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Issues Affecting the Endocrine System

After neurologic disease, endocrine dysfunction is perhaps the most common set of symptoms in adult patients with mitochondrial disease (Finsterer, 2001). The most common endocrinopathy in mitochondrial disease is diabetes mellitus. In fact, mtDNA abnormalities may account for up to 5% of all cases of diabetes. The most common mtDNA abnormality is associated with MELAS syndrome (3243A-G) (Kadowaki, 1994) typically in association with diabetes and sensorineural hearing loss.

Other common endocrinopathies in mitochondrial disease include thyroid dysfunction (hypothyroidism more than hyperthyroidism). Hypoparathyroidism is classically described in Kearns-Sayre syndrome (Harvey, 1992). Adrenal insufficiency is also described (North, 1996). Finally, delayed puberty is described in both males and females although several female patients in our program have shown evidence of precocious puberty. Amenorrhea, primary and secondary, is a more frequent occurrence than testosterone deficiency.

Short stature is a common symptom in mitochondrial disease but often times not fully explored. It may have an endocrine etiology including growth hormone deficiency, growth hormone-releasing hormone deficiencies, or hypothyroidism. Multiple etiologies can occur concurrently (Balestri, 2000). More common, nutritional concerns should also be ruled out given the number of neurologic, neuromuscular, and gastrointestinal issues that can impact patients with mitochondrial disease

Hypothalamic-pituitary-adrenal axis impairment can result in extensive neuroendocrine dysfunction (Balestri, 2000) and includes reduced levels of somatotropic hormone (STH), thyroid stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), luteinizing hormone (LH) or anti-diuretic hormone (ADH) alone or in combination (Finsterer, 2006).

Endocrine abnormalities such as diabetes mellitus or adrenal insufficiency) may evolve over time, presenting initially during periods of physiologic stress (e.g., during significant infections), resolving as the stressor recedes. More vigilant monitoring is needed after such a presentation given the patient's risk for developing a more permanent endocrinopathy.

Differential Diagnosis

-Weight loss - consider diabetes, hyperthyroidism. Also inadequate nutrition: see NUTRITION.

-Weight gain - consider hypothyroidism.

-Short stature - consider growth hormone deficiency, GHRH deficiency, hypothyroidism. Also inadequate nutrition: see NUTRITION.

-Delayed puberty, amenorrhea - consider gonadal dysfunction (hypothalamic, pituitary, gonadal), hypothyroidism.

-Paresthesiae - consider hypoparathyroidism. Also, see ABNORMAL LIMB SENSATIONS.

-Seizures - consider hypoparathyroidism.

-Fatigue - consider hypothyroidism, hyperthyroidism, adrenal insufficiency. Also inadequate nutrition: see NUTRITION. Also autonomic dysregulation: see AUTONOMIC DYSREGULATION. Also, see FATIGUE AND EXERCISE INTOLERANCE.

-Constipation - consider hypothyroidism. Also, see CONSTIPATION.

-Orthostasis - consider adrenal insufficiency. Also autonomic dysregulation: see AUTONOMIC DYSREGULATION.


  1. Many of the symptoms associated with endocrine issues have multiple possible causes, especially given the multi-system nature of mitochondrial disease.
  2. Determine what symptoms are associated and whether or not there are any trigger factors.
  3. Where nutrition and/or fluid intake is a possible cause for the symptoms of concern, determine calorie and/or fluid intake.
  4. Be aware of endocrine involvement with mitochondrial disease. Annual screening for diabetes and thyroid function is reasonable.


  1. When endocrine dysfunction is identified, or abnormal symptoms are persistent and an endocrinopathy cannot be ruled out, referral to an endocrinologist should be considered.


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Bhattacharyya A, Tymms DJ. Mitochondrial defects and endocrine dysfunction. Quarterly J Med 1998;91(5):375-6.

Cassandrini D, Savasta S, Bozzola M, et al. Mitochondrial DNA deletion in a child with mitochondrial encephalopathy, growth hormone deficiency and hypoparathyroidism. J Child Neurol 2006;21:983-5.

DiMauro S, Hirano M, Schon EA. Approaches to the treatment of mitochondrial disease. Muscle Nerve 2006;34(3):265-83.

Finsterer J. Central nervous system manifestations of mitochondrial disorders. Acta Neurol Scand 2006;114:217-38.

Finsterer J, Jarius C, Eichberger H. Phenotype variability in 130 adult patients with respiratory chain disorders. J Inher Metab Dis 2001;24(5):560-76.

Harvey JN, Barnett D. Endocrine dysfunction in Kearns-Sayre syndrome. Clin Endocrinol 1992;37(1):97-103.

Kadowaki T, Kadowaki H, Mori Y et al. A subtype of diabetes mellitus associated with a mutation of mitochondrial DNA. N Engl J Med 1994;330(14):962-8.

Nakhla M, Polychronakos C. Monogenic and other unusual causes of diabetes mellitus. Pediatr Clin N Am 2005;52:1637-50.

North KN, Korson MS, Krawiecki N, et al. Oxidative phosphorylation defect associated with primary adrenal insufficiency. J Pediatr 1996;128:688-92.

Suzuki S, Oka Y, Kadowaki T, et al. Clinical features of diabetes mellitus with the mitochondrial DNA 3243 (A-G) mutation in Japanese: Maternal inheritance and mitochondria-related complications. Diabetes Res Clin Pract 2003;59(3):207-17.

Yialamas MA, Groop LC, Mootha VK. Mitochondrial endocrinology. In Mitochondrial Medicine. DiMauro S, Hirano M, Schon EA, eds. Informa Healthcare, Abingdon UK, 2006, 179-196.

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