Central Hypothyroidism due to Pituitary/Hypothalamic Dysfunction
Karen K. Miller, M.D.

Central hypothyroidism is an important complication of pituitary disease and, because TSH levels are not useful, the diagnosis and therapeutic considerations are difficult.

Central hypothyroidism is defined as a reduction in circulating thyroid hormone as a result of inadequate stimulation of a normal thyroid gland by TSH and may be secondary, due to pituitary disease, or tertiary, due to hypothalamic dysfunction. Causes include all pathologic processes that affect the hypothalamus or pituitary including tumors, Sheehan's syndrome, idiopathic hypopituitarism and infiltrative diseases, such as sarcoidosis, histiocytosis and lymphocytic hypophysitis. Radiation-induced central hypothyroidism is common in patients irradiated for pituitary tumors. Tsang et al. retrospectively examined records of 160 patients who had received radiation for non-functioning pituitary adenomas 8 to 22 years before and found that 65% required thyroid replacement therapy, with 23% of patients' hypothyroidism directly attributable to the radiation therapy received [1]. In addition, hypothyroidism is common in patients receiving radiation for nasopharyngeal or paranasal sinus tumors and brain tumors. Constine et al. evaluated the endocrine function of 32 patients who had received radiation for brain tumors, including gliomas, medulloblastomas and ependymomas, from 2 to 13 years before, and found that 65% had low free T4 levels. The probability of hypothyroidism depended on the amount of radiation received, with doses of more than 5000 rads (50 Gy) to the pituitary and hypothalamus necessary for the development of hypothyroidism. Moreover, the longer the interval since irradiation, the more likely a patient was to have developed hypothyroidism [2]. Therefore, the percentage of patients developing hypothyroidism may have been even higher had the follow-up been longer. In addition, because the onset of hypothyroidism may occur years after the administration of the radiation, constant vigilance for the signs and symptoms of hypothyroidism in this population is imperative and yearly monitoring of thyroid hormone levels obligatory.

As in primary hypothyroidism, the symptoms of central hypothyroidism include fatigue, apathy, weight gain, dry skin, constipation and cold intolerance. Signs include periorbital edema, cool extremities, delayed relaxation of the deep tendon reflexes and bradycardia. The signs and symptoms of central hypothyroidism mimic those of several other common conditions, and this disorder is therefore difficult to diagnose. A low free T4 or free T4 index and a low TSH in the setting of pituitary disease and signs and symptoms of hypothyroidism point in a straightforward manner to the diagnosis of central hypothyroidism. Unfortunately, however, the TSH is most commonly in the normal range in cases of central hypothyroidism, creating a confusing picture. Research has shown that, in some of these cases, a bio-inactive TSH resulting from abnormal glycosylation of the TSH molecule [3-6] explains the higher than expected TSH levels. Therefore, although the serum TSH is measured as normal in routine assays, performed by immunoradiometric assay (IRMA) or immunochemiluminometric assay (ICMA), only a small proportion of the TSH molecules function normally. Although these "normal" TSH values can confound the diagnosis of central hypothyroidism, it should be noted that a "normal" or slightly high TSH is inappropriate when circulating thyroid hormone levels are low, and that in cases of primary hypothyroidism, the TSH would be expected to be much higher. Therefore, TSH is not a useful screen for the diagnosis of this disorder.

The management of central hypothyroidism is further complicated by the fact that the TSH cannot be used to monitor therapeutic response to L-thyroxine therapy. When pituitary pathology is not present, the TSH provides an accurate method of assessing the appropriateness of circulating thyroid hormone levels for each particular patient. However, pituitary or hypothalamic pathology often interrupts the feedback mechanism by preventing normal release of TSH and/or TRH. The consequences of this are two-fold. First, patients with pituitary pathology or who have been irradiated cannot be screened for hypothyroidism with TSH levels alone, as a normal TSH often belies central hypothyroidism. Moreover, the usually routine monitoring of thyroid replacement becomes more problematic. Inadequate replacement doses of l-thyroxine often result in markedly subnormal TSH values. Therefore, TSH values are not reliable as an accurate reflection of thyroid status, and a free T4 or free T4 index must be used to adjust the replacement dose. However, as in primary hypothyroidism, when appropriately diagnosed and treated, management of central hypothyoidism can result in prompt resolution of symptoms.

References

1. Tsang R, Brierley J, Panzarella T, et al., 1994 Radiation therapy for pituitary adenoma: treatment outcome and prognostic factors. Int J Radiat Oncol Biol Phys. 30:557-565.
2. Constine L, Woolf P, Cann D, et al. 1993 Hypothalamic-pituitary dysfunction after radiation for brain tumors. N Engl J Med. 328:87-94.
3. Papandreou M, Persani L, Asteria C, Ronin C, and Beck-Peccoz P. 1993 Variable carbohydrate structures of circulating thyrotropin as studied by lectin affinity chromatography in different clinical conditions. J Clin Endocrinol Metab. 77:393.
4. Miura Y, Perkel V, Papenberg K, Johnson M, and Magner J. 1989 Concanavalin-A, lentil, and ricin lectin affinity binding characteristic of human thyrotropin: differences in the sialylation of thyrotropin in sera of euthyroid, primary and central hypothyroid patients. J Clin Endocrinol Metab. 69:985-995.
5. Taylor T and Weintraub B. 1989 Altered thyrotropin (TSH) carbohydrate structures in hypothalamic hypothyroidism created by paraventricular nuclear lesions are corrected by in vivo TSH-releasing hormone administration. Endocrinology. 125:2189-2203.
6. Magner J, Klibanski A, Fein H, et al. 1992 Ricin and lentil lectin affinity chromatography reveals oligosaccharide heterogeneity of thyrotropin secreted by 12 human pituitary tumors. Metabolism. 41:1009-1015.

Androgen Deficiency and It's Therapy in HIV-Infected Men
Steve Grinspoon, M.D..

Among men with HIV disease, gonadal dysfunction is highly prevalent. In early studies, over half of all men with AIDS demonstrated low testosterone levels. The prevalence of hypogonadism increases with severity of illness, and is most often associated with normal gonadotropin levels in 75% of cases. Potential mechanisms of secondary hypogonadism in HIV-infected men include undernutrition and chronic illness which may reduce GnRH pulsatility, inducing a state of hypogonadotropic hypogonadism. In addition, medications are a potential cause of secondary hypogonadism in this population. Megestrol acetate, a synthetic progestational agent, may result in profound hypogonadism in treated patients. More rarely, mass lesions of the pituitary and hypothalamus are seen and may represent opportunistic infections, such as toxoplasmosis or HIV-related malignancies, including lymphoma. Primary hypogonadism is often idiopathic, but may also be related to opportunistic infection or malignancy. More recent data suggest a lower prevalence of 25% for hypogonadism among HIV-infected men with advanced HIV disease. However, hypogonadism remains prevalent among HIV-infected men, even in the era of highly active antiviral therapy or HAART.

The diagnosis of hypogonadism is best made by determination of the serum free or bioavailable testosterone levels, because of increased SHBG levels in HIV disease. Measurement of gonadotropin levels is useful to differentiate primary from secondary hypogonadism, and in secondary hypogonadism, gonadotropins will be inappropriately low or normal in the setting of low testosterone levels. Imaging of the hypothalamus and pituitary glands is recommended in the setting of headache, visual changes or in association with other signs and symptoms of pituitary disease.

The sequelae of hypogonadism among HIV-infected patients include decreased muscle mass and functional capacity, fatigue and reduced quality of life. Decreased lean body mass is a significant predictor of increased mortality and reduced survival among HIV-infected patients and is therefore an important clinical endpoint in this population. Among men with AIDS wasting, testosterone levels are highly correlated with lean body mass. Furthermore, such patients demonstrate a disproportionate loss of muscle mass, in comparison to weight. Importantly, significant loss of muscle mass or sarcopenia is seen even among stable, protease inhibitor-treated patients, in whom there is a direct correlation between muscle mass and functional status.

The effects of testosterone administration in hypogonadal HIV-infected men were recently investigated. In a randomized, placebo-controlled trial, testosterone was administered at 300 mg intramuscularly every 3 weeks for 6 months. Muscle and lean body mass increased significantly in the testosterone-treated relative to the placebo-treated patients by approximately 3 kg (Figure 1). Importantly, patients reported a subjective benefit with respect to improved overall quality of life, appearance and well being. The testosterone was well tolerated and without adverse effects. The relative change in lean body mass in response to testosterone is equivalent to or greater than that of other anabolic agents used in the AIDS wasting syndrome, including growth hormone. The use of physiologic testosterone administration (200-300 mg IM q 2-3 weeks) for hypogonadal HIV-infected men is now routine, and all such patients, particularly men with the wasting syndrome, should be screened and treated for hypogonadism when appropriate.

Transdermal delivery of testosterone is now an alternative to intramuscular dosing for HIV-infected patients. Two such transdermal products, Androderm (r) and Testoderm (r) are now commercially available, each with a recommended dose of 5 mg/day. Bhasin et al. recently showed a beneficial effect of transdermal testosterone administration (5 mg/day) to significantly increase lean body mass by 1.4 kg over 3 months in hypogonadal men with HIV infection. Potential advantages of transdermal dosing include more stable, steady state testosterone levels. However, further studies are necessary to insure that mean testosterone levels are sufficient in response to transdermal dosing. At the current time, either transdermal or IM therapy is recommended for hypogonadal men with HIV-infection. However, it is recommended that serum testosterone levels be checked at least once after initiation of transdermal therapy to insure adequate levels within the normal range.

A commonly asked question regarding testosterone administration in HIV-infected men is the appropriate duration of therapy. A sustained anabolic effect of testosterone administration on lean body mass of 3.7 kg or 7.6% over 12 months was previously demonstrated. No adverse effects on the prostate or PSA were seen and hematocrit increased 3.5% over this time period. These data suggest that continuation of testosterone for at least one year is beneficial and results in sustained increases in lean body mass. Serial monitoring of the prostate is important with long-term testosterone administration. Among patients who have achieved stable weight and are less ill, discontinuation of testosterone and reassessment of gonadal function is appropriate, as androgen levels may improve with nutritional and immunologic recovery.

An important question is the efficacy of androgen therapy in eugonadal men with the wasting syndrome. At the current time, such supraphysiologic dosing cannot be endorsed because of the potential risks related to prostate, mood and acne. However, studies performed under carefully controlled conditions and with appropriate monitoring are now underway to determine the efficacy of larger dose of testosterone in HIV-infected patients. A final question concerns the role of exercise therapy, in combination with anabolic therapy, to increase functional status in HIV-infected men. Data in non HIV-infected men suggest an additive effect of combined androgen and exercise therapy, but combined anabolic strategies have not been previously studied among men with AIDS wasting.

In summary, recent data suggest that hypogonadism remains an important clinical problem among HIV-infected men, even in the setting of potent antiviral agents. Hypogonadism in HIV-infected men is most often associated with low or inappropriately normal gonadotropin levels but is not often associated with a sellar mass lesion. Recent studies suggest a potent and sustained benefit of androgen therapy to reverse significant underlying muscle loss in hypogonadal HIV-infected men. At the current time, HIV infected patients with evidence of weight loss or muscle weakness and/or clinical symptoms of hypogonadism should be screened and treated for hypogonadism. The use of testosterone to increase lean body mass in eugonadal patients, must be considered experimental until further data are obtained.



Figure Legend: Mean changeńSEM for fat-free mass assessed by dual energy x-ray absorptiometry, lean body mass determined from potassium-40 isotope analysis, and muscle mass from urinary creatinine excretion in patients who received testosterone (left) and placebo (right) over 6 months. * P<0.05 and **P<0.01 for the change from baseline between the testosterone group and the placebo group by analysis of covariance. n="number" of patients for whom paired end of study data are available. Reprinted from Reference 5 (below) with permission of the American College of Physicians.

References:

1. Bhasin S, Storer TW, Asbel-Sethi N, et al. 1998 Effects of testosterone replacement with a nongenital, transdermal system, Androderm, in human immunodeficiency-virus infected men with low testosterone levels. J Clin Endocrinol Metab. 83:3155-3162.
2. Dobs AS, Dempsey MA, Ladenson PW, and Polk BF. 1988 Endocrine disorders in men infected with human immunodeficiency virus. Am J Med. 84:611-6.
3. Grinspoon SK and Bilezikian JB. 1992 HIV disease and the endocrine system. N Engl J Med. 327:1360-1365.
4. Grinspoon S, Corcoran C, Lee K, et al. 1996 Loss of lean body mass and muscle mass correlates with androgen levels in hypogonadal men with acquired immunodeficiency syndrome and wasting. J Clin Endocrinol Metab. 81:4051-4058.
5. Grinspoon S, Corcoran C, Askari H, et al. 1998 Effects of androgen administration in men with aids wasting: a randomized, placebo-controlled, trial. Ann Int Med. 129:18-26.
6. Grinspoon S, Corcoran C, Anderson E, Hubbard J, Basgoz N, and Klibanski A. 1998 Sustained anabolic effects of long-term androgen administration in men with AIDS wasting. Clin Inf Dis. In press.