Pituitary Enlargement Research Articles

Mutations and Pituitary Morphology in a Series of 82 Patients with PROP1 Gene Defects

Background/Aims: Defects of the PROP1 gene are the most prevalent genetic cause of combined pituitary hormone deficiency. Previous observations in affected patients have shown pituitary size ranging from hypoplasia to overt pituitary mass and evolution of size over the lifespan. Methods: We evaluated pituitary size and morphology in PROP1-mutation carriers who originated from Central and Eastern Europe. We analyzed 112 pituitary magnetic resonance imaging (MRI) scans from 82 patients (42 males) aged 2.5–72.7 (median 16.6) years from 60 kindreds. Results: Among the 120 independent PROP1 alleles, the most prevalent mutations were delGA301/302 (99 alleles) and delA150 (13 alleles). Median pituitary height at first MRI was 4.7 mm (range 1.0–20.7) and median volume was 127.6 mm³ (range 7.5–3,087.0). Pituitary size did not differ between sexes and did not correlate with hormonal phenotype, but significantly decreased with increasing age. However, evaluation of individual values suggested a biphasic mode with increasing volume during childhood, peak in adolescence, and subsequent regression in adulthood. Conclusion: Although pituitary size was increased in a number of PROP1-deficient patients, none of them suffered permanent damage from pituitary mass; therefore, any proposed surgery should be postponed as long as possible and ultimately may not be necessary due to the self-limiting nature of the pituitary enlargement.

Panhypopituitarism due to Wegener's granulomatosis

Wegener's granulomatosis (WG) is a multi-system necrotizing granulomatous vasculitis which classically affects the upper respiratory tract, lungs and kidneys. Pituitary participation has been described in 24 patients in the literature to date. The aim of this article is to report a case of pituitary involvement in WG, and to present a literature review on this association. We present a female patient with WG who evolved with central diabetes insipidus (CDI), panhypopituitarism, and mild hyperprolactinemia. MRI showed an infiltrative pattern. Pituitary involvement has been reported in around 1% of patients with WG, mostly in women. It is represented by CDI and hypopituitarism. MRI generally shows pituitary enlargement, stalk thickening and loss of hyperintensity of the neurohypophysis. Permanent endocrine therapy is generally needed. WG should be considered in cases of CDI and hypopituitarism, essentially if a vasculitis is suspected and more common sellar disorders have been ruled out.

A Woman with Positional Headache: A Case of Spontaneous Intracranial Hypotension

A 48-year-old woman presented to the Emergency Department complaining of 3 weeks of intermittent headaches, which she recalled developing progressively after moving heavy boxes. Symptoms clearly worsened when she stood upright, and were relieved by lying down. She denied fever, photophobia, or neck pain. She had no recent history of lumbar puncture or spinal surgery. Her vital signs and her clinical examinationwere normal. However, upon assuming an upright from a supine position, she quickly developed a generalized headache that resolved with head lowering. A non-contrast computed tomographic brain scan revealed subtle extra-axial fluid collections over both frontal lobes. A follow-up brain magnetic resonance imaging (MRI) scan revealed dural enhancement; subdural fluid collections; brain sagging, indicated by a downwardly displaced optic chiasm; and pituitary enlargement (Figure 1). Thoracic spine MRI scan demonstrated an extra-dural collection of cerebrospinal fluid (CSF) (Figure 2). This constellation of findings is diagnostic for spontaneous intracranial hypotension. A specific source for the CSF leak could not be identified, precluding a therapeutic red blood cell patch. Shewas treated conservatively and her headache eventually resolved.

Case seminar: a young female with acute hyponatremia and a sellar mass

In familial cases of combined pituitary hormone deficiency the most common mutations are that of Prophet of Pit 1 (PROP1) gene. PROP1 mutations are associated with deficiencies of growth hormone, thyrotropin, prolactin, and gonadotropins (follicle-stimulating hormone and luteinizing hormone), with evolving adrenocorticotropin (ACTH) deficiency in some cases. On imaging in most patients the pituitary gland is hypoplastic, but occasionally transient pituitary enlargement is found. We report a 22-year-old female initially diagnosed at age 12 with familial hypopituitarism due to PROP1 mutation, who presented with coma and respiratory arrest (acute hyponatremia). She was urgently treated in Intensive Care Unit of Emergency Center with hypertonic saline and stress doses of hydrocortisone, which resulted in the fast increase of plasma osmolality resulting in the osmotic demyelination syndrome. Simultaneously and incidentally on computed tomography scan a large sellar and suprasellar mass were reported as possible Rathke's cleft cyst or craniopharyngioma. Once the patient was stable, ACTH deficiency was documented. She remained replaced with hydrocortisone and subsequently underwent transphenoidal surgery. The removed sellar content revealed no pituitary adenoma or pituitary cells, but only an eosinophilic, colloid-like mass, and necrotic acellular debris. Her sister with hypopituitarism had an empty sella. Genetic testing in both sisters revealed the same homozygous c.150delA mutation in PROP1 gene. Here we report two sisters with the same PROP1 mutation who presented in adulthood with different pituitary morphology, one of them with a large sellar and suprasellar mass, in which transphenoidal surgery provided an extremely rare opportunity for a histopathological analysis of the sellar content. Due to the lack of endocrine care during the transition period hypocortisolism which evolved, a consequence of PROP1 mutation, was not recognized. Empirical use of hydrocortisone in the Intensive Care in our patient with life-threatening acute hyponatremia was appropriate but because glucocorticoid therapy on its own corrects hyponatremia even after stopping hypertonic saline infusion, the risk for over-correction of hyponatremia in ACTH deficiency is high.

Ki-67 and minichromosome maintenance-7 (MCM7) expression in canine pituitary corticotroph adenomas

Pituitary-dependent hyperadrenocorticism (PDH) caused by pituitary corticotroph adenoma is a common endocrine disorder in dogs. The ratio between pituitary height and the area of the brain (P/B) has been used to evaluate the pituitary size. A P/B ratio > 0.31 indicates an enlarged pituitary, whereas a P/B ratio ≤ 0.31 indicates a nonenlarged pituitary. The aim of this study was to investigate the expression of proliferation markers Ki-67 and minichromosome maintenance-7 (MCM7) in canine corticotroph adenomas in enlarged and in nonenlarged pituitaries and to evaluate their relation with the size of canine pituitary corticotroph adenomas. Ki-67 and MCM7 expression in ACTH-positive tumor cells was determined by dual-labeling immunohistochemistry in resected corticotroph adenomas from 15 dogs with PDH. The mean ± SD Ki-67 labeling index (LI) was 0.55% ± 0.59% in corticotroph adenomas with nonenlarged pituitaries and 1.6% ± 0.6% in adenomas with enlarged pituitaries. The MCM7 LI in corticotroph adenomas with nonenlarged pituitaries and in adenomas with enlarged pituitaries was 2.9% ± 2.2% and 10.9% ± 3.7%, respectively. The Ki-67 LI and MCM7 LI were significantly greater in the adenomas with enlarged pituitaries than in the adenomas with nonenlarged pituitaries ( P < 0.01 and P < 0.01, respectively). The MCM7 LI was significantly greater than the Ki-67 LI in adenomas ( P < 0.01). The Ki-67 LI was positively correlated with the MCM7 LI ( r = 0.820, P < 0.01), and the P/B ratio was positively correlated with the Ki-67 LI ( r = 0.560, P = 0.03) and the MCM7 LI ( r = 0.854, P < 0.01). In conclusion, canine corticotroph adenomas in enlarged pituitaries show greater proliferation potential than do adenomas in nonenlarged pituitaries. MCM7 expression was significantly greater than Ki-67 expression in canine pituitary corticotroph adenomas. Thus, MCM7 may be superior to Ki-67 as a proliferation marker in pituitary tumors.

Pituitary enlargement in spontaneous intracranial hypotension—a diagnostic pitfall

Dear Editor Spontaneous intracranial hypotension (SIH) is an uncommon condition characterized by the depletion of cerebrospinal fluid (CSF) volume [3]. Enlargement of the pituitary gland may occur in SIH due to compensatory engorgement of the epidural venous plexus, which is a potential diagnostic pitfall [2]. We report a 46-year-old woman who presented with a 2-week history of headache and a partial right abducens nerve palsy. Her pituitary hormonal profiles were normal except for raised serum alpha-subunit, follicle stimulating hormone and luteinizing hormone levels, compatible with her previous oophorectomy. Magnetic resonance (MR) studies showed an enlarged pituitary gland, which was then diagnosed as a non-functioning pituitary macroadenoma. Less emphasis was placed on other MR findings including bilateral subdural effusion, pachymeningeal enhancement, and sagging of the midbrain, which were suggestive of SIH (Fig. 1). Endoscopic transsphenoidal surgery was performed, which revealed a diffusely enlarged pituitary gland. Biopsy showed no inflammatory or neoplastic changes. Her headache and diplopia resolved 2 weeks later. A follow-up MR study showed complete resolution of the pachymeningeal enhancement, bilateral subdural effusion, and pituitary enlargement. The overall picture was that of SIH that had resolved spontaneously. Fig. 1 a, b Post-contrast T1-weighted coronal images showing an enlarged and homogeneously enhancing pituitary gland, and diffuse pachymeningeal enhancement (arrows); c coronal FLAIR image showing the bilateral subdural effusion (arrows) SIH is most commonly due to spontaneous CSF leakage at the lower cervical and upper thoracic spine. Mechanical stress, meningeal diverticula, and connective tissue disorders have been identified as potential risk factors. The estimated incidence is around 5 per 100,000 per year, with a female predominance and a peak incidence around the 4th decade [8]. Patients may present with orthostatic headache, nausea, vomiting, neck rigidity, and cranial nerve palsies [4]. The characteristic MR findings include pachymeningeal thickening and enhancement, tonsillar descent into the foramen magnum, and subdural effusion [8]. As the craniospinal axis attempts to maintain volume homeostasis in the face of continuous CSF loss, dural hyperemia and associated enlargement of the pituitary gland may occur in up to two-thirds of the cases [6]. The initial MR findings should have raised the suspicion of SIH in our patient. On retrospective enquiry, her headache was indeed postural in nature. We performed surgery with a view to improve her abducens nerve palsy. The latter was a recognized feature of SIH, accounting for up to 80% of reported ocular manifestations of this syndrome [10]. The optic, oculomotor, trochlear, and trigeminal nerves may also be affected [1]. Other unusual pituitary manifestations of SIH include hemorrhage [9] and partial insufficiency [7]. Interestingly, an unusual case of SIH associated with a pituitary macroadenoma and subdural hemorrhage has also been described [5]. The majority of patients with SIH improve on conservative management, and almost all cases with pituitary enlargement have normalization of gland size on follow-up MR [2]. For refractory cases, myelography is the study of choice to identify the site of spinal CSF leakage, followed by definitive treatments such as epidural blood patching, percutaneous placement of fibrin sealant, and open surgical repair. In summary, SIH should be considered in patients who present with postural headache and the characteristic MR findings. Initial conservative management should be adopted, which is effective in the majority of cases. The present case illustrates the importance of careful history taking and clinical examination as well as an awareness of this diagnostic pitfall.

Nonneoplastic enlargement of the pituitary gland in children

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.

Normal pressure form of the spontaneous intracranial hypotension: a case report with pituitary enlargement and asymptomatic pituitary haemorrhage

Spontaneous intracranial hypotension is a rare condition caused by spontaneous cerebrospinal fluid leak and volume depletion. It is initially misdiagnosed as a cause of an orthostatic headache, which is the most important symptom of the syndrome. It can be presented as one of four types: classic form, normal pressure form, normal pachymeninges form and acephalgic form. The diagnosis is made based on the clinical presentation, physical examination, typical cerebrospinal fluid and magnetic resonance imaging findings. We present a case of a 29-year-old woman with uncommon normal pressure form of the spontaneous intracranial hypotension, characterized by normal cerebrospinal fluid opening pressure, and typical clinical and magnetic resonance imaging findings, including the finding of pituitary gland enlargement with asymptomatic pituitary haemorrhage as an unusual complication.

Ｐａｔｔｅｒｎ ｒｅｖｅｒｓａｌ ＶＥＰにて視神経炎が示唆されたリンパ球性下垂体炎の１例

Lymphocytic hypophysitis (LYH) is a rare neuroendocrine disorder characterized by autoimmune inflammation of the pituitary gland. Visual disturbance is one of the most common and serious symptoms of LYH. Most of the visual symptoms in LYH are secondary to compression of the optic chiasm and some reports have described direct inflammatory involvement of the optic pathways. We describe a 30-year-old man with a 9-day history of bilateral blurred vision. Ophthalmic examination demonstrated severely impaired vision without temporal hemianopsia. Hypothyroidism, hypocortisolism, and hypogonadism were detected in laboratory tests. Central diabetes insipidus was diagnosed by a hypertonic saline infusion test. MRI revealed thickening of the pituitary stalk and enlargement of the hypophysis, which was enhanced with gadolinium. High intensity of the posterior lobe was not recognized on T1-weighted images. These findings established a clinical diagnosis of lymphocytic panhypophysitis. Methylprednisolone pulse therapy was introduced and his visual acuity gradually recovered. The anterior pituitary function improved, but desmopressin was still required. Pattern-reversal visual evoked potentials (VEP) have been widely used to detect optic nerve lesions caused by multiple sclerosis and brain tumors. However, there have been no previous reports of their usefulness for LYH. The P100 latency in our case was slightly prolonged and the amplitude was markedly reduced. These findings are similar to ischemic optic neuropathy and other conditions in which axonal damage is prominent. The prolonged latency and low amplitude on VEP examination in this case showed rapid improvement in parallel with the recovery of visual acuity. Taken together, our case implies the usefulness of pattern-reversal VEP for the diagnosis of optic neuritis in LYH, especially for the evaluation of its pathogenic mechanisms.

Pituitary Hyperplasia Secondary to Hypothyroidism Caused by Hashimoto's Thyroiditis in a Female Adolescent

Pituitary enlargement secondary to primary hypothyroidism is a known but uncommon occurrence and is difficult to distinguish on computed tomography (CT) and magnetic resonance imaging (MRI) from primary pituitary tumor. The lack of thyroxine feedback found in uncontrolled primary hypothyroidism leads to elevated levels of thyrotropin-releasing hormone (TRH), which causes both pituitary thyrotroph and lactotroph hyperplasia, increasing the secretion of both thyroidstimulating hormone (TSH) and prolactin. With long-standing hypothyroidism, thyrotroph hyperplasia can result in expansion of the sella turcica and enlargement of the pituitary gland. Pituitary hyperplasia usually regresses following adequate treatment with hormone replacement over a period of a few months. We herein report a case of pituitary hyperplasia associated with hypothyroidism in a short statured female adolescent without the typical clinical features associated with hypothy-

Longitudinal volume changes of the pituitary gland in patients with schizotypal disorder and first-episode schizophrenia

An enlarged volume of the pituitary gland has been reported in the schizophrenia spectrum, possibly reflecting the hypothalamic–pituitary–adrenal (HPA) hyperactivity. However, it remains largely unknown whether the pituitary size longitudinally changes in the course of the spectrum disorders. In the present study, longitudinal magnetic resonance imaging (MRI) data were obtained from 18 patients with first-episode schizophrenia, 13 patients with schizotypal disorder, and 20 healthy controls. The pituitary volume was measured at baseline and follow-up (mean, 2.7years) scans and was compared across groups. The pituitary volume was larger in the schizophrenia patients than controls at baseline, and both patient groups had significantly larger pituitary volume than controls at follow-up. In a longitudinal comparison, both schizophrenia (3.6%/year) and schizotypal (2.7%/year) patients showed significant pituitary enlargement compared with controls (−1.8%/year). In the schizophrenia patients, greater pituitary enlargement over time was associated with less improvement of delusions and higher scores for thought disorders at the follow-up. These findings suggest that the pituitary gland exhibits ongoing volume changes during the early course of the schizophrenia spectrum as a possible marker of state-related impairments.

Early descriptions of acromegaly and gigantism and their historical evolution as clinical entities

Giants have been a subject of fascination throughout history. Whereas descriptions of giants have existed in the lay literature for millennia, the first attempt at a medical description was published by Johannes Wier in 1567. However, it was Pierre Marie, in 1886, who established the term "acromegaly" for the first time and established a distinct clinical diagnosis with clear clinical descriptions in 2 patients with the characteristic presentation. Multiple autopsy findings revealed a consistent correlation between acromegaly and pituitary enlargement. In 1909, Harvey Cushing postulated a “hormone of growth" as the underlying pathophysiological trigger involved in pituitary hypersecretion in patients with acromegaly. This theory was supported by his observations of clinical remission in patients with acromegaly in whom he had performed hypophysectomy. In this paper, the authors present some of the early accounts of acromegaly and gigantism, and describe its historical evolution as a medical and surgical entity.

Pituitary-dependent hyperadrenocorticism and generalised toxoplasmosis in a cat with neurological signs

A 12-year-old female neutered cat presented with acute onset unilateral vestibular syndrome, a spontaneous cutaneous wound, polyuria, polydipsia, and diabetes mellitus. Hyperadrenocorticism was demonstrated by means of hyper-responsiveness to adrenocorticotropic hormone stimulation, elevated urine cortisol-to-creatinine ratio, bilaterally enlarged adrenal glands on abdominal ultrasound, and pituitary enlargement on computed tomography imaging. The cat was euthanased and post-mortem histological examination revealed feline skin fragility syndrome; confirmed a pituitary cromophobe macroadenoma; and generalised toxoplasmosis with tachyzoites in the pancreas, bowel and brain. This report is the first to describe the concurrence of macroadenoma pituitary-dependent hyperadrenocorticism and generalised toxoplasmosis in a cat with central vestibular syndrome.

Primary Hypothyroidism Presenting as a Sellar Mass Which Regressed with Thyroid Hormone Therapy

We describe a15-year-old girl presenting with compensatory pituitary enlargement due to primary hypothyroidism. The hyperplasia regressed following thyroxine administration. The clinical, laboratory and MRI features of the patients are described and the mechanisms of pituitary gland enlargement are discussed.

A Case of Pituitary Hyperplasia Secondary to Primary Hypothyroidism Presenting With Irregular Menses, Galactorrhea, and Hyperprolactinemia

Abstract: Pituitary thyrotroph hyperplasia secondary to primary hypothyroidism is a rare cause of pituitary enlargement. We report a case of pituitary hyperplasia in a young woman thought to have a pituitary macroadenoma with suprasellar extension. A 21-year-old woman was admitted to our hospital, complaining of menstrual irregularity and galactorrhea. Serum thyrotropin and prolactin were high, and serum-free thyroxine was low. Magnetic resonance imaging revealed symmetrical pituitary enlargement associated with contrast enhancement simulating macroadenoma. After adequate hormone replacement therapy with levothyroxine, both symptoms and pituitary hyperplasia regressed within 4 months. It is concluded that pituitary tumor associated with elevated thyroid stimulating hormone and low levels of free T4 should always be treated with replacement thyroxine before other diagnostic tests are ordered.

Ectopic growth hormone-releasing hormone secretion by a bronchial carcinoid tumor: clinical experience following tumor resection and long-acting octreotide therapy

Acromegaly resulting from the ectopic secretion of growth hormone-releasing hormone (GHRH) is rare. We present a case of acromegaly secondary to proven GHRH-secretion by a bronchial carcinoid tumor in a type 1 diabetic subject and document the clinical course pre- and post-resection of the tumor and of subsequent octreotide therapy. A 54-year-old Caucasian man was referred for evaluation of acromegalic symptoms and significantly increased insulin requirements. He had a history of left lung surgery 20 years prior for hemoptysis. Initial laboratory results indicated acromegaly. Fasting serum growth hormone (GH): 26.1 ng/mL (0-5 ng/mL), insulin-like growth factor 1 (IGF-1): 635 ng/mL (87-283 ng/mL), GH at 60 min post-ingestion of 75 grams of oral glucose during a glucose tolerance test: 8.3 ng/mL (normal <1 ng/mL). Pituitary magnetic resonance imaging (MRI) revealed diffuse pituitary enlargement without adenoma. A 4.4 cm left hilar mass was noted on chest computed tomography (CT) scan. Further evaluation for a suspected GHRH-secreting neuroendocrine tumor was pursued. Plasma GHRH level was elevated: 198 pg/mL (<50 pg/mL). Octreoscan showed radiolabelled-octreotide uptake in the left lung mass and pituitary gland. Surgical resection of the lung mass was performed. Immunohistochemical study of the tumor tissue indicated a neuroendocrine tumor secreting GHRH. Postoperatively, serum GHRH, GH and IGF-1 levels fell precipitously. At 10 months, IGF-1 levels were mildly elevated and 7 months of 10 mg long-acting octreotide therapy (Sandostatin(®) LAR(®)) was trialed. At 20 months, off octreotide, serum IGF-1 levels had normalized, acromegalic features were receding, and the patient's daily insulin requirements had decreased by 57%.

Pituitary hyperplasia in children with short stature and primary hypothyroidism

We present eight cases with short stature, pituitary hyperplasia, and hypothyroidism. Pituitary hyperplasia due to primary hypothyroidism was diagnosed on the basis of clinical manifestations, endocrine examination and MRI. After 2 to 6 months of L-thyroxine replacement therapy, the signs of hypothyroidism disappeared; free triiodothyronine, free thyroxine, thyrotropin and prolactin became normal; and pituitary enlargement regressed. In two children, the growth rate remained low when treated with L-thyroxine, but with additional recombinant human growth hormone (rhGH), the height increased by 11 cm per year. No recurrence of lesions was found on follow-up.

Lymphocytic Hypophysitis with a Long Latent Period from Onset of Central Diabetes Insipidus to Development of Pituitary Enlargement

A 61-year-old man presented with central lymphocytic hypophysitis. Initial pituitary MRI imaging was normal, except for loss of the "bright spot" of the posterior lobe. A diagnosis of idiopathic diabetes insipidus was made. Two years later, pituitary gland enlargement with panhypopituitarism was detected. Eight months after commencing a replacement dose of corticosteroid, the pituitary enlargement was reduced in size. These findings resulted in a diagnosis of lymphocytic hypophysitis. In patients with idiopathic diabetes insipidus, it is important to suspect lymphocytic hypophysitis and to perform a long follow-up to repeat endocrinological examinations and pituitary imaging.

Management of Coexisting Thyrotropin/Growth-Hormone-Secreting Pituitary Adenoma and Papillary Thyroid Carcinoma: A Therapeutic Challenge

A thyrotropin (TSH)-secreting pituitary adenoma coexisting with differentiated thyroid carcinoma is rare. There have been only four previously reported cases; three were treated with thyroidectomy followed by pituitary resection and one was treated with thyroidectomy alone. We hereby report the fifth case, in which a patient presented with a TSH/growth-hormone-secreting pituitary macroadenoma coexisting with papillary thyroid carcinoma (PTC). She underwent biochemical testing, ophthalmologic examination, thyroid ultrasonography, Tc-99m-pertechnetate thyroid scan, whole-body positron emission tomography, (111)In-octreotide scan, thyroid fine-needle aspiration biopsy, octreotide treatment, total thyroidectomy, recombinant human TSH radioactive iodine remnant ablation, and continued treatment with octreotide and levothyroxine after thyroidectomy. She has remained asymptomatic for 24 months without biochemical or radiological evidence of pituitary hormone oversecretion, pituitary adenoma enlargement, and PTC recurrence. To our knowledge, this is the first case of a TSH/growth-hormone-secreting pituitary macroadenoma coexisting with PTC being successfully treated with octreotide and levothyroxine after thyroidectomy and recombinant human TSH-stimulated radioactive iodine remnant ablation.

Hypothyroidism: Clinical Features

Hypothyroidism: Clinical Features