Other Endocrine Causes of Hypertension

1

How does acromegaly cause hypertension, and when should it be suspected?

Acromegaly is caused by hypersecretion of growth hormone (GH) usually from the pituitary with peripheral target organ mediation through the excess production of insulin like growth factor 1 (IGF-1). In addition to the classical features of this disease like acral growth, jaw prognathism, and gigantism, IGF-1 causes hypertrophy and growth of multiple other tissues. The heart muscle, adrenal glands, endothelial cell, and kidneys are all targets for excess IGF-1. Pathologically, this results in cardiomyopathy, adrenal hyperplasia (especially aldosterone excess), intravascular volume expansion, and hyperadrenergic vasoconstriction. Hypertension is a prominent feature in one-third of patients presenting with acromegaly. Hypertension is often multifactorial and driven by sodium and water retention, volume expansion, angiotensin II vasoconstriction, increased sympathetic tone, and increased cardiac output. These conditions promote hypertension by the combined increase in stroke volume and peripheral resistance. Other complications of GH excess such as obstructive sleep apnea, diastolic dysfunction, and insulin resistance also contribute to the secondary hypertension of acromegaly.

The diagnosis of acromegaly can be made by measuring IGF-1 levels especially in patients with acral and facial features. It is very reasonable to screen with IGF-1 levels in the setting of known complications of acromegaly including hypertension, cardiomyopathy, sleep apnea, hyperhidrosis, and polyosteoarthritis. Confirmation can be made by the lack of suppression of GH to less than 1 μg/L following an oral glucose load. Radiographic studies, especially magnetic resonance imaging, can identify a pituitary tumor. Multidisciplinary care involving cardiology and endocrinology is essential for these patients to ensure proper evaluation, treatment, and prevention of cardiovascular complications.

2

When should testosterone excess be suspected as a cause of hypertension?

Common clinical signs and symptoms that should raise suspicion of androgen excess or anabolic steroid abuse are listed in Table 11.1 . Virilizing or defeminizing symptoms in women often prompt an evaluation. Androgen excess is more difficult to detect in men and may only be manifest by testicular atrophy and infertility due to decreased spermatogenesis. Testosterone is directly synthesized in the testes in men and in much lesser amounts in the ovaries in women. Testosterone is also derived from the adrenal precursors dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), and androstenedione, which are converted in peripheral tissues (adipose, skin) to testosterone. Testosterone may be converted to the more potent androgen dihydrotestosterone by 5-alpha reductase in peripheral tissues where it activates local androgen receptors, amplifying its local effects.

Endogenous androgen excess can be seen in prolactinoma or polycystic ovarian syndrome (PCOS) or by secretion from a functional adrenal, testicular, or ovarian tumor. Glucocorticoid resistance or congenital adrenal hyperplasia can also cause androgen excess due to overproduction of adrenal androgens. The rapid development of androgen excess signs and symptoms should prompt the evaluation for an androgen secreting tumor. Adrenocortical carcinomas often secrete multiple steroids including DHEA, DHEAS, and cortisol more often than they are produced by adrenal adenomas. Ovarian or testicular tumors may also secrete androgens. Although total serum testosterone is usually elevated in all of these conditions, increased DHEA and DHEAS suggest an adrenal cause of androgen excess.

Although synthetic anabolic androgens are often used to enhance athletic performance, supraphysiological doses of transdermal or intramuscular testosterone are increasingly used for low libido, impotence, anorexia, or muscle wasting. When used appropriately to treat true hypoandrogenism, testosterone replacement is associated with little risk and may be associated with reduced blood pressure and cardiovascular risk.

Anabolic androgen steroids (AAS) derived from testosterone are used by young men (typically aged 20–30) to increase muscle mass or enhance athletic performance, with the vast majority of use by recreational bodybuilders. Other anabolic agents (e.g., human growth hormone, insulin like growth factor (IGF-1), and insulin) are often used cyclically with AAS and other drugs to increase pain tolerance (e.g., opiates or nonsteroidal antiinflammatory drugs), promote fat loss (e.g., thyroxine), or prevent adverse effects of testosterone excess (e.g., aromatase inhibitor or estrogen receptor antagonist). Opiates are frequently used with AAS to augment strength training, therefore opiate dependence is more common in AAS users. Additional concern for human immunodeficiency virus, hepatitis C, and hepatitis B is also warranted in users of injectable AAS. Various androgens are available in oral, transdermal, or injectable forms depending on the specific compound. Hepatotoxicity is a potential toxicity for several oral AAS (stanazolol, 17-α methyl testosterone, oxandrolone), and therefore intramuscular injection is the preferred route of administration for many weightlifters. The Steroid Control Act of 2004 banned most AAS, but they may still be obtained illicitly, and novel testosterone derivatives continue to surface. In addition to intentional AAS use, patients may unknowingly ingest supplements containing an oral AAS, especially in those marketed as an alternative to anabolic steroids or a supplement for sexual enhancement.

Because of the ethics of providing AAS to healthy volunteers to study their cardiovascular effects, the literature relies on cross-sectional studies of current versus former AAS users or control populations. Adverse cardiovascular and metabolic effects of AAS use may only partially reverse with cessation. Current use of AAS is associated with increased 24-hour ambulatory blood pressure, prevalent hypertension, reduced ventricular function, vascular calcification, and aortic stiffness.

Androgen abuse can typically be diagnosed by direct questioning if a trusting patient-physician relationship exists, although many patients are reluctant to offer a history of use. Polycythemia is a frequently observed laboratory clue that should prompt questioning for AAS use. Exogenous testosterone can be detected by an increased urinary testosterone/epitestosterone ratio greater than 4, although common genetic variants in Southeast Asian populations may cause a false negative result. Urinary mass spectrometric assays are performed by specialty laboratories to detect testosterone analogues and derivatives.