Continuing Education Activity

The hypothalamus is the central command center for hormonal regulation. Its effects are primarily carried out by the hormones released from the hypothalamus to their target organs, including the pituitary gland, adrenal gland, thyroid gland, and ovaries and testes. Numerous dysfunctions may manifest as a result of hypothalamic injury, including body temperature, growth, weight, water balance, milk production, emotions, and even sleep cycles. This activity will review the role of the interprofessional team in the evaluation and treatment of hypothalamic dysfunctions.

Objectives:

• Identify the associated signs and symptoms of hypothalamic dysfunction according to the affected area and physiological function.
• Summarize the evaluation in patients with hypothalamic dysfunction.
• Outline the management options available for hypothalamic dysfunction.

Introduction

The hypothalamus is a part of the diencephalon composed of several small nuclei that have different physiologic functions. One of the main functions of the hypothalamus is to maintain homeostasis by controlling the endocrine and autonomic functions; nevertheless, it participates in other functions such as body temperature regulation, appetite, and weight, childbirth, growth, breast milk production, sleep-wake cycle, sex drive, emotions, and behavior. A disorder of the hypothalamus can cause different signs and symptoms, depending on the particular affected area. Clinical manifestations vary, depending on the affected hypothalamic nuclei and their functions. Certain signs and symptoms can be traced to a specific anatomic area because of this functional organization within the hypothalamus.[1]

Anatomically, this structure can be organized in the sagittal plane into three main regions: the anterior, middle, and posterior. Each main region contains hypothalamic nuclei that serve different physiologic functions. The anterior region contains five nuclei: preoptic, paraventricular, supraoptic, suprachiasmatic, and anterior hypothalamic nucleus. The middle region of the hypothalamus is situated directly above the tuber cinereum and the infundibulum and contains three nuclei: the arcuate nucleus, ventromedial nucleus, and dorsomedial nucleus. The posterior region contains the posterior hypothalamic nucleus and the mammillary nucleus in the mammillary bodies. 

Anterior Region

• Preoptic nucleus: the primary function is the production and secretion of gonadotropin-releasing hormone (GnRH) for sex hormone regulation. GnRH is released into the tuberoinfundibular tract and is transported through the hypophyseal portal system to the adenohypophysis. This nucleus also participates in initiating non-rapid eye movement sleep via the inhibition of histaminergic neurons in the hypothalamus and cholinergic and noradrenergic neurons in the brainstem. It also is involved in thermoregulation.
• Paraventricular nucleus: participates in the production and secretion of several hormones, predominantly oxytocin. It also produces and secretes small amounts of vasopressin, also called antidiuretic hormone (ADH). Another hormone produced is a corticotropin-releasing hormone (CRH), which regulates adrenocorticotropin hormone secretion by the anterior pituitary. It also produces thyroid releasing hormone (TRH), which will control hormonal secretion by the thyroid. This nucleus contains glutamate and AngII-releasing neurons, which induce sympatho-excitatory effects, whereas gamma-aminobutyric acid and nitric oxide-releasing neurons induce sympatho-inhibitory effects. These sympathetic effects, when deregulated, have some influence on heart failure.[2]
• Supraoptic nucleus: its secretory functions are similar to the paraventricular nucleus, but its primary function is the production and secretion of vasopressin. This nucleus also produces and secretes oxytocin to a lesser degree than the paraventricular nucleus.
• Suprachiasmatic nucleus: this nucleus receives direct input from retinal ganglion cells and synchronized body functions with periods of light and dark to a circadian rhythm. It projects to the pineal gland, which secretes the hormone melatonin, a sleep-inducing hormone.
• Anterior hypothalamic nucleus: it controls body temperatures, and its function includes cooling or reducing the body temperature.

Middle Region

• Arcuate nucleus: this nucleus releases growth hormone-releasing hormone (GHRH) and produces prolactin-inhibiting hormone (dopamine).
• Ventromedial nucleus: this is the center of satiety or fullness.
• Dorsomedial nucleus: this is an emotional response center. Stimulation of this nucleus, in animal experiments, produced aggressive behavior that lasts only as long as the stimulus is applied. It is also involved with blood pressure, heart rate, and gastrointestinal stimulation.

Posterior Region

• Mammillary nucleus: this nucleus is part of the limbic system, a system that is responsible for memory, behavior, motivation, and motivation. Degeneration of this nucleus classically occurs in Korsakoff syndrome. It is involved in memory, changes in emotion, and heart failure.
• Posterior hypothalamic nucleus: this region participates in blood pressure regulation, pupillary dilation, and thermoregulation, particularly body temperature conservation, such as shivering when a person is cold.

Etiology

 There are numeous causes of hypothalamic dysfunction:

• Brain surgery[3][4][5]
• Traumatic brain injury[6][7][8]
• Brain tumors[9][10][11][12]
• Radiation[13][14]
• Chemotherapy[15][16][17][18]
• Nutritional deficiencies (anorexia nervosa)[19]
• Brain aneurysms[20][21]
• Genetic disorders (Prader-Willi syndrome, Kallmann syndrome)[22][23][24][25]
• Infections[26][27]
• Inflammatory disease (multiple sclerosis, neurosarcoidosis)[28][29]
• Paraneoplastic syndromes[30]
• Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation syndrome[31][32]

Epidemiology

The epidemiology of hypothalamic dysfunction depends on the patient's clinical presentation and etiology. Hypothalamic dysfunction accounts for almost 20 to 35% of the cases of secondary amenorrhea in the United States.[33] Pediatric cancer survivors can present a prevalence of 40.2% for hypothalamic-pituitary dysfunction, predominantly for growth hormone (GH).[16][18] Traumatic brain injury in children will increase their risk three times for developing central endocrine dysfunction compared to the general population.[34] In children with dysfunction, girls have a 2:1 predominance. In the general population with traumatic brain injury, the incidence of hypopituitarism had been reported in the range of 11 to 80%.[35][36][37]

Pathophysiology

The majority of the hypothalamic dysfunction syndromes affect the hypothalamic-pituitary-adrenal axis. Hypothalamic releasing hormones produced at the hypothalamus descend the tuberoinfundibular tract and are transported through the hypophyseal portal system to the adenohypophysis. The adenohypophysis produces specific hormones that are released into the systemic circulation for their effect on the target organs. Many disorders produce hypothalamic hyposecretion, which will cause pituitary hyposecretion. When a hypothalamic inhibitory hormone is altered, then pituitary hypersecretion will occur with its clinical manifestations.

Neurosecretory hypothalamic hormones are produced and packed in the magnocellular cells of the hypothalamus, whose axons project to the neurohypophysis transporting the hormones. The neurohypophysis stores them in the herring bodies, and when needed, they are released into the neurohypophyseal capillaries, which then carry the hormones into the systemic circulation. Disorders affecting the hypothalamus will affect two neurohormones, vasopressin and oxytocin. These hormones will affect the reabsorption of water by the distal tubules of the kidney, the uterine contractions during labor, milk ejection reflex, and sexual response.

Cocaine addiction had been recently associated with hypothalamic dysfunction.[38] Diets with abundant saturated fatty acids cause mitochondrial dysfunction and inflammatory response in the hypothalamus, producing hypothalamic dysfunction, which promotes obesity.[39][40][41][42][43]

History and Physical

The history and physical examination of patients with suspected hypothalamic dysfunction must be tailored according to the patient's clinical manifestation since the signs and symptoms are typically non-specific. Family history for genetic disorders must be obtained.

A lesion affecting either the production or pulsatile secretion of GnRH, which occurs in the preoptic nucleus, can lead to anovulation and amenorrhea, as seen in hypothalamic amenorrhea in which a majority of women exhibit due to a persistent slow frequency of GnRH pulses.[1] Patients with a hypothalamic amenorrhea disorder tend to be very thin or muscular, with deficient adipose tissue. They may also present with lanugo, anxiety, and amenorrhea due to leptin hormone deficiency resulting in hypothalamic dysfunction and, ultimately, estrogen deficiency[33]; nevertheless, these patients' signs and symptoms can also be explained by other different conditions such as hypothyroidism or anorexia nervosa.

Frohlich syndrome causes excessive eating associated with obesity and delayed puberty. It is caused by trauma or tumors affecting the eating centers and the secretion of GHRH and GnRH. Patients present short stature and small testes. The nuclei affected are the arcuate, preoptic, and ventromedial.[44][45]

Kallmann syndrome produces delayed puberty and is associated with anosmia. It is caused by the reduced production of GnRH.[24][25]

In patients with central hypothyroidism, symptoms include fatigue, weight loss, feeling cold all the time, and constipation. Those patients where the adrenal axis is affected have very similar symptoms, including fatigue, weakness, poor appetite, and weight loss.

Children with hypothalamic dysfunction will present short stature, obesity, hypothermia, hypodipsia, developmental delay, generalized seizures, gelastic seizures, and delayed puberty, although sometimes they have precocious puberty.

Evaluation

The diagnostic workup for hypothalamic dysfunction depends on the patient's clinical condition, signs, and symptoms. Typical workup includes blood and urine laboratory tests such as:

• Serum cortisol
• Serum estrogen
• Pituitary hormones (adrenocorticotropic hormone, growth hormone, thyroid-stimulating hormone, luteinizing hormone, follicle-stimulating hormone, prolactin)
• Testosterone
• Thyroid hormones
• Sodium levels
• Blood and urine osmolality

Other diagnostic tests include:

• Brain imaging: magnetic resonance imaging (gold standard) or computed tomographic scan (for emergency cases)
• Visual field test
• Genetic analysis
• Autoimmune markers

Treatment / Management

Treatment depends on the etiology of the hypothalamic dysfunction, as well as the patient's presenting signs and symptoms.

• For tumors, surgery or radiation may be required. Hypothalamic gliomas are usually observed. A biopsy can be performed for those not involving the optic chiasm and tracts.
• For hypothalamic hamartomas, if symptomatic with uncontrolled seizures, surgery is recommended. Thermoablation and radiosurgery can also be used.
• For hormonal deficiencies, therapeutic hormone replacement is used. 
• Nutritional guidance and certain medicines may be used to regulate the patient's appetite.
• Delayed puberty in Frohlich syndrome is treated in males with human chorionic gonadotropin and later with testosterone; in females with estrogen and later estrogen-progestin.[44][45]
• Kallmann syndrome requires lifelong sex hormone replacement.[24][25]

Differential Diagnosis

Sometimes, it is difficult to differentiate between pituitary dysfunction and hypothalamic dysfunction. Depending on the patient's condition, certain diseases can mimic the signs and symptoms of hypothalamic dysfunction:

• In hormonal deficiencies, the differential diagnosis includes pituitary gland lesions as well as the target organ involved (central hypothyroidism due to hypothalamic or anterior pituitary dysfunction vs. thyroid gland dysfunction).[46]
• In electrolyte imbalances, such as hypernatremia due to diabetes insipidus, causes include central diabetes insipidus (due to lack of ADH production and secretion by the hypothalamus) vs. nephrogenic diabetes insipidus (due to ADH resistance or ADH receptor malfunction in the collecting duct of the kidneys).[47][48]
• Increased appetite can result from genetic abnormalities causing hypothalamic dysfunction, as seen in Prader-Willi syndrome, or can be due to other conditions such as hyperthyroidism.[22][23]
• Sleep disorders may be caused by a deficiency in hypothalamic hormones such as orexin/hypocretin or melanin-concentrating hormone.[49] Still, other diagnoses such as substance use, stimulants that alter sleep, psychiatric conditions such as generalized anxiety disorder or major depressive disorder, and REM-sleep behavior disorders can affect sleep patterns.

Prognosis

Prognosis depends on the patient's resulting condition. Many of the manifestations caused by hypothalamic dysfunctions are treatable, in particular, hormone deficiency or overproduction. In patients with a hormone deficiency, hormone replacement therapy is the primary treatment. In cases such as Prader-Willi syndrome, the resulting obesity caused by presumed dysfunction in the ventromedial nucleus of the hypothalamus, treatment requires an interdisciplinary approach to control the patient's hunger and appetite bursts.[50]

Complications

Hormonal deficiencies, such as low production of TRH or CRH, can cause central hypothyroidism or adrenal insufficiency, respectively. These may result in systemic complications such as heart problems and elevated cholesterol in the case of central hypothyroidism and low blood pressure and electrolyte disturbances in the setting of adrenal insufficiency. In those cases with a small production of GHRH, complications will include weakness, short stature, osteoporosis, and high cholesterol. Pituitary sex hormones and oxytocin deficiencies will produce complications or infertility, erection problems, breastfeeding problems, labor difficulty, osteoporosis, and decreased sexual stimulation and response.

For structural causes of hypothalamic dysfunction, as seen in patients with a brain tumor, the complications associated are elevated intracranial pressure, seizures, blindness, or visual field defects.

Deterrence and Patient Education

One of the main functions of the hypothalamus is to maintain homeostasis by controlling the endocrine and autonomic functions. Clinical manifestations vary, depending on the affected hypothalamic nuclei and their function.

The hypothalamus participates in other functions such as body temperature regulation, appetite and weight, childbirth, growth, breast milk production, sleep-wake cycle, sex drive, and even emotions and behavior. Symptoms may include anovulation and amenorrhea, increased appetite, sleep disorders, and behavior disorders.

Many etiologies can not be prevented, but nutritional deficiencies like anorexia nervosa can be avoidable. Nutritional guidance is advised.

Many of the conditions caused by hypothalamic dysfunctions are treatable, in particular, hormone deficiency or overproduction. In patients with a hormone deficiency, hormone replacement therapy is the primary treatment.

Enhancing Healthcare Team Outcomes

Disorders of the hypothalamus frequently pose a diagnostic dilemma. One of the main functions of the hypothalamus is to maintain homeostasis by controlling the endocrine and autonomic functions. The hypothalamus participates in other functions such as body temperature regulation, appetite and weight, childbirth, growth, breast milk production, sleep-wake cycle, sex drive, and even emotions and behavior. Because of this wide variety of physiologic roles, a lesion or disease of the hypothalamus can produce different signs and symptoms, depending on the particular affected area.

Clinical manifestations vary, depending on the affected hypothalamic nuclei and their function. Patients with disorders of the hypothalamus may exhibit non-specific signs and symptoms such as vomiting, nausea, hypernatremia, hyponatremia, and diuresis. The cause of disorders of the hypothalamus may be due to a myriad of disorders, including tumoral, trauma, surgery, inflammatory, infectious, and genetic etiologies. The cause is difficult to know without proper imaging studies.

While the endocrinologist is almost always involved in the care of patients with disorders of the hypothalamus, it is often essential to consult with an interprofessional team of specialists that include a neurosurgeon, pediatrician, and neurologist.

Nurses are also vital members of the interprofessional group as they will monitor the patient and assist with the education of the patient and family. For those patients that require surgery in the postoperative period for hypernatremia, seizure prophylaxis, pain, and wound infection, the pharmacist will ensure that the patient is on the appropriate antibiotics, analgesics, antiemetics, antiepileptics, and antidiuretic medications. The neuroradiologist also plays a vital role in determining the etiology. Women of childbearing age may experience problems during labor and later with breastfeeding.

The care provided to the patient must use an evidence-based approach for evaluation and management. The outcomes of disorders of the hypothalamus depend on the cause. An interprofessional team provides an integrated approach to achieve the best possible outcomes. Collaboration and communication are crucial elements for better results.