Children with congenital midline defects or optic atrophy (which suggests the presence of septo-optic dysplasia) [12] [5] and boys with micropenis due to deficit gonadotropin hormones (GH) [13] [14] should be suspected to have hypopituitarism. However, there are children without any findings of hypothalamus or pituitary-related conditions, but are still diagnosed with hypopituitarism. In cases like these, the child only shows stunted growth due to deficient GH.

Central hypopituitarism is found in some children who require medical attention due to abnormal thyroid functions. Girls with this condition may experience amenorrhea, either primary or secondary. Growth failure is the most commonly seen feature of hypopituitarism. It is seen as a decrease in growth rate for age. The clinical presentation of the condition is dominated by the underlying pathology, its speed of onset and severity of hypopituitarism. Space-occupying lesions that cause hypopituitarism may lead to symptoms such as visual abnormalities, headache and rarely, changes in personality, cerebrospinal fluid (CSF) rhinorrhea and temporal lobe epilepsy.

Less severe ACTH deficiency can manifest along with other illnesses, however, pituitary apoplexy can result in severe hypopituitarism which presents as a medical emergency.
Panhypopituitarism may present in the child acutely with deficient cortisol or thyroid hormones or chronically with a continuous and progressive deficiency in pituitary hormones. Nonspecific symptoms are most frequently seen in the form of exercise intolerance, abdominal pain, loss of axillary and pubic hair weakness or fatigue, Increase in weight, decrease in libido, and irregular menstruation.

Hormones affected in hypopituitarism have different physiological effects  in children. A deficiency in gonadotropic hormone can affect the metabolism and growth, causing hypoglycemia and stunted height. Gonadotropin deficiency results in prenatal micropenis and in older children cause interrupted or delayed puberty. Deficiency of corticotrophin hormone interferes the metabolism of carbohydrate, protein, and lipid molecules resulting in weight loss, hypotension, hypoglycemia, weakness and in worst cases, death of patients. Hypothyroidism results from thyrotropin hormone deficiency results. Its diagnosis is often missed as the clinical manifestations may be non-specific and depends upon the extent of hormone deficiency. Besides various signs and symptoms resulting from the pressure effects on the pituitary gland and stalk, a complex picture of hormone excess and deficiency can be produced by actively secreting tumors e.g. macroadenoma secreting GH causing hypogonadism and acromegaly.

Pituitary hormone loss is a progressive and slow process which may take several months or years. Occasionally hypopituitarism starts suddenly rapid development of symptoms. It is the growth hormone which is affected first in hypopituitarism, followed by luteinizing hormone. Adrenocorticotropin (ACTH), follicle-stimulating hormone (FH), prolactin and thyroid stimulating hormone (TSH) are lost much later in the stage [9].

• Fatigue

  For this reason, it is important to avoid certain quick fixes or tricks commonly used for normal instances of fatigue or tiredness if you think you are suffering from chronic fatigue. [healtheo360.com]

  She presented with severe headaches, generalized fatigue, dizziness, hypotension, difficulties with balance and coordination, polyuria, and polydipsia. [ncbi.nlm.nih.gov]

  We ask about general symptoms (anxious mood, depressed mood, fatigue, pain, and stress) regardless of condition. Last updated: March 8, 2020 [patientslikeme.com]

• Weight Loss

  Unintentional Weight Loss Defined as > 10% usual body weight loss over 6 months. It has been estimated that roughly 5-10% of outpatients over the age of 65 will present in the ambulatory setting for evaluation of unintentional weight loss. [ucsfmed.wordpress.com]

  He presented with a few months of postural dizziness and hypotension, weight loss, fever, strabismus of right eye and a superficial abdominal wall mass. At this time he had no history of malignancy. [ncbi.nlm.nih.gov]

  Symptoms include fatigue, weight loss, decrease in sex drive, infertility, sensitivity to cold, decreased facial or body hair in men, and puffiness of the face. Acquired panhypopituitarism can occur as a result of tumors in the pituitary gland. [medicinenet.com]

• Cold Intolerance

  Characteristic signs of the disorder are failure to lactate, amenorrhea (in females), weakness, cold intolerance, lethargy, and loss of libido and of axillary and pubic hair. [medical-dictionary.thefreedictionary.com]

  A 41-year-old man presented with extreme fatigue, cold intolerance and anorexia with 20 kg weight loss in the last 6 months. His medical history was unremarkable. He snorted cocaine twice a week during the last 6 years. [ncbi.nlm.nih.gov]

  Thyroid stimulating hormone (TSH) deficiency leads to weight gain, cold intolerance, constipation, dry skin, non-pitting edema, slow reflexes, and bradycardia. Prolactin deficiency is asymptomatic unless the patient is a lactating mother. [medicaljoyworks.com]

  He also had cold intolerance and decreased libido. Review of systems was negative for nausea vomiting diarrhea, chest pain, dyspnea or abdominal pain. He denied any weight loss or focal weakness. [pubs.sciepub.com]

  There was history of cold intolerance, constipation and proximal weakness. However, he did not seek formal medical advice at that time due to lack of awareness and poverty. [ijem.in]

• Myxedema

  The clinical presentation of the panhypopituitarism patient can vary from asymptomatic or subclinical cases to life-threatening myxedema coma. [omicsgroup.org]

  Myxedema coma was among the differential diagnoses, although it was not apparent given the absence of hyponatremia with normal deep tendon reflexes and normal serum creatine phosphokinase levels. [austinpublishinggroup.com]

  Some clinical states that result from the acute decline in pituitary production may lead to increased mortality risk, such as deficiency of ACTH leading to adrenal crisis or TSH deficiency causing myxedema coma and death.[15] Deterrence and Patient Education [statpearls.com]

• Male Hypogonadism

  hypogonadism, and estradiol for female hypogonadism (usually with a progestogen to inhibit unwanted effects on the uterus). [en.wikipedia.org]

• Vomiting

  A 32-year-old man presented with vomiting and diarrhea. Laboratory data showed that he had transient hypercalcemia, primary thyrotoxicosis due to painless thyroiditis and panhypopituitarism. [ncbi.nlm.nih.gov]

  Acute presentation: 46 year old patient was admitted as an emergency with vomiting, hypotension and serum cortisol of 26 nmol/L indicative of adrenal failure. [endocrine-abstracts.org]

• Nausea

  A 71-year-old man manifested appetite loss, nausea and vomiting with hyponatremia and adrenal insufficiency. Hormonal evaluation and cranial MRI revealed a panhypopituitarism with empty sella. [ncbi.nlm.nih.gov]

  Decreased appetite Short stature in childhood Infertility Anemia (low red blood cells) Hot flashes Irregular or missed periods Loss of pubic hair Inability to produce breast milk Decreased facial/body hair in men Poor growth Micro-penis Stomach pain Nausea [healtheo360.com]

  The chief complaints, as given by the patient's mother, were nausea and vomiting, drowsiness, extreme weakness, and mental confusion. [jamanetwork.com]

  Six months later, she continued to complain of severe headaches and nausea. Computed tomography showed no significant change in the sellar mass. Subsequently, transsphenoidal surgery was performed. [ekjm.org]

• Abdominal Pain

  Clinical manifestations during these attacks are mainly abdominal pain, chest pain and arthritis but also myalgia, skin manifestations and scrotal swelling [ 4, 5 ]. [ijpeonline.biomedcentral.com]

  Adrenocorticotropic hormone (ACTH) deficiency manifests as weakness, abdominal pain, weight loss, hypoglycemia, nausea, vomiting, anorexia, and postural hypotension. [medicaljoyworks.com]

  Symptoms are often non-specific and include a large abdominal mass, abdominal distension/pain, failure to thrive, diarrhea, vomiting and jaundice. [orpha.net]

  Review of systems was negative for nausea vomiting diarrhea, chest pain, dyspnea or abdominal pain. He denied any weight loss or focal weakness. There was no past surgical history, he is allergic to penicillin, NSAIDS and IV contrast dye. [pubs.sciepub.com]

  Nonspecific symptoms are most frequently seen in the form of exercise intolerance, abdominal pain, loss of axillary and pubic hair weakness or fatigue, Increase in weight, decrease in libido, and irregular menstruation. [symptoma.com]

• Loss of Appetite

  Further he presented with nausea, vomiting, loss of appetite, rapid weight loss, diffuse body pain and fatigue. No headache, blurred vision, or fever were reported. [ncbi.nlm.nih.gov]

  This can cause tiredness, weakness, dizziness or light-headedness, blackouts (usually as a result of low blood pressure), low blood sugar levels, low sodium levels, weight loss, loss of appetite, nausea, vomiting and diarrhoea (see the article on Addison's [yourhormones.info]

  She had a 2-month history of polyuria, polydipsia, nocturia, lightheadedness upon standing up quickly, fatigue, loss of appetite, and 15 kg of weight loss from a baseline weight of 60 kg. [bmcendocrdisord.biomedcentral.com]

• Morning Sickness

  Hydrocortisone 10 mg daily replaced cortisone acetate; the dose was increased according to the symptoms of morning sickness. [ncbi.nlm.nih.gov]

• Orthostatic Hypotension

  He stated that he had no physical discomfort, no gynecomastia, no signs of orthostatic hypotension, and normal urine frequency, and he indicated no symptoms of hypothyroidism. He never had any facial, axillary, or pubic hair. [academic.oup.com]

• Muscle Weakness

  Exposure to cold initially causes muscle stiffness in these individuals, and prolonged cold exposure leads to temporary episodes of mild to severe muscle weakness that may last for several hours at a time. [ghr.nlm.nih.gov]

  Homepage Rare diseases Search Search for a rare disease Paramyotonia congenita of Von Eulenburg Disease definition Paramyotonia congenita of Von Eulenburg is characterised by exercise- or cold-induced myotonia and muscle weakness. [orpha.net]

  The primary symptoms are stiffness and weakness in the muscles, especially in the face, neck, arms, and hands. Episodes of muscle stiffness can last anywhere from a few minutes to several hours. [healthline.com]

  The abnormal ratio interferes with normal muscle contraction and relaxation, causing bouts of muscle weakness and stiffness. [rarediseases.org]

• Alopecia

  […] prominent feature, it is called simmonds' disease or pituitary cachexia. juvenile panhypopituitarism most frequent in German shepherd dogs but also in other breeds; puppy dwarfism not apparent until 2-3 months old; small stature, delayed dentition, alopecia [medical-dictionary.thefreedictionary.com]

  […] granulomatous iridocyclitis<br />Variable vitritis, exudative retinal detachments<br />Commoner in pigmented races<br />Associated extraocular features important in diagnosis<br />CSF pleocytosis, neck stiffness, seizures, paralysis (CNS)<br />Vitiligo, alopecia [slideshare.net]

  […] absence of a history of penetrating ocular trauma Absence of other ocular disease entities Bilateral panuveitis Neurological and auditory manifestations Integumentary findings, not preceding the onset of central nervous system or ocular disease such as alopecia [eyewiki.aao.org]

• Loss of Pubic Hair

  (low red blood cells) Hot flashes Irregular or missed periods Loss of pubic hair Inability to produce breast milk Decreased facial/body hair in men Poor growth Micro-penis Stomach pain Nausea/vomiting Constipation Excessive thirst Excessive urination [healtheo360.com]

  They may include: Fatigue Weight loss Decreased sex drive Sensitivity to cold or difficulty staying warm Decreased appetite Facial puffiness Anemia Infertility Hot flashes, irregular or no periods, loss of pubic hair, and inability to produce milk for [mayoclinic.org]

  Other general symptoms of panhypopituitarism are hypersensitivity to cold, decreased appetite, anemia, infertility, loss of pubic hair, lack of body hair, facial swelling, inhibited sexual desire, etc. [lifepersona.com]

• Breast Atrophy

  Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) deficiency typically presents as amenorrhea, atrophic vaginitis, infertility, hot flushes and breast atrophy in females, and testicular atrophy, erectile dysfunction, and decreased libido [medicaljoyworks.com]

• Headache

  A 49 years old man, with a history of aggression at the age of 18 years by a pair of scissors, who consulted for unilateral migraine headaches look straight. [ncbi.nlm.nih.gov]

  We report the case of a post-traumatic panhypopituitarism discovered 31 years later on the occasion of paroxysmal headache. [panafrican-med-journal.com]

  Her headache resolved, but the pituitary functions did not improve. [ekjm.org]

• Lethargy

  The clinical manifestations range from nonspecific weakness and lethargy to sudden collapse and death, depending on the rapidity of onset of the disease, type and number of pituitary cells affected, and severity of hormonal deficiencies. [medicaljoyworks.com]

  Characteristic signs of the disorder are failure to lactate, amenorrhea (in females), weakness, cold intolerance, lethargy, and loss of libido and of axillary and pubic hair. [medical-dictionary.thefreedictionary.com]

  […] puberty), secondary amenorrhea, irregular menstrual cycles, infertility Males: delayed puberty, loss of libido, infertility, testicular atrophy, loss of facial, axillary and/or pubic hair, gynecomastia TSH deficiency: weight gain, cold intolerance, lethargy [amboss.com]

  It can occur in the early hours of life with hyporeactivity, lethargy, severe hypoglycemia. [omicsonline.org]

• Somnolence

  A 21-year-old man presented with headache, hypotonia, hypothermia, and somnolence, deteriorating to a Glasgow Coma Scale score of 3 within days. Hormonal testing revealed panhypopituitarism. [ncbi.nlm.nih.gov]

  In pituitary apoplexy, immediate surgery is warranted if visual field disturbances or oculomotor palsies develop suddenly or if somnolence progresses to coma because of hypothalamic compression. [msdmanuals.com]

• Behavior Problem

  Effects of febrile seizures on emotion, behavior, learning and memory in rats; 热性惊厥对大鼠情感行为及学习记忆的影响 2. The study of behavior problem in children with a history of febrile seizures 热性惊厥影响患儿行为的研究 3. [dictall.com]

• Primary Amenorrhea

  amenorrhea (delayed puberty), secondary amenorrhea, irregular menstrual cycles, infertility Males: delayed puberty, loss of libido, infertility, testicular atrophy, loss of facial, axillary and/or pubic hair, gynecomastia TSH deficiency: weight gain, [amboss.com]

  At the age of 15 she was evaluated for primary amenorrhea. [oatext.com]

  Endocr J 42 : 83 – 88 5 Crottaz B, Uske A, Reymond MJ, Rey F, Temler E, Germond M, Gomez F 1996 Normogonadotropic primary amenorrhea in a growth hormone-deficient woman with ectopic posterior pituitary: gonadotropin pulsatility and follicle-stimulating [academic.oup.com]

• Secondary Amenorrhea

  The patient who suffered from secondary amenorrhea was found a nonfunctioning pituitary macroadenoma, and the hormone test showed serum cortisol, FT3, FT4, thyrotropic hormone, and prolactin were at normal range. [ncbi.nlm.nih.gov]

  (delayed puberty), secondary amenorrhea, irregular menstrual cycles, infertility Males: delayed puberty, loss of libido, infertility, testicular atrophy, loss of facial, axillary and/or pubic hair, gynecomastia TSH deficiency: weight gain, cold intolerance [amboss.com]

  Girls may have primary or secondary amenorrhea. Polyuria and polydipsia due to central diabetes insipidus may also be a presenting symptom. Rarely, patients with ACTH deficiency may present with hyponatremia. [emedicine.medscape.com]

• Sexual Dysfunction

  In men it produces sexual dysfunction and micropenis (if the problem appears in childhood). [lifepersona.com]

Diagnosing a child with hypopituitarism can be done by determining the hormonal deficiency and identifying the cause. It consists of a detailed clinical examination and biochemical studies.
Hypothyroidism, which occurs secondary to the TSH deficiency is easiest to diagnose. Head MRI should be done in all the children suspected to have with panhypopituitarism. This is an important step to determine underlying tumors or structural abnormalities potentially causing the condition [15].

Also, due to frequent delay in bone age in patients with hypopituitarism, a left hand and wrist radiography are helpful in determining bone age. Though, it has found to have low sensitivity and specificity. Visual field examination is important while doing the physical examination. Simultaneous assessment of basal anterior pituitary and target organ hormone helps in providing important information to establish the cause of hypopituitarism. Baseline tests include thyroxine, TAH, FSH, LH, prolactin, testosterone/estradiol, 9 am cortisol and insulin-like growth factor 1.
Evidence of hypopituitarism from clinical and biochemical studies would then necessitate imaging studies of the hypothalamic‐pituitary region. MRI is the investigation of choice [9]. A CT scan with contrast is a good alternative in cases where MRI study is not possible.

• Delayed Bone Age

  Furthermore, the hand-wrist X-ray showed delayed bone age [Figure 3], and bone densitometry revealed osteoporosis [total T-score −4.5 (spine) and −3.3 (hip)]. There were no alterations in the karyotype (46, XY). [ijem.in]

• Hyponatremia

  Although most cases are mild and relatively asymptomatic, it is important clinically because: i) acute severe hyponatremia can cause substantial morbidity and mortality, ii) mortality is higher in patients with hyponatremia who have a wide range of underlying [endocrine-abstracts.org]

  A 71-year-old man manifested appetite loss, nausea and vomiting with hyponatremia and adrenal insufficiency. Hormonal evaluation and cranial MRI revealed a panhypopituitarism with empty sella. [ncbi.nlm.nih.gov]

  Some patients may be referred with hyponatremia due to adrenal glands dysfunction, in spite of the necessary studies for the evaluation of patients with hyponatremia, checking the serum cortisol level is needed to rule out hypoadrenalism [ 8, 9 ]. [omicsgroup.org]

The treatment of panhypopituitarism is directed towards the underlying cause and the replacement of deficit hormones. Management involves surgery, medical therapy, radiotherapy or a combination of any of these options. Cases of GH secreting microadenoma are managed best with surgical excision of the tumor [16] whereas, treatment with dopamine agonists is required in cases of macroprolactinoma [17]. In cases where pituitary or peripituitary tumors do not respond to medical management and causes pressure effects, surgery is the usually required option.

Assessment of the pituitary hormone status is necessary after treatment to determine the functional improvement [10] [11]. Target hormone replacement is done in all cases except those with ADH or GH deficiency or in cases of desired fertility, where deficit hormone is replaced. All the deficit hormones are replaced in panhypopituitarism and lifelong hormone replacement is required. The goal of hormone replacement is to achieve the desired levels of circulating hormones in the blood, to maintain the normal physiology and avoid deficiency symptoms with least side effects.

Thyroid hormone deficiency is replaced by L-thyroxine, which is given empty stomach at 100-150 ug every morning. The aim of the therapy is to attain the normal T4 levels. deficiency of adrenal hormones is managed by hydrocortisone or prednisone, which stimulate the normal circadian rhythm of cortisol. In women with ACTH deficiency low doses of dehydroepiandrosterone are useful. Deficiency of FSH or LH depends on the gender and desire for fertility. Estrogen and progesterone are required in premenopausal women. Testosterone is only required in men with hypogonadism without desiring fertility. In severe growth hormone deficiency, GH therapy is beneficial. It is given as a subcutaneous injection once daily, usually in the evening time. GH therapy helps with exercise capacity, skeletal integrity, body composition and improves quality of life.

Adrenal crisis is the most common acute complication that can result from the medical management of hypopituitarism. Adrenal crisis occurs when glucocorticoid hormone therapy is administered inappropriately or when a child has a concurrent illness that requires increasing doses of glucocorticoids. Meticulous monitoring is the best approach to prevent any adverse effects from thyroid supplements or sex steroid therapy. Stable patients usually have a favorable outcome with hormonal therapy.

Acquired panhypopituitarism is commonly associated with hypothalamic or pituitary tumors and surgical or radiological treatment associated with them. Craniopharyngiomas, optic gliomas and pituitary dysgerminomas have been identified as one of the common causes panhypopituitarism [4]. Deficiencies of pituitary hormones are seen in various congenital midline defects such as septo-optical dysplasia (also known as the de Morsier syndrome), facial clefts, or the presence of a single central incisor [5]. About three fourths of patients diagnosed with optic nerve hypoplasia were found to have abnormal hormone levels in blood [6]. The common causes of panhypopituitarism in adults are pituitary gland adenomas, post radiation therapy, sellar mass lesions, Sheehans syndrome, pituitary gland apoplexy, granulomatous infiltrative conditions and empty sella syndrome. The characteristic imaging finding is seen in most of these etiologies.
Panhypopituitarism that results from genetic mutation can have normal neuroimaging results, but the defects appear early in the life and not in the adulthood [7]. Of all the different causative conditions for adult hypopituitarism, pituitary adenoma and its treatment either by surgery or radiation therapy is found to be most frequently seen.

Regal, et al [8] released a report showing the prevalence of panhypopituitarism as 45 in every 100,000 individuals. The incidence rate was found to be 4 per 100,000 per year in normal population. Approximately 50% of subjects found to have deficiency of three to five pituitary hormones.

Reduction of pituitary hormones results in impairment of target hormone production due to the loss of trophic stimuli. Normally, target hormones at their sub physiologic levels stimulate the pituitary gland, resulting in the increased production of trophic hormones. In hypopituitarism, due to the decreased or absent response of the pituitary gland, production of target hormones is decreased. Hence, the patient presents with low levels of trophic hormones in the presence of low target hormone levels.

Macroadenomas greater than 1 cm in diameter can be linked to one or more trophic hormonal deficiencies in 30% of patients [9] as a result of direct compression. Consequentially, the destruction of the proximal normal tissue from prolonged compression leads to glandular hyposecretion. Other possible mechanisms for the development of panhypopituitarism includes a primary effect of a tumor mass on the vascular portal system (also called the pituitary stalk), elevated intrasellar pressure that later affects portal circulation, and focal necrosis of pituitary tissues that resulted from prolonged inefficient supply of portal blood [10] [11]. Functions of the pituitary gland are rarely affected by microadenomas that are less than 1 cm [11]. Microadenomas that secrete prolactin often manifest with symptoms of hypogonadism due to the suppression of gonadotrophins production (follicle-stimulating hormone FSH and luteinising hormone LH) by prolactin.

Panhypopituitarism due to congenital defects, syndromes or genetic deficiencies is not preventable. However, certain steps should be taken to help achieve better management.

Children who are diagnosed with hypopituitarism may require close monitoring and continuous assessment by a pediatric endocrine specialist. Regular monitoring of physical growth and free T4 levels is required to measure the efficiency of T4 replacement. Signs and symptoms of cortisol excess or deficiency are helpful in determining the efficiency of cortisol replacement therapy. Monitoring of pubertal status is important. It also helps in determining any risks involved with sex or thyroid hormone treatment. 

Panhypopituitarism is a condition resulting due to the deficit or inadequate anterior pituitary hormones. The condition manifests as growth failure in children and with varied local, as well as systemic effects in adults [1]. It is also called as partial hypopituitarism [2] [3].

Panhypopituitarism is characterized by an inadequacy or deficiency of hormone produced by the anterior part of the pituitary gland. It commonly occurs due to other secondary causes that affect the pituitary gland, either by interfering with the hypothalamic secretion of pituitary hormones or by destroying or reducing it function. A deficiency of one or more pituitary hormones occurs in underactive pituitary gland. Panhypopituitarism can occur due to several factors, including pituitary gland tumors, certain inflammatory conditions or decreased blood supply to the gland. 

The presentation of the condition depends on the deficiency of the involved hormone. The patient may present with short stature, inability to produce breast milk, fatigue or intolerance to cold.

The diagnosis is made by assessing the levels of pituitary hormones in the blood and imaging studies of the gland. Treatment involves surgical removal of pituitary tumors, replacement of the deficient hormone with the synthetic one or radiation therapy.

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2. Prabhakar VK, Shalet SM. Aetiology, diagnosis, and management of hypopituitarism in adult life. Postgrad Med J. 2006 Apr;82(966):259-66.
3. Jostel A, Lissett CA, Shalet MS. In: Hypopituitarism in Endocrinology. 5th ed. Degroot LJ, Jameson JL, editors. Philadelphia: Elsevier Saunders; 2006. pp. 397–409.
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17. Colao A, Annunziato L, Lombardi G. Treatment of prolactinomas. Ann Med. 1998 Oct;30(5):452-9.