for the prevention of hypothalamic obesity,​​ ​and it is of utmost importance that patients diagnosed with a craniopharyngioma be referred to a major medical center with demonstrated experience in treating such tumors in order to assure optimal outcomes in this hard-to-treat cohort.1​​

Standard therapuetic options include surgery, proton therapy, radiation therapy, chemotherapy or some combination of these which should ideally be aimed at preserving hypothalamic integrity.  As well—a phase 2 clinical trial that aims to preserve hypothalamic function is underway at St. Jude Children’s Research Hospital using proton therapy to treat the tumor.6

When pediatric craniopharyngiomas are treated with surgical resection, presurgical imaging should be done to achieve the most accurate grading with the goal of hypothalamic-sparing to minimize long-term adverse effects.7

Hypothalamic obesity can arise due to the tumor, as an adverse effect of surgery, and from radiotherapy;3 therefore, experience in treating craniopharyngiomas and a thorough understanding possible patient outcomes should be considered when advising a family to seek treatment from a neurosurgeon, radiation oncologist, and treatment facility.

Strategies for this Difficult-to-Treat Condition

Hypothalamic obesity is considered a treatment-resistant condition. A limited number of studies have looked at pharmacological treatments for hypothalamic obesity. One promising treatment is carbetocin, an oxytocin analogue; Dykens et al, recently completed a small, randomized, placebo-controlled trial demonstrating significant improvement in hyperphagia during treatment with carbetocin (an oxytocin analogue) in 17 children who were between 10-18 years with Prader-Willi syndrome.8

Case Study Demonstrates Efficacy of Combination Therapy

Based on the experience of a case-based study,9 ​Eugenie A. Hsu, PhD, a psychologist at Kaiser Permanente Oakland Medical Center in California, achieved success with a combination of low-dose intranasal oxytocin and naltrexone in a 13-year old child.​ Naltrexone, an opiate antagonist, ​appears effective in deterring hedonic eating, enhancing the effects of oxytocin. ​

Oxytocin is a ​hypothalamic ​neuropeptide responsible for energy regulation​ and has been shown to exert anorexigenic effects in animal studies: however, unlike other hypothalamic and pituitary hormones, oxytocin is not routinely replaced in patients diagnosed with hypopituitary craniopharyngioma.​9  ​

In this case report,9 the patient exhibited improved satiety and decreased preoccupation with food following therapeutic treatment with a combination of oxytocin and naltrexone, says Dr. Hsu.

“In addition, this patient achieved a decreased body mass index from obese to normal, which is one of the primary interests of individuals with hyperphagia and hypothalamic obesity. It’s important to note that the diet (lower carb, and limited access to sugar) remained the same from one year prior to initiation of the study and through the 48-week trial; otherwise, the patient was permitted an open kitchen with free access to food after oxytocin’s effect started to kick in,” Dr. Hsu tells EndocrineWeb.

Stimulants, such as dextroamphetamine and methylphenidate have been shown to provide a modest reduction in the velocity of weight gain in patients with hypothalamic obesity​​.4 ​Therapies that target efferent pathways may be more efficacious, as one of the primary mechanisms stimulating appetite in this form of obesity may be a primary excess of insulin. 

Christian L. Roth, MD, professor of medicine at the University of Washington in Seattle, is currently studying the prescribing of the GLP-1R agonist, exenatide, in children and adults with hypothalamic obesity so we should look out for these results to inform treatment going forward.

A variety of medications may prove useful in this specific patient population, such bupropion/naltrexone, phentermine/topiramate, pram​i​lintide, as well as other common weight loss agents, such as orlistat, which have not been studied in this population but may be considered.

How Do Common Endocrinopathies Complicate Weight Control?

Compounding the problem of a severely slowed metabolism, hyperphagia, decreased physical activity, hyperinsulinemia, and disrupted negative feed-back inhibition of satiety signals, is the presence of multiple endocrinopathies in many individuals with hypothalamic obesity.5 ​Careful management of hormonal deficits, including cortisol, thyroid, and growth hormone, presents as an essential management strategy for weight control in these patients.5

Glucocorticoid excess is another factor involved in of significant weight gain, impaired glucose metabolism, sleep disturbances and defects in bone metabolism and growth. These patients should be given the lowest dose (glucocorticoid) possible to avoid symptoms of adrenal insufficiency to avoid stimulating weight gain.

Thyroid replacement should be targeted at the fT4 receptor in patients falling in the upper third of the normal range in order to maximize metabolism. ​In a small study of 10-24 year old young adults with hypothalamic obesity who were given liothyronine in addition to levothyroxine, some benefit was found.

Adults and children who may not be growth hormone-deficient also benefit from adult doses of human growth hormone, in order to induce a state of anabolism and increase energy. GH doses should be titrated to keep IGF- 1 levels in within the median range.5

Consider the Viability of Bariatric Surgery

In pediatric craniopharyngioma patients, nonreversable bariatric procedures are controversial because of legal and ethical considerations;however, there are surgeons at major pediatric obesity centers, such as Thomas Inge, MD, PhD, director of adolescent bariatric surgery and the Akers Endowed Chair in Pediatric Surgery at Children’s Hospital Denver in Colorado, who perform gastric bypass procedures in children with hypothalamic obesity after diet and pharmacologic interventions have failed.

Rose et al,4 found that Roux-en-Y gastric bypass has been shown to be the most effective type of bariatric surgery for hypothalamic obesity, although longer-term data are needed to determine the lasting long-term effects of surgery on weight control. “Surgical therapies should be considered for hypothalamic obesity patients with extreme levels of obesity who are at risk of early elevation of comorbidities and cardiovascular mortality​,” according to the authors.

Exercise aimed at increasing lean body mass, such as weight training, yoga, pilates, barre, etc, are likely to be very helpful at increasing resting energy expenditure and decreasing fat mass.

The Role of Dietary Intervention Guided by an Experienced Dietitian

Due to the dearth of literature on the right diet for patients with hypothalamic obesity, I draw on the lessons learned with my son to create a resource for others. In ​Hungry for Solutions​,10 I provide detailed nutritional strategies that have been effect​ive​ in prompting a 40-pound weight loss, in my nine-year old child​, and subsequently, as well as substantial weight loss in several other children with hypothalamic obesity​, thereby avoiding the need for any of them to require bariatric surgery.

My book is written for young patients and their parents; however, I have included a chapter for dietitians, physicians and nurse practitioners, as a clinical guide for counseling patients with hypothalamic obesity.

What seems to be the most effective nutritional intervention for sustained weight loss and decreased comorbidities in many children with this rare form of obesity is a low or controlled carbohydrate (50-100 grams per day), very low sugar, low processed food plan.10 

Another option worth considering is a ketogenic or very low carbohydrate diet (< 50 grams of carbohydrate per day), which may be beneficial in patients in whom a low or controlled-carb diet does not lead to sufficient weight loss; these patients should be monitored closely for sodium abnormalities.

Parents should be advised that it may be a necessity to prohibit open access to food in children with a diagnosis of hypothalamic obesity; putting a lock on food storage areas is best done when the child exhibits behaviors like food seeking or stealing.10

The most important takeaway message for clinicians is that the management that hypothalamic obesity must be aggressive. Healthcare practitioners must be willing to initiate interventions sooner and to consider progressive, combination therapies to best serve their patients who do not have the luxury of waiting years for multicenter drug trials.

In my experience, treatment of hypothalamic obesity is most successful when it is attacked from several angles simultaneously. Therefore, a multimodal plan that includes: diet, physical activity, pharmacologic, aggressive thyroid replacement to maximize metabolism, prescribing the lowest glucocorticoid dose possible, and using adult doses of human growth hormone supplementation, even in the absence of a growth hormone deficiency, should be initiated.

“Until hypothalamic obesity sufferers can rely upon a gold standard intervention, I assert that successfully treating hypothalamic obesity demands thinking outside the box with cutting-edge approaches,” says Dr. Hsu.

"Given the multiple mechanisms that likely drive excess weight gain in hypothalamic obesity, it is likely that individualized, rational combinations of therapies may be most effective in this condition," Shana McCormack, MD, MTR, scientific director of the Neuroendocrine Center at Children’s Hospital of Philadelphia, tells EndocrineWeb. Dr. McCormack is currently studying the efficacy of prescribing intranasal oxytocin for hypothalamic obesity in both children and adults.

Neither the author or Dr. Hsu have any relevant financial conflicts; Dr. McCormack serves on the board of Rhythm Pharmaceuticals, Reata Pharmaceuticals, and is the principal investigator of a study supported by Levo Pharmaceuticals.

Continue Reading:
Adults with Obesity: Clinical Practice Guideline for Office Visits
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