Gonadotrofinomas: análisis multicéntrico y retrospectivo de 66 pacientes / Gonadotrophinomas: multicenter and retrospective analysis of 66 patients

Objetivo: Analizar la presentación clínica, radiológica, bioquímica y el comportamiento posquirúrgico de una cohorte de pacientes portadores de gonadotrofinomas. Pacientes y Métodos: Se evaluaron pacientes con gonadotrofinomas estudiados en nueve centros endocrinológicos de la ciudad de Bs.As. durante el período 1983 a 2003. El criterio de inclusión fue la inmunohistoquímica (IH) positiva para hormona luteinizante (LH), folículoestimulante (FSH) y/o alfa subunidad (ASU). Los adenomas plurihormonales fueron excluidos. Resultados: Fueron analizados 66 pacientes de 51,8 ± 12,1 (X +/- DS) años (39 varones). Los síntomas mas frecuentemente observados fueron las alteraciones visuales (72,8%), seguidas por el hipogonadismo y las cefaleas. El 10,6% se diagnosticaron en forma incidental. El 98,5% fueron macroadenomas, 56,9% de los cuales correspondieron a un estadio Hardy (EH) 3 y 29,6% a un EH 4. El tiempo de seguimiento fue de 47,8 meses (r: 5-168). El hipogonadismo definido bioquímicamente se presentó en el 82,4% de los pacientes. En su mayoría presentaban niveles bajos o inapropiadamente normales de gonadotrofinas, pero 4 mujeres y 3 varones presentaron niveles séricos elevados y disociados de FSH y LH. La hiperprolactinemia por desconexión fue observada en 45,2% de la población (X: 65.6 ng/ml r: 30-172). El hipopituitarismo se detectó en 25,7% de los casos. La cirugía fue transeptoesfenoidal (TSE) en 80%; una segunda operación fue realizada en el 28% de la población. La IH fue positiva por orden de frecuencia para LH, FSH y ASU o las 3 combinaciones. La evolución posquirúrgica evidenció mejoría en el campo visual (CV) en el 41%. La presencia de restos tumorales y/o recidiva fue del 84%. Se indicó radioterapia en 37% y la sustitución hormonal fue necesaria en el 65% de los pacientes.

The aim of our study was to describe the clinical-biochemical and radiologic presentation and the post surgery outcome in a cohort of patients with gonadotrophinomas. Patients were selected from nine Endocrinology Units of the city of Buenos Aires from 1983 at 2003. The inclusion criteria was defined by nonfunctinoning pituitary adenomas with positive innmunohistochemical (IH) for luteinizing hormone (LH), follicle-stimulating hormone (FSH) and/or alpha subunit (ASU). Innmunohistochemically plurihormonal adenomas were excluded. Sixty six patients were analyzed, aged 51,8 ± 12,1 (X +/- DS) years; (39 men). More prevalent symptoms were visual alterations (72,8%), hypogonadism and headaches. Eleven percent was diagnosed as incidentalomas. Ninety eight percent were macroadenomas, 56,9% was Hardy stage (HS) 3 and 29,6% was HS 4. The patients were followed up for 47,8 months (r: 5-168). Hypogonadism was biochemically found in 82,4%. The majority showed low or inappropriately normal levels of gonadotrophins except for 4 women and 3 men that had high and dissociated levels. Hyperprolactinemia was observed in 45,2% and was interpreted as an interference with normal dopamine inhibition of prolactin secretion (X+/-DS: 65.6+/- ng/ml, r: 30-172). Hypopituitarism was found in 25,7% of the patients. Transsphenoidal surgery was carried out in 80% and in 28% a second surgery was needed. The IH was positive for LH, FSH and ASU in this order of frequency or its combinations. Tumor persistency and/or recurrency were found in 84% of the patients. Forty one percent showed improvement of visual defects. Radiotherapy was indicated in 37% and hormonal replacement was needed in 65% of the patients.

Expression of adrenocorticotropic hormone, prolactin and transcriptional factors in clinically nonfunctioning pituitary adenoma.

We describe here a case of a clinically nonfunctioning pituitary adenoma, but with expression of ACTH and PRL. A 42-year-old woman was referred to our department for further evaluation of pituitary tumor. She had no acromegaloid features, and no typical Cushingoid features. She had no galactorrhea, and had regular menses. GH, IGF-I, LH, FSH, TSH, ACTH and cortisol levels in blood were all within the normal ranges, while PRL levels were mildly elevated. Both ACTH and cortisol levels were adequately increased in response to CRH, and both were suppressed by a small dose of dexamethasone. Plasma ACTH and cortisol levels were decreased at night, suggesting the circadian rhythms for plasma ACTH levels were undisturbed. Based on these findings we did not clinically suspect ACTH-producing tumor, however immunohistochemistry revealed ACTH immunoreactivity in the pituitary adenoma. Therefore, the tumor was considered a silent corticotroph adenoma. PRL was co-expressed in a significant subpopulation of ACTH-immunoreactive tumor cells. Ptx1, Neuro D1, and T pit were densely expressed and Pit-1 was sparsely expressed in the nuclei of adenoma cells. It is therefore possible that a tumor originating in an immature or uncommited adenohypophysial stem cell may later differentiate into different cell types due to a combination of certain specific transcriptional factors.

Histopathological analyses of silent pituitary somatotroph adenomas using immunohistochemistry, in situ hybridization and confocal laser scanning microscopic observation.

To characterize the morphological and functional aspects of silent somatotroph adenomas with paradoxical responses of GH in TRH or GnRH provocation tests, which are considered to be a useful strategy for endocrinological identification of silent somatotroph adenomas, we examined three silent somatotroph adenomas histopathologically. The adenomas were investigated by immunohistochemistry, including the highly sensitive catalyzed signal amplification system, the non-radioisotopic in situ hybridization method, and confocal laser scanning microscopy. GH production and GH-immunopositive secretory granules in the adenoma cells were demonstrated histopathologically, and the adenomas were interpreted as being densely granulated somatotroph adenomas. Endocrinological identification of silent somatotroph adenomas in combination with paradoxical responses of GH in TRH or GnRH provocation tests may elucidate the increasing number of silent somatotroph adenomas that have been regarded as mammotroph or clinically inactive adenomas. One should be aware of the differences between the previously reported silent somatotroph adenomas, most of which are sparsely granulated somatotroph adenomas, a somatotroph adenomas with paradoxical and the silent somatotroph adenomas, most of which are sparsely granulated somatotroph adenomas, and the silent somatotroph adenomas with paradoxical responses of GH in TRH or GnRH provocation tests, which are densely granulated somatotroph adenomas.

Caracterización hormonal de los adenomas hipofisarios no funcionantes / Hormonal characterization of the non fuctioning pituitary adenomas

Se estudiaron 98 pacientes con adenomas no funcionantes, 34 hombres y 64 mujeres, realizando un estudio hormonal en suero para conocer su perfil endocrino. Con tal objeto, se efectuaron determinaciones de hormona folículo estimulante y hormona luteinizante (FSH, LH), prolactina (PRL), estadiol (E2), testosterona (T), cortisol, hormona del crecimiento (GH), hormona adrenocorticotrópica (ACTH), hormona estimulante del tiroides (TSH) y gastrina (Ga) por radioinmunoanálisis. Los resultados mostraron marcado hipergonadotropismo en el 47//de los pacientes, con niveles séricos de FSH y LH muy elevados y un incremento inesperado de la concentración de Ga (Grupo I). En contraste, el resto de los pacientes tuvo concentraciones normales o bajas de gonadotrofinas y Ga (Grupo II). El grupo I mostró una relación inversa entre los niveles de gonadotropinas y esteroides gonadales (E2 o T) con cifras significativamente menores que los valores normales y los encontrados en el Grupo II (<0,00l) en el cual la relación fue lineal positiva. Tambien se observó una relación directa entre la concentración de FSH conTSH (r=0,75) y Ga (r=0,80), probablemente por los neurotransmisores que determinan la secreción de estas hormonas. La TSH al igual que las hormonas tiroideas, tuvo cifras más elevadas en el Grupo I, mientras que los valores de PRL fueron más bajos (P<0,0001). La concentración de GH y ACTH fuer normal en ambos,no obstante,el 33 por ciento de los pacientes del Grupo II presentó hipocortisolismo e hipotiroidismo. La edad promedio de los pacientes analizada por décadas, no fue estadísticmente diferente entre los grupos y no explica las diferencias encontradas, aunque en el Grupo I predominaron las mujeres. En éstas, la elevación de FSH podría estar condicionada por la deficiencia gonadal, acorde a la edad de las pacientes (49,8 Ð 9,6 años), sin embargo, algunos valores fueron extraordinariamente elevados y existe la posibilidad de que la hipófisis en condiciones patológicas, como es la forma adenomatosa,pueda producir en forma autónoma,moléculas de LH y FSH alteradas y carentes de actividad biológica, o bien, subunidad Ó libre, como se ha demostrado en algunos gonadotropomas. Por otra parte, algunos de los casos con TSH elevada podrían considerarse verdaderos TS-Homas, que no suprimen su secreción a pesar de la elevada concentración de hormonas tiroideas. Así, podría decirse que dentro de los no funcionantes, están enmarcados algunos de estos adenomas. Se concluye que, desde el punto de vista hormonal, los adenomas del Grupo II son los verdaderos no funcionantes

Caracterización hormonal de los adenomas hipofisarios no funcionantes / Hormonal characterization of the non fuctioning pituitary adenomas

Se estudiaron 98 pacientes con adenomas no funcionantes, 34 hombres y 64 mujeres, realizando un estudio hormonal en suero para conocer su perfil endocrino. Con tal objeto, se efectuaron determinaciones de hormona folículo estimulante y hormona luteinizante (FSH, LH), prolactina (PRL), estadiol (E2), testosterona (T), cortisol, hormona del crecimiento (GH), hormona adrenocorticotrópica (ACTH), hormona estimulante del tiroides (TSH) y gastrina (Ga) por radioinmunoanálisis. Los resultados mostraron marcado hipergonadotropismo en el 47//de los pacientes, con niveles séricos de FSH y LH muy elevados y un incremento inesperado de la concentración de Ga (Grupo I). En contraste, el resto de los pacientes tuvo concentraciones normales o bajas de gonadotrofinas y Ga (Grupo II). El grupo I mostró una relación inversa entre los niveles de gonadotropinas y esteroides gonadales (E2 o T) con cifras significativamente menores que los valores normales y los encontrados en el Grupo II (<0,00l) en el cual la relación fue lineal positiva. Tambien se observó una relación directa entre la concentración de FSH conTSH (r=0,75) y Ga (r=0,80), probablemente por los neurotransmisores que determinan la secreción de estas hormonas. La TSH al igual que las hormonas tiroideas, tuvo cifras más elevadas en el Grupo I, mientras que los valores de PRL fueron más bajos (P<0,0001). La concentración de GH y ACTH fuer normal en ambos,no obstante,el 33 por ciento de los pacientes del Grupo II presentó hipocortisolismo e hipotiroidismo. La edad promedio de los pacientes analizada por décadas, no fue estadísticmente diferente entre los grupos y no explica las diferencias encontradas, aunque en el Grupo I predominaron las mujeres. En éstas, la elevación de FSH podría estar condicionada por la deficiencia gonadal, acorde a la edad de las pacientes (49,8 9,6 años), sin embargo, algunos valores fueron extraordinariamente elevados y existe la posibilidad de que la hipófisis en condiciones patológicas, como es la forma adenomatosa,pueda producir en forma autónoma,moléculas de LH y FSH alteradas y carentes de actividad biológica, o bien, subunidad O libre, como se ha demostrado en algunos gonadotropomas. Por otra parte, algunos de los casos con TSH elevada podrían considerarse verdaderos TS-Homas, que no suprimen su secreción a pesar de la elevada concentración de hormonas tiroideas. Así, podría decirse que dentro de los no funcionantes, están enmarcados algunos de estos adenomas. Se concluye que, desde el punto de vista hormonal, los adenomas del Grupo II son los verdaderos no funcionantes

Follicle stimulating hormone-secreting pituitary adenoma: inappropriate secretion and effect of pulsatile luteinizing hormone releasing hormone analogue (buserelin) administration.

A patient with an FSH secreting pituitary adenoma is reported. Elevated FSH and serum free alpha-subunit (SU) with low levels of LH and testosterone (T) were found. Immunostaining showed the presence of alpha-SU, FSH-beta and LH-beta subunits. LHRH analogue (buserelin) was administered in a pulsatile manner, by portable computerized infusion pump sc for ten days. During the first 24 h of treatment FSH, LH (p less than 0.001) and T (p less than 0.01) rose significantly. Ten days later, the expected desensitization phenomenon did not occur, but further increases of T (8.4 +/- 2.6, mean +/- SD, vs 17.4 +/- 4.1 nmol/l, p less than 0.001) and FSH (58.9 +/- 9.6 vs 70.7 +/- 3.8 mlU/ml, p less than 0.001) were registered. LH decreased (12.5 +/- 2.4 vs 7.1 +/- 0.6 mlU/ml, p less than 0.001) at day 10, but remained higher than basal level (5.0 +/- 0.6, p less than 0.001). Free alpha-SU also rose (2.8 +/- 0.4 vs 4.4 +/- 1.7 mlU/ml, p less than 0.001) after ten days of treatment. The chronic stimulatory effect of analogue on LH with a lack of desensitization suggests tumorous secretion despite a partially preserved negative feedback of testosterone. Low basal LH levels, in some patients with FSH secreting tumors may not be due to tumor mass effect, but rather may be the consequence of altered LH production and/or secretion by the tumor. Although buserelin may not have a therapeutic effect, it is of use in differential diagnosis of hypergonadotropinemia.

[Glycoprotein hormone alpha subunit as a marker of pituitary adenoma]. / Podjednostka alfa hormonów glikoproteinowych jako znacznik gruczolaków przysadki.

Blood serum FSH, LH, prolactin and testosterone as well as urinary excretion of 17KS and 17-OHCS were determined in 8 patients with chromophobe pituitary adenomas treated by transphenoidal microsurgical removal or craniotomy with or without subsequent telecobalt therapy. It was found te disease tends to recur in the majority of patients despite the type of therapy. Recurrence is accompanied by gonadotropins hyposecretion, increase in prolactin secretion, secretory disorders in the gonads and adrenals; an increase in prolactin secretion is proportional to the intensity of the compression symptoms. Bromocriptine in a daily doses ranging from 5.0 to 7.5 mg decreases prolactin levels in the recurrent chromophobe pituitary adenomas and does not affect their proliferation.

Hyperthyroidism and high serum levels of TSH associated with pituitary tumour.

We report a 28-year-old male with persistent clinical and laboratory findings of hyperthyroidism associated with marked elevated serum levels of TSH and no response to TRH despite hemithyroidectomy and subsequent antithyroid drug therapy two years previous to admission to our hospital. Subsequent skull X-rays, CT scans and angiographic findings demonstrated the presence of a pituitary tumour. After operation and radiation therapy T3, T4 and TSH levels returned to normal values. Seven years later the patient is still euthyroid. We conclude that hyperthyroidism in our patient was due to excessive secretion of TSH by the pituitary tumour.

The effect of dopamine agonist therapy on large functionless pituitary tumours.

Fifteen patients (12 male) with large pituitary tumours and serum prolactin levels below 1000 mU/l were given dopamine agonist therapy (bromocriptine, mesulergine or pergolide) for a mean of 9 months (range 3-36 months). Serum prolactin became undetectable in all. Despite this, significant suprasellar extensions and any associated neurological defect remained in 14 patients, who therefore were referred for surgery. In one patient there was evidence of spontaneous pituitary infarction unrelated to dopamine agonist therapy. At operation 12 patients had apparently functionless pituitary adenomas which failed to immunostain for prolactin, one had an epidermoid cyst and one a Rathke's pouch cyst. We conclude that patients with large pituitary tumours and only a mildly elevated serum prolactin are unlikely to have prolactinomas, and that such tumours are not likely to show significant tumour shrinkage with medical treatment with dopamine agonists.

Discordant serum alpha-subunit and FSH concentrations in a woman with a pituitary tumour.

We have studied a women who presented at the age of 51 with a large FSH and alpha-subunit producing pituitary adenoma. Following insertion of ventriculo-peritoneal shunts and external pituitary irradiation there was no change in the elevated serum concentrations of FSH, and alpha-subunit over a four year period although she developed both ACTH and TSH deficiency. Various drugs, however, did alter the FSH and alpha-subunit concentrations and these changes suggest possible mechanisms controlling FSH secretion. Ethinyloestradiol 0.03 mg daily for three weeks suppressed serum FSH to 77% of the basal level (240 +/- 35 i.u./l to 184 +/- 20 i.u./l) but alpha-subunit rose to 130% of basal level (281 +/- 50 ng/ml to 366 +/- 40 ng/ml). On ethinyloestradiol 0.1 mg daily, FSH suppressed to 17% of basal (40 +/- 11 i.u./l) with no change in alpha-subunit concentration, while on 0.2 mg daily suppression of FSH was similar but alpha-subunit fell to 59% of basal (190 +/- 28 ng/ml). Dexamethasone, 3 mg daily for one week reduced FSH to 53% of the initial concentration and alpha-subunit to 74% while bromocriptine 7.5 mg daily for three months, reduced FSH to 39% and alpha-subunit to 66% of basal. Neither thyroxine, 0.2 mg daily for four weeks, nor an LHRH analogue, (Buserelin, Hoechst) 200 micrograms, three times daily for three months elicited any effect. Chromatography on Sephadex G100 showed that serum FSH and alpha-subunit both had Kav values somewhat lower than those of their standard counterparts (FSH, 0.20 vs 0.25; alpha-subunit 0.35 vs 0.45).(ABSTRACT TRUNCATED AT 250 WORDS)

Gonadotrophin and alpha subunit secretion by human 'functionless' pituitary adenomas in cell culture: long term effects of luteinizing hormone releasing hormone and thyrotrophin releasing hormone.

The long-term effects of LHRH and TRH on gonadotrophin alpha subunit, FSH and LH secretion by cell cultures of four human chromophobic pituitary tumours have been examined. The tumours derived from one male and three female patients who presented because of visual disturbance but had no evident endocrine symptoms. Subsequent serum hormone analysis showed the FSH to be high in the male but low or normal in the post-menopausal females whereas LH levels were low in all patients. In culture, basal hormone secretion could be maintained for periods up to 63 d. All tumours secreted alpha subunit and FSH, but much lower amounts of LH. Addition of LHRH or TRH for a period of 12 to 41 d showed that alpha subunit, FSH and LH secretion were stimulated by LHRH from one tumour, by LHRH and TRH from two tumours. There was always a rapid decline in the LH secretion. The tumour which secreted FSH predominantly was stimulated by TRH. We conclude that human pituitary 'functionless' adenomas can secrete gonadotrophin alpha subunit and FSH in vitro and that secretion can be stimulated during long term releasing hormone experiments. LH secretion, however, cannot be maintained.

Hypothyroidism secondary to biologically inactive thyroid-stimulating hormone secretion by a pituitary chromophobe adenoma: recovery after removal of the tumor.

A 50-year-old man, suffering from a large pituitary adenoma and panhypopituitarism, was found to have severely elevated thyrotrophin (thyroid-stimulating hormone [TSH]) levels (greater than 20.2 microunits/mL). The thyroxine (T4) level was low (less than 3.0 micrograms/dL). Thyroid sodium iodide I 131 uptake was low (5% at 24 hours). A TSH test result was normal, with a 24-hour 131I uptake of 52% and a normal-looking thyroid gland on scintiscan. After surgical removal of the pituitary chromphobe adenoma, T4 levels returned to normal (6.8 micrograms/dL) and TSH levels improved substantially (9.0 microunits/mL). Findings from repeated 131I uptake tests were normal (22% at 24 hours). Other pituitary functions improved also. These results suggest that the patient had biologically inactive TSH produced by the tumor. Removal of the tumor probably enabled recovery of the active TSH with the return of normal thyroid uptake and T4 production. Whenever hypothyroidism and high levels of TSH coexist with pituitary dysfunction, a TSH test is needed to distinguish between primary hypothyroidism and hypothyroidism secondary to biologic inactive TSH.

Sparsely granulated prolactin cell adenomas of the pituitary gland. Correlation of ultrastructure with plasma hormone level.

The possible relationship between the preoperative plasma prolactin levels of patients having a sparsely granulated prolactin cell adenoma of the pituitary gland and the morphology of the tumors was studied by means of quantitative electron microscopy. To this end, a number of ultrastructural variables were chosen which are generally regarded to be indicative of cellular activity and which could be determined in a quantitative or semiquantitative way. These variables were determined in 19 adenomas from 17 patients and plotted against the corresponding prolactin levels. It appeared that marked endocrine activity was associated with a small number of granules per cell, a high frequency of exocytosis, and a marked development of the rough endoplasmic reticulum. Granule size and development of Golgi apparatus and lysosomes were not at all, or only poorly correlated with the plasma hormone levels. Finally, the number of mitochondria per cell showed a totally unexpected inverse correlation with endocrine activity. Due to the close mutual correlation existing between several of the variables investigated, combining them in a multivariate analysis did not significantly improve the correlation with the hormone level.

[Prolactin producing adenomas of the pituitary gland with primary localization in the sinus sphenoidalis (author's transl)]. / Prolaktinproduzierende Hypophysenadenome (Prolaktinome) mit Keilbeinhöhlenmanifestation.

The radio-immuno-assay of the pituitary hormone prolactin represents the basis for a functional differentiation of the so-called chromophobic adenomas. Two thirds of these tumors produce this hormone. For a long period of growth these adenomas are localized in the middle of the sella turcica. Their first direction of growth is towards the sinus sphenoidalis. At the ENT-clinic of the Cologne University two prolactin producing adenomas have been detected as the cause of suspected changes of the sinus sphenoidalis. The need for an endocrinological diagnosis in cases of unknown processes of the sinus sphenoidalis, the indication for surgery, and the medicamental treatment of these tumors with 2-Br-alpha-Ergocriptine (Parlodel) is discussed.

Growth of a prolactinoma during pregnancy. Case report and review.

A patient with hyperprolactinaemia and anovulation is described. Ovulation was induced with bromocriptine and the ensuing pregnancy caused rapid deterioration of vision and neurosurgical intervention. The management of hyperprolactinaemic infertility and the complications occurring during pregnancy in these patients are discussed.

Calcitonin serum levels in different pituitary diseases. A preliminary report.

The calcitonin (CT) concentration has been determined in the serum of 17 patients with different pituitary diseases. More or less elevated levels were found in 7 of them. No definite correlation has been observed between the immunoreactive CT and the different pituitary hormones.