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.

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.

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.

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.

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.

Impairment of GH secretion in adults with primary empty sella.

Primary empty sella (PES) is generally not associated with overt endocrine abnormalities, although mild hyperprolactinemia and, in children, deficient GH secretion have been reported. The aim of this multi-center collaborative study was to evaluate basal and stimulated GH secretion in a large series of adult PES patients. The study group consisted of 51 patients [41 women and 10 men, age range: 20-78 yr; (mean+/-SD) 47+/-11 yr]; results were compared with those in normal subjects (Ns) (Ns: no.=110, 55 women, age: 20-50 yr, 37+/-14 yr), and in hypopituitaric patients (HYP) with GH deficiency (HYP: no.=44,17 women, age: 20-72, 49+/-16 yr). Baseline IGF-I levels and GH responses to insulin-induced hypoglycemia (insulin tolerance test, ITT) and/or GHRH+arginine (ARG) stimulation tests were evaluated. PES patients were also subdivided according to BMI in lean (BMI <28 kg/M2 no.=22) or obese (BMI >28 kg/m2 no.=29). PES patients had serum total IGF-I concentrations (mean+/-SE: 142.2+/-9.6 ng/ml) higher than HYP patients (77.4+/-6.4 ng/ml, p<0.001), but lower than Ns (213.3+/-17.2 ng/ml, p<0.005), with no differences between lean and obese PES subjects. The increase in serum GH concentrations following ITT and/or GHRH+ARG stimulation tests, although higher than that observed in HYP patients, was markedly reduced with respect to Ns. No difference was observed in the GH response to provocative tests between lean and obese PES patients. When individual GH responses to ITT or GHRH+ARG were taken into account, a large proportion of PES patients (52% after ITT, 61% after GHRH+ARG) showed a GH peak increase below the 1st centile of normal limits. Serum IGF-I levels in PES patients with blunted GH responses to provocative tests were significantly (p<0.001) lower in PES patients with normal GH responses, and a positive correlation was observed between IGF-I levels and serum GH peak concentrations after GHRH+ARG. In conclusion, the results of the present study provide evidence that adult PES patients often have an impairment of GH secretion, as indicated by the blunted GH response to ITT and GHRH+ARG provocative tests, and by the reduction in serum IGF-I levels. These changes are independent of body mass.

Use of novel bone biopsy system to study molecular effects of growth hormone in human bone--a pilot study.

In this study, we have examined whether a novel bone biopsy system combined with reverse transcription-polymerase chain reaction (RT-PCR) or differential display PCR (ddPCR) can be used to detect specific mRNAs induced by growth hormone (GH) in human bone. In a 58-year-old man with complete GH deficiency as a result of empty sella, bone biopsies were taken before, and 5 and 24 h after administration of 24 recombinant human GH. Insulin-like growth factor binding protein-3 (IGFBP-3) mRNA levels in this patient, measured in a semiquantitative RT-PCR assay, increased about 40% 24 h after GH administration. This increase was not seen in a healthy control who did not receive GH, suggesting that the increase was an effect of GH rather than of the biopsy itself. Several differentially expressed mRNAs were detected by ddPCR. Thus, this pilot study suggests that our novel bone biopsy system may be suitable for in vivo studies of the molecular effects of substances with essential functions in human bone.

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.

Hipofisitis linfocitica: Revisión bibliográfica / Lymphocytic hypophysistis: A review of the literature

Se realizó una actualización temática sobre la hipofisitis linfocítica, entidad infrecuente que afecta, principalmente, a mujeres embarazadas o en el período posparto. Se considera un desorden caracterizado por inflamación crónica y destrucción de la hipófisis, que puede causar una muerte súbita por la hipocortisolemia secundaria a la afectación del eje hipotálamo-hipófiso-adrenal. En el cuadro clínico inicial, la cefalea y los trastornos visuales, con silla turca agrandada, pueden conducir al diangóstico erróneo de adenoma hipofisario no funcionante, por lo cual es importante el diagnóstico diferencial, para no someter a las enfermas a una intervención quirúrgica innecesaria. La función endocrina puede variar desde la normalidad hasta el panhipopituitarismo, mientras que en su patogenia, no completamente definida, se sugiere la causa autoinmune. Se señala la posibilidad de ocurrencia subclínica, así como una atrayente hipótesis para explicar la presencia de silla turca vacía en mujeres multíparas. Se concluye que no siempre es necesaria la intervención quirúrgica y que se deben estudiar las pacientes mediante exámenes de campos visuales y tomografía computarizada cada 4 ó 6 meses, con evaluación de la función adenohipofisaria entre 6 y 12 meses después de las primeras manifestaciones (AU)

Hipofisitis linfocitica: Revision bibliografica / Lymphocytic hypophysistis: A review of the literature

Se realizo una actualizacion tematica sobre la hipofisitis linfocitica, entidad infrecuente que afecta, principalmente, a mujeres embarazadas o en el periodo posparto. Se considera un desorden caracterizado por inflamacion cronica y destruccion de la hipofisis, que puede causar una muerte subita por la hipocortisolemia secundaria a la afectacion del eje hipotalamo-hipofiso-adrenal. En el cuadro clinico inicial, la cefalea y los trastornos visuales, con silla turca agrandada, pueden conducir al diangostico erroneo de adenoma hipofisario no funcionante, por lo cual es importante el diagnostico diferencial, para no someter a las enfermas a una intervencion quirurgica innecesaria. La funcion endocrina puede variar desde la normalidad hasta el panhipopituitarismo, mientras que en su patogenia, no completamente definida, se sugiere la causa autoinmune. Se senala la posibilidad de ocurrencia subclinica, asi como una atrayente hipotesis para explicar la presencia de silla turca vacia en mujeres multiparas. Se concluye que no siempre es necesaria la intervencion quirurgica y que se deben estudiar las pacientes mediante examenes de campos visuales y tomografia computarizada cada 4 o 6 meses, con evaluacion de la funcion adenohipofisaria entre 6 y 12 meses despues de las primeras manifestaciones

Association of arginine vasopressin-secreting cell, steroid-secreting cell, adrenal and islet cell antibodies in a patient presenting with central diabetes insipidus, empty sella, subclinical adrenocortical failure and impaired glucose tolerance.

A 36-year-old woman with central diabetes insipidus (DI), diagnosed when she was 7, was referred to our Endocrine Unit in January 1993 for further hormonal investigations. Clinical and laboratory findings confirmed the diagnosis of central DI. Cranial computed tomography and magnetic resonance imaging showed only an empty sella. Moreover, we noted impaired glucose tolerance and unusual findings of subclinical adrenocortical failure, i.e. high plasma renin activity with normal aldosterone levels, high ACTH despite normal basal and ACTH-stimulated cortisol levels. Immunological study of the patient's serum showed the presence of arginine vasopressin (AVP)-secreting cell antibodies (Abs), steroid-producing cell Abs, adrenal and islet cell Abs. The following aspects of our case are stressed and discussed: (1) the presence of AVP-secreting cell Abs 29 years after the diagnosis of DI; (2) the association between DI, empty sella and subclinical autoimmune adrenocortical failure with unusual hormonal findings, and (3) impaired glucose tolerance with islet cell antibody positivity.

[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.

[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.

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.

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.