Central Hypothyroidism: A Cushing's Disease problem, too

Since approximately 80% of Cushing's Disease/Syndrome is caused by a pituitary adenoma, other hormones produced by the interaction of the hypothalamic-pituitary-adrenal (HPA) axis are often deficient. This includes thyroid-stimulating hormone (TSH).

Primary hypothyroidism is often detected by elevated TSH values. This is due to the normal feedback-loop of the HPA axis. Central hypothyroidism (CH), however, is not typically detected by measuring TSH which is low due to a disruption of the pituitary's stimulus and is not produced as needed. The most common cause is a pituitary adenoma.

In Mechanisms Related to the Pathophysiology and Management of Central Hypothyroidism, the authors state, "Given that the prevalence of pituitary adenomas in the general population is greater than 10%, the true prevalence of CH might be much higher than that reported". When speaking of the method of measuring TSH levels alone, they say this "approach works, however, only if the hypothalamic-pituitary-thyroid axis is normal. Conversely, the strategy of first-line TSH measurement can miss patients with CH."

The authors give a very nice synopsis of the HPA axis' role in thyroid regulation and function. The diagrams are well-done, also. In Table 1, the causes of CH are listed:

Table 1. Causes of Central Hypothyroidism

Cause	Congenital	Acquired
Classic causes
Space-occupying lesions (brain or pituitary; pituitary adenoma, craniopharygioma, etc.)	Yes	Yes
Radiation	No	Yes
Vascular disease (Sheehan syndrome, etc.)	Yes	Yes
Nonclassic causes
Traumatic brain injury or subarachnoid hemorrhage	No	Yes
Drug-induced (bexarotene, carbemazepine, etc.)	No	Yes
Growth hormone therapy	No	Yes
Infection (lymphocytic adenohypophysitis, lymphocytic hypophysitis)	No	Yes
Set point diseases (infant's born to mothers with inadequately controlled Graves disease, etc.)	Yes	No
Genetic mutations	Yes	No
Idiopathic	Yes	Yes

CH usually appears concurrently with other hormone deficiencies. "Hormone deficiencies were seen for luteinizing hormone/follicle-stimulating hormone (LH/FSH) in 85% of patients, growth hormone in 65%, adrenocorticotropic hormone (ACTH) in 62%, TSH in 60%, antidiuretic hormone in 23% and prolactin in 15%."

The authors also detail non-classic causes of CH, including genetic mutations. With one familial case inheritance was determined to be autosomal recessive. Interestingly, the values of TSH measured varied by assay with one mutation.

The researchers make a case for using free T4 and free T3 to determine CH while levels of TSH have no diagnostic value. They also indicate that although the "nocturnal surge of serum TSH level has been used to assess CH, this approach is still controversial. MRI could be required for most suspected cases of CH to detect origin of hypothalamic or pituitary disorders."

Treatment is much the same as for any hypothyroidism. Levoxythyroxine is the first line of treatment. They also carefully point out the following:

Deficiencies of hormones other than TSH should be considered before starting
treatment. When ACTH deficiency is also present, glucocorticoid therapy should
be started at least 1 week before initiation of levothyroxine to avoid increased
consumption of cortisol and worsening of the ACTH deficiency, which can
induce crisis. (emphasis mine)

An algorithm was developed for treating CH sufferers. Interestingly, this does not show using any form of T3, although there are folks who do not convert forms of T4 to the needed T3. They do empasize, however, the importance of achieving "free T4 in the upper end of the normal range rather than within the middle or lower values".

On a positive note for those who have or will undergo pituitary surgery, they authors conclude, "Surgery is reported to lead to an improvement in anterior pituitary function in approximately 35% of patients with pituitary adenoma and CH."

Masanobu Yamada, Masatomo Mori (2008). Mechanisms related to the pathophysiology and management of central hypothyroidism Nature Clinical Practice Endocrinology & Metabolism, 4 (12), 683-694 DOI: 10.1038/ncpendmet0995