Version May 2024
INTRODUCTION — In the early acquired immunodeficiency syndrome (AIDS) epidemic, the diverse endocrine manifestations of human immunodeficiency virus (HIV) infection were more often a consequence of opportunistic infections, neoplasms, or concomitant systemic illness. The widespread use of potent antiretroviral therapy has led to a decline in the incidence of glandular infiltration by opportunistic infections and neoplasms and has generated increased attention toward the metabolic complications of HIV therapy, including insulin resistance, dyslipidemia, and alterations in body fat distribution.
This topic review will address the assessment and management of pituitary and adrenal disorders in patients with HIV. Issues related to HIV lipodystrophy including metabolic syndrome, bone and calcium disorders, and thyroid dysfunction in this population are discussed elsewhere. (See "Epidemiology, clinical manifestations, and diagnosis of HIV-associated lipodystrophy" and "Treatment of HIV-associated lipodystrophy" and "Bone and calcium disorders in patients with HIV" and "Thyroid gland dysfunction in the patient with HIV".)
GENERAL PRINCIPLES — In general, the diagnosis and treatment of a specific endocrinopathy in a patient with HIV infection does not differ from that in an immunocompetent individual. There are, however, some special considerations. HIV infection may cause changes in pituitary and adrenal function that are adaptive and do not require treatment. Furthermore, many of the signs and symptoms of pituitary and adrenal dysfunction are nonspecific and can overlap with other non-endocrine disorders that are common in with HIV. Finally, many medications that are used to treat HIV infection and its complications can induce endocrine dysfunction (table 1), including affecting pituitary and adrenal hormones.
OPPORTUNISTIC INFECTIONS AND CANCERS — In the era of potent antiretroviral therapy (ART), infections and malignancies (ie, Kaposi sarcoma and lymphoma) in the adrenal and pituitary glands are rare in patients with HIV though they may be observed in patients not receiving ART and those with antiretroviral drug-resistant infection (table 2).
Tissue is generally required for a definitive diagnosis. When technically feasible, fine-needle aspiration (FNA) biopsy of the adrenal gland provides a less invasive alternative to open biopsy. Pheochromocytoma must always be excluded before FNA biopsy of the adrenal gland is performed. Standard functional testing should also be performed since clinically significant endocrine dysfunction may accompany glandular infection or infiltration of the pituitary or adrenal glands.
PITUITARY GLAND — The pituitary gland secretes and releases hormones that directly affect the functions of the thyroid gland, the adrenal gland, and the gonads as well as influencing growth, milk production, and water balance. (See "Hypothalamic-pituitary axis" and "Causes of hypopituitarism".)
The specific effects of HIV infection on pituitary function are discussed below.
Alterations in pituitary function — Anterior pituitary functional reserve is usually maintained, as evidenced by studies administering hypothalamic releasing hormones (ie, gonadotropin-, thyrotropin-, and corticotrophin-releasing hormones) to patients with HIV at various stages of illness [1-3]. Post-stimulation peak levels of growth hormone (GH), prolactin, thyroid-stimulating hormone (TSH), and adrenocorticotropic hormone (ACTH) may even be modestly increased, suggesting enhanced pituitary responsiveness due to subclinical target organ dysfunction [4].
Despite the normal response to gonadotropin-releasing hormone (GnRH), which excludes significant follicle-stimulating hormone (FSH) or luteinizing hormone (LH) deficiency, hypogonadotropic hypogonadism is commonly observed in patients with AIDS [5] as a consequence of hypothalamic dysfunction. This abnormality is likely due to a variety of factors, including the presence of chronic systemic illness, which suppresses the hypothalamic-pituitary-gonadal axis.
Published reports have demonstrated conflicting results as to whether or not prolactin levels are increased compared with HIV-seronegative controls [1,6-9]. In a large study of 192 clinically stable HIV-infected men, 21 percent were found to have hyperprolactinemia [10]. Although there was no HIV-seronegative control group in this study, this prevalence is greater than would be expected in the general population. The cause for elevations in prolactin is unknown but is hypothesized to be related to immunologic dysregulation. Other researchers have suggested that these higher serum prolactin levels are due to increases in macroprolactin, a glycosylated isoform of prolactin that is not biologically significant [11].
In contrast to the anterior pituitary gland, posterior pituitary function is often abnormal in patients with AIDS. In a study of 103 hospitalized AIDS patients, 36 were found to have serum sodium less than 130 mEq/L [12]. Hyponatremia was attributed to the syndrome of inappropriate antidiuretic hormone (ADH) secretion (SIADH) in 23 subjects. There was no definitive evidence, however, of a primary pituitary disorder since there were other confounding factors, including pulmonary infection (most notably Pneumocystis pneumonia) and treatment with medications known to affect fluid and electrolyte metabolism (eg, trimethoprim). (See "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)" and "Causes of hypotonic hyponatremia in adults".)
The somatotropic axis — HIV infection itself does not affect circadian GH secretion, as evidenced by frequent sampling studies among men with asymptomatic HIV infection and clinically stable AIDS [13]. The somatotropic axis, however, is influenced by nutritional status and body composition, leading to characteristic abnormalities in patients with AIDS wasting and the HIV-associated lipodystrophy syndrome (table 3). (See "Epidemiology, clinical manifestations, and diagnosis of HIV-associated lipodystrophy".)
HIV-associated lipodystrophy — In HIV-associated lipodystrophy, normal GH pulse frequency and insulin-like growth factor (IGF)-1 levels are observed, but there are lower mean GH concentrations, basal GH concentrations, and GH pulse amplitude [14]. Reduced GH levels are inversely correlated with visceral obesity in HIV lipodystrophy [14]. Abnormal response rates to GH stimulation testing with growth hormone releasing hormone (GHRH)-arginine are common [15], with up to one-third demonstrating biochemical GH deficiency (GHD) [16]. The clinical significance of this GHD, however, remains unclear and is less severe than that in patients affected by a true GHD secondary to pituitary disease [17]. Men with HIV demonstrate biochemical GHD more frequently than women, which has been attributed to differences in adipose tissue distribution [18]. Reduced GH levels are also found in generalized obesity. Tesamorelin, a GHRH agonist, is one of several treatments available for the reduction of excess abdominal fat in patients with HIV with lipodystrophy. (See "Epidemiology, clinical manifestations, and diagnosis of HIV-associated lipodystrophy" and "Treatment of HIV-associated lipodystrophy", section on 'Fat accumulation'.)
AIDS wasting — AIDS wasting appears to be associated with an acquired GH-resistant state, with decreased levels of IGF-1 and IGF-1 binding protein-3 in the setting of increased GH [19].
Effects of ART on pituitary function — The body composition changes associated with ART may affect GH secretion and action, but the specific effects of individual medications on the somatotropic axis have not been determined. (See "Epidemiology, clinical manifestations, and diagnosis of HIV-associated lipodystrophy".)
Marked elevations in prolactin levels, accompanied by symptomatic galactorrhea, were reported in four patients treated with protease inhibitors, although three of these patients had received medications known to cause hyperprolactinemia (metoclopramide or fluoxetine) [20] (see "Causes of hyperprolactinemia"). Use of opioids is also associated with hyperprolactinemia.
Clinical manifestations — Damage to the anterior pituitary can occur suddenly or slowly, can be mild or severe, and can affect the secretion of one, several, or all of its hormones. As a result, the clinical presentation of anterior pituitary hormone deficiencies can vary significantly. The spectrum of clinical manifestations of hypopituitarism is described in a separate topic review. (See "Clinical manifestations of hypopituitarism".)
Evaluation of pituitary dysfunction — When hypopituitarism is suspected, we perform the following initial laboratory tests and have them collected at 8:00 am (due to the diurnal variation in cortisol levels):
●Prolactin
●TSH and Free T4
●Cortisol and ACTH
●IGF-1
●LH and Testosterone (in men)
●FSH, LH, and estradiol (in amenorrheic or oligomenorrheic premenopausal women)
TSH alone is inadequate to diagnose secondary hypothyroidism, since it can be low, normal, or even slightly elevated in the setting of a low Free T4. If deficiency of one or more pituitary hormones is confirmed, magnetic resonance imaging (MRI) of the pituitary should be performed. The diagnosis of pituitary dysfunction based on results of these laboratory tests is discussed in detail elsewhere. (See "Diagnostic testing for hypopituitarism".)
Regardless of etiology, hypopituitarism is treated with physiologic hormone replacement and requires both biochemical and clinical monitoring of treatment. (See "Treatment of hypopituitarism".)
ADRENAL GLAND — The major adrenal steroid hormones include the glucocorticoids (particularly cortisol), mineralocorticoids (particularly aldosterone) and androgens, which can also be aromatized to estrogens. Abnormalities in adrenal gland function can lead to electrolyte disturbances, hyper- or hypotension, and changes in sex hormones. (See "Adrenal steroid biosynthesis".)
The effect of HIV infection on adrenal gland function is discussed below.
Alterations in adrenal function — Several characteristic alterations in adrenal steroid hormone metabolism have been observed in HIV-infected individuals. These shifts in hormone metabolism may simply signify an adaptive response to systemic illness and often do not require treatment.
Elevated basal cortisol levels may be accompanied by diminished responsiveness to adrenocorticotropic hormone (ACTH) stimulation [21]. This can lead to an incorrect interpretation of the standard ACTH stimulation test if a "subnormal" increase in cortisol levels is considered diagnostic without taking into account the absolute cortisol levels. (See "Diagnosis of adrenal insufficiency in adults".)
Given that elevated cortisol levels may be present without higher levels of ACTH, non-pituitary factors (eg, cytokines) may be directly promoting adrenal steroidogenesis [22]. Moreover, patients with advanced HIV disease often have an attenuated pituitary-adrenal response to corticotrophin-releasing hormone (CRH) infusion [23].
Increased ACTH levels may be accompanied by:
●Increased cortisol levels suggesting hypothalamic activation [24]
●Low or normal cortisol levels suggesting that the rises in ACTH may be compensatory in the setting of clinical or subclinical adrenal insufficiency
●Paradoxically elevated levels of cortisol despite Addisonian symptoms and signs suggesting peripheral glucocorticoid resistance [25]
Since the signs and symptoms of glucocorticoid deficiency are relatively nonspecific and often overlap with manifestations of AIDS, this diagnosis is frequently considered in patients with HIV infection. Prior to the availability of potent antiretroviral therapy (ART), pathologic changes in the adrenal gland were noted commonly at autopsy [26,27]. Depending on the stage of HIV infection, the presence of suggestive clinical signs and symptoms, and the method of diagnostic testing used, the proportion of patients thought to have adrenal insufficiency varied considerably but, in many cases, exceeded 5 percent [28]. Frankly elevated ACTH levels were rarely observed, suggesting that, in those with a subnormal response to ACTH, a secondary (ie, hypothalamic-pituitary) etiology was more likely.
Although the prevalence appears to be greater than in the general population, clinically significant adrenal insufficiency remains rare in patients with HIV. Overt hormone deficiencies are uncommon given the adrenal gland's high functional reserve; 80 to 90 percent destruction of the adrenal gland is usually required before adrenal failure is clinically apparent. Nevertheless, since untreated adrenal insufficiency has such potentially dire consequences, we recommend evaluation for glucocorticoid deficiency in a patient with AIDS, refractory hypotension, and critical illness. (See "Clinical manifestations of adrenal insufficiency in adults".)
Hyporeninemic hypoaldosteronism, which may present with hyperkalemia, hyponatremia, and metabolic acidosis, was reported in the early AIDS epidemic in a small case series [29]. As originally described in non-HIV infected patients with this condition [30], ACTH-stimulated cortisol levels were normal.
Dehydroepiandrosterone replacement therapy — Despite its wide availability and acceptability by HIV-infected patient populations, we suggest not routinely using dehydroepiandrosterone (DHEA) until its efficacy and safety have been proven in larger randomized clinical trials.
DHEA is an adrenal steroid hormone with weak androgenic activity. It has been investigated for its proposed anti-aging and immunomodulatory effects in a variety of clinical settings, including HIV disease. Low DHEA levels and elevated cortisol to DHEA ratios are found in HIV infection, particularly in the setting of body composition changes due to either lipodystrophy or malnutrition. In several cross-sectional studies, low serum concentrations of DHEA have been associated with low CD4 cell counts, weight loss, and progression to AIDS [31-33]. In early in vitro studies, DHEA appeared to inhibit HIV-1 replication and activation in cell culture [34-36]. Clinical trials of DHEA treatment in patients with HIV have found some improvements in quality of life and depression symptoms but no benefit on immune function, metabolism, or body composition [37-39]. These trials were limited by small size and, in one case, lack of blinding.
Effects of medications on adrenal function
Antiretroviral drugs — ART-associated lipohypertrophy (eg, dorsocervical fat pad enlargement and visceral adiposity) is not associated with overt hypercortisolism, despite phenotypic similarities to Cushing's syndrome [40]. Furthermore, these patients demonstrate normal diurnal cortisol variation and normal cortisol secretory dynamics after administration of ovine CRH [41]. (See "Epidemiology, clinical manifestations, and diagnosis of HIV-associated lipodystrophy" and "Epidemiology and clinical manifestations of Cushing syndrome".)
Pharmacokinetic boosters with glucocorticoids — Exogenous glucocorticoids, given by any route, should be used with caution and carefully monitored among patients using pharmacokinetic boosters. In particular, if a person with HIV has an indication for an inhaled or intra-articular glucocorticoid, we suggest switching to an antiretroviral regimen that does not contain a protease inhibitor or cobicistat. If changing antiretroviral regimens is not desirable or feasible, because of HIV drug resistance or intolerance to other antiretroviral medications, then beclomethasone is the safest inhaled steroid to coadminister with a protease inhibitor or cobicistat [42].
Iatrogenic Cushing's syndrome can result from the coadministration of ritonavir or cobicistat and synthetic glucocorticoids, such as nasal or inhaled fluticasone, inhaled budesonide, intra-articular triamcinolone, or topical ocular glucocorticoids [43-51]. The effects of these drugs on cytochrome P450 lead to prolongation of the half-life of the synthetic glucocorticoid. The resultant high plasma levels of glucocorticoid cause features of classic Cushing's syndrome and suppression of endogenous ACTH and cortisol levels (secondary adrenal insufficiency), such that abrupt withdrawal may precipitate an Addisonian crisis. The typical phenotype of Cushing's syndrome may not be recognized when pre-existing ART-associated lipodystrophy is present, given the similarities in clinical presentation (eg, visceral adiposity, peripheral lipoatrophy). In a retrospective study of 171 patients with HIV who received local steroid injections, a surprisingly high risk of subsequent adrenal dysfunction was reported (11 percent of the 81 patients who were also using protease inhibitors) [52].
Other medications used in patients with HIV — Adrenocortical function can be altered by other medications used in the treatment of HIV infection:
●Ketoconazole inhibits adrenal steroidogenesis and can lead to glucocorticoid deficiency in patients with impaired adrenal reserve.
●Rifampin can lower circulating cortisol levels through enhanced clearance of cortisol.
●Megestrol acetate, a synthetic progestin with intrinsic glucocorticoid-like activity, can suppress both the hypothalamic-pituitary-adrenal and the hypothalamic-pituitary-gonadal axes when administered chronically for appetite stimulation. Long-term exposure can lead to iatrogenic Cushing's syndrome, diabetes mellitus, and Addisonian crisis if the drug is withdrawn abruptly.
●Opiate use can also be associated with suppression of the hypothalamic-pituitary-adrenocortical (HPA) axis; the subsequent cortisol response to ACTH stimulation may be reduced [53].
Evaluation and treatment of adrenal dysfunction — As in other clinical situations complicated by acute or chronic illness, the optimal method of adrenal functional testing and the normal range for cortisol response are controversial.
The standard ACTH stimulation test (administration of 250 mcg cosyntropin intramuscularly or intravenously, with cortisol levels checked at baseline, 30 and 60 minutes later) is the most widely available and most frequently performed test. A post-stimulation peak cortisol level greater than 18 to 20 mcg/dL generally excludes adrenal insufficiency. This threshold is based on older serum cortisol assays, and specific monoclonal antibody immunoassays or liquid chromatography-tandem mass spectrometry may have lower thresholds for a normal response (14 to 15 mcg/dL) depending on the assay used [54].
Clinicians should note that since the standard stimulation test employs a supraphysiologic dose of ACTH, it is not sensitive in patients with partial or acute pituitary dysfunction. Insulin-induced hypoglycemia or the metyrapone test are sometimes necessary to confirm the diagnosis of suspected secondary adrenal insufficiency in patients with HIV [55], although these tests are challenging to perform in routine clinical practice. (See "Determining the etiology of adrenal insufficiency in adults".)
Assessment of clinically significant adrenal insufficiency in patients with HIV can be further complicated by hypoalbuminemia since total cortisol levels are typically measured. In a study of 66 critically ill patients, the 36 patients with albumin <2.5 g/dL and subnormal ACTH-stimulated total cortisol concentrations were subsequently found to have normal adrenal function and elevated free cortisol concentrations [56].
With the above caveats, a standard ACTH test should be performed initially. If this test is normal, but adrenal insufficiency is still suspected, we recommend consultation with an endocrinologist.
If adrenal insufficiency is confirmed, a baseline ACTH level is useful to distinguish between a primary and secondary etiology:
●A high ACTH level indicates primary adrenal insufficiency, which in a patient with HIV is most often due to an infiltrative process of the adrenal glands, such as tuberculosis, histoplasmosis, or cytomegalovirus adrenalitis.
●A low or normal ACTH level usually implies central adrenal insufficiency. In the latter group, without a known exposure to an exogenous agent that can suppress the HPA axis (eg, glucocorticoids, megestrol acetate), magnetic resonance imaging (MRI) scan of the pituitary should be obtained to exclude an anatomic abnormality. (See "Determining the etiology of adrenal insufficiency in adults".)
The approach to the treatment of the patient with HIV with glucocorticoid insufficiency is the same as in the HIV-seronegative patient. Glucocorticoid replacement therapy should be initiated using the lowest possible doses (typically hydrocortisone 15 to 20 mg/day) that relieve clinical symptoms. Patients with documented adrenal insufficiency require higher doses of glucocorticoids during periods of stress, such as acute illness and/or surgery. The addition of fludrocortisone may be necessary in the setting of primary adrenal failure with concomitant mineralocorticoid deficiency (usually manifested biochemically by hyponatremia, hyperkalemia and metabolic acidosis).
It is not clear whether patients who have elevated basal cortisol levels with a blunted response to standard ACTH stimulation testing require replacement therapy, since some will respond to prolonged (72-hour) ACTH infusion [21]. These challenging cases must be evaluated individually, taking into account the potential benefits on clinical symptoms and the risks of adverse effects. Some practitioners advocate treating these patients with glucocorticoids only during periods of stress, limiting steroid exposure as much as possible. (See "Treatment of adrenal insufficiency in adults".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary care of adults with HIV".)
SUMMARY AND RECOMMENDATIONS
●In the early AIDS epidemic, endocrine abnormalities were usually due to infiltrative diseases and systemic illness. In the era of potent antiretroviral therapy (ART), there has been a decline in opportunistic infections and malignancies but an increased incidence of metabolic complications, some related to medications. (See 'Introduction' above.)
●In general, the diagnosis and treatment of pituitary and adrenal disorders in a patient with HIV infection does not differ from that in an immunocompetent individual. (See 'General principles' above.)
●Anterior pituitary functional reserve is usually maintained, whereas posterior pituitary function may be abnormal in a patient with AIDS. (See 'Alterations in pituitary function' above.)
●The somatotropic axis is influenced by nutritional status and body composition, leading to characteristic abnormalities in patients with AIDS wasting and HIV-associated lipodystrophy syndrome. (See 'The somatotropic axis' above.)
●Although the prevalence of glucocorticoid deficiency appears to be greater than in the general population, clinically significant adrenal insufficiency is rare but should be considered in the patient with AIDS, hypotension, and critical illness. (See 'Alterations in adrenal function' above.)
●Low dehydroepiandrosterone (DHEA) levels and elevated cortisol to DHEA ratios are found in HIV infection, particularly in the setting of body composition changes due to either lipodystrophy or malnutrition. We suggest not routinely using DHEA replacement therapy in this setting (Grade 2C). The available clinical trials of DHEA replacement therapy in HIV-infected patients are limited, and the efficacy and safety of this therapy remain unproven. (See 'Dehydroepiandrosterone replacement therapy' above.)
●Certain medications can lead to cortisol insufficiency or excess. Iatrogenic Cushing's syndrome can result from the coadministration of ritonavir or cobicistat and synthetic glucocorticoids (usually inhaled or injected into joints), whereas medications such as rifampin can lower circulating cortisol levels through enhanced clearance of cortisol. (See 'Effects of medications on adrenal function' above.)
●A standard adrenocorticotropic hormone (ACTH) stimulation test should be ordered as the initial approach for evaluation of adrenal function. If adrenal insufficiency is confirmed, an ACTH level should be drawn to help differentiate between primary and secondary adrenal insufficiency. (See 'Evaluation and treatment of adrenal dysfunction' above.)
ACKNOWLEDGMENT — UpToDate gratefully acknowledges John G Bartlett, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Infectious Diseases.
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