Is It Real?

Chapter 50


Occult Hyperadrenocorticism


Is It Real?




Because of the high incidence of hyperadrenocorticism (HAC) and the nonspecific clinical signs, older dogs are commonly screened for HAC with the low-dose dexamethasone suppression test (LDDST) or the standard adrenocorticotropic hormone (ACTH) stimulation test with measurement of serum cortisol before and after ACTH injection. Neither the LDDST nor ACTH stimulation test is perfect, however. For the LDDST and ACTH stimulation test, the sensitivity is approximately 95% and 80%, respectively, for diagnosing HAC. The specificity of the LDDST has been estimated to be 44% to 73%, whereas the specificity of the ACTH stimulation test is 59% to 86%. Because HAC occurs in older dogs, patients tested for HAC often have concurrent disease. At the least, if these dogs do not have HAC, they have a nonadrenal illness causing the clinical signs. Generally, the more severe the nonadrenal illness present, the more likely a false-positive test result for HAC is to occur.


Because of the imprecision of the tests, HAC can sometimes be a difficult diagnosis to make. Clinicians may be faced with situations in which their clinical impression is that patients have HAC, but the tests do not confirm the diagnosis, and no alternative diagnosis is identified. To explain such circumstances, much interest has focused more recently on a syndrome termed occult HAC. Dogs with occult HAC allegedly have clinical signs or routine laboratory abnormalities, or both, consistent with classic HAC but with normal LDDST and ACTH stimulation test results. Occult HAC is supposedly caused by diversion of the normal adrenocortical pathways for cortisol and aldosterone synthesis into overproduction of sex hormones instead. The syndrome is diagnosed by performance of an ACTH stimulation test with measurement of serum sex hormone concentrations before and after administration of ACTH.


However, it is the authors’ opinion that conclusive evidence for the existence of occult HAC as a sex hormone–mediated condition is lacking. Here we evaluate the evidence both for and against the existence of occult HAC. In evaluating adrenal secretion of sex hormones and cortisol precursors, whether basal or ACTH-stimulated concentrations were measured in any study must be taken into account. For the diagnosis of standard HAC, determination of basal cortisol concentration is unreliable and never used by itself. No evidence exists that measurement of basal serum sex hormone concentrations are any more reliable for diagnosis of adrenal dysfunction. The following discussion focuses on ACTH-stimulated concentrations.



Adrenal Sex Hormone and Cortisol Precursor Secretion as a Cause of Bilaterally Symmetrical Alopecia



Evidence in Favor


Apart from the adrenal glands, sex hormones secreted from other sources can cause alopecia. A syndrome of castration-responsive alopecia has been recognized. Hyperestrogenism and hyperprogesteronism associated with Sertoli cell tumors, for example, can lead to bilaterally symmetrical alopecia.


The first report of clinical signs thought to be due to elevations in adrenal-derived sex hormone concentrations described bilaterally symmetrical alopecia and hyperpigmentation in seven Pomeranians (Schmeitzel and Lothrop, 1990). Classic HAC was ruled out on the basis of normal ACTH stimulation test and LDDST results. Progesterone, 17α-hydroxyprogesterone (17OHP), 11-deoxycortisol, dehydroepiandrosterone sulfate (DHEAS), testosterone, androstenedione, and estradiol were measured before and after administration of ACTH in 7 affected Pomeranians, 12 unaffected Pomeranians, and 19 non-Pomeranian control dogs. Only ACTH-stimulated 17OHP concentrations differed between affected and unaffected Pomeranians, but ACTH-stimulated progesterone and DHEAS concentrations were significantly higher in both affected and unaffected Pomeranians compared with controls. Given the constellation of abnormalities in affected and unaffected dogs, it was hypothesized the alopecia was due to a partial deficiency of 21-hydroxylase, an enzyme needed for cortisol synthesis. In humans with 21-hydroxylase deficiency, cortisol is not synthesized and its precursors, most notably 17OHP and androgens, accumulate. Because affected Pomeranians had normal cortisol concentrations, the enzyme deficiency was assumed to be partial. Family members of human patients with congenital adrenal hyperplasia have sex hormone elevations to a lesser magnitude and no clinical signs, explaining the findings (i.e., increased progesterone and DHEAS levels) in the unaffected Pomeranians (many of the affected and unaffected Pomeranians in the study were related). Subsequently, other dogs with alopecia X were reported to have ACTH-stimulated sex hormone concentrations above the reference range.



Evidence Against


Of six sex hormones assessed by Schmeitzel and Lothrop (1990) in the seven Pomeranians with alopecia X, only ACTH-stimulated serum 17OHP was significantly different between affected and unaffected dogs. However, when affected male and female dogs were assessed separately, the males did not have elevated serum 17OHP concentrations. In 276 dogs with alopecia X, only 73% had at least one basal or post-ACTH sex hormone concentration above the normal range (i.e., 27% had no elevations). Despite the preponderance of elevations in sex hormone concentrations, no consistent sex hormone abnormalities were identified. Of the ACTH-stimulated hormone concentrations, elevated progesterone was the most common abnormality, but it was found in only 36.2% of the patients. It was concluded that it is more appropriate to refer to alopecia X as “alopecia associated with follicular arrest rather than equating it with an adrenal hormone imbalance” (Frank et al, 2003).


Candidate genes in which mutations could cause the sex hormone abnormalities, including 21-hydroxylase and enzymes in the cortisol synthesis pathway, have been cloned. No mutations have been identified.



17α-Hydroxyprogesterone, Other Sex Hormones, and Cortisol Precursors as Causes of Occult Hyperadrenocorticism



Evidence in Favor


In a study of 24 dogs with clinical and routine laboratory findings suggestive of HAC, 11 dogs were assigned to group 1 that had typical HAC with elevated cortisol responses to ACTH. Of 13 dogs with normal ACTH response test results, 6 had positive LDDST results (group 2A), 4 had negative LDDST results (group 2B), and 3 had low plasma cortisol concentrations throughout testing so that the LDDST was uninterpretable (group 2C). Despite the variation in serum cortisol concentrations on the tests for standard HAC, all 23 dogs had elevated ACTH-stimulated 17OHP concentrations. It was concluded that ACTH-stimulated serum 17OHP concentration is elevated in dogs with classic and occult HAC, and measurement of serum 17OHP concentration is a marker of adrenal dysfunction (Ristic et al, 2002). Numerous other studies have since documented elevations in sex hormone concentrations in dogs with various forms of hypercortisolemia, either pituitary-dependent HAC (PDH) or HAC due to an adrenal tumor (AT).


In cases in which cortisol and sex hormones are both elevated, which hormones are causing clinical signs of HAC is difficult or impossible to determine. However, sporadic reports exist of dogs with sex hormone–secreting AT and low serum cortisol concentrations in which clinical signs of HAC were present, ostensibly secondary to the sex hormones.

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Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Is It Real?
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