Hypopituitarism differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Iqra Qamar M.D.[2], Ahmed Elsaiey, MBBCH [3]

Overview

Hypopituitarism must be differentiated from Sheehan's syndrome, lymphocytic hypophysitis, pituitary apoplexy, hypothyroidism, Addison's disease, empty sella syndrome, hypogonadotropic hypogonadism, Simmonds' disease, hypoprolactinemia, and menopause.

Differentiating hypopituitarism from other Diseases

Hypopituitarism should be differentiated from other diseases like Sheehan's syndrome, lymphocytic hypophysitis, pituitary apoplexy, hypothyroidism, Addison's disease, empty sella syndrome, hypogonadotropic hypogonadism, Simmonds' disease, hypoprolactinemia, and menopause.

Diseases	Onset	Manifestations					Diagnosis
		History and Symptoms				Physical examination	Laboratory findings	Gold standard	Imaging	Other investigation findings
		Trumatic delivery	Lactation failure	Menstrual irregularities	Other features
Panhypopituitarism	Chronic	-	+	Oligo/amenorrhea	Polyuria Polydipsia Features of hypothyroidism and hypoadrenalism	Growth failure B/L hemianopsia Papilledema	All pituitary hormones decreased	MRI		Left hand and wrist radiograph for bone age
Sheehan's syndrome	Acute	++	++	Oligo/amenorrhea	Adrenal insufficiency symptoms Hypothyroidism features	Breast tissue atrophy Decreased axillary and pubic hair growth	Pancytopenia Eosinophilia Hyponatremia Low fasting plasma glucose Decreased levels of anterior pituitary hormones in blood	Dx is clinical Most senitive test: low baseline prolactin levels w/o response to TRH	CT/MRI: Sequential changes of pituitary enlargement followed by Shrinkage and necrosis leading to decreased sellar volume or empty sella	Pituitary hormone stimulation tests (Metoclopramide and clomiphene citrate stimulation tests)
Lymphocytic hypophysitis	Acute	+/-	+	Oligo/amenorrhea	Associated with autoimmune conditions Generalized headache Retro-orbital or Bitemporal pain Mass lesion effect such as visual field defects	DI Autoimmune thyroiditis	Decreased pituitary hormones(Gonadotropins most common) Hyperprolactinemia(40%) GH excess	Pituitary biopsy: lymphocytic infiltration	CT & MRI: Features of a pituitary mass Diffuse and homogeneous contrast enhancement	Assays for: Anti-TPO Anti-Tg Ab
Pituitary apoplexy	Acute	+/-	++	Oligo/amenorrhea	Severe headache Nausea and vomiting Paralysis of eye muscles (diplopia) Changes in vision	Visual acuity defects CN palsies (nerves III, IV, V , and VI)	Decreased levels of anterior pituitary hormones in blood.	MRI	CT scan without contrast: Hemorrhage on CT presents as a hyperdense lesion MRI: If inconclusive CT	Blood tests may be done to check: PT/INR and aPTT Pituitary hormonal assay
Empty sella syndrome	Chronic	-	+	Oligo/amenorrhea	Erectile dysfunction Headache Low libido	Signs of raised intracranial pressure may be present Nipple discharge	Decreased levels of pituitary hormones in blood.	MRI	Empty sella containing CSF	Pituitary hormone stimulation tests (Metoclopramide and clomiphene citrate stimulation tests)
Simmond's disease/Pituitary cachexia	Chronic	+/-	+	Oligo/amenorrhea	Cachexia Premature aging	Progressive emaciation Loss of body hair	Decreased levels of anterior pituitary hormones in blood.	MRI		Pituitary hormone stimulation tests (Metoclopramide and clomiphene citrate stimulation tests)
Primary hypothyroidism	Chronic	+/-	-	Oligomenorrhea/menorrhagia	Cold intolerance Constipation	Dry skin Bradycardia Hair loss Myxedema Delayed relaxation phase of deep tendon reflexes	Low T3,T4 High TSH Rest of pituitary hormone levels WNL	TSH levels	Done to rule out any pituitary cause	Assays for anti-TPO and anti-Tg Ab FNA biopsy
Primary Hypogonadotropic hypogonadism	Chronic	-	-	Oligo/amenorrhea	Hot flushes Energy and mood changes Decreased libido		Low estrogen, testosterone High FSH/LH		Done to rule out any pituitary cause	Genetic tests  (karyotype) Measurement of total and free testosterone and 17-hydroxyprogesterone concentrations
Hypoprolactinemia	Chronic	-	+	-	Infertility Subfertiliy	Puerperal agalactogenesis	No workup is necessary		Done to rule out any pituitary cause	Prolactin assay in 3rd trimester LH, FSH Thyrotropin and free thyroxine
Primary adrenal insufficiency/Addison's disease	Chronic	-	-	-	Hypoglycemia Hypotension	Dehydration Hyperpigmentation loss of pubic and axillary hair	Hyponatremia with/without hyperkalemia Plasma renin activity to aldosterone ratio	Abdominal CT	Abdominal CT	Serum cortisol testing Serum ACTH testing Anti-adrenal Ab testing
Menopause	Chronic	-	+/-	Oligo/amenorrhea	Hot flashes Insomnia Weight gain and bloating Mood changes	Vaginal atrophy Loss of pelvic muscle tone	↑ FSH ↓ Estradiol and inhibin	FSH > LH

Differentiating different causes of hypothyroidism

Various kinds of hypothyroidism can be differentiated from each other on the basis of history and symptoms and laboratory findings:

Disease		History and symptoms			Laboratory findings							Additional findings
		Fever	Goiter	Pain	TSH	Free T4	T3	T3RU	Thyroglobin	TRH	TPOAb
Primary hypothyroidism	Autoimmune	+	+/- Diffuse	-	↑	↓	N/↓	Normal	N/↑	Normal	↑	May be accompanied by other autoimmune diseases
	Thyroiditis	+	+/-	+	↑	↓	Normal	Normal	N/↑	Normal	Normal	Infectious thyroiditis associated with neck pain
	Others	-	+/-	-	↑	↓	Normal	Normal	N/↑	Normal	Normal	History of hyperthyroidism Drug history
Transient hypothyroidism		+/-	-	+/-	↑	↑	Normal	Normal	↑	Normal	Normal	May present primarily with hyperthyroidism
Subclinical hypothyroidism		-	-	-	↑	Normal	Normal	Normal	↑	Normal	N/↑	Asymptomatic
Central Hypothyroidism	Pituitary	+	-	-	N/↓	N/↓	N/↓	↓	Normal	Normal	Normal	Other pituitary hormone deficiencies signs
	Hypothalamus	+	-	-				↑	Normal	↓	Normal	Other pituitary hormone deficiencies signs
Resistance to TSH/TRH		-	-	-	↑	N/↓	N/↓	Normal	Normal	↑/↓	Normal	Rare

Differentiating Hypogonadism from other Diseases

Hypogonadism must be differentiated from diseases that cause delayed puberty or infertility. These diseases include congenital diseases as Klinefelter syndrome, Kallmann syndrome and cryptorchidism. The diseases also include testicular torsion and orchitis in males, polycystic ovary syndrome, pelvic inflammatory disease, and endometriosis in females.

Diseases		Clinical findings	Diagnosis	Manangement
Congenital diseases	Klinefelter syndrome	Clinical features of Klinefelter syndrome are as the following: Language learning impairment. Neuropsychological testing often reveals deficits in executive functions. Delays in motor development.	Karyotyping Semen count Serum estradiol levels (a type of estrogen) Serum follicle stimulating hormone Serum luteinizing hormone Serum testosterone	Testosterone therapy may be indicated to treat the symptoms of the disease
	Kallmann syndrome	Clinical features of Kallmann syndrome include: Hypogonadism Anosmia	Serum follicle stimulating hormone Serum luteinizing hormone Serum testosterone Gonadotropin hormones	Testosterone replacement therapy Estrogen replacement therapy (in females)
	Cryptorchidism	Clinical features of cryptorchidism include: Empty scrotum Inguinal fullness	Ultrasonography may be indicated to locate the gonads	Treatment of cryptorchidism is mainly surgical in order to reduce the risk of malignancy Orchiopexy surgery is recommended in order to reposition the undecsended testes.
Male diseases	Testicular torsion	Patients of testicular torsion usually present with following: Sudden onset of severe pain in one testicle, with or without a previous predisposing event Swelling within one side of the scrotum (scrotal swelling) Nausea or vomiting Lightheadedness Bell clapper deformity of testes on examination	Scrotal ultrasound Urinalysis to exclude bacterial infection	Management is mainly surgical through detorsion and fixation of the affected testes.
	Orchitis	Clincial features of orchitis include the following: Scrotal swelling Scrotal pain urinary tract infections Nausea, vomiting and chills Prehn's sign positive Costovertebral angle tenderness  Fever	Urethral Gram stain Urinalysis Urine culture PCR to detect the presence of Neisseria gonorrheae and Chlamydia trachomatis Scrotal ultrasound is the diagnostic imaging of choice in cases of acute scrotum.	Bed rest and limitation of physical activity Use of cold packs Analgesia Non-steroidal anti-inflammatory drugs (NSAIDs) Levofloxacin in bacterial infeciton.
Female diseases	Polycystic ovarian syndrome (PCOS)	Possible clinical findings in cases of PCOS: Amenorrhea Oligoamenorrhea Ovarian cysts Pelvic pain Dysparuenia Acne Hirsutism Anxiety and depression Sleep apnea	Blood testosterone level LH and FSH levels Pelvic ultrasound	Clomiphene citrate and metformin to manage infertility. Cyproterone acetate for the treatment of acne and hirsutism. Spironolactone
	Pelvic inflammatory disease	Patients usually present with the following: Bilateral abdominal pain Abnormal uterine bleeding Urinary frequency Abnormal vaginal discharge Fever Decreased bowel sounds	Nucleic acid amplification tests is the best laboratory test for PID. Transvaginal utrasonography	Broad spectrum antibiotics Hospitalization
	Endometriosis	Clinical features of endometriosis include the following: Dyspareunia Nausea and vomiting Intermenstrual spotting Prolonged menstrual bleeding and increased amount of bleeding (menorrhagia) Acute abdomen	Features of iron deficiency anemia may be present such as: Low MCV, Low MCHC Elevated RBC distribution width Elevated levels of serum cancer antigen-125 in some cases.[1] Increased levels of interleukin 1, chemoattractant protein-1 and interferon gamma may be present in patients with endometriosis. These are useful markers to monitor the disease activity and progression.[2]	Medical therapy: Gonadotrophin releasing hormone agonists Oral contraceptive pills Aromatase inhibitors Surgery: Conservative removal of the endometrial tissues by laser or electrocautry Definitive surgeryhysterectomy with bilateral salpingo-oophorectomy.

Disease	Differentiating symptoms							Differentiating laboratory findings			Gold standard test
	Hypotension	Abdominal pain	Anorexia/ weight loss	Muscle weakness	Hypoglycemia	Skin pigmentation	Other symptoms	Hyponatremia	Cortisol levels	Other labs
Addison's disease	+	+	+	+	+	+		+	Low		ACTH stimulation test
Myopathies (polymyositis, hereditary myopathies)	-	-	-	+	-	Heliotrope rash and Gottron's sign	Muscle tenderness	-	Normal	-	Muscle biopsy
Celiac disease	-	+	+	-	-	Dermatitis herpetiformis	Greasy stools Increased fecal fat	-	Normal	-	Abnormal small bowel biopsy
Syndrome of inappropriate anti-diuretic hormone (SIADH)	-	-	-	-	-	-	-	+	Normal	Decreased osmolality Euvolemia Sodium in urine typically >20 mEq/L	Water deprivation test
Neurofibromatosis	-	-	+	+	-	Axillary- and inguinal-area freckling	Occasional development of peripheral sarcomas May have overgrowth of subcutaneous tissues	-	-	-	Biopsy of skin tissue
Peutz-Jeghers syndrome		+				+	Melanotic hyperpigmentation of the skin and mucous membranes	-	Normal		Colonic imaging showing the small intestinal polyps
Porphyria cutanea tarda	-	+	-	-	-	Blisters on sun-exposed sites	Associated liver disease (usually hepatitis C) Hypertrichosis	-	Normal or elevated	High level of porphyrins in the urine
Salt-depletion nephritis	+	Flank pain	-	-	-	-	Fever Dysuria Pyuria Oliguria	+	Elevated	<15:1 BUN:CR
Bronchogenic carcinoma	-	-	+	-	-	+	Cough Dyspnea Hemoptysis	-	Elevated	Increased ACTH and Hypokalemia	Cytological or histological evidence of lung cancer in sputum, pleural fluid, or tissue
Anorexia nervosa	+	-	+	+	+	-	Distorted body image Oligomenorrhea	-	Elevated	-	Psychiatric condition

Disease	Clinical Findings	Laboratory findings	Management
Somatotroph adenoma: Acromegaly	Clinical features of acromegaly are due to high level of human growth hormone (hGH): Soft tissue swelling of the hands and feet Brow and lower jaw protrusion Enlarged hands Enlarged feet Arthritis and carpal tunnel syndrome Increase in teeth spacing Macroglossia (enlarged tongue) Heart failure Kidney failure Compression of the optic chiasm leading to loss of vision in the outer visual fields (typically bitemporal hemianopia) Headache Diabetes mellitus Hypertension Cardiomegaly	Elevated insulin-like growth factor-1 (IGF-1) levels Elevated growth hormone levels	Medical management: Octreotide Bromocriptine Surgical management: Endonasal transsphenoidal surgery Radiation therapy
Corticotroph adenoma: Cushing's syndrome	Clinical features of Cushing's syndrome are due to increased levels of cortisol: Rapid weight gain, particularly of the trunk and face with sparing of the limbs (central obesity) Proximal muscle weakness A round face often referred to as a "moon face" Excess sweating Headache The excess cortisol may also affect other endocrine systems and cause, for example: Insomnia Reduced libido Impotence Amenorrhea Infertility Patients frequently suffer various psychological disturbances, ranging from euphoria to psychosis. Depression and anxiety are also common.	Dexamethasone suppression test 24 hour urinary measurement of cortisol	Medical management: Pasireotide Cabergoline Ketoconazole Metyrapone Mitotane Mifepristone Surgical management: Transsphenoidal pituitary resection
Hypothyroidism	Clinical features of hypothyroidism are due to deficiency of thyroxine: Fatigue Cold intolerance Decreased sweating Hypothermia Coarse skin Weight gain Hoarseness Goiter Fullness in the throat and neck Depression Emotional lability Attention deficit	Elevated TSH Low T4 Low T3 Elevated anti-thyroid antibodies(anti-TPO)	Levothyroxine
Chronic renal failure	There are no pathognomonic symptoms associated with chronic renal failure. Common non-specific symptoms of chronic renal failure include: Malaise Nausea Unintentional weight loss Pruritus Lower extremity edema Sleep disorders	Urinalysis: Albuminuria Hematuria Pyuria Red cell or white cell casts and crystals Fluid and electrolyte disturbances: Hyponatremia Hyperkalemia Hyperphosphatemia Hyperchloremia Metabolic acidosis Hypocalcemia Endocrine and metabolic disturbances: Hyperuricemia Hypertriglyceridemia Decreased HDL levels Vitamin D deficiency Increased Parathyroid hormone levels Hematologic abnormalities: Normocytic normochromic anemia Lymphocytopenia Leukopenia Thrombocytopenia	Medical management: Blood pressure management Control of blood glucose Protein restriction Management of anemia Management of electrolyte disturbance Dialysis Surgical management Kidney transplant
Liver disease: Cirrhosis	The clinical features of liver cirrhosis are very nonspecific. These include: Right upper quadrant abdominal pain Fever Fatigue and weakness Loss of appetite Diarrhea Nausea and vomiting Weight loss Abdominal pain and bloating when fluid accumulates in the abdomen Itching Menstrual irregularities	Elevated aminotransferases (AST & ALT) Elevated alkaline phosphatase (ALP) Elevated gamma-glutamyl transpeptidase Elevated bilirubin Low albumin Elevated prothrombin time Elevated globulin Hyponatremia Anemia Leukopenia and neutropenia Thrombocytopenia	Medical management: Treatment is usually directed towards the treatment of complications like ascites, esophageal varices, hepatic encephalopathy, hepatorenal syndrome, and spontaneous bacterial peritonitis. Some chronic constitutional symptoms that should be treated include: Pruritis: Cholestyramine is the drug of choice Hypogonadism: Topical testosterone preparations Osteoporosis: Calcium and vitamin D Pain management: NSAIDS, celecoxib, opioids Nutrition: Adequate caloric and protein intake, and multivitamin supplementation Surgical management: Liver transplantation
Seizure disorder	The clinical features of seizure disorder may include: Change in alertness, orientation and time perception Mood changes, such as unexplainable fear, panic, joy, or laughter Changes in sensation of the skin, usually spreading over the arm, leg, or trunk Vision changes, including seeing flashing lights Rarely, hallucinations (seeing things that aren't there) Falling, loss of muscle control, occurs very suddenly Muscle twitching that may spread up or down an arm or leg Muscle tension or tightening that causes twisting of the body, head, arms, or legs Shaking of the entire body Tasting a bitter or metallic flavor	Electroencephalogram	Medical management: Antiepileptic medications
Medication-induced	Clinical features of hyperprolactinemia after a specific period of regular medication ingestion	Discontinuation of the medication for 3 days and remeasurement of prolactin levels	Change to alternate medication

References