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.^[1]^[2]^[3]^[4]^[5]^[6]^[7]

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	Physical examination	Laboratory findings	Gold standard	Imaging	Other investigation findings
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
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
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:^[8]^[9]^[10]

Disease		History and symptoms			Laboratory findings							Additional findings
Disease		Fever	Goiter	Pain	TSH	Free T4	T3	T3RU	Thyroglobin	TRH	TPOAb	Additional findings
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
Central Hypothyroidism	Hypothalamus	+	-	-	N/↓	N/↓	N/↓	↑	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:^[11] 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:^[12] 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:^[13] 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.
Male diseases	Orchitis	Clincial features of orchitis include the following:^[14]^[15] 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:^[16] 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.^[17] Cyproterone acetate for the treatment of acne and hirsutism. Spironolactone
	Pelvic inflammatory disease	Patients usually present with the following:^[18]^[19] 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:^[20] 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.

References

↑ Sato N, Sze G, Endo K (1998). "Hypophysitis: endocrinologic and dynamic MR findings". AJNR Am J Neuroradiol. 19 (3): 439–44. PMID 9541295.
↑ Powrie JK, Powell M, Ayers AB, Lowy C, Sönksen PH (1995). "Lymphocytic adenohypophysitis: magnetic resonance imaging features of two new cases and a review of the literature". Clin. Endocrinol. (Oxf). 42 (3): 315–22. PMID 7758238.
↑ Honegger J, Schlaffer S, Menzel C, Droste M, Werner S, Elbelt U, Strasburger C, Störmann S, Küppers A, Streetz-van der Werf C, Deutschbein T, Stieg M, Rotermund R, Milian M, Petersenn S (2015). "Diagnosis of Primary Hypophysitis in Germany". J. Clin. Endocrinol. Metab. 100 (10): 3841–9. doi:10.1210/jc.2015-2152. PMID 26262437.
↑ Thodou E, Asa SL, Kontogeorgos G, Kovacs K, Horvath E, Ezzat S (1995). "Clinical case seminar: lymphocytic hypophysitis: clinicopathological findings". J. Clin. Endocrinol. Metab. 80 (8): 2302–11. doi:10.1210/jcem.80.8.7629223. PMID 7629223.
↑ Imura H, Nakao K, Shimatsu A, Ogawa Y, Sando T, Fujisawa I, Yamabe H (1993). "Lymphocytic infundibuloneurohypophysitis as a cause of central diabetes insipidus". N. Engl. J. Med. 329 (10): 683–9. doi:10.1056/NEJM199309023291002. PMID 8345854.
↑ Hsieh CY, Liu BY, Yang YN, Yin WH, Young MS (2011). "Massive pericardial effusion with diastolic right ventricular compression secondary to hypothyroidism in a 73-year-old woman". Emerg Med Australas. 23 (3): 372–5. doi:10.1111/j.1742-6723.2011.01425.x. PMID 21668725.
↑ Dejager S, Gerber S, Foubert L, Turpin G (1998). "Sheehan's syndrome: differential diagnosis in the acute phase". J. Intern. Med. 244 (3): 261–6. PMID 9747750.
↑ Invalid <ref> tag; no text was provided for refs named pmid19949140
↑ Invalid <ref> tag; no text was provided for refs named pmid18177256
↑ Invalid <ref> tag; no text was provided for refs named pmid18415684
↑ Denschlag, Dominik, MD; Clemens, Tempfer, MD; Kunze, Myriam, MD; Wolff, Gerhard, MD; Keck, Christoph, MD (October 2004), "Assisted reproductive techniques in patients with Klinefelter syndrome: A critical review", Fertility and Sterility, 82 (4): 775–779, doi:10.1016/j.fertnstert.2003.09.085CS1 maint: Date and year (link)
↑ Virtanen HE, Bjerknes R, Cortes D, Jørgensen N, Rajpert-De Meyts E, Thorsson AV; et al. (2007). "Cryptorchidism: classification, prevalence and long-term consequences". Acta Paediatr. 96 (5): 611–6. doi:10.1111/j.1651-2227.2007.00241.x. PMID 17462053.
↑ Schmitz D, Safranek S (2009). "Clinical inquiries. How useful is a physical exam in diagnosing testicular torsion?". J Fam Pract. 58 (8): 433–4. PMID 19679025.
↑ Trojian TH, Lishnak TS, Heiman D (2009). "Epididymitis and orchitis: an overview". Am Fam Physician. 79 (7): 583–7. PMID 19378875.
↑ Stewart A, Ubee SS, Davies H (2011). "Epididymo-orchitis". BMJ. 342: d1543. PMID 21490048.
↑ Christine Cortet-Rudelli, Didier Dewailly (2006). "Diagnosis of Hyperandrogenism in Female Adolescents". Hyperandrogenism in Adolescent Girls. Armenian Health Network, Health.am. Unknown parameter |month= ignored (help)
↑ Legro RS, Barnhart HX, Schlaff WD (2007). "Clomiphene, Metformin, or Both for Infertility in the Polycystic Ovary Syndrome". N Engl J Med. 356 (6): 551–566. PMID 17287476.
↑ Brunham RC, Gottlieb SL, Paavonen J (2015). "Pelvic inflammatory disease". N. Engl. J. Med. 372 (21): 2039–48. doi:10.1056/NEJMra1411426. PMID 25992748.
↑ Ford GW, Decker CF (2016). "Pelvic inflammatory disease". Dis Mon. 62 (8): 301–5. doi:10.1016/j.disamonth.2016.03.015. PMID 27107781.
↑ Murphy AA (2002). "Clinical aspects of endometriosis". Ann N Y Acad Sci. 955: 1–10, discussion 34-6, 396–406. PMID 11949938.

Template:WH Template:WS

[pmid9541295-1] Sato N, Sze G, Endo K (1998). "Hypophysitis: endocrinologic and dynamic MR findings". AJNR Am J Neuroradiol. 19 (3): 439–44. PMID 9541295.

[pmid7758238-2] Powrie JK, Powell M, Ayers AB, Lowy C, Sönksen PH (1995). "Lymphocytic adenohypophysitis: magnetic resonance imaging features of two new cases and a review of the literature". Clin. Endocrinol. (Oxf). 42 (3): 315–22. PMID 7758238.

[pmid26262437-3] Honegger J, Schlaffer S, Menzel C, Droste M, Werner S, Elbelt U, Strasburger C, Störmann S, Küppers A, Streetz-van der Werf C, Deutschbein T, Stieg M, Rotermund R, Milian M, Petersenn S (2015). "Diagnosis of Primary Hypophysitis in Germany". J. Clin. Endocrinol. Metab. 100 (10): 3841–9. doi:10.1210/jc.2015-2152. PMID 26262437.

[pmid7629223-4] Thodou E, Asa SL, Kontogeorgos G, Kovacs K, Horvath E, Ezzat S (1995). "Clinical case seminar: lymphocytic hypophysitis: clinicopathological findings". J. Clin. Endocrinol. Metab. 80 (8): 2302–11. doi:10.1210/jcem.80.8.7629223. PMID 7629223.

[pmid8345854-5] Imura H, Nakao K, Shimatsu A, Ogawa Y, Sando T, Fujisawa I, Yamabe H (1993). "Lymphocytic infundibuloneurohypophysitis as a cause of central diabetes insipidus". N. Engl. J. Med. 329 (10): 683–9. doi:10.1056/NEJM199309023291002. PMID 8345854.

[pmid21668725-6] Hsieh CY, Liu BY, Yang YN, Yin WH, Young MS (2011). "Massive pericardial effusion with diastolic right ventricular compression secondary to hypothyroidism in a 73-year-old woman". Emerg Med Australas. 23 (3): 372–5. doi:10.1111/j.1742-6723.2011.01425.x. PMID 21668725.

[pmid9747750-7] Dejager S, Gerber S, Foubert L, Turpin G (1998). "Sheehan's syndrome: differential diagnosis in the acute phase". J. Intern. Med. 244 (3): 261–6. PMID 9747750.

[pmid19949140-8] Invalid <ref> tag; no text was provided for refs named pmid19949140

[pmid18177256-9] Invalid <ref> tag; no text was provided for refs named pmid18177256

[pmid18415684-10] Invalid <ref> tag; no text was provided for refs named pmid18415684

[fertstert2004-11] Denschlag, Dominik, MD; Clemens, Tempfer, MD; Kunze, Myriam, MD; Wolff, Gerhard, MD; Keck, Christoph, MD (October 2004), "Assisted reproductive techniques in patients with Klinefelter syndrome: A critical review", Fertility and Sterility, 82 (4): 775–779, doi:10.1016/j.fertnstert.2003.09.085CS1 maint: Date and year (link)

[pmid17462053-12] Virtanen HE, Bjerknes R, Cortes D, Jørgensen N, Rajpert-De Meyts E, Thorsson AV; et al. (2007). "Cryptorchidism: classification, prevalence and long-term consequences". Acta Paediatr. 96 (5): 611–6. doi:10.1111/j.1651-2227.2007.00241.x. PMID 17462053.

[pmid19679025-13] Schmitz D, Safranek S (2009). "Clinical inquiries. How useful is a physical exam in diagnosing testicular torsion?". J Fam Pract. 58 (8): 433–4. PMID 19679025.

[pmid19378875-14] Trojian TH, Lishnak TS, Heiman D (2009). "Epididymitis and orchitis: an overview". Am Fam Physician. 79 (7): 583–7. PMID 19378875.

[pmid21490048-15] Stewart A, Ubee SS, Davies H (2011). "Epididymo-orchitis". BMJ. 342: d1543. PMID 21490048.

[AMN-16] Christine Cortet-Rudelli, Didier Dewailly (2006). "Diagnosis of Hyperandrogenism in Female Adolescents". Hyperandrogenism in Adolescent Girls. Armenian Health Network, Health.am. Unknown parameter |month= ignored (help)

[17] Legro RS, Barnhart HX, Schlaff WD (2007). "Clomiphene, Metformin, or Both for Infertility in the Polycystic Ovary Syndrome". N Engl J Med. 356 (6): 551–566. PMID 17287476.

[pmid25992748-18] Brunham RC, Gottlieb SL, Paavonen J (2015). "Pelvic inflammatory disease". N. Engl. J. Med. 372 (21): 2039–48. doi:10.1056/NEJMra1411426. PMID 25992748.

[pmid27107781-19] Ford GW, Decker CF (2016). "Pelvic inflammatory disease". Dis Mon. 62 (8): 301–5. doi:10.1016/j.disamonth.2016.03.015. PMID 27107781.

[pmid11949938-20] Murphy AA (2002). "Clinical aspects of endometriosis". Ann N Y Acad Sci. 955: 1–10, discussion 34-6, 396–406. PMID 11949938.

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Hypopituitarism differential diagnosis

Overview

Differentiating hypopituitarism from other Diseases

Differentiating different causes of hypothyroidism

Differentiating Hypogonadism from other Diseases

References

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