Clinical presentation, evaluation and case management of primary empty sella syndrome: a retrospective analysis of 10-year single-center patient data.

BACKGROUND: Primary Empty Sella (PES) syndrome is an increasingly common disorder, mostly diagnosed as an incidental finding during brain imaging scans. We intended to review the clinical management and hormonal profile of patients with PES. METHODS: The study included ten-year retrospective analysis of registry containing PES cases in the period 2007 to 2017, from a single tertiary care center. The keyword 'primary empty sella' was used to retrieve patient details from the radiology unit. The clinical and biochemical profile of PES patients was analyzed. Case management of PES patients and their rate of referral to endocrinologists was explored. RESULTS: The registry had 765 cases with a male: female ratio of 1:3.8 suggesting female predominance by almost four times. Although not significant, the onset of disease was earlier for males [Mean ± standard deviation (SD) (46.7 years ±17.3 vs 48.8 years±14.1), p = 0.110]. Almost 79% of the cases were found as an incidental finding during Magnetic Resonance Imaging. Of the total PES cases, only 20% were referred to the endocrinologists and the rest were handled by general physicians. Only 1-2.5% of the cases were evaluated for gonadal, growth and adrenal hormones by the general physicians. The hormonal evaluation by the endocrinologists was also found to be sub-optimal. Headache and visual disturbances were the most common presenting complaints followed by menstrual abnormalities. Endocrine abnormalities like thyroid dysfunction, hyperprolactinemia, hypogonadism and hypocortisolism were highly prevalent among those assessed. CONCLUSION: There is a gross under-evaluation of hormonal assessment and minimal case-referral to Endocrinologists. PES is associated with varying degrees of hormonal dysfunction, and hence early assessment and management is needed. Establishing a standard protocol for diagnosis and case management is essential with the involvement of a multidisciplinary team consisting of endocrinologists, neurologists, primary care phys icians and ophthalmologists.

Primary pituitary abscess followed by empty sella syndrome in an adolescent girl.

Primary pituitary abscess is a rare pituitary pathology, particularly at a young age and is characterized by atypical clinical features making the diagnosis difficult. Correct diagnosis and therapy are mandatory due to the potentially lethal outcome of pituitary infection. We report the case of an adolescent girl presenting with headache, diabetes insipidus and central thyro-gonadic insufficiency with no history of infection, in whom the intra-operative diagnosis of primary pituitary abscess was made. Bacterial cultures indicated infection with Streptococcus spp. One year after neurosurgery and antibiotic therapy, recovery of diabetes insipidus and pituitary insufficiency was documented except for persistence of subnormal growth hormone secretion. Post-surgery, pituitary magnetic resonance imaging revealed an empty sella syndrome.

Evaluation of oxidative stress effects on different macromolecules in adult growth hormone deficiency.

Adult growth hormone deficiency (GHD) is being increasingly recognized to cause premature mortality exacerbated by oxidative stress. A case-control observational study has been performed with the primary objective of evaluating new parameters of oxidative stress and macromolecular damage in adult GHD subjects: serum nitrotryptophan; Total Antioxidant Capacity expressed as LAG time; urinary hexanoil-lysine; urinary dityrosine and urinary 8-OH-deoxyguanosine. GHD was diagnosed using Growth Hormone-Releasing Hormone 50µg iv+arginine 0,5 g/Kg test, with a peak GH response <9 µg /L when BMI was <30 kg/m2 or <4 µg/L when BMI was >30 kg/m2. Patients affected by adult GHD were divided into three groups, total GHD (n = 26), partial GHD (n = 25), and controls (n = 29). Total Antioxidant Capacity, metabolic and hormonal parameters have been determined in separate plasma samples; nitrotryptophan in serum samples; hexanoil-lysine, dityrosine, 8-OH-deoxyguanosine in urine samples. Assessment of hexanoil-lysine exhibited a trend to increase in comparing total GHD vs partial and controls, although not significant. Values of 8-OH-deoxyguanosine did not significantly differ among the three groups. Significant lower levels of dityrosine in partial GHD vs total and controls were found. No significant difference in nitrotriptophan serum levels was found, while significantly greater values of Total Antioxidant Capacity were showed in total and partial GHD vs controls. Thus, our result confirm that oxidative stress is increased both in partial and total adult GHD. The lack of compensation by antioxidants in total GHD may be connected to the complications associated to this rare disorder.

Erythroleukaemia, diabetes insipidus and hypophyseal damage: Two case reports.

We report on two cases of patients who developed diabetes insipidus (DI) before acute erythroleukaemia (EL). A brain MRI showed an empty sella turcica in one case and hypothalamo-hypophyseal peduncle damage in the second case. Reduced levels of TGF-beta1 and Vitamin D3, with associated EVI-1 over-expression and karyotypic abnormalities were documented. These two cases show specific chromosomal/molecular alterations in EL with DI. The hypothesis of pituitary involvement in erythroleukemogenesis is discussed.

Primary empty sella: a histologic and immunocytologic study.

A primary "empty" sella turcica was found incidentally at autopsy, and the anterior lobe of the pituitary gland was studied with the immunoperoxidase technique. All five adenohypophysial cell types, ie, somatotrophs, lactotrophs, corticotrophs, thyrotrophs, and gonadotrophs (containing follicle-stimulating hormone [FSH] and luteinizing hormone [LH], were present in adequate numbers and were well granulated, indicating normal hormone storage.

Ghrelin main action on the regulation of growth hormone release is exerted at hypothalamic level.

Ghrelin, a recently isolated hormone, seems to participate in the physiological regulation of GH secretion. Exogenously administered ghrelin stimulates GH discharge in all species so far tested including man, but whether this action is exerted at pituitary or alternatively at hypothalamic level is not known at present. To understand the point of ghrelin action a group of patients with organic lesion mainly in the hypothalamic area and matched controls were studied. Patients showed a severe GH deficiency after hypothalamic stimulation (ITT), but partial response after GHRH administration. Cases and controls were tested on three separate days by either ghrelin; GHRH; and ghrelin plus GHRH; always at 1 micro g/Kg iv. The mean GH peak after stimulation in the patients were: 0.4 +/- 0.1 micro g/L by ITT; 3.1 +/- 0.5 micro g/L after GHRH; 2.0 +/- 0.8 micro g/L after ghrelin; and 9.6 +/- 2.9 micro g/L after the combination of GHRH plus ghrelin. In the controls GHRH induced a GH peak of 21.2 +/- 7.5 micro g/L, and 75.1 +/- 16.0 micro g/L after ghrelin with a peak after GHRH + ghrelin of 103.5 +/- 26.4 micro g/L. These data indicate that when hypothalamic structures are not operative ghrelin, either alone or in combination with GHRH, is not able to significantly release GH. In addition to postulating a hypothalamic point of action for the ghrelin-induced GH secretion, these results suggests that ghrelin will not have significant clinical utility in patients with GH deficiency due to organic lesion.

Endocrinology of pseudotumor cerebri.

This article will review the endocrine function of obese young women with pseudotumor cerebri and primary empty sella syndrome. The literature can be difficult to interpret. Much of it predates the era of CT scanning. Often, cases of primary and secondary empty sella syndrome are comingled. The author reviews specific endocrinologic disorders that have sometimes been associated with increased intracranial pressure excluding pituitary adenomas.

ACTH deficiency and TSH hypersecretion in a patient with empty sella turcica.

In a 49-year-old woman with empty sella syndrome, corticotropin (ACTH) deficiency and various abnormalities, including increased thyrotropin (TSH) secretion, growth hormone (GH) deficiency, and inappropriately high insulin with early phase hypoglycemia, during an oral glucose tolerance test were found. Existence of serum antipituitary antibody suggested that the empty sella and ACTH deficiency may be caused by an autoimmune destruction of the pituitary gland. All of the accompanying abnormalities except for increased TSH secretion were corrected with glucocorticoid supplement. Thyroidal responses to an increase and decrease of endogenous TSH were qualitatively normal, indicating that the patient's TSH was biologically active and the set point of hypothalamic-pituitary feedback regulation for TSH secretion was shifted.

A case of glomerular lipidosis accompanied by familial combined hyperlipidemia and panhypopituitarism.

This is a report of a case of glomerular lipidosis with familial combined hyperlipidemia and panhypopituitarism. A 60-yr-old woman was admitted for evaluation of hyponatremia. Administration of hydrocortisone normalized the level of serum Na. A pituitary hormone-stimulating test and brain computed tomography revealed panhypopituitarism with an empty sella. Glucocorticoid deficiency due to secondary hypoaldosteronism was thought to have caused the Na loss. She had been treated for thyroid dysfunction and hyperlipidemia with replacement of thyroid hormone and a lipid-lowering drug. Hyperlipidemia changed from type V into IIa in 4 yr. Furthermore, one of her brothers and one of her sons were suspected to have type IV hyperlipidemia. Familial combined hyperlipidemia accompanied by secondary hypothyroidism was thought to have increased the levels of both total cholesterol and triglyceride. Two renal biopsies in 3 yr showed lipid deposits in the mesangial cells and indicated a positive correlation between the levels of serum lipids and lipid deposits in glomeruli, which suggested an important role of abnormal lipid metabolism in the progression of glomerular lipidosis.

[Primary empty sella turcica: clinical aspects and hormonal study of 15 cases]. / Silla turca vacía primaria: aspectos clínicos y estudio hormonal de 15 casos.

The goal pursued has been to analyze clinical observations and hormonal studies of patients with empty sella turcica (EST), in order to review this disorder and determine if it can be considered a real syndrome. Fifteen patients with EST (3 men and 12 women) and mean age of 45.6 +/- 17.9 years have been prospectively studied. In the hypothalamus-hypophysis study, reserves of thyrotropin (TSH), prolactin (PRL), gonadotropins (FSH and LH), growth hormone (GH), adrenocorticotropin (ACTH) and cortisol were assessed. In addition, thyroid hormones and, for men, testosterone, were determined. The pathogenic mechanism was explained in two cases (13.3%). We registered headache in 10 patients, obesity in 8, arterial hypertension in 2 and diabetes mellitus in 2. Multiparity antecedent was found in 2 cases. The hormonal study was abnormal in two cases (40%). Most common abnormalities were hyperprolactinemia (3 cases), deficit of gonadotropins (3 cases), without coexisting both of them in any case, and deficit of GH (2 cases). EST is frequently associated with endocrine disfunction, although clinical implications are rare. The absence of common clinical manifestations in most cases questions the EST as a real syndrome.

[A diabetic patient with empty sella syndrome accompanied by stimulated guanidinoacetic acid metabolism].

Since urinary guanidinoacetic acid (GAA) derives from the kidneys, its detection is suggested to be associated with renal disease. We have been making a practice of investigating renal GAA production in diabetic patients, using a citrulline/creatine loading test. We noted a marked increase in urinary GAA excretion in 1 patient. Since GAA-synthesis is hormonally regulated, we made a through investigation of endocrine function in this patient. She was a 58-year-old woman with a 15-year history of diabetes mellitus, proliferative diabetic retinopathy, and negative microalbuminuria. There was a high plasma GH level and urinary 17-KS analysis revealed an increase in the adrenal androgen-derived fractions. Based on the X-ray finding of ballooning of the sella turcica and the MRI data, empty sella syndrome was diagnosed. It was suggested that stimulated anabolic hormone release had accelerated renal nitrogen metabolism and induced aggravation of her retinopathy. The findings in this patient implied the involvement of hormones in the development of diabetic complications.

Blood-cerebrospinal fluid barrier for prolactin in empty sella syndrome.

In six patients with "empty sella" syndrome (ESS), three primary (pESS) and three secndary (sESS), the ratio of serum to cerebrospinal fluid (CSF) concentrations of prolactin (PRL) was 6.6 +/- 0.7 (mean +/- SEM) (range 5.5--9.6), with a significant correlation between serum and CSF levels of PRL (r = 0.93 p less than 0.01). A control group of ten normal subjects showed similar values. The hyperprolactinemia found in two cases of pESS did not change the serum/ CSF ratio of PRL. The acute release of PRL into the serum following TRH i.v. did not increase the PRL level in CSF either in control subjects or ESS, with one exception. In a case of sESS consecutive to the treatment with bromocriptine (for 6 months) of an invasive prolactinoma, TRH i. v. released PRL into the CSF but not into the blood, and the serum/ CSF ratio of PRL was very low, until a new cure with bromocriptine (for 3 months) mormalised it. It is suggested that the blood-CSF barrier for PRL is similar in ESS and in normal subjects, with the exception of sESS following incomplete remission of some invasive prolactinomas, in which the high permeability of BCB may be explained both by hemodynamic changes in the pituitary portal vascular system and by a new source of PRL which release it directly into the CSF, bypassing the blood route.

Empty sella associated with inappropriate TSH secretion.

A child diagnosed with long-standing primary hypothyroidism at age 10 and subsequent pseudotumor cerebri after initiation of thyroid therapy developed an empty sella and inappropriate thyrotropin secretion. No other evidence of thyroid hormone resistance was evident nor was there evidence of other endocrine dysfunction. This case confirms previous reports of a relationship between autoimmune thyroid disease, pseudotumor cerebri, empty sella and inappropriate anterior pituitary function.

[Primary empty sella turcica: clinical, radiological and hormonal evaluation]. / Silla turca vacía primaria: evaluación clínica, radiológica y hormonal.

A retrospective study of 33 patients diagnosed of primary empty sella turcica has been done. Main clinical feature was cephalea, which was present in 51.1% of cases. Diagnosis was done based in Neuroradiologic studies (CAT, Cisternography, Pneumocisternography, Nuclear Magnetic Resonance) finding sellar size being significantly smaller in cases studied after 1980. After Hypophyseal function study, 19 patients did not show any endocrinological disorders, in the other 14 (42.4%), hyperprolactinemia was the most frequent finding (7 patients, 23.3%). 17.8% of cases showed a lowered response of Growth Hormone to insulinic Hypoglycemia. In two cases Panhypopituitarism was found and in case Insipidus diabetes was diagnosed.

Coexistence of primary empty sella and silent corticotrophic adenoma.

Primary empty sellae are rarely associated with an intact pituitary adenoma. Most of such cases are documented clinically and radiographically. This paper reports a case of coexistence of primary empty sella and a silent corticotrophic adenoma in a 61-year-old woman. The en bloc preparation of the sella turcica demonstrates the anatomical relationship of the empty sella and the flattened pituitary gland and the adenoma. The immunostain shows the presence of all five cell types of the adenohypophysis.