Department of Internal Medicine, Endocrine Unit, Bellaria Hospital (M.F.-F.), 40139 Bologna, Italy; and Department of Internal Medicine, University of Modena and Reggio Emilia (A.B., V.R., C.C.), 41100 Modena, Italy
Address correspondence to: Marco Faustini-Fustini, M.D., Department of Internal Medicine (Endocrine Unit), Ospedale Bellaria-Padiglione "Tinozzi," Via Altura, 3, 40139 Bologna, Italy. E-mail: marco.faustini{at}ausl.bologna.it.
To the editor:
Reading the article by den Ouden et al. (1) evoked some questions and remarks.
First, the intriguing history of gigantism with hypopituitarism warrants some comment. In their review of the literature, the authors state that "to date, six adult untreated panhypopituitarism patients have been described." Of these, only three attained normal or tall stature, in addition to their patient. To our knowledge, other six adult patients have been reported in the medical literature (2, 3, 4, 5, 6). In 1963, a 32-yr-old man with evidence of hypopituitarism, eunuchoid habitus and proportions, tall stature (height, 195.5 cm; weight, 85.35 kg; body mass index, 22.3 kg/m2), slipped epiphyses, and continuing linear growth was described (2). At the time, pituitary gigantism associated with a deficiency of other pituitary hormones was suggested, but a subsequent revaluation with specific tests of GH reserve led to the definitive diagnosis of panhypopituitarism (3). In 1964, Sarver et al. (4) reported three other patients with hypopituitarism and tall or normal stature. Again, Sarver et al. tried to explain the phenotype with a kind of "fractional hypopituitarism" coupled with pituitary gigantism. In 1967, two other similar cases were reported, but insulin-induced hypoglycemia produced no significant increase in GH concentrations, providing evidence for the diagnosis of panhypopituitarism (5). Notably, at that time physicians widely ignored the skeletal effects of estrogen, a finding that has recently led to a radical change in our thinking.
Second, we are aware that a lack of estrogenic effect on the skeleton may have had a crucial role in the patients pattern of growth, which reminds the authors of the growth curve depicted in men with congenital estrogen deficiency. By contrast, other patients with untreated hypopituitarism have short adult height without evidence of continuing linear growth. A possible explanation of these differences, as the authors point out, is the involvement of factors other than GH and IGF-I (such as insulin, differences in insulin sensitivity, and unknown growth factor). There is also another possibility. Still unknown is the amount of estrogen necessary for epiphyseal closure, although it has been established that estrogens are effective on growth plate even at serum levels not detectable by conventional commercial kits (7). Perhaps, a complete estrogen deficiency cannot be applied to all the patients with untreated hypopituitarism. Such a hypothesis, however, cannot be demonstrated to date because ultrasensitive assays of serum estradiol are far from being commonly used in clinical practice. There is also evidence for a role of paracrine/autocrine/intracrine mechanisms in the physiology of bone and cartilaginous growth plate. Aromatase, as well as estrogen receptors, is expressed in human bone. Like other extragonadal sites of estrogen biosynthesis, however, bone is dependent on circulating C19 precursors. Furthermore, findings in animals and humans support the notion that local estrogen production is of physiological significance in bone (7). If so, then individual differences in the amount of locally produced estrogen could play a part in the variable pattern of linear growth in adults with untreated hypopituitarism. Accordingly, in severe male hypogonadism, two groups of untreated adult men with similar circulating sex steroids have been identified, the former with a complete epiphyseal closure at 19 yr of age, and the latter with open epiphyses and delayed bone age at more than 19 yr (8). Another experiment of nature may help us with this issue. In 17-hydroxylase deficiency, impaired production of sex hormones leads to abnormalities of sexual development, eunuchoid skeleton, bone age retardation, and osteoporosis. Interestingly, tall stature may occur, but only in sporadic cases with severe enzyme deficiency (9). Again, in these cases, the amount of C19 precursors might be too low for adequate estrogen biosynthesis.
Finally, surprisingly, the patient reported by den Ouden et al. (1) seems to have no evidence of decreased bone mineral density (BMD). We have some concerns about this finding. Previous studies of patients with hypogonadotropic hypogonadism, estrogen insensitivity, or aromatase deficiency have shown that a prolonged lack of estrogen results in eunuchoid skeletal proportions and reduced BMD (7). More recently, in the attempt to enhance linear growth by delaying epiphyseal closure, a group of adolescents with normally timed puberty and short stature was treated with an LH releasing hormone agonist for 3.5 yr (10). As a result, adult height increased by 0.6 SD to the detriment of their BMD (-1.6 below the population mean).
Received April 8, 2003.
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