The hypothalamus is small, and lesions that come to clinical attention often achieve a considerable size before their recognition, so they are rarely limited to a specific population of neurons or a single hormone axis [1]. Quite the contrary, the complexity of hypothalamic function generally implies a highly heterogeneous and multifaceted presentation of hypothalamic disorders. It should also be noted that the clinical picture varies depending on the patient's developmental stage at the onset of hypothalamic dysfunction.

• Postnatal growth largely depends on the hypothalamic–pituitary–growth axis, and the hypothalamus may either promote or inhibit the release of growth hormone. Accordingly, hypothalamic dysfunction may result in short stature and obesity (due to growth hormone deficiency), or gigantism and acromegaly (excess of growth hormone) [2].
• Hypothalamic dysfunction with disorders of the hypothalamic–pituitary–thyroid axis may result in tertiary hypothyroidism. The latter may be accompanied by poor performance and fatigue, intolerance to cold, bradycardia, myxedema, dry skin, alopecia, constipation, and weight gain. Symptoms like agitation and anxiety, intolerance to heat, excessive sweating, tachycardia, palpitations, arrhythmia, increased bowel movements, increased appetite, and weight loss may hint at hyperthyroidism, which may similarly be caused by hypothalamic dysfunction.
• Deficiencies in the hypothalamic–pituitary–adrenal axis may give rise to tertiary adrenal insufficiency [3]. Affected individuals may suffer from fatigue, generalized weakness, hypotension, and gastrointestinal disorders. They may lose their appetite and weight. The excessive production of corticotropin-releasing hormone may induce tertiary Cushing syndrome, which may manifest in growth retardation, truncal weight gain, rounded face, acne, plethora, striae, hirsutism, hypertension, glucose intolerance or diabetes mellitus, proximal muscle wasting, osteoporosis, nephrolithiasis, as well as amenorrhea and impotence [4].
• The hypothalamic–pituitary–gonadal axis regulates sexual development [5]. Abnormalities in this hormone axis may cause hypogonadotropic hypogonadism. While male infants may show micropenis and cryptorchidism, this condition is most commonly diagnosed on the basis of delayed or absent puberty. Hypogonadotropic hypogonadism may also be associated with sexual dysfunction and infertility. On the other hand, increased levels of gonadotropin-releasing hormone may induce central precocious puberty.
• Both hypoprolactinemia and hyperprolactinemia may be related to hypothalamic dysfunction. These conditions are primarily associated with sexual dysfunction and infertility [6]. In women, they may also cause lactation failure or galactorrhea, respectively.
• Defective regulation of melanotropin release has been linked to abnormal food intake and weight issues, but the respective conditions are poorly characterized.
• Vasopressin acts on the kidneys to reduce water excretion [7]. Accordingly, abnormalities in the release of vasopressin may affect the overall volume of body fluid and the osmolality of blood: On the one hand, vasopressin deficiency provokes central diabetes insipidus with polyuria, polydipsia, and high risks of dehydration, hyperosmolality, and hypovolemia. Excess of vasopressin, on the other hand, is also known as syndrome of inappropriate antidiuretic hormone secretion and water retention, hypoosmolality, and hyponatremia. Finally, damage to the hypothalamic osmoreceptors may produce essential hypernatremia.
• The consequences of abnormal oxytocin release are incompletely understood. Lack of oxytocin has recently been linked to the development of psychiatric disorders associated with impairments in social functioning, such as autism spectrum disorders, schizophrenia, and anxiety disorders [8]. High levels of oxytocin may favor the development of benign prostatic hyperplasia in men.

Besides the aforementioned symptoms, patients with hypothalamic dysfunction frequently suffer from disorders of body temperature, namely with hypothermia, hyperthermia, or poikilothermia [1]. They may also present with sleep disorders, eating disorders, and mood swings and are more likely to develop depression [9].

Depending on the underlying condition, additional symptoms may be present, such as headaches, vomiting, and ophthalmological abnormalities.

• Weight Gain

  We report a patient with hypothalamic dysfunction accompanying volitional weight reduction, whose body weight never fell below ideal body weight and whose hypothalamic function improved following weight gain. [ncbi.nlm.nih.gov]

  Clinical description Disease onset is between 1.5 to 7 years of age with dramatic weight gain (approximately 9-13 kg over a 3-12 month period) associated with alveolar hypoventilation in a previously healthy child. [orpha.net]

  weight gain associated with oligomenorrhea and acne 4 28 19.5 5.3 1.7 Subsequent weight gain associated with oligomenorrhea without evidence of hyperandrogenism 5 29 24.4 7.7 27 Subsequent weight gain associated with oligomenorrhea without evidence of [academic.oup.com]

  Symptoms may include feeling cold all the time, constipation, fatigue, or weight gain, among others. If the adrenal glands are affected, there may be symptoms of low adrenal function. [medlineplus.gov]

• Fatigue

  We discuss three hypothalamic mechanisms of fatigue in multiple sclerosis: (1) general hypothalamic-pituitary-adrenal axis hyperactivity, (2) disordered orexin neurotransmission, (3) abnormal cortisol secretion. [ncbi.nlm.nih.gov]

  Symptoms may include feeling cold all the time, constipation, fatigue, or weight gain, among others. If the adrenal glands are affected, there may be symptoms of low adrenal function. [medlineplus.gov]

  Women and men may experience a lower sex drive, infertility or fatigue. In children and adolescents, delayed puberty is usually the only symptom. [mayoclinic.org]

  Fatigue on top of fatigue is deadening. This is something no physician has ever spoken to me about, even when I bring it up. [brainline.org]

• Hypothermia

  Hypothermia due to hypothalamic dysfunction can result in several systemic complications with complete recovery of all symptoms by rewarming. [ncbi.nlm.nih.gov]

  Citation metadata Abstract : Shapiro syndrome, a rare disorder originally described by Shapiro and Plum in 1967, is characterized by episodic hypothermia and hyperhydrosis associated with agenesis of the corpus callosum. [go.gale.com]

  […] intervals for thyrotropin in an area of Northern Italy: the Pordenone thyroid study (TRIPP). 61 Tozzoli R...Bagnasco M 29340973 2018 8 Pediatric Adrenal Insufficiency: Diagnosis, Management, and New Therapies. 61 Bowden SA...Henry R 30515225 2018 9 Hypothermia [malacards.org]

• Male Hypogonadism

  hypogonadism and infertility 9.1 Definitions and classification of disorders 9.2 Normal male endocrinology 9.2.1 The male gamete: spermatogenesis, maturation, function 9.2.2 Endocrine and local testicular regulation 9.2.3 Testicular hormones 9.3 Evaluation [oxfordmedicine.com]

  Measurement of the serum testosterone concentration is usually the most important single diagnostic test for male hypogonadism because a low value usually indicates hypogonadism. [aetna.com]

• Shivering

  This occurs through shivering, vasoconstriction, pilo-erection, and inhibition of sympathetically induced sweating. Integration of cold sensory input and the warm sensory input from the anterior hypothalamus occurs in the posterior hypothalamus. [emedicine.medscape.com]

  The posterior hypothalamic nucleus helps regulate body temperature by causing shivering and blocking sweat production. The role of the mammillary nuclei is less clear. Doctors believe it’s involved in memory function. [healthline.com]

  If it receives the signal that the temperature is too cold, the body will create its own heat by shivering. To maintain homeostasis, the hypothalamus is responsible for creating or controlling many hormones in the body. [medicalnewstoday.com]

• Overeating

  These findings suggest that continued use of metreleptin over a longer time frame may have beneficial effects on bone metabolism. [pnas.org]

  Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem. [clinicaladvisor.com]

  Research suggests that there may be a fluidity between PCOS and HA in many amenorrheic patients such that women may have significant cross-over between both entities. [haveababy.com]

  Over time, having too much glucose in your blood can cause health problems, such as heart disease, nerve damage, eye problems, and kidney disease.E23.2 Безвкусен диабет. [uzade.me.ht]

  Martin founded the practice over 30 years ago to provide outstanding care to hopeful parents. [fertilitysa.com]

• Sweating

  Here, we described a case with Shapiro syndrome who presented to our psychiatry clinic with recurrent episodic profuse sweating and depression. Sweating attacks and depression remitted after successful treatment with amitriptyline. [go.gale.com]

  Skin sympathetic nerve activity, skin blood flow (by laser Doppler flowmetry), sweating, blood pressure, and pulse rate were monitored during changes of core (tympanic) temperature in the patients and seven healthy controls. [ncbi.nlm.nih.gov]

  Temperature elevation is met with cooling measures: sympathetic activation of sweat glands is augmented, and sympathetic vasoconstriction is inhibited. Increased antidiuretic hormone (ADH) secretion causes water retention and greater sweating. [emedicine.medscape.com]

  Common terms that describe VMS are hot flashes/flushes and night sweats. Research in this field has yet to elucidate the biological details explaining the causes of VMS. [karger.com]

  The anterior region of the hypothalamus also helps regulate body temperature through sweat. It also maintains circadian rhythms. These are physical and behavioral changes that occur on a daily cycle. [healthline.com]

• Headache

  The patient's headaches resolved postoperatively, but the bitemporal hemianopsia and endocrinological function were unchanged. [ncbi.nlm.nih.gov]

  Malfunction of this area of the brain may give rise to cluster headaches. Causes The hypothalamus helps keep the body's internal functions in balance. [mountsinai.org]

  Tumor symptoms may include headache or loss of vision. Hypothyroidism symptoms may include feeling cold all the time, constipation, fatigue, or weight gain, among others. Low adrenal function symptoms may include dizziness or weakness. [indiatoday.in]

  Tumor symptoms may include headache or loss of vision. If the thyroid is affected, there may be symptoms of an underactive thyroid (hypothyroidism). Symptoms may include feeling cold all the time, constipation, fatigue, or weight gain, among others. [medlineplus.gov]

• Polyneuropathy

  […] complications E08.40 Diabetes mellitus due to underlying condition with diabetic neuropathy, unspecified E08.41 Diabetes mellitus due to underlying condition with diabetic mononeuropathy E08.42 Diabetes mellitus due to underlying condition with diabetic polyneuropathy [en.wikisource.org]

  […] neurological manifestations Use additional code to identify manifestation, as: diabetic: amyotrophy (353.1) gastroparalysis (536.3) gastroparesis (536.3) mononeuropathy (354.0-355.9) neurogenic arthropathy (713.5) peripheral autonomic neuropathy (337.1) polyneuropathy [theodora.com]

Both direct, non-stimulated measurements of hormone levels and provocation tests are carried out to identify and localize abnormalities in the function of the hypothalamus, pituitary, and peripheral glands. Dynamic testing is recommended to determine if low levels can be raised by the stimulation of hormone synthesis or release, and if elevated levels are suppressible [10]. In this context, it should be noted that levels of hypothalamic hormones as determined in common serum samples don't necessarily correlate with concentrations in hypothalamic-hypophysial portal serum. In order to increase the reliability of results, such analyses should be interpreted with simultaneous measurements of downstream hormones like pituitary tropic and non-tropic hormones as well as peripheral effector hormones. Furthermore, circadian rhythms should be considered when choosing the ideal time of the day to obtain blood samples.

In any case, the diagnosis of hypothalamic dysfunction should be complemented by a thorough workup aiming at the identification of the causes of this condition. The patient's medical history may play a crucial role in this context, as do the results of neuroimaging and the analysis of cerebrospinal fluid [1]. Hereditary conditions associated with hypothalamic dysfunction may be suspected in case of a positive family history, which should prompt the screening for gene defects known to predispose for the respective disorder.

• Hyperprolactinemia

  At age 6 years the reported patients presented with precocious puberty, by age 12 years she had hypernatremia presumed secondary to central diabetes insipidus and was treated with DDAVP, and at age 14 was identified to have hyperprolactinemia. [ncbi.nlm.nih.gov]

  Other symptoms of hypothalamic dysfunction may include hyperprolactinemia, central hypothyroidism, water balance disorder, abnormal growth hormone response, adrenocortical insufficiency or puberty disorders. [orpha.net]

  • In a 21-year-old woman with McCune-Albright syndrome, acromegaly and hyperprolactinemia with hypopituitarism developed secondary to a large pituitary tumor. [jamanetwork.com]

• Hypoglycemia

  The impaired hormonal responses to insulin-induced hypoglycemia, with recovery after 4 weeks of rest, indicate hypothalamic dysfunction and may be a diagnostic marker of the overtraining syndrome. [ncbi.nlm.nih.gov]

  The standard test for growth hormone deficiency is the insulin-induced hypoglycemia test. This test does carry some risk from the induced hypoglycemia. [medical-dictionary.thefreedictionary.com]

  […] without coma Code first (T36-T50) to identify drug E16.1 Other hypoglycemia Functional hyperinsulinism Functional nonhyperinsulinemic hypoglycemia Hyperinsulinism NOS Hyperplasia of pancreatic islet beta cells NOS Excludes1: hypoglycemia in infant of [en.wikisource.org]

  E code to identify cause, if drug-induced 251.2 Hypoglycemia, unspecified Hypoglycemia: NOS reactive spontaneous Excludes: hypoglycemia: with coma (251.0) in diabetes mellitus (250.8) leucine-induced (270.3) 251.3 Postsurgical hypoinsulinemia Hypoinsulinemia [theodora.com]

  Since the cortex is responsible for the secretion of corticosteroids (and sex hormones), these hormone levels will be decreased or absent in adrenal insufficiency which leads to decreased availability of glucose, causing hypoglycemia and reduced renal [clientswithendocrinedisorders.weebly.com]

Treatment largely depends on the underlying condition and may comprise pharmacotherapy, surgical interventions, and radiation:

• If at all possible, the cause of hypothalamic dysfunction should be removed and the patient's ability to auto-regulate autonomous and endocrine processes restored.
• In some cases, though, the irreversible destruction of hypothalamic tissue or inherent gene defects may not allow for causal treatment. In this context, hormone replacement therapy is of major importance to compensate for any deficiencies. Rather than replacing the hypothalamic hormone, patients are generally treated with the effector hormones of the respective peripheral glands. Similarly, inhibitors of hormone action may be administered to counteract excess hormone secretion [9].
• Beyond that, patients should be provided symptomatic care according to their individual needs. Metabolic decompensation is a possibly life-threatening complication of hypothalamic dysfunction and should be prevented at all costs. Dietary adjustments may help to this effect, but most patients must adhere to a strict medical treatment regimen.

If the cause of hypothalamic dysfunction cannot be removed, therapy must be continued throughout life. Patients should be informed about the possible consequences of any lack of compliance and be encouraged to partake in monitoring programs.

The extent and cause of hypothalamic dysfunction, the severity of the disease, and the presence of comorbidities all affect the patient's prognosis. Notwithstanding, irreversible hypothalamic dysfunction may partially be compensated by pharmacotherapy: Appropriate hormone replacement or antihormone therapy can improve the quality of life and prevent complications. It should generally be kept in mind that the time course of the development of hormonal disorders varies, and predictors of hypothalamic-pituitary dysfunction are unreliable [10].

Hypothalamic dysfunction may be provoked by very different conditions. Numerous benign and malignant diseases may interfere with the physical integrity of the hypothalamus, with blood supply and drainage. Limited blood supply would result in hypoxia and nutrient deficiencies, but the latter may also be caused by metabolic disorders. Additionally, infectious diseases as well as autoimmune disorders may trigger hypothalamic inflammation, which is likely to alter the function of hypothalamic neurons. Any of the aforementioned conditions leading to hypothalamic function may affect the hypothalamus only, involve adjacent brain regions, additional parts of the central nervous system or even the entire body. Moreover, different lesions may produce identical signs and symptoms, and similar pathologies may result in distinct clinical pictures.

Hypothalamic dysfunction is usually acquired, but certain hereditary conditions may interfere with the operation of the hypothalamus and result in congenital hypothalamic disorders. Hereditary diseases with hypothalamic dysfunction comprise, but are not limited to, Prader-Willi syndrome, de Morsier syndrome, Kallmann syndrome, the syndrome of inappropriate antidiuretic hormone secretion, Kleine-Levin syndrome, Bardet-Biedl syndrome, Wolfram syndrome, familial diabetes insipidus, Pallister-Hall syndrome, rapid-onset obesity with hypothalamic dysfunction, and Shapiro syndrome.

A more detailed list of possible etiologies of hypothalamic dysfunction has been compiled by Braunstein [11].

Due to the heterogeneity of causes, precise data regarding the incidence and prevalence of hypothalamic dysfunction cannot be provided. Patients of any age may be affected: Although most conditions involving hypothalamic dysfunction are acquired, it may be present at birth. Developmental malformations and hereditary disorders as enumerated in the previous paragraph may be accompanied by congenital hypothalamic dysfunction [11]. While gender preference or ethnic predisposition may be described for certain etiologies, hypothalamic dysfunction may essentially affect everyone.

The hypothalamus is the "command center" of the endocrine and autonomous nervous system. In order to understand the possible implications of hypothalamic dysfunction, the multiple tasks of this organ should be considered.

• Neurosecretory cells produce releasing hormones such as growth hormone-releasing hormone (GHRH), thyrotropin-releasing hormone (TRH), corticotropin-releasing hormone (CRH), and gonadotropin-releasing hormone (GnRH). These hormones stimulate the anterior pituitary to release growth hormone, thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH).
• Similarly, hypothalamic inhibiting hormones enter the hypophyseal portal system and suppress the release of certain hormones. In detail, somatostatin inhibits the release of growth hormone, and prolactin release-inhibiting hormone and melanotropin release-inhibiting hormone reduce the secretion of prolactin and melanotropin, respectively.
• Prohormones for vasopressin and oxytocin are synthesized in the hypothalamus and transported to the posterior pituitary, where they are stored, cleaved, and eventually released into circulation.

As for the majority of disorders resulting in hypothalamic dysfunction, no recommendations can be given to prevent this condition. In general, safety measures to protect the integrity of the brain may help to reduce the incidence of traumatic brain injury with hypothalamic dysfunction. The avoidance of consanguineous marriage as well as the education of the population regarding the possible consequences of this practice may contribute to decreasing the incidence of hereditary disorders associated with hypothalamic lesions. Furthermore, the early diagnosis of any cerebral pathology may allow for the initiation of treatment before the hypothalamus becomes involved.

Hypothalamic dysfunction is no entity but a pathological condition that may arise in the scope of diverse disorders such as cerebrovascular accidents, infectious diseases affecting the central nervous system, autoimmune conditions, metabolic disturbances, traumatic brain injury, neoplasms, and neurodegeneration, among others. Furthermore, hypothalamic dysfunction is part of syndromes like syndrome of inappropriate antidiuretic hormone secretion, Kallmann syndrome, and Kleine-Levin syndrome, among others.

The hypothalamus is a rather small but vital part of the brain. It may be considered the upper control center of the endocrine and autonomous nervous system. The hypothalamus is involved in the regulation of numerous processes, such as growth, respiration, circulation, body temperature, sexual behavior, hunger and thirst, energy management and water and electrolyte balance. Accordingly, hypothalamic dysfunction may manifest in many different, often contrasting ways:

• On the one hand, hypothalamic hormone deficiencies may result in fatigue, weakness, intolerance to cold, hypotension, myxedema, short stature and obesity as well as delays in sexual development.
• By contrast, the increased release of hypothalamic hormones may produce agitation and anxiety, intolerance to heat, tachycardia and palpitations, increased appetite, weight loss, and precocious puberty.

The diversity of signs and symptoms associated with hypothalamic dysfunction may be explained by the fact that hypothalamic hormones act on the pituitary and distinct peripheral glands, such as the thyroid and adrenal glands, gonads, and kidneys.

Hypothalamic dysfunction may be caused by any condition affecting the physical integrity or functionality of the hypothalamus. Developmental malformations, genetic disorders, traumatic brain injury and tumors, infectious diseases, immunological and metabolic diseases, cerebrovascular accidents, and neurodegenerative disorders may all produce hypothalamic lesions. The diagnosis of the underlying condition may thus pose a major challenge but is essential to design the optimum treatment regimen.

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