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Pituitary in Turner Syndrome
The Pituitary in Turner Syndrome B. W. Scheithauer,1 K. Kovacs,3 E. Horvath,3 W. F. Young, Jr.,2 and R. V. Lloyd1 Abstract Although Turner syndrome is not uncommon, studies of the pituitary in this condition are few. We undertook a histochemical and immunohistochemical study of four cases. As expected, “gonadal failure cells” were seen, but without recognizable gonadotroph hyperplasia. No gonadotroph adenomas were encountered. Instead, three silent corticotroph microadenomas were seen; their etiology remains unexplained. The question of whether the simultaneous occurrence of Turner syndrome and silent corticotroph adenoma is causal or incidental cannot be answered on the basis of the study of our material. Because these two diseases are rare, an etiologic association has to be considered. For example, it is possible that (a) protracted stimulation of gonadotrophs leads to transdifferentiation to corticotrophs, a hypothesis supported by the fact that normal and neoplastic gonadotrophs can contain ACTH and that some corticotroph adenomas produce LH and/or alpha subunit, (b) corticotrophs develop gonadotropin-releasing hormone (GnRH) receptors and undergo neoplastic transformation when exposed to continuous elevation of GnRH, FSH, and/or LH levels, and (c) the genetic defect in Turner syndrome promotes the formation of corticotroph adenomas. Key Words: Turner syndrome; pituitary.
Introduction
From the Departments of 1Laboratory Medicine and Pathology as well as 2 Endocrinology and Metabolism, Mayo Clinic, Rochester, MN, USA and the 3Department of Pathology, St. Michaels Hospital, University of Toronto, Toronto, ON, Canada. Address correspondence to Dr. B. W. Scheithauer, Department of Laboratory Medicine and Pathology, 200 First Street, SW, Rochester, MN 55905. E-mail: scheithauer.bernd@ mayo.edu Endocrine Pathology, vol. 16, no. 3, 195–200, Fall 2005 © Copyright 2005 by Humana Press Inc. All rights of any nature whatsoever reserved. 1046–3976/05/16:195–200/ $30.00
Turner syndrome affects one in every 2500 live births. The first seven cases were described in 1938 and featured sexual infantilism, webbing of the neck, and cubitus valgus [1]. The genetic basis of the disorder became apparent with the demonstration of a 45X karyotype [2]. It was of note that urinary gonadotrophins were increased and that the gonads were “streak ovaries” devoid of germ cells. Although the gonads are normal until 12 wk gestation, thereafter they degenerate in the absence of the second X chromosome. By birth few if any oocytes remain. As a result, lack of end organ function drives both the hypothalamus and pituitary. To date, no systematic histochemical or immunohistochemical studies of the pitu-
itary in Turner syndrome have been reported. We investigated four glands with special reference to changes in gonadotrophic cells and the occurrence of pituitary adenomas. Clinical Data Case 1. The patient was a 40-yr-old, 148 cm tall female also having neurocutaneous melanosis with diffuse cerebrospinal involvement; cerebrospinal fluid cytology showed malignant cells. Serum cortisol levels were reportedly 30 µg/dL AM (NL, 7–25) and 18 µg/dL PM (NL, 5–15). No clinical evidence of Cushing’s disease was noted. No information regarding hormone replacement was available. At autopsy, ovaries were
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barely discernable as white nodular foci. The cause of death was adult respiratory distress syndrome complicating meningeal melanomatosis. Case 2. The patient was a 65-yr-old, 123 cm tall female with no clinical evidence of Cushing’s disease. Ovaries were not identifiable. The cause of death was pneumonia. Case 3. The patient was a 37-yr-old, 145 cm tall female with no clinical evidence of Cushing’s disease. The ovaries were small and tubular (0.8 × 0.2 × 0.2 cm). The cause of death was a ruptured aortic aneurysm. Case 4. The patient was a 74-yr-old female with no clinical evidence of Cushing’s disease. She had received no hormonal replacement therapy. Ovaries were not identifiable. The cause of death was peritonitis, sepsis, and terminal adult respiratory distress syndrome.
Methods Four autopsy-derived pituitary glands from patients with Turner syndrome were retrieved from the files of the Mayo Clinic Tissue Registry. All had been formalinfixed and horizontally sectioned. Hematoxylin–eosin, periodic acid–Schiff, and the Gordon–Sweet method for reticulin fibers were applied. Immunohistochemistry was performed using the streptavidin–biotin peroxidase complex technique and antibodies to growth hormone (GH), prolactin (PRL), adrenocorticotropin (ACTH), follicle stimulating and luteinizing hormones (FSH/LH), thyroid-stimulating hormone (TSH), alpha subunit, Ki-67 antigen, S-100 protein, and glial fibrillary acidic protein (GFAP). Antibody sources, and dilutions, as well as control methods have previously been reported [3,4].
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Results All four pituitary glands were normal in size. No adenomas were grossly apparent. Microscopically, each gland exhibited moderate numbers of large, round to oval, FSH/LH immunoreactive cells with eccentric nuclei and striking cytoplasmic vacuolization (“gonadal failure cells”) (Fig. 1). Neither diffuse nor nodular hyperplasia of gonadotrophic cells was definitely evident. Corticotroph cell hyperplasia was seen in Cases 3 and 4. In addition, three glands (Cases 2, 3, 4) showed a small ACTH immunoreactive adenoma (Fig. 2 top), this despite lack of evidence of cortisol excess. No Crooke’s hyaline change was seen in normal or neoplastic corticotrophs (Fig. 2 bottom), its absence being in keeping with the endocrinologically non-functioning nature of the corticotrophic tumors found (“silent corticotroph adenomas”). Cells producing GH, PRL, and TSH were normal in number and appearance. No nuclear labeling for Ki-67 was noted. Varying numbers of folliculostellate cells were labeled for S100 protein and/or GFAP. Discussion Pertinent to our discussion of the pituitary in Turner syndrome is the affect of gonadal dysgenesis and resultant primary hypogonadism upon pituitary gonadotrophs. Well recognized is cytoplasmic vacuolization of gonadotrophs due to marked dilation of rough endoplasmic reticulum, a change observed in both rats and humans [5–7]. Termed “gonadal deficiency cells,” they are seen in any form of gonadal failure, including castration. Although gonadotroph hyperplasia would logically be expected, none has been reported and none was definitely seen in our series. This certainly differs from other situations of end-organ failure. For example,
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Fig. 1. (left) Case 4. Gonadal deficiency cells were a prominent feature. Note their conspicuous cytoplasmic vacuolization and eccentricity of nuclei (above, arrows), as well as FSH immunoreactivity (below). Fig. 2. (right) Case 3. Silent corticotroph cell adenoma. Note sharp demarcation from compressed parenchyma (H&E, above). Immunoreactivity for ACTH is well seen (below). Note lack of Crooke’s hyaline change in nontumoral corticotrophs.
in untreated hypothyroidism [8] and Addison’s disease [9] both diffuse and nodular TSH and ACTH hyperplasia are conspicuous features. As for adenomas in end-organ failure, TSH-containing tumors have been reported in hypothyroidism [8], as have ACTH adenomas in the setting of adrenal failure [9]. Interestingly, gonadotroph adenomas comprise 10–15% of all adenohypophyseal tumors and occur almost exclusively in old age, a time of gonadal failure. A link between such adenomas and hypogonadism has long been suspected [10]. Albeit rare, pituitary adenomas have been described in Turner syndrome. Func-
tional tumors predominate. Some have been classified according to their endocrine effects, such as one macroadenoma in the setting of acromegaly [11] and one microadenoma associated with amenorrhea [12]. To date, only a single adenoma in Turner syndrome has been fully immunohistochemically characterized, a PRL-producing microadenoma in a 12-yr-old girl [13]. Lastly, two endocrine-inactive lesions were incidental radiographic findings [14,15]. The question of whether the simultaneous occurrence of Turner syndrome and silent corticotroph adenoma is causal or incidental cannot be answered on the basis of the study of our material. Because these
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two diseases are rare, the possibility of an etiologic association has to be considered. It may be that protracted stimulation of gonadotrophs leads to transdifferentiation to corticotrophs. This hypothesis is supported by the immunohistochemical findings that normal gonadotrophs can contain ACTH [16,17]. It was also relevant that some gonadotroph adenomas exhibit immunoreactivity for ACTH and that some corticotroph adenomas produce LH and/or alpha subunit [18]. It is possible that corticotrophs may develop GnRH receptors and, as a result, may undergo neoplastic transformation when exposed to continuous elevations of GnRH, FSH, and/or LH. One must also entertain the possibility that the genetic defect in Turner syndrome promotes the formation of corticotroph adenomas. These suggested mechanisms require further study. It should be noted, that the human pars distalis accommodates two distinct populations of proopiomelanocortin (POMC) producing cells: (a) anterior lobe corticotrophs, the differentiation of which depends on corticotroph-specific neuro D1 signaling, and (b) pars intermedia (PI) corticotrophs, which do not require this transcription factor. Contrary to still widely held views, the PI of the human pituitary is not rudimentary. Following normal fetal development, cells of the PI migrate into the anterior lobe, thus accounting for the lack of an anatomically distinct intermediate lobe at its original site. The process is apparently not complete in that the remaining PI POMC-producing cells give rise to the so-called “basophil invasion” seen in later life. The presence of PI-derived cells within the pars nervosa results from their often marked hyperplasia in advanced age, an alteration unassociated with clinical signs and symptoms of hypercortisolism or any other endocrinopathy. The age-related occurrence of basophil invasion suggests
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that it represents a compensatory response to the functional decline of the yet unidentified target tissue of these presumably POMC-derived cells. The physiologic function of the mammalian PI is still shrouded in mystery. However, the severe sex steroid deficiency that characterizes Turner syndrome may be related to hyperplasia and neoplasia of PI-derived POMC cells. The occurrence of the latter hints at a physiologic function of the PI, perhaps regulation of androgen production by the adrenal cortex. In summary, the pituitary in Turner syndrome features both gonadal deficiency cells and pituitary adenomas of varying type. The latter may be either endocrinologically functioning or nonfunctioning. The relatively high frequency of silent corticotrophic adenomas remains unexplained.
References 1. Turner HH. A syndrome of infantilism, congenital webbed neck and cubitus valgus. Endocrinology 23:566–574, 1938. 2. Ford CE, Jones KW, Polani PE, De Almeida JC, Briggs JH. A sex-chromosome anomaly in a case of gonadal dysgenesis (Turner’s syndrome). Lancet 1(7075):711–713, 1959. 3. Kovacs K, Lloyd R, Horvath E, et al. Silent somatotroph adenomas of the human pituitary. A morphologic study of three cases including immunocytochemistry, electron microscopy, in vitro examination, and in situ hybridization. Am J Pathol 134(2):345–353, 1989. 4. Kovacs K, Stefaneanu L, Horvath E, et al. Effect of dopamine agonist medication on prolactin producing pituitary adenomas. A morphological study including immunocytochemistry, electron microscopy and in situ hybridization. Virchows Arch A Pathol Anat Histopathol 418(5):439–446, 1991. 5. Horvath E. Pituitary hyperplasia. Pathol Res Pract 183(5):623–625, 1988. 6. Horvath E, Kovacs K. Fine structural cytology of the adenohypophysis in rat and man. J Electron Microsc Tech 8(4):401–432, 1988.
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7. Horvath E, Kovacs K, Scheithauer BW. Pituitary hyperplasia. Pituitary 1(3–4):169–179, 1999. 8. Scheithauer BW, Kovacs K, Randall RV, Ryan N. Pituitary gland in hypothyroidism. Histologic and immunocytologic study. Arch Pathol Lab Med 109(6):499–504, 1985. 9. Scheithauer BW, Kovacs K, Randall RV. The pituitary gland in untreated Addison’s disease. A histologic and immunocytologic study of 18 adenohypophyses. Arch Pathol Lab Med 107(9):484–487, 1983. 10. Kovacs K, Horvath E, Rewcastle NB, Ezrin C. Gonadotroph cell adenoma of the pituitary in a women with long-standing hypogonadism. Arch Gynecol 229(1):57–65, 1980. 11. Bolanowski M, Lomna-Bogdanov E, Kosmala W, et al. Turner’s syndrome followed by acromegaly in the third decade of life: an unusual coincidence of two rare conditions. Gynecol Endocrinol 16(4):331–334, 2002. 12. Gaspar L, Julesz J, Kocsis J, Pasztor E, Laszlo F. Mosaic Turner’s syndrome and pituitary microadenoma. Exp Clin Endocrinol 86(1):87–92, 1985.
199 13. Dotsch J, Schoof E, Hensen J, Dorr HG. Prolactinoma causing secondary amenorrhea in a woman with Ullrich-Turner syndrome. Horm Res 51(5):256–257, 1999. 14. Pejaver RK, Watson AH. Pituitary microadenoma in Turner’s syndrome. Br J Clin Pract 49(4):223–224, 1995. 15. Mermilliod JA, Gatchair-Rose A, Svec F. Pituitary tumor and low gonadotropins in a patient with Turner’s syndrome. J La State Med Soc 147(12):540–543, 1995. 16. Moriarty GC, Garner LL. Immunocytochemical studies of cells in the rat adenohypophysis containing both ACTH and FSH. Nature 265(5592):356–358, 1977. 17. Moriarty GC. Adenohypophysis: ultrastructural cytochemistry. A review. J Histochem Cytochem 21(10):855–894, 1973. 18. Scheithauer BW, Horvath E, Kovacs K, Lloyd RV. Tumours of the adenohypophysis. In: Solcia E, Kloppel G, Sobin LH, eds. Histologic Typing of Endocrine Tumours. Berlin: Springer, 2000, p. 15.
