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Last updated: April 27, 2022
Years published: 2021
NORD gratefully acknowledges Shana E. McCormack, MD, MTR, Scientific Director, Neuroendocrine Center in the Division of Endocrinology and Diabetes, Childrenโs Hospital of Philadelphia; M. Jennifer Abuzzahab, MD, Pediatric Endocrinologist, McNeely Pediatric Diabetes Center and Endocrine Clinic, Childrenโs Minnesota; Ashley H. Shoemaker, MD, MSCI, Assistant Professor of Pediatrics, Vanderbilt University Medical Center; and Christian L. Roth, MD, Professor, Seattle Childrenโs Hospital, for the preparation of this report.
Summary
โHypothalamic obesityโ refers to excess weight gain that may follow from an injury to the hypothalamus, a brain region with many important functions. The hypothalamus affects energy intake, by regulating how much we eat, and energy expenditure, by regulating how much energy our bodies use. Damage to the hypothalamus disrupts the carefully coordinated balance between energy intake and expenditure, often leading to increased calorie intake and/or decreased calorie burning, and thereby to rapid weight gain. This weight gain can be difficult to reverse with currently available treatments. The term โhypothalamic obesityโ in clinical practice, and for the purposes of this report, is often used to refer specifically to obesity caused by anatomical injury to the hypothalamus. In contrast to these acquired forms of hypothalamic obesity, there are many genetic disorders that affect the function of the hypothalamus and include a tendency to excess weight gain, for example, Prader-Willi syndrome. Also, some individuals born with malformations of the brain may also experience hypothalamic dysfunction and excess weight gain. These genetic or inborn conditions highlight the importance of the hypothalamus for metabolism. For purposes of this report, however, the focus is on acquired hypothalamic obesity. Frequently, acquired hypothalamic obesity is a complication of the surgical removal of a hypothalamic brain tumor, or a complication of the tumor itself. Tumors that arise from the pituitary gland or invade the hypothalamus such as craniopharyngiomas, germinomas, gliomas, hamartomas and pituitary adenomas.1 Other causes of acquired hypothalamic obesity include traumatic brain injury, infectious or inflammatory injury, radiation or hemorrhage (bleeding in the brain).
The hypothalamus regulates the balance between eating calories and burning off calories; damage to this area affects different people in different ways. Some individuals are excessively hungry (hyperphagia) and/or are not easily satisfied by food. Others gain weight rapidly even when restricting calories due to a low resting metabolic rate which results in the individual burning fewer calories (energy) at rest, and individuals also tend to have lower levels of physical activity and exercise. The etiology, magnitude and severity of abnormalities in hypothalamic regulation of energy balance distinguish hypothalamic obesity from โcommonโ forms of obesity.
The hypothalamus influences other body functions besides energy balance, and as a result, individuals with hypothalamic obesity can also have other related health problems. One very frequently encountered health problem is hypopituitarism. The pituitary gland is often called the โmaster glandโ because it governs the production of endocrine hormones throughout the body. The pituitary gland, in turn, receives signals from the hypothalamus. Individuals with damage to the hypothalamus and/or pituitary often require medications to treat endocrine hormone deficiencies. Without proper supplementation, some of these hormone deficiencies, such as growth hormone deficiency or hypothyroidism, can also contribute to the development of obesity. Other health issues include fluid and electrolyte balance problems, difficulties with heart rate and blood pressure regulation, sleep problems, day-night (circadian) problems and difficulties with body temperature regulation. Tumors in this area can also damage the optic nerves and chiasm, leading to visual impairment, including blindness. Hypothalamic injury, along with the condition that produced the injury, can have complex psychosocial effects as well, on both the affected individual and their family.
Currently, there are no FDA approved treatments specifically for hypothalamic obesity, highlighting a substantial unmet need. There are strategies that may have some benefit, though responses are not uniform in all affected individuals. Indeed, there is substantial variation between individuals with hypothalamic obesity, thus the most appropriate management approach will be personalized and delivered by an experienced, multi-disciplinary team. Nutrition, physical activity, behavior, medication and in some cases, surgery, can all play a role. Identifying and treating related disorders is critical. It is also vital to ensure there are mental and behavioral health supports in place to help individuals with hypothalamic obesity thrive while also managing their medical conditions.
History
Some of the earliest insights about the many roles of the hypothalamus in health and disease come from historical descriptions of individuals with hypothalamic brain tumors.2 Individuals with hypothalamic tumors often came to medical attention for the combination of obesity and hormone deficiencies. Notably, both Dr. Joseph Babinski (in 1900)3 and Dr. Alfred Froehlich (in 1901)4 described individuals with tumors in the hypothalamic/pituitary region who developed obesity and did not experience typical pubertal development. Critically, Dr. Paul Ehrlich (in 1904) argued that it was damage to the hypothalamus, and not the pituitary, that lead to the symptoms of the tumor. Subsequent studies by Dr. Harvey Cushing and others in experimental animal models showed that hypothalamic injury was the true cause of the weight gain and hormone problems.2
Historically, acquired hypothalamic obesity has been referred to as Froehlich syndrome or adiposogenital dystrophy, but these terms are no longer in widespread clinical use.
The key clinical feature of acquired hypothalamic obesity is excess weight gain following injury to the hypothalamus. The patientโs clinical presentation depends on the cause of the injury. For individuals with hypothalamic obesity related to brain tumors, a minority are obese at the time they are diagnosed with the brain tumor, suggesting that the brain tumor has already caused damage leading to weight gain that is unfortunately likely to be persistent.5 More often, weight gain occurs after the tumor is removed surgically, suggesting a side effect of traditional surgical approaches is hypothalamic obesity and excess weight gain.6 Newer, less invasive surgical techniques, including endoscopic endonasal techniques (approaching the tumor through the nose) may be less likely to cause hypothalamic damage that leads to obesity.7,8 For individuals with hypothalamic damage from other causes, for example, traumatic brain injury or inflammation, the weight gain tends to begin at the time of the injury or very shortly after the acute problem has been treated.
The most common concern expressed by individuals with hypothalamic obesity is how resistant the weight gain is to conventional approaches to weight management, such as healthy nutrition, caloric restriction, and exercise. Another frequent observation is that individuals with hypothalamic obesity use less energy, both at rest9,10 and/or with physical activity and exercise.11 Because their bodies use less energy, individuals find that they can continue to gain weight even when caloric intake is restricted. Some, but not all, individuals also experience a severe disorder of appetite regulation, called hyperphagia, or excess appetite, and rarely feel satisfied after meals.12 These abnormal eating behaviors are often distressing to individuals and families, and further contribute to weight gain. The hypothalamus also regulates other body functions that, when disrupted, cause symptoms. For example, individuals can have difficulty initiating and sustaining sleep. They can have excess daytime sleepiness, related to sleep impairment and also to problems maintaining circadian (day-night) alignment. Some individuals experience difficulties maintaining body temperature within typical range. Some also have challenges with regulating heart rate and blood pressure in response to the bodyโs needs. Individuals with hypothalamic hamartomas can have a particular kind of seizure called gelastic seizures. Tumors located in this area can also lead to damage of the optic nerves and chiasm, leading to visual impairment, including blindness. While hypothalamic and pituitary damage often leads to delayed puberty and hypogonadism, sometimes hypothalamic injury causes early puberty development, which first manifests as breast development in girls and testicular enlargement in boys. Often, individuals are affected by pituitary hormone deficiencies, most notably diabetes insipidus, or vasopressin deficiency, which affects fluid balance. (See โRelated Disordersโ and โClinical Testing and Work-upโ sections below for additional details regarding hypopituitarism.)
The single most important cause of acquired hypothalamic obesity is injury to the parts of the hypothalamus that regulate energy balance. Magnetic resonance imaging (MRI) studies have found that damage in particular areas in the hypothalamus towards that back of the brain, including the mamillary bodies, predicts obesity after surgical resection of a brain tumor.13 Other risk factors for the development of future obesity include obesity at the time of treatment, and in individuals with brain tumors, papilledema, or swelling in the back of the eye indicating high pressure around the brain, at time of initial diagnosis.5 Finally, children whose mothers had higher body mass index (BMI) at diagnosis were also at increased risk for future obesity, indicating that complex genetic and environmental factors can continue to contribute to weight gain even in hypothalamic forms of obesity.14
Multiple factors likely combine to cause excess weight gain after hypothalamic injury, and individuals vary in the extent to which they experience these different phenomena.15 These factors include: decreased energy use (both at rest, and with activity), increased appetite and decreased sense of being full after meals, chronically high circulating levels of the energy-storing hormone insulin, potential resistance to the appetite-regulating hormone leptin, disordered sleep and circadian phase regulation, pituitary hormone deficiencies and psychosocial factors that influence healthful behaviors.16,17 The potential roles for disordered signaling by enteroendocrine hormones and/or neuropeptides that regulate energy balance (e.g., ghrelin, oxytocin) are the focus of investigation. Much remains to be learned from ongoing research.
The epidemiology of acquired forms hypothalamic obesity directly reflects the epidemiology of the underlying causes of hypothalamic injury and rates of associated obesity. Multiple hypothalamic/pituitary brain tumors can lead to hypothalamic obesity. In one registry study, individuals with craniopharyngioma accounted for the majority (62%) of the cohort. By some estimates, there are 0.5-2.5 new cases of craniopharyngioma per 1 million individuals per year.18,19 The adamantinomatous sub-type of craniopharyngioma presents typically at one of two times in life, childhood (ages 5-15y) or middle adulthood (45-60y), while the papillary sub-type occurs almost entirely in adults.20 The epidemiology of the other types of tumors and injuries that lead to hypothalamic obesity demonstrates that this condition can affect individuals at any age.
The diagnosis of hypothalamic obesity is suspected when excess weight gain occurs in the context of a hypothalamic injury, as suggested by brain imaging studies. The diagnosis is additionally supported when the timing of the injury coincides with the onset of brisk and recalcitrant weight gain. The presence of one or more hypothalamic/pituitary hormone deficits is also evidence of clinically relevant injury.21 These signals (evidence of hypothalamic injury by brain imaging, timing of weight gain related to the injury and frequently the presence of other hormone deficits) help distinguish acquired hypothalamic obesity from prevalent โcommonโ obesity that occurs from a complex interaction of genetic and environmental risk factors.
Clinical Testing & Work-Up
Clinical testing in the setting of hypothalamic obesity includes evaluation for disorders related to potential associated hypothalamic/pituitary hormone deficiencies: diabetes insipidus (vasopressin deficiency), adrenal insufficiency (cortisol deficiency), hypothyroidism (thyroid hormone deficiency), growth hormone deficiency, and hypogonadism (deficiency of sex steroids or estrogen in females and testosterone in males). Also, it is important that individuals be evaluated for the myriad potential downstream health effects of obesity, including fatty liver disease, type 2 diabetes mellitus, abnormal lipid profile, sleep-disordered breathing, pseudotumor cerebri syndrome, orthopedic problems and psychosocial/mental health disorders.22 These complications of obesity may occur at excess rates in individuals with hypothalamic obesity as compared to individuals with โcommonโ obesity with similar body mass index (BMI).
At the time of this writing, there are no FDA approved therapies specifically for hypothalamic obesity. Currently, treatment includes evaluation and treatment of the underlying condition and other health problems, as well as trying a variety of strategies to manage obesity, which unfortunately is often not responsive to treatment. Hypothalamic obesity is most appropriately addressed by an experienced, well-coordinated, multi-disciplinary team that designs and implements an individualized treatment approach. This approach should take into consideration other medical problems that the patient has, as well as patient/family circumstances and preferences. Ongoing care for the cause of the injury can help minimize the risk or extent of further hypothalamic injury. For survivors of brain tumors, care includes regular imaging surveillance to ensure early detection of any tumor recurrence. Management of hypothalamic obesity is complex, and includes optimization of pituitary hormone replacement, nutrition (often, lower- or controlled carbohydrate approaches and/or portion control are trialed), physical activity and exercise, mental and behavioral health interventions and sometimes weight loss medications and/or or metabolic/bariatric surgery.17 Overall, aside from surgery, the benefits, if any, of these interventions are modest, and may not be experienced by all patients. Medications with some evidence for potential benefit in at least a sub-set of patients include stimulants, Metformin, and glucagon-like peptide 1 receptor (GLP1R) agonists23; the GLP1R agonist class of medications is growing, and includes agents already approved for โcommonโ forms of both adolescent and adult obesity.23,24 Other medications already approved for use in โcommonโ obesity are also often trialed in hypothalamic obesity, with variable degrees of success. For some patients, metabolic/bariatric surgery is an alternative to consider that may be helpful. For all individuals, it is critical to support both the patient and family at diagnosis and over time, since hypothalamic obesity can have significant impact on function and quality of life.
Individuals with hypothalamic obesity may or may not benefit from newly developed treatments for โcommonโ obesity, and such treatments may pose unique risks in the setting of conditions like hypopituitarism. An important area of research is studying the effects of treatments for โcommonโ obesity specifically in individuals with hypothalamic obesity, with particular emphasis on safety. Since hypothalamic obesity may have causes distinct from โcommonโ obesity, treatments that address, for example, other potential hypothalamic/pituitary hormone problems such as oxytocin deficiency25 or autonomic dysfunction26 may hold promise. Individuals vary in their presentation and experience of hypothalamic obesity, and also experience different responses to treatments. Research is currently focused on strategies to identify the most appropriate treatment approach for each unique individual. Multiple metabolic processes contribute to hypothalamic obesity, so it is expected that a combination of treatments may be most effective. However, how best to combine existing and/or novel therapies is not yet known. Patients and families, in partnership with the research community, can help to address these important questions.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Raymond A. Wood Foundation (includes information on hypopituitarism and hypothalamic obesity)
Website: www.rawoodfoundation.org/hypothalamic-obesity
Obesity Medicine Society (includes information on obesity)
Website: www.obesitymedicine.org
Pediatric Endocrine Society (includes information on hormone replacement and obesity)
Website: www.pedsendo.org
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23. Roth CL, Perez FA, Whitlock KB, Elfers C, Yanovski JA, Shoemaker AH, Abuzzahab MJ. A Phase 3 Randomized Clinical Trial using Once-Weekly GLP-1 Receptor Agonist in Adolescents and Young Adults with Hypothalamic Obesity. Diabetes Obes Metab. 2020. Epub 2020/10/08. doi: 10.1111/dom.14224. PubMed PMID: 33026160.
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