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Endocrine
Endocrine Manifestations of HIV
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Introduction
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Adrenal Insufficiency
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transparent imageDefinition
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transparent imageIncidence
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transparent imageDifferential Diagnosis
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transparent imageClinical Evaluation and Work-Up
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transparent imageTreatment
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Testicular Function: Hypogonadism
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transparent imageDefinition
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transparent imageIncidence and Epidemiology
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transparent imageDifferential Diagnosis
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transparent imageEvaluation and Work-Up
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transparent imageTreatment
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transparent imageFuture Directions and General Conclusions
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Pituitary Dysfunction
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transparent imageAnterior Pituitary Dysfunction
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transparent imagePosterior Pituitary Function and Osmoregulation
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transparent imageIncidence
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transparent imageDifferential Diagnosis and Evaluation
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transparent imageWork-Up and Treatment
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Pancreatic Dysfunction
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transparent imageIncidence and Epidemiology
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transparent imageEvaluation and Treatment
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Calcium Metabolism
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Thyroid Function
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References
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Introduction
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A number of endocrine abnormalities develop in patients with HIV infection, although many are likely to be nonspecific responses to infection, stress, and malnutrition. Others are due to infiltration of endocrine glands by tumor or infection. This chapter reviews adrenal, testicular, pituitary, pancreatic, calcium, and thyroid abnormalities in HIV infection.

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Adrenal Insufficiency
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Definition
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Adrenal insufficiency is a relative or absolute deficiency of the adrenal glucocorticoid and/or mineralocorticoid hormones required for normal homeostasis.

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Incidence
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Of all endocrine deficiencies in patients with HIV disease, adrenal insufficiency received the most attention early in the epidemic. Authors of several series reported a high incidence at autopsy of adrenal involvement.(1-3) Bricaire et al. found abnormal adrenal glands in 64 of 83 patients with HIV disease at postmortem examination(1); 37 showed inflammation and 22 showed necrosis. Cytomegalovirus (CMV) was present in the adrenals in 44 cases, Kaposi's sarcoma (KS) in 3, and cryptococcosis, toxoplasmosis, and tuberculosis in 1 each. Other reports confirm the extremely high incidence of adrenal CMV.(2,3) In one series, CMV was present in 81 of 164 patients with HIV disease at autopsy, and 75% of patients with CMV infection had CMV involvement of the adrenals.(2) The adrenal gland was the third most common site for CMV in the other series of patients with HIV disease, following the lungs and gastrointestinal tract.(3)

In a nude-mouse model of T cell deficiency, murine CMV replicates in high titer in the adrenal gland, resulting in destructive adrenalitis.(4) Researchers have questioned the clinical significance of these adrenal pathologic lesions, however, in patients with HIV. In an autopsy study of 41 patients by Glasgow et al.,(5) necrosis was always less than 70% and in only one case was greater than 55%. This percentage is far less than the extent of adrenal destruction usually required for adrenal insufficiency given that 80 to 90% of the adrenal gland can be necrotic without impairing adrenal function.(6)

Consistent with the expectation that observed adrenal pathology is insufficient to cause clinical problems, the incidence of clinical or biochemical adrenal insufficiency in patients with HIV disease is in fact much lower than the incidence of adrenal involvement found at autopsy, despite a number of case reports reporting the association.(7,8) Of the 32 autopsies with pathologic involvement of the adrenal in the study by Glasgow et al.,(5) only two had been suspected premortem of having adrenal insufficiency. In a careful study of endocrine abnormalities in ambulatory patients with advanced HIV disease,(9) 36 of 39 tested had a normal response to adrenocorticotropic hormone (ACTH) (serum cortisol greater than 20 mg/dl), with a mean baseline value of 14 (+/- 1) rising to 30 (+/- 2) at 60 minutes. It is important to recognize that although hyponatremia, hyperkalemia, and hypotension are extremely frequent in patients with advanced HIV disease,(10-13) these findings do not mean adrenal insufficiency is common (see subsequent discussion).

Certain drugs used in patients with advanced HIV disease can affect adrenal function.(14-17) Ketoconazole, which is used to treat certain fungal infections, inhibits adrenal corticosteroid synthesis and blunts the cortisol response to ACTH.(15) This effect may be an under recognized cause of impaired adrenal reserve and even frank adrenal insufficiency with Addisonian crisis.(16) Rifampin also alters the metabolism of glucocorticoids, thereby increasing hormone excretion values or necessitating higher exogenous steroid doses to maintain therapeutic effect.(17)

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Differential Diagnosis
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Unexplained hyperkalemia persisting despite normal cortisol response to ACTH may represent hyporeninemic hypoaldosteronism, which has been described in hospitalized patients with HIV disease.(13,18,19) Characteristic findings in these patients include hyperkalemia, usually hyponatremia, mild acidosis, normal basal and ACTH-stimulated cortisol levels, low basal aldosterone levels(particularly in relation to high serum potassium levels), low basal renin, and impaired aldosterone response to furosemide.(13) Guy et al.(18) reported a specific mineralocorticoid deficiency syndrome, with low serum sodium, high potassium, postural hypotension, high serum cortisol, and high plasma renin activity but low aldosterone, and high urinary sodium in a patient with AIDS and Pneumocystis carinii pneumonia (PCP). Finally, Lachaal and Venuto(19) described hyperkalemia in 19 of 20 hospitalized patients with advanced HIV disease treated with pentamidine for PCP. Hyperkalemia (> 5 mEq/L) was observed in every AIDS patient given pentamidine for more than 6 days. These patients had serum potassium levels ranging from 5.1 to 8.7 mEq/liter and mild to severe azotemia (creatinine 1.5 to 11.8 mg/dl). Life-threatening hyperkalemia occurred in some patients despite only a modest reduction in creatinine clearance. Acidosis (bicarbonate 14 to 21 mEq/L) was present, and both of the only two patients tested had low plasma renin and aldosterone concentrations. The implication is that pentamidine frequently induces nephrotoxicity and/or hyporeninemic hypoaldosteronism, which can lead to life-threatening hyperkalemia.

Serum potassium concentration normalizes with mineralocorticoid therapy alone (fludrocortisone, 0.1 to 0.2 mg/day) in these patients. Therefore, it is important to make the diagnosis and so avoid unnecessary glucocorticoid treatment, with its potentially immunosuppressive action. The etiology of hyporeninemic hypoaldosteronism in both HIV-infected and non-HIV-infected patients is not known.

Classic adrenal destruction is not the only cause of abnormal adrenal laboratory results in AIDS. An intensive study of adrenal function(20) revealed that the basal serum cortisol level is increased in hospitalized patients with advanced HIV disease, compared with non-HIV-infected patients, presumably due to stress. In the group with advanced HIV disease, the mean ACTH response was normal, but steroids of the 17-deoxy series (corticosterone and 18-hydroxy-desoxycorticosterone [DOC]) were significantly lower, although aldosterone and 18-hydroxycortisone were in the normal range. Prolonged ACTH administration (3 days) exaggerated the differences, with greater reductions in 18-hydroxy-DOC, corticosterone, DOC, and cortisol in the HIV-infected than in the non-HIV-infected patients. Of the HIV-infected patients with reduced 17-deoxy steroids, all had low ACTH (less than 20 pmol/L), low aldosterone, hyperkalemia, and hypotension, consistent with both functional adrenal insufficiency and an impairment of pituitary response. Oberfield et al.(21) also reported a similar subtle impairment in 18-DOC response to ACTH in 10 HIV-infected children with normal basal and ACTH-stimulated serum cortisol, whereas Vilette et al.(22) described high serum cortisol in conjunction with low ACTH levels. Vilette et al.(20) concluded that factors other than pituitary ACTH stimulate cortisol -- perhaps factors secreted directly from HIV-infected immune cells. From a clinical perspective, however, the implications of these observations remain uncertain. For instance, the answer to the question "can an impaired 17-deoxy steroid response to ACTH predict impending adrenal insufficiency?" remains unknown.

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Clinical Evaluation and Work-Up
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Diagnosing adrenal insufficiency in patients with advanced HIV disease can be difficult when classic biochemical criteria are not met (e.g., basal cortisol levels less than 5 mg/dl and ACTH-stimulated increase of less than 7 mg/dl). Some clinicians use the absolute cortisol level after ACTH stimulation, a peak value of 20 mg/dl or more indicating normal adrenal reserve.(23) On the basis of studies on patients with advanced HIV disease studied at San Francisco General Hospital, Membrano et al. proposed defining the normal response in AIDS as peak levels of 22 mg/dl or greater.(20)

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Treatment
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Treating proven adrenal insufficiency in HIV disease is essentially the same as in other clinical settings. Stress doses (180 to 200 mg of hydrocortisone in divided doses) are indicated during acute illnesses. Chronic replacement with supraphysiologic doses of glucocorticoids (e.g., greater than 30 mg hydrocortisone daily) should be avoided, to prevent worsening an already immunosuppressed condition. HIV disease, however, is not a contraindication to pharmacologic glucocorticoid therapy (e.g., in central nervous system toxoplasmosis). Ketoconazole should be used with caution and adrenal function monitored.(15) Clinicians should also be aware of the effects of rifampin on steroid metabolism.(17)

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Testicular Function: Hypogonadism
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Definition
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Hypogonadism refers to insufficient secretion of sex steroids by the gonads to maintain normal physiologic function dependent on these hormones, including reproductive function, secondary sexual characteristics, body composition, and mood and behavioral actions.

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Incidence and Epidemiology
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Hypogonadism is an area of increasing clinical importance in HIV disease. In one study of patients with HIV disease, the most common endocrine abnormality was a low serum testosterone level.(9) Patients with symptomatic HIV infection had serum testosterone levels of 292 +/- 70 ng/dl; patients with advanced HIV disease had serum testosterone levels of 401 +/- 30 ng/dl. Both of these levels were significantly lower than in patients with asymptomatic HIV infection (567 +/- 49) and non-HIV-infected controls (608 +/- 121). The testosterone value was beneath the lower limit of normal in 42% of symptomatic HIV-infected patients (3 of 7) and 50% of patients with advanced HIV disease (20 of 40). Clinically, 67% (28 of 42) of patients with advanced HIV disease complained of loss of libido and 33% complained of impotence. Other studies confirmed the below normal testosterone levels.(22,24)

Hypogonadism was hypogonadotropic in 75% of cases (18 of 24)(9); however, seven of eight patients given gonadotropin-releasing hormone (GnRH) had a normal gonadotropin response. This result suggests, but does not prove, that pituitary function was normal and the lesion was in the central nervous system (CNS). The finding that low serum testosterone correlated with weight loss and a low lymphocyte count was consistent with CNS etiology, because stress or weight loss are known to cause central hypogonadotropic hypogonadism in other settings.(25,26) Coodley et al.(27) reported that weight loss preceded the fall in serum total testosterone concentrations in men during the course of progressive HIV disease. This finding is consistent with the concept that the hypogonadism represents a nonspecific stress or starvation response or hypothalamic hypogonadism, as is commonly observed in young women (i.e., in anorexia nervosa). The fact that 55% of hypogonadal versus 26% of eugonadal men died within 12 months was also consistent with a nonspecific causality.

Low testosterone levels with elevated luteinizing hormone and follicle-stimulating hormone levels have also been reported(22) in patients with symptomatic or advanced HIV disease, suggesting primary testicular failure in this group. Consistent with this clinical observation is a pathologic report(28) of histologic inflammation and interstitial fibrosis compared to normal control subjects (28% vs. 9% and 51% vs. 4%, respectively), and impaired spermatogenesis scores (> 50% reduced). Thus, primary testicular failure may also occur in addition to hypothalamic hypogonadism in advanced HIV infection and correlate with degree of illness.

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Differential Diagnosis
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The central differential diagnostic question is whether the reduced serum testosterone concentrations observed in these often ill, often wasted patients is functionally important, thus deserving of therapeutic attention. Many of the symptoms of hypogonadism in both men and women are nonspecific and overlap with those of depression or chronic illness: e.g., fatigue, loss of energy, loss of libido, depressed affect, poor-self image. The occurrence of these symptoms in conjunction with low-normal serum testosterone levels in men with AIDS therefore does not necessarily mean that the symptoms are due to hypogonadism. More specific symptoms of hypogonadism, including changes in the pattern of hair growth (loss of pubic or auxiliary hair), reduced beard growth, testicular atrophy, sexual dysfunction, or gynecomastia, are usually not present.

Moreover, the range of "normal" for serum testosterone levels in men is quite wide in most laboratories, e.g., 250 to 1100 ng/dl. Most patients with advanced HIV disease do not have frankly low serum testosterone levels (below 250 ng/dl) but have "borderline" low levels in the lowest 20% (e.g., 250 to 450 ng/dl) but not frankly below "normal." Population surveys in men with AIDS-wasting syndrome(9,29) reveal the most common values for total testosterone to be between 250 and 450 ng/dl (observed in >60% of men), in contrast to seronegative controls, in whom the most common values were 450 to 700 ng/dl (observed in > 60% of men). If HIV-seropositive men had a baseline testosterone concentration measured before developing symptomatic HIV infection, the fact that a fall in hormone level had occurred would be apparent, but most subjects do not have predisease comparison levels.

Until recently, little or no data addressed the functional importance of these borderline-low serum testosterone levels. Strawford et al.(30) performed a randomized study of nandrolone decanoate (a testosterone analogue) vs placebo in men with serum testosterone concentrations of < 450 ng/dl. The treated groups (65 to 200 mg IM per week) showed significant nitrogen retention, positive nitrogen balance, and increased lean body mass, quality of life measures, and exercise performance. Accordingly, borderline-low total testosterone levels appear to be functionally important, in that androgen therapy at moderate doses, even in the absence of supervised resistance exercise, had a significant positive impact in these patients.

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Evaluation and Work-Up
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The diagnosis of hypogonadism should be considered in patients with HIV infection and weight loss (or loss of lean body mass without weight loss), specific symptoms of hypogonadism (altered hair growth, beard growth, testicular atrophy, sexual dysfunction) or nonspecific symptoms (fatigue, loss of libido, loss of energy, etc.). The most useful test is the total serum testosterone concentration, with or without gonadotrophin levels (luteinizing hormone (LH) or follicular stimulating hormone [FSH]). Measuring total testosterone is a considerably less expensive test than that to measure free testosterone and is technically less demanding, thus more reproducible from one laboratory to the next. Although the laboratory "normal range" will often range from 200 or 250 ng/dl to 1,000 or 1,100 ng/dl, recent evidence(30) suggests that values in the lower 20th to 25th percentile (e.g., < 450 or 500 ng/dl) are likely to have functional consequences and should be considered for replacement therapy. Particularly in the setting of weight loss, poor lean tissue response to nutritional support, or symptoms consistent with hypogonadism, laboratory criteria for clinically significant hypogonadism should be more inclusive than the laboratory "normal range." Using a cut-off of < 500 ng/dl should eliminate the need to measure free testosterone, which is a more expensive test but in some patients may be low when total testosterone is not frankly low.

Serum LH and FSH are typically low or normal in the presence of reduced serum testosterone levels in men with HIV disease.(9,29) The finding of elevated gonadotropins indicates primary gonadal failure.

It might be a useful strategy for clinicians to measure a baseline serum total testosterone level in HIV-seronegative men prior to the development of symptoms. A substantial fall in concentrations that nevertheless remain in the statistically "normal" range will then provide objective evidence to support replacement therapy.

Hypogonadism is also probably common in HIV-infected women, especially those with weight loss, although less data are available on this subject. Serum testosterone levels in women are difficult to use as diagnostic tests because of the low values and interindividual variability among women. Serum estradiol is a useful index of gonadal function in women.

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Treatment
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Several treatment options are available for hypogonadism in men. The standard therapy has been intramuscular (IM) testosterone given every 1 to 3 weeks to provide roughly 100 mg per week (e.g., 200 mg q 2 week, 300 mg q 3 wk). Intramuscular testosterone is usually given as the enanthate or ciprionate esters. This therapy is convenient but has several disadvantages. The IM injections may be painful, particularly in cachectic individuals. The cost of biweekly office visits may offset the low expense of the medicine. Most importantly, this route of delivery provides a very unphysiologic hormone profile with marked supraphysiologic testosterone levels for several days post-injection and then subphysiologic levels after 7 to 10 days. This up-and-down pattern of hormone levels may result in suboptimal clinical response. The sequence of supra- then infraphysiology levels may have psychologic effects, including feelings of dependence on the medication as well as drug-seeking behavior by patients.

Alternative therapeutic approaches include transdermal and oral routes of androgen administration. Skin patches are available either as trans-scrotal patches or transdermal patches. Trans-scrotal patches take advantage of the thin skin of the scrotum (the thinnest skin on the male body, along with the eyelids) to deliver hormone without requiring irritants or agents that increase drug permeation. Although this route reproduces the constant levels observed in normal subjects, the idea of wearing a scrotal patch is often unattractive and this option is refused by many patients. In addition, women obviously cannot use this therapy. Systemic transdermal patches are a newer option that may be more acceptable to some patients, but the need for permeation enhancers to increase hormone flux across the skin can lead to local dermatologic problems in users. The ideal patch has not yet been developed.

Oral androgens are also available. Oxandrolone is an oral androgen that is currently approved for use in AIDS-associated weight loss at a daily dose of up to 20 mg. Minimal data are available as to its efficacy or safety in AIDS. At the much higher dose often taken for non-FDA-approved uses, such as body building, liver problems, including tumors, have been reported. At the 20 mg/day dose, oxandrolone has been given in large clinical trials to men with advanced liver disease and has been found to be safe and well tolerated. Whether hepatotoxicity will occur in AIDS is not known.

Certain androgens may have different potencies for so-called anabolic compared to androgenic actions.(31) The former refers to effects on body composition (lean tissue accrual), strength, and perhaps energy level and fatigue, as well. The latter refers to reproductive functions and secondary sexual characteristics, such as libido, erectile function, hair growth (beard, pubic, and axillary hair, male-pattern baldness), sebaceous gland production, vocal chord changes, prostate growth, spermatogenesis, etc. No existing androgen is specific for either class of actions.(31) In fact, there exists only one androgen receptor for all tissues (whether "androgenic" or "anabolic"), unlike beta agonists on antihistamine agents, for example, for which tissue selectivity of receptors allows for targeted therapeutic actions. The basis of androgen selectivity, to the extent that it exists, is therefore limited to tissue differences in sex steroid hormone metabolizing enzymes. For this reason, all "anabolic" steroids are able to support reproductive and sexual function, although perhaps not with identical relative efficiency as testosterone itself, and high doses of any agent have the potential for virilization in women. Nevertheless, some clinicians find it useful to combine testosterone at replacement or subreplacement doses with a moderate dose of an "anabolic" androgen (nandrolone, oxandrolone), in the hope of maximizing lean tissue accrual with fewer androgenic side effects. The efficacy of combination therapies remains unproven, however.

Clinicians should also recognize that all exogenous androgenic agents suppress the endogenous reproductive hormonal axis (hypothalamus-pituitary-testes). Serum testosterone, LH, and FSH levels will fall, depending on the agent, dose, and route of administration. Thus, subjects treated with oxandrolone or nandrolone will exhibit a drop in total testosterone level and subjects receiving IM testosterone injections q 2 to 3 weeks will have low levels in the period before each injection.

The suppressive effect on endogenous hormone levels is exaggerated if megestrol acetate is administered concurrently.(32) A suppressed endogenous gonadal axis does not represent clinical hypogonadism, of course, when exogenous hormone administration is the cause. Patients should be reassured about this fact, because testicular atrophy may be worrisome to them. The clinical significance of a suppressed gonadal hormone axis relates to the period following cessation of exogenous hormone treatment, if treatment is discontinued. Most individuals recover endogenous hormone production after cessation of therapy, but it may take weeks or even months to do so, during which time hypogonadal symptoms may recur. Patient education and reassurance is important during this period.

Treatment options in women with HIV-associated hypogonadism are less well studied. Standard hormone replacement therapy involves the use of oral estrogen (e.g., Premarin 0.625 mg daily) and progesterone (10 mg daily) or of oral contraceptive preparations. Some clinicians have considered adding a low dose of an androgen preparation (e.g., oxandrolone, 2.5 mg daily) in women with AIDS-associated weight loss, but this approach has not been tested and may result in androgenic side effects.

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Future Directions and General Conclusions
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The topic of hypogonadism in general, and androgen therapy in particular, is beginning to emerge as an important and somewhat complex area of AIDS medicine. Many quality of life issues in HIV disease may relate to hypogonadism and its treatment, but much remains speculative at present. The next few years should see a number of questions answered through properly designed clinical studies currently in progress. In the meantime, clinicians can help their patients to navigate the uncertainties and often exaggerated claims in this area by application of clinical judgment and by keeping up with the evolving literature.

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Pituitary Dysfunction
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Disorders of the pituitary have been described in AIDS, but remain unusual.

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Anterior Pituitary Dysfunction
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A report describes pituitary infiltration by Toxoplasma gondii causing hypopituitarism in a patient with advanced HIV disease.(33) The evidence for pituitary dysfunction in the absence of a mass lesion is only indirect (i.e., inadequate ACTH response to adrenal insufficiency(20) and hypogonadotropic hypogonadism,(9) although the latter may well not be due to pituitary dysfunction; see above). Reports also describe elevated serum prolactin levels correlating with progression of HIV disease in men with advanced HIV disease,(34) although the clinical significance of this finding is unknown and another study did not reproduce this finding.(35) A direct autopsy study(36) of pituitary glands from 49 patients with advanced HIV disease found no increased incidence of adenomas or micronodules in comparison to normal males, although about 10% of adenohypophyses and 4% of posterior pituitaries showed involvement with CMV. There was no pituitary involvement in patients with KS (0 of 23), lymphoma (0 of 12), or Mycobacterium avium intracellulare.

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Posterior Pituitary Function and Osmoregulation
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Incidence
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Vitting et al.(10) observed hyponatremia in over 50% of hospitalized patients with advanced HIV disease studied either retrospectively or prospectively. Other reports similarly cite serum sodium concentrations of less than 130 mEq per liter in 31%(11) and 36% of patients with HIV disease.(12) Although the incidence is highest in acutely ill hospitalized patients with opportunistic infections, especially pulmonary infections, the incidence of hyponatremia is also high in stable outpatients(e.g., 20%).(11)

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Differential Diagnosis and Evaluation
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Vitting et al.(10) concluded that hyponatremia is due to stress- or drug-induced syndrome of inappropriate antidiuretic hormone secretion (SIADH). These authors reported inappropriately high urine osmolarity in all cases and measurable serum antidiuretic hormone (ADH) in 15 of 16 subjects. ADH levels were highest in patients who died in the hospital. There was frequently an iatrogenic contribution to the hyponatremia (hypotonic fluid therapy), and many individuals had pulmonary disease or were receiving either opiate or barbiturate therapy, which are recognized stimuli for ADH release. Hyponatremia was associated with a high in-hospital mortality rate (30%).

ADH secretion can also be stimulated by volume depletion. Cusano et al.(11) reported that 88% of hyponatremic patients had evidence of hypovolemia based on response to intravenous saline infusion. They identified no obvious source of volume loss in 83% of these hypovolemic patients, but further investigation indicated high urine sodium losses without renal or adrenal insufficiency. Elevated serum ADH and usually elevated plasma renin and aldosterone concentrations were reported. Low central venous pressures with a reduced creatinine clearance that improved after intravenous saline administration (68 to 94 ml/min) further supported the presence of volume depletion, resulting in a nonosmolar stimulus for ADH secretion and hyponatremia.

Finally, Agarwal et al.(12) reported a role for both etiologies, with 12 of 36 hyponatremic patients having evidence for volume depletion (correction after saline therapy), whereas 23 had SIADH and only one had adrenal insufficiency. Generally normal serum renin and aldosterone concentrations in these patients was the major biochemical difference from the patients described by Cusano et al.,(11) arguing against a volume-depleted state in the former group.

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Work-Up and Treatment
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For the clinician, it may be difficult to differentiate between renal salt-wasting and SIADH, other than by the response to therapeutic interventions (saline administration, water restriction). Empiric therapy may therefore provide diagnostic clues as well. In summary, isolated hyponatremia is very common in patients with advanced HIV disease, is associated with poor prognosis, and is most frequently due to SIADH or renal salt-wasting, although adrenal insufficiency occasionally is the cause.

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Pancreatic Dysfunction
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Definition
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Pancreatic dysfunction may result in hypoglycemia (from hyperinsulinemia) or diabetes (from hypoinsulinemia).

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Incidence and Epidemiology
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The endocrine pancreatic disturbance of most clinical importance in HIV infection occurs in patients receiving pentamidine treatment for PCP. Pentamidine-induced hypoglycemia is extremely common in patients with advanced HIV disease treated for PCP (14 to 28%).(37,38) For unknown reasons, this incidence is much higher than in non-HIV-infected patients treated with pentamidine for PCP (a range of 6.2 to 9.1%).(39,40) Moreover, symptomatic hypoglycemia is more common among patients with advanced HIV disease (25%)(38) than among non-HIV-infected patients (12%).(39)

The basis of pentamidine hypoglycemia is well understood. Pentamidine is a potent beta cell toxin,(39) so much so that it has been used experimentally for treating malignant insulinomas.(40) Destruction of beta cells may result in an unphysiologic release of stored insulin with resulting hypoglycemia. Patients experiencing pentamidine hypoglycemia can therefore develop diabetes mellitus, with or without ketoacidosis.(39,41) It is important to recognize that the long tissue half-life of pentamidine can result in hypoglycemia days or weeks after discontinuing a therapeutic course.(37,38) The true incidence of pentamidine hypoglycemia is therefore likely to be even greater than estimated from in-hospital studies.

It is possible to predict patients at greatest risk for pentamidine hypoglycemia.(37,38) The most important predictors are azotemia (40% of hypoglycemic patients in one study(37) and 100% in another(38) developed azotemia during pentamidine therapy), total dose and duration of pentamidine therapy, and a history of previous pentamidine therapy.(37) In such patients, the clinician must maintain extreme vigilance to prevent this potentially life-threatening complication. Conversely, patients who have recovered from PCP should under go blood or urine tests for diabetes.

The reason for the increased sensitivity of patients with advanced HIV disease to pentamidine hypoglycemia is unknown. There are reports of CMV(42) or CMV DNA(43) in the pancreases of patients with advanced HIV disease at autopsy. Another possibility is that interleukin-1, which is known to be a beta cell toxin,(44) may be elevated in patients with advanced HIV disease and with chronic fevers and infections. This association, however, has yet to be demonstrated. A small proportion of patients treated for HIV disease who receive the antiviral drug didanosine (ddI) develop diabetes,(45) which may be preceded by low level or subclinical pancreatitis.

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Evaluation and Treatment
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Monitoring for diabetes is the same as in HIV-seronegative persons, namely, by measuring fasting blood glucose levels. The diagnosis of diabetes if rendered when repeated fasting blood glucose levels exceed 140 mg/dl. Insulin is used for treatment. Post-pentamidine hypoglycemia is more difficult to monitor because it may occur several weeks after completion of a therapeutic course. Low fasting blood sugar levels in combination with high or normal insulin levels suggests the diagnosis of pentamidine-induced hypoglycemia. Treatment is by diet (frequent, small meals) and patient education (warning about the signs and symptoms of low blood sugar).

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Calcium Metabolism
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Calcium metabolism is generally normal in advanced HIV disease, but there are some exceptions. Four patients with advanced HIV disease with lymphoma exhibited hypercalcemia(46) with high urinary calcium excretion. Parathyroid hormone (PTH) was suppressed, but in one patient, 1,25-dihydroxy-vitamin D (1,25-D) was significantly elevated. Patients with advanced HIV disease without lymphoma had normal serum and urine calcium and 1,25-D values. The patient with 1,25-D-mediated hypercalcemia had a small, noncleaved B cell lymphoma, stage IV, and was successfully treated with chemotherapy. Serum calcium fell from 14.4 to 9.4 mg/dl and 1,25-D fell from 129 to 22 pg/ml, supporting the hypothesis of extrarenal 1,25-D synthesis.

Reports also describe hypercalcemia in disseminated CMV infection in patients with advanced HIV disease.(47) Serum PTH was suppressed, as was 1,25-D, and hypercalcemia occurred before the patient had become immobile. The authors speculated that osteoclastic bone resorption caused the hypercalcemia, in part based on the patient's hypocalcemic response to calcitonin. One report describes unexplained hypercalcemia in a patient with advanced HIV disease without CMV, which was not responsive to calcitonin.(48)

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Thyroid Function
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Any chronic illness associated with malnutrition or inflammation can cause abnormalities in thyroid function tests. This condition is called "euthyroid sick" syndrome, to indicate that the thyroid gland is normal but that systemic illness has altered thyroid hormone physiology. It would therefore not be surprising if thyroid function abnormalities were common in patient with advanced HIV disease. Some reports, however, note normal thyroid function tests (TFTs) in HIV-infected subjects (e.g., normal TFTs and response to thyrotropin-releasing hormone),(9) whereas others describe abnormalities in TFTs in HIV infection.(49,50) Patients hospitalized with PCP had the low triiodothyronine (T) levels expected in severe nonthyroidal illness. A low T level correlated with hypoalbuminemia and hyponatremia(49) and was an accurate predictor of mortality in hospitalized patients with advanced HIV disease.(49,50) LoPresti et al.(51) reported that patients with advanced HIV disease exhibited unique alterations in thyroid hormone indices. They reported that, in contrast to other sick patients, patients with advanced HIV disease failed to increase reverse T. Others have reported, however, the classic changes of the euthyroid sick syndrome(48,49) (MK Hellerstein, C Grunfeld, unpublished observations). Reports describe pneumocystosis of the thyroid gland,(52) CMV involvement of the thyroid,(53) and KS involvement of the thyroid.(54)

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References

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6.  Symmington T. Functional Pathology of the Human Adrenal Gland. Baltimore: Williams & Wilkins 1969;68-86.
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7.   Greene LW, Cole W, Greene JB, et al. Adrenal insufficiency as a complication of the acquired immunodeficiency syndrome. Ann Intern Med 1984;101:497-498.
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9.   Dobs AS, Dempsey MA, Ladenson PW, et al. Endocrine disorders in men infected with human immunodeficiency virus. Am J Med 1988;84:611-616.
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