Department of Neurosurgery, Frenchay Hospital, Bristol, United Kingdom; and 2 Semmes-Murphey Neurologic and Spine Institute, Memphis, Tennessee

Transcription

1 J Neurosurg Pediatrics 7: , 7: , 2011 Nonneoplastic enlargement of the pituitary gland in children A review Kristian Aquilina, F.R.C.S., 1 and Frederick A. Boop, M.D. 2 1 Department of Neurosurgery, Frenchay Hospital, Bristol, United Kingdom; and 2 Semmes-Murphey Neurologic and Spine Institute, Memphis, Tennessee Primary neoplasms of the pituitary gland are uncommon in children. Physiological enlargement of the gland, however, is universal and can sometimes be confused with a tumor. Due to widespread availability of MR imaging, the number of children referred to pediatric neurosurgeons with an enlarged pituitary associated with nonspecific symptoms, most commonly headache, is increasing. In this review, the authors illustrate two common causes of pituitary enlargement in children, namely physiological hypertrophy of puberty, more commonly seen in females, and secondary hyperplasia caused by hypothyroidism. The importance of early and accurate diagnosis, without recourse to extensive endocrine investigations or inappropriate surgery, is underscored. (DOI: / PEDS10509) Key Words adolescence hypothyroidism galactorrhea pituitary hyperplasia pituitary hypertrophy The increasing availability of MR imaging has led to a rise in the number of referrals of children with pituitary abnormalities to pediatric neurosurgeons. Although pituitary adenomas are rare in children, most children presenting with pituitary enlargement still undergo extensive endocrine investigations and imaging over a prolonged follow-up period, particularly when this is associated with headaches, irregular menses, or other symptoms of possible endocrine origin. It is not uncommon to find children in whom neurosurgical intervention has been recommended for what is physiological hypertrophy of the gland. In this review, we present examples of two important causes of pituitary enlargement in children, one primary and one secondary, and we review the relevant literature in the hope that neurosurgeons can better understand the indications for surgical intervention in these children. Physiological pituitary hypertrophy in teenage girls is well recognized in the radiology literature. 12,14,19,28,35,43,44,54 A Medline search ( ) using the key words pituitary hypertrophy and adolescence yielded 43 articles, but only 5 of these studies were related to physiological hypertrophy, 4 of which discussed imaging characteristics on CT or MR imaging. 12,14,28,54 Review of the bibliographies of these articles yielded an additional 6 studies that evaluated age- or sex-related changes in the pituitary demonstrated on CT or MR imaging. 19,35,43,44,51 Only 1 study included a clinical overview of patients with suspected physiological hypertrophy. 10 Pituitary hypertrophy due to hypothyroidism or other end organ failure has been well described in children. 5,6,11,13,15,20,31,32 Although the features of both conditions may closely mimic pituitary adenoma on MR imaging, extensive endocrine investigations or surgery is not warranted in either. Case Reports Case 1 This 14-year-old girl presented with a 2-week history of intermittent headache, predominantly frontal, associated with fatigue and lethargy. There were no symptoms related to her vision. She had noted galactorrhea over the previous 9 months. Her menses remained regular during the entire period. There was no other relevant medical history. Her visual acuity and fields were normal. There was no neurological deficit on examination. In particular, her visual status, including visual fields, was normal. Magnetic resonance imaging demonstrated an en- 510 J Neurosurg: Pediatrics / Volume 7 / May 2011

2 Nonneoplastic enlargement of the pituitary gland Fig. 2. Case 2. Left: Midsagittal T1-weighted noncontrast MR image showing pituitary enlargement. Right: Postcontrast coronal image through the sella demonstrating diffuse enhancement of the enlarged gland with encroachment of its elevated superior border on the inferior surface of the chiasm. Fig. 1. Case 1. Midsagittal (A) and coronal (B) noncontrast T1- weighted MR images showing diffuse pituitary enlargement with a convex superior surface, causing mild upward bowing of the optic chiasm. The gland is uniformly isointense to gray matter. The normal hyperintensity of the neurohypophysis is evident in the posterior region of the gland. Midsagittal (C) and coronal (D) MR images obtained immediately after contrast administration, demonstrating diffuse and uniform enhancement of the pituitary gland. larged pituitary gland, with a symmetrically convex superior margin (Fig. 1). The adenohypophysis measured 9.2 mm in height, 9.4 mm in sagittal transverse diameter, and 13.3 mm in coronal transverse diameter. There was no suggestion of hematoma or blood products within the pituitary gland. The lesion was uniformly isointense to gray matter on T1-weighted and FLAIR imaging and exhibited immediate uniform enhancement after Gd administration; it was sharply defined. The pituitary stalk was not thickened and demonstrated normal hyperintensity on T1-weighted imaging; it was central and not deviated. The tuber cinereum was also normal. The optic chiasm exhibited a mild upward bowing. The cavernous sinus contained no abnormality. The patient was referred to neurosurgery by her pediatrician for surgical consideration. Free T4, T3 and thyroid-stimulating hormone, as well as random serum cortisol, were within normal limits. Serum prolactin and growth hormone levels were normal at 18 and 2.3 ng/ml -1, respectively. Follicle-stimulating hormone and luteinizing hormone were appropriate for the time point on the menstrual cycle. The patient was managed symptomatically, with improvement in headaches on nonsteroidal antiinflammatory drugs. Case 2 This 6-year-old girl presented with a syncopal episode. Over the previous 6 months, her body weight had increased by 30 pounds and she complained of constant fatigue and disinterest in playing. She had no headaches or visual disturbances. Neurological examination, including evaluation of visual acuity and fields, was unremarkable. Magnetic resonance imaging demonstrated a homogeneously enlarged pituitary gland, up to 10 mm in height, J Neurosurg: Pediatrics / Volume 7 / May 2011 which enhanced uniformly on contrast administration (Fig. 2). The normal hyperintense posterior pituitary was evident on the noncontrast T1-weighted imaging. The superior surface of the pituitary gland abutted the optic chiasm, but no significant chiasmal displacement or distortion was seen. The patient s pediatrician referred her to neurosurgery for surgical evaluation. Endocrine studies showed elevated thyroid-stimulating hormone level (> 100 U ml -1 ), with free T4 below 0.3 ng/ml -1 and T3 below 20 ng/ml -1. Prolactin was normal at 16 ng/ml -1. Morning serum cortisol was also within normal limits. The patient underwent thyroid hormone replacement. There was an immediate improvement in her endocrine symptoms and subsequent resolution of her pituitary enlargement. Discussion There are 4 different epochs when pituitary gland enlargement may be normal and confused with tumor. The first is in the perinatal period and is the result of the withdrawal of maternal hormonal support. The second is in adolescence and is associated with maturation of glandular tissues in the body. The third is during pregnancy, again associated with hormonal fluxes within the body. The fourth period is at menopause. 54 Pituitary hyperplasia in adolescence was initially described in a small number of individuals in whom the disorder was demonstrated on coronal CT scans. 44 In one study the authors evaluated 27 thin-section coronal CT scans acquired in young people (age 8 21 years) without suspicion of pituitary disease; they compared these scans with those obtained in older people (age years) with similar images. The authors observed a significant increase (up to 8.2 mm) in mean gland height in three girls years of age. A convex superior margin to the pituitary was also much more common in the younger group, particularly in females. Previous reports, based on CT and postmortem findings, had not stratified individuals according to age and concluded that the mean height of the normal pituitary gland was between 4.8 and 6 mm in females and between 3.5 and 5.3 mm in males. 9,39,52 Only 4% of glands had a convex upper margin. 39 It should be noted that extensive variations in sellar shape and size have been documented, and these, particularly when the 511

3 K. Aquilina and F. A. Boop sellar floor is flat and the sella is shallow, may lead to apparent convexity of the superior pituitary margin. 7,60 Magnetic resonance imaging has led to greater precision in the measurement of pituitary gland size, correlating well with measurements obtained on CT and, in addition, providing triplanar information that proved easier to interpret. 58 In an MR imaging study in 35 healthy volunteers, evaluating coronal, sagittal, and axial measurements of the pituitary, the authors identified the height of the gland measured on the midsagittal image as the best single measure of gland volume. 35 Although the study did not include children and adolescents, a negative correlation with increasing age was identified, underlining the importance of age-specific normative data for pituitary gland size; this was subsequently confirmed in a larger study in 71 adult volunteers. 12 A study assessing the development and aging of brain midline structures on MR images showed that there was a growth spurt in the height of the gland in individuals between 10 and 15 years of age. Although the mean height for girls was higher than that for boys, a statistically significant difference could not be demonstrated in a sample of 22 patients. 19 Other studies with small numbers of patients in the teenage group reached similar conclusions. 51 A larger data set, including 64 patients between 11 and 20 years of age, was evaluated in a subsequent study. 14 Patients who were pregnant, breast feeding, or receiving exogenous hormone therapy were excluded; a detailed medical questionnaire was also administered to confirm endocrine normality in the remaining patients. In patients younger than 12 years no sex difference was demonstrated; the maximum pituitary height was 6 mm. In contrast, several pituitary glands in teenage girls measured 7 10 mm in height. A pituitary growth spurt was evident in the early teenage years, particularly in girls. Teenage boys also had a significantly enlarged gland compared with pediatric and young-adult males, reaching a maximal height of 7 mm. Young adults (age range years) were found to have significantly smaller glands than teenagers up to 9 mm in women and 7 mm in men. A similar study also identified a statistically significant sex difference in mean pituitary height in the 10 to 19 year-old age group on midsagittal MR images. 54 Differences in the shape of the pituitary gland have also been described. 14 In males, at all ages, only 21% of glands assessed in one study showed any tendency to upward convexity. In females, however, age-related differences were evident. In 53% of females between 11 and 20 years of age, upward convexity was demonstrated; 8 glands (25%) were nearly spherical on sagittal images. The authors concluded that the nearly spherical shape of the pituitary gland in teenage females should be considered a normal developmental feature; investigation for an underlying adenoma is not indicated. Although several studies have demonstrated a general trend toward reduction of pituitary height with increasing age, 19,35,44,51 Tsunoda et al., 54 in a study involving 1020 patients between 10 to 78 years of age, identified an increase in the 50 to 59 year age group in women. The authors speculated that this is likely related to the perimenopausal decline in circulating gonadal hormones, with associated loss of negative feedback and an increase in serum levels of gonadotrophic hormones leading to compensatory pituitary hypertrophy. 54 Correlation of the Tanner stages of puberty in girls with serial serum concentrations of sex hormones has clearly demonstrated a significant increase in folliclestimulating hormone, luteinizing hormone, estradiol, and estrone around puberty. 33 The association between such hormonal changes and pituitary hypertrophy has also been demonstrated in animal models. Chronic administration of estradiol in the adult Sprague-Dawley male rat leads to pituitary hyperplasia, as confirmed on MR imaging, and subsequent removal of estradiol stimulation causes a reduction in size of up to 60%. 46 In particular, chronic estrogen administration causes prolactin cell hyperplasia. 49 This has been observed in male-to-female transsexuals given long-term estrogen therapy. 29 Several chronic changes in the hormonal environment have been associated with changes in pituitary size. The morphology of the lactotrophs is known to respond dramatically to changing functional demands; 22 the pronounced pituitary hypertrophy occurring during pregnancy and lactation is due to lactotrophs hyperplastic proliferation. 21,50 An extensive immunohistochemical study showed that multiparous women continue to have a higher number of lactotrophs than nulliparous women, implying that this process is never completely reversed; however, there was no significant difference in the number of lactotrophs between males and nulliparous females at any age. 4 This would suggest that physiological hypertrophy in adolescence is not simply lactotrophic hyperplasia. Hypothyroidism, as shown in Case 2, is an important cause of pituitary enlargement and needs to be distinguished from pituitary adenoma. It has been described both in congenital and in juvenile hypothyroidism, often of autoimmune origin. 11,20,31 It is significantly commoner in females. 23 Severe forms are often associated with lactotroph hyperplasia. 22,27,41 Lack of thyroxine feedback in uncontrolled primary hypothyroidism causes thyrotroph and lactotroph hypertrophy, which regresses with treatment, usually over weeks to several months. 5,47,48,55 These patients often present with symptoms related to their hypothyroidism but also with galactorrhea, headache, and visual disturbance related to pituitary enlargement. 24,59 It should be noted that anything distending the diaphragma sellae may cause cephalgia. On MR imaging, pituitary hyperplasia is evident in up to 70% of patients with primary hypothyroidism. 27,59 In such situations, differentiation from prolactinomas necessitates evaluation of thyroid-stimulating hormone levels. 17 Other correlations between hormonal changes and pituitary size have been identified. Teenage girls with anorexia nervosa do not exhibit the expected physiological pubertal hypertrophy of the pituitary on MR imaging. 28 Children with central precocious puberty have a pituitary size similar to that found in pubertal children. 18,43 In a study of 47 girls with precocious puberty, the pituitary height was well correlated with luteinizing hormone/follicle-stimulating hormone peak ratio, leading the authors to speculate that gland height reflects changes in the degree of hypothalamus-pituitary activation J Neurosurg: Pediatrics / Volume 7 / May 2011

4 Nonneoplastic enlargement of the pituitary gland Pituitary hypertrophy has been identified as an important cause of pituitary incidentaloma, abnormalities of the pituitary gland found when imaging asymptomatic patients. 10 Computed tomography and MR imaging have revealed pituitary lesions between 3 and 10 mm in diameter in 4 20% of healthy subjects. 38 In one study, of 41 incidental pituitary masses, 7 occurred in nulliparous females, age years, and were characterized by diffuse pituitary enlargement with gland height exceeding 9 mm. 10 Four patients presented with nonspecific headache. Apart from changes related to polycystic ovary syndrome in 2 patients, no endocrine abnormalities were identified. On contrastenhanced MR imaging, the pituitary was homogeneously enlarged without abnormalities; the superior margin was convex in all cases and abutted the optic chiasm in 4 cases. In these patients, the Goldmann visual field perimetry was essentially normal. Two patients had undergone transsphenoidal surgery for suspected nonfunctioning adenomas; pituitary histological, immunocytochemical, and electron microscopic findings were consistent with a normal adenohypophysis. There was no evidence of pituitary hyperplasia, which the authors attributed to sampling error. During 2 8 years of follow-up, the patients clinical and hormonal status remained stable, without pituitary tumor development. The authors did not specify whether the expected age-dependent reduction in pituitary size occurred in these patients. They recommended that incidentalomas occurring in other age groups, with heterogeneity of the pituitary gland on plain and contrast-enhanced images and with an abnormal baseline hormone profile, cannot be classified as pituitary hypertrophy and require complete evaluation to exclude a pituitary tumor. 10 Headache is an important component of the symptomatology in young women presenting with pituitary hypertrophy. It is common in cases of pituitary tumors, occurring in up to 70% of patients at presentation, but its mechanism is unclear. 1,34 Its incidence appears unrelated to tumor size and cavernous sinus invasion. 1,34 It is more common in cases of acromegaly and prolactinomas, suggesting a potential biochemical component. 1 A study measuring intrasellar pressure at transsphenoidal surgery for macroadenomas demonstrated a significant difference between patients with and without headache, concluding that, independent of tumor size, intrasellar pressure is likely to be relevant to the cause of headache. 3 Headaches also occur in Rathke cleft cysts, in which their periodicity may reflect an intermittent inflammatory reaction. 56 Transsphenoidal surgery has been shown to lead to symptomatic improvement in up to 80% of patients, even when the cysts were small. 16,40 However, even nonfunctioning microadenomas are associated with a high incidence of headache, and, in one study, transsphenoidal surgery and resection of the tumor led to an improvement in headache. 16 It is difficult to speculate on the causes of headache in pituitary hypertrophy; the lack of an endocrine abnormality would suggest, as in nonfunctioning adenomas, an effect related to the increased pituitary size and dural distention. The presence, in these patients, of a symptomatic pituitary mass, sometimes associated with galactorrhea, raises concern about the possibility of a prolactinoma, the J Neurosurg: Pediatrics / Volume 7 / May 2011 commonest pediatric pituitary tumor. 25,26,37,57 The majority of pediatric prolactinomas occur in females during adolescence. 36,37,42 In large series of pediatric pituitary adenomas, the commonest presenting features were headache and visual disturbances. 25,37,57 In one study, all 30 females with prolactinomas had primary or secondary amenorrhea on presentation. 2,57 Between 77% and 100% of females with prolactinomas have galactorrhoea. 2,8 Although not uncommon around puberty, even in normal adolescents, this symptom may be difficult to elicit in teenagers. 45 Prolactin levels are elevated, with serum levels corresponding to adenoma size. 2 In contrast, patients with pituitary hypertrophy have normal menses, do not develop visual disturbances, and have an essentially normal endocrine profile. Although nonfunctioning pituitary adenomas represent the commonest pituitary tumors in adults, where they tend to occur in the 3rd to 4th decades, they are rare in childhood, and only constitute up to 6% of pediatric cases. 26 These tend to arise from gonadotroph cells and are very large on presentation; they are often associated with symptoms related to hypopituitarism and development arrest. 53 Corticotrophin-secreting adenomas are also rare in childhood; children with these adenomas present with Cushing syndrome and generally at a younger age than patients with prolactinomas. 30 Conclusions The increasing availability of MR imaging has led to an increase in the referral of teenage girls with physiological pituitary hypertrophy to pediatric neurosurgeons for potential surgery. This is a well-documented physiological change occurring in the early to mid-teenage years. The absence of visual symptoms, homogeneous pituitary enlargement on MR images, and a normal endocrine profile exclude a pituitary adenoma, the most important differential diagnosis. Simple endocrine evaluation, including thyroid function tests, is necessary to exclude pituitary enlargement due to end-organ failure, such as primary hypothyroidism. Control of symptoms, predominantly headache, and careful follow-up are in most cases sufficient to confidently exclude more serious pathology. Disclosure The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. Author contributions to the study and manuscript preparation include the following. Conception and design: Boop. Acquisition of data: both authors. Drafting the article: Aquilina. Critically revising the article: Boop. Reviewed final version of the manuscript and approved it for submission: both authors. Study supervision: Boop. References 1. Abe T, Matsumoto K, Kuwazawa J, Toyoda I, Sasaki K: Headache associated with pituitary adenomas. Headache 38: , Acharya SV, Gopal RA, Bandgar TR, Joshi SR, Menon PS, Shah NS: Clinical profile and long term follow up of children and adolescents with prolactinomas. Pituitary 12: ,

5 K. Aquilina and F. A. Boop 3. Arafah BM, Prunty D, Ybarra J, Hlavin ML, Selman WR: The dominant role of increased intrasellar pressure in the pathogenesis of hypopituitarism, hyperprolactinemia, and headaches in patients with pituitary adenomas. J Clin Endocrinol Metab 85: , Asa SL, Penz G, Kovacs K, Ezrin C: Prolactin cells in the human pituitary. A quantitative immunocytochemical analysis. Arch Pathol Lab Med 106: , Ashley WW Jr, Ojemann JG, Park TS, Wippold FJ II: Primary hypothyroidism in a 12-year-old girl with a suprasellar pituitary mass: rapid regression after thyroid replacement therapy: case report. J Neurosurg 102 (4 Suppl): , Atchison JA, Lee PA, Albright AL: Reversible suprasellar pituitary mass secondary to hypothyroidism. JAMA 262: , Bruneton JN, Drouillard JP, Sabatier JC, Elie GP, Tavernier JF: Normal variants of the sella turcica. Radiology 131:99 104, Cannavò S, Venturino M, Curtò L, De Menis E, D Arrigo C, Tita P, et al: Clinical presentation and outcome of pituitary adenomas in teenagers. Clin Endocrinol (Oxf) 58: , Chambers EF, Turski PA, LaMasters D, Newton TH: Regions of low density in the contrast-enhanced pituitary gland: normal and pathologic processes. Radiology 144: , Chanson P, Daujat F, Young J, Bellucci A, Kujas M, Doyon D, et al: Normal pituitary hypertrophy as a frequent cause of pituitary incidentaloma: a follow-up study. J Clin Endocrinol Metab 86: , Desai MP, Mehta RU, Choksi CS, Colaco MP: Pituitary enlargement on magnetic resonance imaging in congenital hypothyroidism. Arch Pediatr Adolesc Med 150: , Doraiswamy PM, Potts JM, Figiel GS, Boyko OB, Krishnan KR: MR imaging of physiologic pituitary gland hypertrophy in adolescence. Radiology 178: , Ehirim PU, Kerr DS, Cohen AR: Primary hypothyroidism mimicking a pituitary macroadenoma. Pediatr Neurosurg 28: , Elster AD, Chen MY, Williams DW III, Key LL: Pituitary gland: MR imaging of physiologic hypertrophy in adolescence. Radiology 174: , Eom KS, See-Sung C, Kim JD, Kim JM, Kim TY: Primary hypothyroidism mimicking a pituitary macroadenoma: regression after thyroid hormone replacement therapy. Pediatr Radiol 39: , Fleseriu M, Yedinak C, Campbell C, Delashaw JB: Significant headache improvement after transsphenoidal surgery in patients with small sellar lesions. Clinical article. J Neurosurg 110: , Grubb MR, Chakeres D, Malarkey WB: Patients with primary hypothyroidism presenting as prolactinomas. Am J Med 83: , Gupta R, Ammini AC: Precocious puberty with pituitary gland hyperplasia: two cases in one family. Pediatr Radiol 26: , Hayakawa K, Konishi Y, Matsuda T, Kuriyama M, Konishi K, Yamashita K, et al: Development and aging of brain midline structures: assessment with MR imaging. Radiology 172: , Hopper NW, Albanese A: Primary hypothyroidism in a child mimicking a pituitary macroadenoma. Horm Res 63:61 64, Horvath E: Fine structural cytology and immunohistochemistry of the non-adenomatous pars distalis of the human pituitary. Pathol Res Pract 183: , Horvath E, Kovacs K, Scheithauer BW: Pituitary hyperplasia. Pituitary 1: , Horvath E, Lloyd RV, Kovacs K: Propylthiouracyl-induced hypothyroidism results in reversible transdifferentiation of somatotrophs into thyroidectomy cells. A morphologic study of the rat pituitary including immunoelectron microscopy. Lab Invest 63: , Joshi AS, Woolf PD: Pituitary hyperplasia secondary to primary hypothyroidism: a case report and review of the literature. Pituitary 8:99 103, Kane LA, Leinung MC, Scheithauer BW, Bergstralh EJ, Laws ER Jr, Groover RV, et al: Pituitary adenomas in childhood and adolescence. J Clin Endocrinol Metab 79: , Keil MF, Stratakis CA: Pituitary tumors in childhood: update of diagnosis, treatment and molecular genetics. Expert Rev Neurother 8: , Khawaja NM, Taher BM, Barham ME, Naser AA, Hadidy AM, Ahmad AT, et al: Pituitary enlargement in patients with primary hypothyroidism. Endocr Pract 12:29 34, Kornreich L, Shapira A, Horev G, Danziger Y, Tyano S, Mimouni M: CT and MR evaluation of the brain in patients with anorexia nervosa. AJNR Am J Neuroradiol 12: , Kovacs K, Stefaneanu L, Ezzat S, Smyth HS: Prolactin-producing pituitary adenoma in a male-to-female transsexual patient with protracted estrogen administration. A morphologic study. Arch Pathol Lab Med 118: , Kunwar S, Wilson CB: Pediatric pituitary adenomas. J Clin Endocrinol Metab 84: , Kuroiwa T, Okabe Y, Hasuo K, Yasumori K, Mizushima A, Masuda K: MR imaging of pituitary hypertrophy due to juvenile primary hypothyroidism: a case report. Clin Imaging 15: , Lee CY, Hsu HH, Lai HY, Lee ST: Rapid progression of hypothyroidism-related pituitary hyperplasia. Case report. J Neurosurg Pediatr 2: , Lee PA, Xenakis T, Winer J, Matsenbaugh S: Puberty in girls: correlation of serum levels of gonadotropins, prolactin, androgens, estrogens, and progestins with physical changes. J Clin Endocrinol Metab 43: , Levy MJ, Jäger HR, Powell M, Matharu MS, Meeran K, Goadsby PJ: Pituitary volume and headache: size is not everything. Arch Neurol 61: , Lurie SN, Doraiswamy PM, Husain MM, Boyko OB, Ellinwood EH Jr, Figiel GS, et al: In vivo assessment of pituitary gland volume with magnetic resonance imaging: the effect of age. J Clin Endocrinol Metab 71: , Merke DP, Fields JD, Keil MF, Vaituzis AC, Chrousos GP, Giedd JN: Children with classic congenital adrenal hyperplasia have decreased amygdala volume: potential prenatal and postnatal hormonal effects. J Clin Endocrinol Metab 88: , Mindermann T, Wilson CB: Pediatric pituitary adenomas. Neurosurgery 36: , Molitch ME: Approach to the incidentally discovered pituitary mass. Cancer Treat Res 89:73 90, Muhr C, Bergström K, Grimelius L, Larsson SG: A parallel study of the roentgen anatomy of the sella turcica and the histopathology of the pituitary gland in 205 autopsy specimens. Neuroradiology 21:55 65, Nishioka H, Haraoka J, Izawa H, Ikeda Y: Headaches associated with Rathke s cleft cyst. Headache 46: , Ozbey N, Sariyildiz E, Yilmaz L, Orhan Y, Sencer E, Molvalilar S: Primary hypothyroidism with hyperprolactinaemia and pituitary enlargement mimicking a pituitary macroadenoma. Int J Clin Pract 51: , Partington MD, Davis DH, Laws ER Jr, Scheithauer BW: Pituitary adenomas in childhood and adolescence. Results of transsphenoidal surgery. J Neurosurg 80: , Pérignon F, Brauner R, Argyropoulou M, Brunelle F: Precocious puberty in girls: pituitary height as an index of hypothalamo-pituitary activation. J Clin Endocrinol Metab 75: , J Neurosurg: Pediatrics / Volume 7 / May 2011

6 Nonneoplastic enlargement of the pituitary gland 44. Peyster RG, Hoover ED, Viscarello RR, Moshang T, Haskin ME: CT appearance of the adolescent and preadolescent pituitary gland. AJNR Am J Neuroradiol 4: , Rohn RD: Galactorrhea in the adolescent. J Adolesc Health Care 5:37 49, Rudin M, Briner U, Doepfner W: Quantitative magnetic resonance imaging of estradiol-induced pituitary hyperplasia in rats. Magn Reson Med 7: , Sarlis NJ, Brucker-Davis F, Doppman JL, Skarulis MC: MRIdemonstrable regression of a pituitary mass in a case of primary hypothyroidism after a week of acute thyroid hormone therapy. J Clin Endocrinol Metab 82: , Scheithauer BW, Kovacs K, Randall RV, Ryan N: Pituitary gland in hypothyroidism. Histologic and immunocytologic study. Arch Pathol Lab Med 109: , Scheithauer BW, Kovacs KT, Randall RV, Ryan N: Effects of estrogen on the human pituitary: a clinicopathologic study. Mayo Clin Proc 64: , Scheithauer BW, Sano T, Kovacs KT, Young WF Jr, Ryan N, Randall RV: The pituitary gland in pregnancy: a clinicopathologic and immunohistochemical study of 69 cases. Mayo Clin Proc 65: , Suzuki M, Takashima T, Kadoya M, Konishi H, Kameyama T, Yoshikawa J, et al: Height of normal pituitary gland on MR imaging: age and sex differentiation. J Comput Assist Tomogr 14:36 39, Syvertsen A, Haughton VM, Williams AL, Cusick JF: The computed tomographic appearance of the normal pituitary gland and pituitary microadenomas. Radiology 133: , Thapar K, Kovacs K, Laws ER: The classification and molecular biology of pituitary adenomas. Adv Tech Stand Neurosurg 22:3 53, Tsunoda A, Okuda O, Sato K: MR height of the pituitary gland as a function of age and sex: especially physiological hypertrophy in adolescence and in climacterium. AJNR Am J Neuroradiol 18: , Valenta LJ, Tamkin J, Sostrin R, Elias AN, Eisenberg H: Regression of a pituitary adenoma following levothyroxine therapy of primary hypothyroidism. Fertil Steril 40: , Ward TN, St Germain DL, Comi RJ, Cromwell LD: Rathke s cleft cyst as a secondary cause of headache: a case report. Cephalalgia 21: , Webb C, Prayson RA: Pediatric pituitary adenomas. Arch Pathol Lab Med 132:77 80, Wiener SN, Rzeszotarski MS, Droege RT, Pearlstein AE, Shafron M: Measurement of pituitary gland height with MR imaging. AJNR Am J Neuroradiol 6: , Yamamoto K, Saito K, Takai T, Naito M, Yoshida S: Visual field defects and pituitary enlargement in primary hypothyroidism. J Clin Endocrinol Metab 57: , Zagga AD, Ahmed H, Tadros AA, Saidu SA: Description of the normal variants of the anatomical shapes of the sella turcica using plain radiographs: experience from Sokoto, Northwestern Nigeria. Ann Afr Med 7:77 81, 2008 Manuscript submitted November 7, Accepted February 15, Address correspondence to: Frederick A. Boop, M.D., Semmes- Murphey Neurologic and Spine Institute, 1211 Union Avenue, Suite 200, Memphis, Tennessee faboop@aol.com. J Neurosurg: Pediatrics / Volume 7 / May