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 its 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 two nuclei: the posterior hypothalamic nucleus, and the mammillary nucleus in the mammillary bodies.
Anterior Region
Middle Region
Posterior Region
There are numeous causes of hypothalamic dysfunction:
The epidemiology of hypothalamic dysfunction depends on the patient's clinical presentation and the 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 three times their risk 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]
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 produced 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]
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 interrogated.
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 patient's 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).
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:
Other diagnostic tests include:
Treatment depends on the etiology of the hypothalamic dysfunction, as well as the patient's presenting signs and symptoms.
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:
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 patient's hunger and appetite bursts.[50]
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.
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 its 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 of the 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.
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 its function. The 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 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.
[1] | Marshall JC,Eagleson CA,McCartney CR, Hypothalamic dysfunction. Molecular and cellular endocrinology. 2001 Oct 25; [PubMed PMID: 11604221] |
[2] | Rigas A,Farmakis D,Papingiotis G,Bakosis G,Parissis J, Hypothalamic dysfunction in heart failure: pathogenetic mechanisms and therapeutic implications. Heart failure reviews. 2018 Jan; [PubMed PMID: 29052045] |
[3] | Cook N,Miller J,Hart J, Parent observed neuro-behavioral and pro-social improvements with oxytocin following surgical resection of craniopharyngioma. Journal of pediatric endocrinology [PubMed PMID: 27166717] |
[4] | Spallone A,Izzo C,Giannone C, Hypothalamic dysfunctions as a late consequence of surgical opening of the lamina terminalis. A controversial hypothesis. Neuro endocrinology letters. 2012; [PubMed PMID: 23160226] |
[5] | de Vetten L,Bocca G, Systemic effects of hypothermia due to hypothalamic dysfunction after resection of a craniopharyngioma: case report and review of literature. Neuropediatrics. 2013 Jun; [PubMed PMID: 23047234] |
[6] | Krahulik D,Zapletalova J,Frysak Z,Vaverka M, Dysfunction of hypothalamic-hypophysial axis after traumatic brain injury in adults. Journal of neurosurgery. 2010 Sep; [PubMed PMID: 19929195] |
[7] | Tudor RM,Thompson CJ, Posterior pituitary dysfunction following traumatic brain injury: review. Pituitary. 2019 Jun; [PubMed PMID: 30334138] |
[8] | Javed Z,Qamar U,Sathyapalan T, Pituitary and/or hypothalamic dysfunction following moderate to severe traumatic brain injury: Current perspectives. Indian journal of endocrinology and metabolism. 2015 Nov-Dec; [PubMed PMID: 26693424] |
[9] | Puget S,Garnett M,Wray A,Grill J,Habrand JL,Bodaert N,Zerah M,Bezerra M,Renier D,Pierre-Kahn A,Sainte-Rose C, Pediatric craniopharyngiomas: classification and treatment according to the degree of hypothalamic involvement. Journal of neurosurgery. 2007 Jan; [PubMed PMID: 17233305] |
[10] | Feng Y,Ni M,Wang YG,Zhong LY, Comparison of neuroendocrine dysfunction in patients with adamantinomatous and papillary craniopharyngiomas. Experimental and therapeutic medicine. 2019 Jan; [PubMed PMID: 30651764] |
[11] | Marcus HJ,Rasul FT,Hussein Z,Baldeweg SE,Spoudeas HA,Hayward R,Jeelani NUO,Thompson D,Grieve JP,Dorward NL,Aquilina K, Craniopharyngioma in children: trends from a third consecutive single-center cohort study. Journal of neurosurgery. Pediatrics. 2019 Dec 20; [PubMed PMID: 31860822] |
[12] | Castro-Dufourny I,Carrasco R,Pascual JM, Chordoid glioma: A new paradigm of hypothalamic dysfunction? Pituitary. 2017 Jun; [PubMed PMID: 27798757] |
[13] | Bhandare N,Kennedy L,Malyapa RS,Morris CG,Mendenhall WM, Hypopituitarism after radiotherapy for extracranial head and neck cancers. Head [PubMed PMID: 18446838] |
[14] | Sfeir JG,Kittah NEN,Tamhane SU,Jasim S,Chemaitilly W,Cohen LE,Murad MH, Diagnosis of GH Deficiency as a Late Effect of Radiotherapy in Survivors of Childhood Cancers. The Journal of clinical endocrinology and metabolism. 2018 Aug 1; [PubMed PMID: 29982753] |
[15] | Rose SR,Schreiber RE,Kearney NS,Lustig RH,Danish RK,Burghen GA,Hudson MM, Hypothalamic dysfunction after chemotherapy. Journal of pediatric endocrinology [PubMed PMID: 14960022] |
[16] | van Iersel L,Li Z,Srivastava DK,Brinkman TM,Bjornard KL,Wilson CL,Green DM,Merchant TE,Pui CH,Howell RM,Smith SA,Armstrong GT,Hudson MM,Robison LL,Ness KK,Gajjar A,Krull KR,Sklar CA,van Santen HM,Chemaitilly W, Hypothalamic-Pituitary Disorders in Childhood Cancer Survivors: Prevalence, Risk Factors and Long-Term Health Outcomes. The Journal of clinical endocrinology and metabolism. 2019 Dec 1; [PubMed PMID: 31373627] |
[17] | Chemaitilly W,Armstrong GT,Gajjar A,Hudson MM, Hypothalamic-Pituitary Axis Dysfunction in Survivors of Childhood CNS Tumors: Importance of Systematic Follow-Up and Early Endocrine Consultation. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2016 Dec 20; [PubMed PMID: 27998231] |
[18] | Clement SC,Schouten-van Meeteren AY,Boot AM,Claahsen-van der Grinten HL,Granzen B,Sen Han K,Janssens GO,Michiels EM,van Trotsenburg AS,Vandertop WP,van Vuurden DG,Kremer LC,Caron HN,van Santen HM, Prevalence and Risk Factors of Early Endocrine Disorders in Childhood Brain Tumor Survivors: A Nationwide, Multicenter Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2016 Dec 20; [PubMed PMID: 27998218] |
[19] | Baskaran C,Misra M,Klibanski A, Effects of Anorexia Nervosa on the Endocrine System. Pediatric endocrinology reviews : PER. 2017 Mar; [PubMed PMID: 28508601] |
[20] | Sayama T,Inamura T,Matsushima T,Inoha S,Inoue T,Fukui M, High incidence of hyponatremia in patients with ruptured anterior communicating artery aneurysms. Neurological research. 2000 Mar; [PubMed PMID: 10763501] |
[21] | Nguyen BN,Yablon SA,Chen CY, Hypodipsic hypernatremia and diabetes insipidus following anterior communicating artery aneurysm clipping: diagnostic and therapeutic challenges in the amnestic rehabilitation patient. Brain injury. 2001 Nov; [PubMed PMID: 11689095] |
[22] | Angulo MA,Butler MG,Cataletto ME, Prader-Willi syndrome: a review of clinical, genetic, and endocrine findings. Journal of endocrinological investigation. 2015 Dec; [PubMed PMID: 26062517] |
[23] | Alves C,Franco RR, Prader-Willi syndrome: endocrine manifestations and management. Archives of endocrinology and metabolism. 2020 May-Jun; [PubMed PMID: 32555988] |
[24] | Laitinen EM,Vaaralahti K,Tommiska J,Eklund E,Tervaniemi M,Valanne L,Raivio T, Incidence, phenotypic features and molecular genetics of Kallmann syndrome in Finland. Orphanet journal of rare diseases. 2011 Jun 17; [PubMed PMID: 21682876] |
[25] | Maione L,Dwyer AA,Francou B,Guiochon-Mantel A,Binart N,Bouligand J,Young J, GENETICS IN ENDOCRINOLOGY: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing. European journal of endocrinology. 2018 Mar; [PubMed PMID: 29330225] |
[26] | Dhanwal DK,Vyas A,Sharma A,Saxena A, Hypothalamic pituitary abnormalities in tubercular meningitis at the time of diagnosis. Pituitary. 2010 Dec; [PubMed PMID: 20495961] |
[27] | Mohammed H,Goyal MK,Dutta P,Sharma K,Modi M,Shah F,Shree R,Jain A,Jain G,Khandelwal N,Sharma N,Lal V, Hypothalamic and pituitary dysfunction is common in tubercular meningitis: A prospective study from a tertiary care center in Northern India. Journal of the neurological sciences. 2018 Dec 15; [PubMed PMID: 30321796] |
[28] | Burfeind KG,Yadav V,Marks DL, Hypothalamic Dysfunction and Multiple Sclerosis: Implications for Fatigue and Weight Dysregulation. Current neurology and neuroscience reports. 2016 Nov; [PubMed PMID: 27662896] |
[29] | Rao R,Dimitriades VR,Weimer M,Sandlin C, Neurosarcoidosis in Pediatric Patients: A Case Report and Review of Isolated and Systemic Neurosarcoidosis. Pediatric neurology. 2016 Oct; [PubMed PMID: 27524272] |
[30] | Ma GM,Chow JS,Taylor GA, Review of paraneoplastic syndromes in children. Pediatric radiology. 2019 Apr; [PubMed PMID: 30877339] |
[31] | Graziani A,Casalini P,Mirici-Cappa F,Pezzi G,Giuseppe Stefanini F, Hypoventilation improvement in an adult non-invasively ventilated patient with Rapid-onset Obesity with Hypothalamic Dysfunction Hypoventilation and Autonomic Dysregulation (ROHHAD). Pneumologia (Bucharest, Romania). 2016 Oct-Dec; [PubMed PMID: 29543408] |
[32] | Al-Harbi AS,Al-Shamrani A,Al-Shawwa BA, Rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation in Saudi Arabia. Saudi medical journal. 2016 Nov; [PubMed PMID: 27761566] |
[33] | Meczekalski B,Katulski K,Czyzyk A,Podfigurna-Stopa A,Maciejewska-Jeske M, Functional hypothalamic amenorrhea and its influence on women's health. Journal of endocrinological investigation. 2014 Nov; [PubMed PMID: 25201001] |
[34] | Ortiz JB,Sukhina A,Balkan B,Harootunian G,Adelson PD,Lewis KS,Oatman O,Subbian V,Rowe RK,Lifshitz J, Epidemiology of Pediatric Traumatic Brain Injury and Hypothalamic-Pituitary Disorders in Arizona. Frontiers in neurology. 2019; [PubMed PMID: 32038466] |
[35] | Ghigo E,Masel B,Aimaretti G,Léon-Carrión J,Casanueva FF,Dominguez-Morales MR,Elovic E,Perrone K,Stalla G,Thompson C,Urban R, Consensus guidelines on screening for hypopituitarism following traumatic brain injury. Brain injury. 2005 Aug 20; [PubMed PMID: 16195185] |
[36] | Aimaretti G,Ambrosio MR,Benvenga S,Borretta G,De Marinis L,De Menis E,Di Somma C,Faustini-Fustini M,Grottoli S,Gasco V,Gasperi M,Logoluso F,Scaroni C,Giordano G,Ghigo E, Hypopituitarism and growth hormone deficiency (GHD) after traumatic brain injury (TBI). Growth hormone [PubMed PMID: 15135791] |
[37] | Popovic V, GH deficiency as the most common pituitary defect after TBI: clinical implications. Pituitary. 2005; [PubMed PMID: 16508711] |
[38] | Zhang S,Zhornitsky S,Le TM,Li CR, Hypothalamic Responses to Cocaine and Food Cues in Individuals with Cocaine Dependence. The international journal of neuropsychopharmacology. 2019 Dec 1; [PubMed PMID: 31420667] |
[39] | Samodien E,Johnson R,Pheiffer C,Mabasa L,Erasmus M,Louw J,Chellan N, Diet-induced hypothalamic dysfunction and metabolic disease, and the therapeutic potential of polyphenols. Molecular metabolism. 2019 Sep; [PubMed PMID: 31300352] |
[40] | Razolli DS,Moura-Assis A,Bombassaro B,Velloso LA, Hypothalamic neuronal cellular and subcellular abnormalities in experimental obesity. International journal of obesity (2005). 2019 Dec; [PubMed PMID: 31548571] |
[41] | Sergi D,Williams LM, Potential relationship between dietary long-chain saturated fatty acids and hypothalamic dysfunction in obesity. Nutrition reviews. 2020 Apr 1; [PubMed PMID: 31532491] |
[42] | Carraro RS,Souza GF,Solon C,Razolli DS,Chausse B,Barbizan R,Victorio SC,Velloso LA, Hypothalamic mitochondrial abnormalities occur downstream of inflammation in diet-induced obesity. Molecular and cellular endocrinology. 2018 Jan 15; [PubMed PMID: 28760600] |
[43] | Araujo EP,Moraes JC,Cintra DE,Velloso LA, MECHANISMS IN ENDOCRINOLOGY: Hypothalamic inflammation and nutrition. European journal of endocrinology. 2016 Sep; [PubMed PMID: 27006108] |
[44] | Zárate A,Saucedo R, [The adiposogenital distrophy or Frohlich syndrome and the beginning of the concept of neuroendocrinology]. Gaceta medica de Mexico. 2007 Jul-Aug; [PubMed PMID: 17969845] |
[45] | Castro-Dufourny I,Carrasco R,Prieto R,Pascual JM, Infundibulo-tuberal syndrome: the origins of clinical neuroendocrinology in France. Pituitary. 2015 Dec; [PubMed PMID: 26093764] |
[46] | Gupta V,Lee M, Central hypothyroidism. Indian journal of endocrinology and metabolism. 2011 Jul; [PubMed PMID: 21966662] |
[47] | Garrahy A,Moran C,Thompson CJ, Diagnosis and management of central diabetes insipidus in adults. Clinical endocrinology. 2019 Jan; [PubMed PMID: 30269342] |
[48] | Refardt J, Diagnosis and differential diagnosis of diabetes insipidus: Update. Best practice [PubMed PMID: 32387127] |
[49] | Ono D,Yamanaka A, Hypothalamic regulation of the sleep/wake cycle. Neuroscience research. 2017 May; [PubMed PMID: 28526553] |
[50] | Swaab DF, Prader-Willi syndrome and the hypothalamus. Acta paediatrica (Oslo, Norway : 1992). Supplement. 1997 Nov; [PubMed PMID: 9401539] |