[Hypoplasia adrenal congenita of anencephalic type: two cases with pituitary abnormalities and review of literature]. / L'hypoplasie surrénale congénitale de type anencéphalique: deux cas avec anomalies hypophysaires, sans mutation de DAX-1 et SF-1 et revue de la littérature.

Hypoplasia adrenal congenita is an extremely uncommon disease of early onset. This condition can be lethal in the absence of treatment. Some forms are due to the congenital adrenal hypoplasia of anencephalic type whose origin is even unknown. Here, we present two cases of congenital adrenal hypoplasia of anencephalic type with pituitary abnormalities. The two male newborns died because adrenal insufficiency in the neonatal period. The adrenal glands were hypoplastic with a histological structure of anencephalic type Immunocytochemical study of the pituitary revealed an absence of the gonadotrophs. No mutation of DAX 1 and SF-1 was found.

A standardised diagnostic approach to pituitary neuroendocrine tumours (PitNETs): a European Pituitary Pathology Group (EPPG) proposal.

The 2017 World Health Organization (WHO) classification proposes to type and subtype primary adenohypophyseal tumours according to their cell lineages with the aim to establish more uniform tumour groups. The definition of atypical adenoma was removed in favour of high-risk adenoma, and the assessment of proliferative activity and invasion was recommended to diagnose aggressive tumours. Recently, the International Pituitary Pathology Club proposed to replace adenoma with the term of pituitary neuroendocrine tumour (PitNET) to better reflect the similarities between adenohypophyseal and neuroendocrine tumours of other organs. The European Pituitary Pathology Group (EPPG) endorses this terminology and develops practical recommendations for standardised reports of PitNETs that are addressed to histo- and neuropathologists. This brief report presents the results of EPPG's consensus for the reporting of PitNETs and proposes a diagnostic algorithm.

B-RAF mutations are a rare event in pituitary adenomas.

Pituitary tumors are a relatively common neoplasia whose pathogenesis is still largely unknown. Recent studies have revealed frequent activating mutations of the gene for B-RAF, an effector of Ras protein in the mitogen-activated protein kinase pathway, in several malignancies, including melanoma, thyroid, colorectal and ovarian cancer. However, analyses of B-RAF mutations in pituitary tumors have not been reported so far. Therefore, in the present study we have investigated the presence of the B-RAF mutations, by polymerase chain reaction (PCR) amplification of the hot spot exons 11 and 15, followed by direct sequencing, in 50 human pituitary adenomas, including 25 NFPA and 25 secreting adenomas (10 GH, 5 PRL, 6 LH and/or FSH, 4 GH/PRL). We found only one V600E mutation in a NFPA sample, suggesting that B-RAF mutations are a rare event in pituitary tumorigenesis.

Familial pituitary adenomas with a heterogeneous functional pattern: clinical and genetic features.

Familial pituitary adenoma is a rare syndrome which may present either as isolated lesions, or in association with other endocrine tumors, for example in the frame of multiple endocrine neoplasia (MEN-1) or Carney complex (CNC). The most frequently described forms of familial isolated pituitary adenoma (FIPA) are familial somatotropinomas or prolactinomas. Recently, some cases of familial isolated somatotropinoma have been associated with germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. The present report shows heterogeneous FIPA with 3 subtypes of tumor in 3 individuals of the same family: somatotropinoma in the proband, giant prolactinoma in a brother, and gonadotroph cell macroadenoma in the father. A prospective survey also suggested the occurrence of a silent microadenoma in the proband's sister. Clinical screening was performed in the 3 affected members, the 4th suspected case, and 9 additional, asymptomatic relatives. They had no clinical evidence of associated endocrine lesion suggesting MEN-1 or CNC. Genetic screening for germline mutation of the MEN-1, the gene encoding the protein kinase A (PKA) type 1 alpha regulatory subunit (R1 alpha) (PRKAR1alpha) and AIP gene was negative in 2 affected members. In conclusion, these data suggest that familial pituitary adenomas can occur with a heterogeneous functional pattern that is distinguished from MEN-1 or CNC. The absence of mutation of the recently described AIP gene suggests the implication of other predisposing gene(s). Collaborative, multicentric studies are needed to further define the location of gene(s) involved in heterogeneous FIPA.

[Nelson's syndrome: course of aggressive pituitary corticotroph adenoma]. / Syndrome de Nelson: évolution d'un adénome hypophysaire corticotrope agressif.

Nelson's syndrome was defined in 1958 as the association of an expanding pituitary tumor with high ACTH secretion after bilateral adrenalectomy for Cushing's disease. Pituitary MRI and ACTH measurements led to the definition of Nelson's syndrome as the proliferation of a corticotrophic microadenoma or an aggressive and highly proliferative tumor residue induced by the decreased glucocorticoid inhibition after bilateral adrenalectomy. Now, the problem is not the definition of Nelson's syndrome but rather the identification of markers predictive of tumor growth. Based on a typical case and a review of the literature, we point out some predictive markers of tumor growth after bilateral adrenalectomy: young age at diagnosis, presence of tumor residue on pituitary MRI before adrenalectomy, markers of tumor aggressiveness (Ki-67>3%, mitoses, nuclear PTTG) and increase of ACTH levels during the first months following adrenalectomy.

From pituitary adenoma to pituitary neuroendocrine tumor (PitNET): an International Pituitary Pathology Club proposal.

The classification of neoplasms of adenohypophysial cells is misleading because of the simplistic distinction between adenoma and carcinoma, based solely on metastatic spread and the poor reproducibility and predictive value of the definition of atypical adenomas based on the detection of mitoses or expression of Ki-67 or p53. In addition, the current classification of neoplasms of the anterior pituitary does not accurately reflect the clinical spectrum of behavior. Invasion and regrowth of proliferative lesions and persistence of hormone hypersecretion cause significant morbidity and mortality. We propose a new terminology, pituitary neuroendocrine tumor (PitNET), which is consistent with that used for other neuroendocrine neoplasms and which recognizes the highly variable impact of these tumors on patients.

Spontaneous prolactin transplantable tumor in the Wistar/Furth rat (SMtTW): a new animal model of human prolactinoma.

Two spontaneous prolactinomas, removed from 28-mo-old female Wistar/Furth rats, were grafted by serial passages under the kidney capsule and the skin in 117 females of the same consanguineous strain. The hosts, aged between 2 and 10 mo, were free of estrogen treatment. These transplantable tumors, named SMtTW1 and SMtTW2, were studied until the fifth serial passage. The percentage of success was 100% under the kidney capsule and 20% under the skin. From the radioimmunoassays of prolactin (PRL), growth hormone, and adrenocorticotropic hormone and the immunocytochemical results, the tumors secrete PRL only. The PRL tumoral secretion was detected after 3 to 5 mo of graft; at 8 mo, mean plasma PRL values reached 5150 ng/ml (normal value, 15.2 ng/ml). Plasma growth hormone and adrenocorticotropic hormone values remained normal. Like the primary tumors, the grafted tumors were benign, grew slowly, and were sparsely granulated well-differentiated prolactinomas with exocytosis. They remained identical during the first serial passages. The secretion and the growth of SMtTW2 were inhibited by bromocriptine. In the light of our knowledge of the human prolactinoma, the spontaneous transplantable prolactinoma of the rat may be considered to be an animal model closer to the human pathology than the estrogen-induced "tumors" and the induced transplantable tumors. It is easier to use than the spontaneous prolactinoma of the rat.

Polysialylated-neural cell adhesion molecule expression in rat pituitary transplantable tumors (spontaneous mammotropic transplantable tumor in Wistar-Furth rats) is related to growth rate and malignancy.

Pituitary adenomas are usually benign neuroendocrine tumors. However, some of those that are histopathologically undistinguishable behave aggressively and metastasize. The polysialylated neural cell adhesion molecule (PSA-NCAM), which is highly expressed during the development of the brain and pituitary, is detected in some neuroendocrine tumors and might be relevant as a prognostic marker in pituitary tumors. In the present study, we have searched for PSA-NCAM expression in four lineages of rat pituitary transplantable tumors (SMtTW). Each lineage, maintained by serial tumor grafts under the kidney capsule and skin, differed in its GH/Prl secretion, growth rate, and malignant behavior. PSA-NCAM expression, detected by immunohistochemistry and Western blotting and quantified by ELISA, varied according to the SMtTW lineage. The benign tumors, SMtTW2, with a low growth rate never expressed PSA-NCAM. Another benign lineage, SMtTW3, with a high growth rate expressed a low amount of PSA-NCAM. The highest PSA-NCAM expression was seen in tumors that grew beneath the skin, invaded the kidney, and metastasized (SMtTW4). Tumors of the SMtTW10 lineage, which behaved as either benign or malignant tumors, were heterogeneous in terms of PSA-NCAM expression. In this rat transplantable pituitary tumor model, PSA-NCAM expression correlated in decreasing order with: (a) invasiveness (P < 0.0001), (b) metastases (P = 0.004), (c) ability to grow under the skin (P = 0.006), and (d) growth rate under the kidney capsule (P < 0.01), but not with hormone secretion (r = 0.207). This model, which is very similar to the human pathology, suggests that PSA-NCAM evaluation is of interest in the diagnosis of malignancy and the prognosis of human pituitary tumors. In addition, the SMtTW tumors could be instrumental in evaluating the effects of new therapeutic agents modulating PSA-NCAM expression.

Morphofunctional modifications associated with the inhibition by estradiol of MtTF4 rat pituitary tumor growth.

The MtTF4 pituitary tumor has been induced in Fischer rats by chronic estrogen administration. Recently, we reported that sustained pharmacological treatment of Fischer rats with 17 beta-estradiol inhibited the growth of the MtTF4 tumor transplanted s.c. The present work describes the associated morphofunctional changes occurring in the tumor during 17 beta-estradiol inhibition. It is shown that a 7-day 17 beta-estradiol treatment resulted in an increase of the surface area of cells, nuclei, nucleoli, Golgi complexes, and rough endoplasmic reticulum and an increase in the number of euchromatin-rich nuclei. Flow cytometry analysis of DNA distribution suggested that estradiol affects the cell progression through the early S phase. The ratio of RNA to DNA increased significantly, reflecting cell hypertrophy. Moreover, there was a significant increase in tumor prolactin concentration and a marked enhancement in the intensity of the immunocyto-chemical reaction with rat prolactin antiserum. On the other hand, cell mitoses were dramatically decreased. These morphofunctional changes indicate that the inhibition of the tumor growth by estradiol is accompanied by an evolution of the tumor cell population towards a more differentiated state. However, it cannot be decided whether 17 beta-estradiol induces a shift from a proliferative state to a differentiated state or whether 17 beta-estradiol treatment results in a selection of a subpopulation of tumor cells that are slow growing and more differentiated.

Clinical and histological correlations in prolactinomas, with special reference to bromocriptine resistance.

BACKGROUND: Prolactinomas usually exhibit a benign course and can be safely and effectively managed by dopamine agonists (DA). However, some are locally invasive and may show resistance to DA therapy, and the management of such cases remains controversial. The aim of the present study was to determine whether histological features and markers of cell proliferation correlated to the clinical behaviour of prolactinomas and with DA resistance. METHOD: This retrospective study included 74 cases (36 men and 38 women) who had monohormonal prolactinomas removed by transsphenoidal surgery. The prolactinomas were categorized on the basis of tumour size (48 macroadenomas), invasion of the cavernous sinus (n = 31), and resistance to bromocriptine (BRC) therapy (n = 14). Group 1 consisted of non-invasive microprolactinomas (n = 24), group 2 of non-invasive macroprolactinomas (n = 19), group 3 of invasive non-BRC-resistant tumours (n = 19), and group 4 of invasive BRC-resistant tumours (n = 12). The later group included one case of carcinoma with bone and lung metastases. Seven additional parameters were studied, these being age, sex, basal prolactin (PRL) levels, the Ki-67 and PCNA labelling indices (LI), mitotic count, and cellular atypia. FINDINGS: Age and preoperative PRL levels did not correlate to the histological parameters studied. Tumour size and invasion were related to cellular atypia and the Ki-67 LI. BRC-resistant tumours were more frequently invasive (12/14) than BRC-responsive tumours (11/30; p = 0.002) and were more frequent in men than in women (33 versus 5%; p = 0.003). BRC-resistant tumours had a higher Ki-67 LI and mitotic count (4.2+/-2.0% and 4+/-1, respectively) than other tumours (0.7+/-0.2% and 1+/-0, respectively; p<0.05). The strongest correlations with tumoural staging were seen with male sex and high mitotic activity. Six out of the 12 invasive BRC-resistant macroprolactinomas, including the PRL secreting carcinoma, exhibited histological features of aggressiveness (a mitotic count >/=3 [i.e. in the fourth quartile] and/or a high Ki-67 LI and cellular atypia). CONCLUSIONS: In this surgical retrospective series, histological signs of aggressiveness are present in 50% of invasive and BRC-resistant prolactinomas, which are more frequent in men than in women. This fits with the behaviour of BRC-resistant prolactinomas, which can continue to grow despite DA treatment. These findings justify the long-term follow up of these tumours, and the use of surgery and/or radiotherapy if there is concern about the control of tumour growth.

[Development of the human adrenal glands]. / Le développement de la surrénale humaine.

The human adrenal is an endocrine gland located at the superior part of the kidney. Composed of the adrenal cortex of mesoblastic origin and the adrenal medulla of neuroectoblastic origin, the human fetal adrenal grows considerably during the first three months of development. From 12 to 18 weeks of development (WD), the weight of the adrenals increases seven-fold. The gland's weight doubles from 18 to 28 WD and from 28 to 36 WD. At birth, the two adrenals weigh on average 10 g. At the 8th week, two zones are individualized in the adrenal cortex: the definitive zone and the fetal inner zone. At the second trimester, according to ultrastructural and biochemical studies, a third zone, called the transition zone, is individualized between the definitive zone and the fetal inner zone. The definitive zone persists, but the origin of the three zones (glomerular, fascicular and reticular) of adult adrenal cortex is not known. The fetal inner zone regresses from the 5th month of gestation and disappears totally one year after birth. At the 8th week, the immature neuroblasts migrate to the definitive zone, then to the fetal inner zone to compose the adrenal medulla, which develops essentially after birth and during the first year. Before the 10th week, the human fetal adrenal is able to produce steroid hormones, in particular dehydroepiandrosterone sulfate (DHEA-S); the secretion of cortisol remains discussed. The development of the human fetal adrenal is complex and is under the control of hormones (ACTH, LH and betaHCG), growth factors (ACTH essentially) and transcription factors (essentially SF1 and DAX-1). Knowledge of morphological and molecular phenomena of this development permits to understand the pathophisiology of congenital adrenal deficiencies.

[Histological and molecular study of fetal human adrenal cortex (12-36 wk)]. / Etude histologique et moléculaire de la corticosurrénale foetale humaine (12e-36e SD). La corticosurrénale foetale humaine (12e-36e SD).

Histological and functional characteristics of the fetal human adrenals was studied in 119 normal fetuses aged 12 to 36 weeks development (WD). Immunocytochemical detection of steroidogenesis enzyme (3beta-HSD and P450 c21) and evaluation of cell proliferation using two nuclear markers (Ki-67 and PCNA) were performed in 70 of them. The human fetal adrenal cortex is composed of two morphologically distinct zones: the definitive peripheral zone and the fetal inner zone. From the 12th WD, we observed expression of an adherence protein (NCAM) and two steroidogenesis enzymes (3beta-HSD and P450 c21) in the definitive zone cells, attesting to the capacity of these cells to synthesize mineralocorticoids and/or cortisol. In the fetal zone, only P450 c21 immunoreactivity was detected. From the 14th WD, a transitional zone between the definitive zone and the fetal zone was identified by immunocytochemistry, with expression of 3b-HSD from the 21st WD. Only cells of the definitive zone proliferated from the 12th to 25th WD. The indexes of proliferation of PCNA and Ki-67, 40% and 25% respectively, decreased gradually and were lower than 1% at the 25th WD.

Inhibitory effects of the dopamine agonists quinagolide (CV 205-502) and bromocriptine on prolactin secretion and growth of SMtTW pituitary tumors in the rat.

The SMtTW tumor, a spontaneous PRL-secreting transplantable tumor, is the only available animal model sensitive to dopamine agonists. This model has been used to compare the long term in vivo effects of CV 205-502 (CV) and bromocriptine (BR) on PRL secretion and tumor growth. These two drugs were given for 2 months to female Wistar-Furth rats bearing either small or large tumors 4 and 6 months after the graft. Untreated grafted rats served as control. In all rats treated with 5 or 10 mg/kg.day BR or 0.3 mg/kg.day CV, a normalization of plasma PRL levels was observed whatever the pretreatment levels (plasma PRL or CV or BR-treated rats, < 15 ng/ml vs. 28253 ng/ml in control rats 8 months after graft). An inhibition of tumor growth was found for both small and large tumors, but the tumors never disappeared completely (mean tumor weights at autopsy, 440 and 660 mg in BR and CV groups vs. 5270 mg in control group 8 months after graft). Experiments performed with increasing doses of BR (0.15-5 mg/kg.day) or CV (0.03-0.6 mg/kg.day) indicated that CV is effective at doses 5-10 times lower than those of BR. A shrinkage under treatment and a regrowth after drug withdrawal were demonstrated for large tumors by in vivo ultrasonographic measurements of tumor size. Histological and ultrastructural effects were similar for the two drugs: decrease in hemorrhage, reduction of the cell size and secretory activity, increase in immunoreactive PRL cellular content, and inhibition of exocytosis. There was no difference in the PRL mRNA content of treated and untreated tumors, as assessed by in situ hybridization. In conclusion, CV and BR exhibit similar inhibitory effects on tumor growth and PRL secretion. These effects are rapidly and fully reversible after drug withdrawal. The present results give a complete account of the actions of the two dopamine agonists under conditions comparable to those used in the treatment of human prolactinomas.

Cell-to-cell communication in the anterior pituitary: evidence for gap junction-mediated exchanges between endocrine cells and folliculostellate cells.

The ability of rat anterior pituitary cells to communicate through gap junctions (GJ) was studied using a fluorescent molecule, Lucifer Yellow (LY), which freely passes through GJ channels. The probe was introduced into the cell cytoplasm by using either the cut-end loading method on intact tissue, or cell microinjection on cultured cells. The identification of communicating cells was performed by immunofluorescence labeling of specific hormones in endocrine cells and of S100 protein in folliculostellate (FS) cells. Rat anterior pituitary cells in their physiological organization, i.e. in the intact tissue, exhibited a high level of coupling through GJ. LY-labeled cells were found up to 300-microns apart from its site of introduction. The communicating cells were primarily PRL cells, GH cells, and FS cells. Only a few LH, TSH, and ACTH cells were labeled with LY. Anterior pituitary cells, isolated from the rat tissue by mild protease treatment and cultured for 3 days, reestablished functional GJ as demonstrated by microinjection of LY into individual cells. By immunolabeling of specific hormones and/or S100 protein, we found a GJ coupling between FS cells, and between FS cells and endocrine cells, including PRL cells. The communication between FS cells was by far the most frequent. In conclusion, we demonstrate the presence of functional GJ between anterior pituitary cells of the same type and between anterior pituitary cells having distinct differentiated functions.

Differential actions of the dopamine agonist bromocriptine on growth of SMtTW tumors exhibiting a prolactin and/or a somatotroph cell phenotype: relation to dopamine D2 receptor expression.

Dopamine (Da) and Da agonists are known to inhibit secretion and proliferation of normal and tumoral PRL cells, through receptors of D2 subtype. Because of the lack of an experimental model, the relationship between bromocriptine (BR) sensitivity and D2 receptor expression is poorly documented. Such a relationship was analyzed using five lineages of spontaneous transplantable rat pituitary tumors (SMtTW) exhibiting different PRL/GH phenotypes. From plasma PRL and GH concentrations of rats bearing the tumors and tumor messenger RNA contents, tumors were classified as PRL (SMtTW2), somatotroph (SMtTW10), or somatomammotroph (SMtTW5) tumors. Two lineages (SMtTW3 and SMtTW4) represented variants producing PRL and GH but with a high predominance of PRL. With the exception of SMtTW4 tumors, which were malignant, all the tumors were benign and differed in their growth rate. Hormone production and growth of tumors with a PRL or a somatomammotroph phenotype were reduced by about 90% under BR treatment, whereas somatotroph tumors and the PRL malignant tumors were totally insensitive to BR. D2 receptor messenger RNA was present in all BR-sensitive tumors and was not detected in BR-resistant tumors. In conclusion, using five lineages of SMtTW tumors that are representative of the most frequent tumors encountered in human pituitary pathology, we found a full concordance between tumor responses to BR and the expression of D2 receptor by the tumors. The identification of a tumor lineage with a malignant phenotype, secreting high amounts of PRL and presenting a resistance to BR, supports the idea that Da-resistant prolactinomas are aggressive tumors.

Sex-related difference in the growth of prolactinomas: a clinical and proliferation marker study.

Prolactinomas in women commonly present as small intrasellar tumors, but are usually much larger in men. This discrepancy has generally been attributed to differences in the delay before diagnosis. However, studies comparing clinical and pathological correlates of growth of these tumors in both sexes are lacking. We conducted a retrospective study comparing 45 men and 51 women bearing prolactinoma to determine whether the predominance of large tumors in men was due to a delay in diagnosis or, rather, to a fundamental sex-related difference in tumor growth. Basal PRL levels (mean +/- SEM, 2789 +/- 573 ng/mL) and mean tumor diameter (26 +/- 2 mm) were significantly higher in men than in women (292 +/- 74 ng/mL and 10 +/- 1 mm, respectively; P < 0.001), but were not correlated to the age at diagnosis or the duration of symptoms. Giant tumors (n = 8) occurred in males only. The frequencies of bromocriptine-resistant tumors (30 vs.5%; P < 0.01) and invasive macroadenomas (52 vs.27%; P < 0.001) were significantly greater in men than those in women. Lastly, macroprolactinomas in males exhibited higher indexes of proliferating cells by Ki-67 immunoreactivity (2.6 +/- 1.1% of positive nuclei) than did similar tumors in female patients (0.4 +/- 0.2%; P = 0.08). We conclude that the predominance of large prolactinomas in men is due to a high frequency of rapidly growing tumors, which are often invasive and frequently bromocriptine resistant.

Gonadotropin-releasing hormone agonists are unsuccessful in reducing tumoral gonadotropin secretion in two patients with gonadotropin-secreting pituitary adenomas.

Whether GnRH agonist treatment leads to reduced gonadotropin secretion and tumor volume in patients with gonadotropin-secreting pituitary adenomas is controversial. We studied the effect of GnRH analog treatment in two such patients, one with a recurrent FSH- and LH-secreting pituitary adenoma (patient 1) and one with a recurrent FSH- and alpha-subunit-secreting pituitary adenoma (patient 2). Patient 1 was treated with 200 micrograms Buserelin daily for 65 days, and patient 2 received three injections of 3 mg [D-Trp6]-LHRH formulated in microcapsules at 21-day intervals. In both patients, plasma FSH, LH (RIA), and alpha-subunit concentrations increased initially and remained above the pretreatment values throughout the treatment period. Plasma LH, measured by immunoradiometric assay, remained well above the detection limit. Plasma bioactive LH and testosterone became undetectable in patient 2, but did not change in patient 1. In neither patient did pituitary tumor size (determined by computed tomographic scan) change during treatment. We conclude that 1) the overall effect of GnRH analogs in patients with gonadotroph cell adenomas is stimulation of gonadotropin release by the tumor, although LH release varies according to how plasma LH is measured, possibly related to the origin of the hormone (normal or tumor gonadotroph cells), and 2) GnRH analog treatment does not reduce tumor size.

Somatotropic adenoma manifested by galactorrhea without acromegaly.

In two of eight premenopausal women with somatotropic adenomas, galactorrhea was the earliest clinical feature, associated in one patient with amenorrhea. These two patients did not have clinically evident acromegaly. Mean basal serum GH levels were elevated and did not decrease after glucose ingestion. Both patients had modest hyperprolactinemia. Histological and immunocytological studies of the adenomas showed numerous adenomatous somatotropic cells and some alpha-subunit- and PRL-containing cells. In these patients, the origin of the hyperprolactinemia was not clear. In one patient, elevated GH secretion was probably responsible for the galactorrhea, since it disappeared after surgical treatment despite persistence of hyperprolactinemia. In conclusion, galactorrhea, isolated or associated with amenorrhea, can be the only clinical manifestation of a somatotropic adenoma.

A human beta-endorphin pituitary adenoma.

A beta-endorphin (beta END)-containing pituitary adenoma was demonstrated by immunocytochemical, biochemical, and ultrastructural methods in a 43-yr-old man who had impotence, slight testicular atrophy, and an enlarged sella turcica (grade II0), but no manifestations of Cushing's disease. Preoperative hormone data revealed hyperprolactinemia (97 ng/ml), low plasma cortisol levels without circadian rhythm, undetectable plasma ACTH, and normal plasma FSH and LH levels, with an impaired response to LRH. After hypophysectomy, these hormone levels normalized and responded normally to dynamic tests. Immunocytochemically, 30% of the tumor cells reacted only with beta END antiserum. beta END immunoreactivity was the only component revealed by RIA and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. A characteristic ultrastructural aspect is also described. These findings demonstrate dissociation in the secretion of the proopiomelanocortin-derived peptides and suggest a relationship between hyperprolactinemia and tumor secretion of beta END.

Paradoxical response of thyrotropin to L-dopa and presence of dopaminergic receptors in a thyrotropin-secreting pituitary adenoma.

We studied the dopaminergic control of TSH secretion in a patient with hyperthyroidism due to a TSH-secreting pituitary adenoma. A 34-yr-old previously thyroidectomized woman had mild clinical hyperthyroidism and a diffuse goiter without exophthalmos. She complained of headaches and had bitemporal hemianopsia. Serum T4 and T3 by RIA were elevated, and TSH was 112 microU/ml (normal range, 1.1-7.2). The alpha-subunit to TSH molar ratio was 1.7 (normal, less than 1), as reported in other patients with tumoral TSH hypersecretion. After TRH, a marked increase in TSH occurred. There was no evidence of pituitary deficiency. Skull x-rays and computerized axial tomography revealed an intrasellar tumor with suprasellar extension. Selective transsphenoidal adenomectomy was performed, and a pituitary tumor was removed. The tumor was almost entirely composed of cells reactive with antihuman beta TSH serum by indirect immunofluorescence. A unique feature of this patient was the marked increase in TSH levels after L-dopa administration. To our knowledge, this paradoxical response has never been reported previously in such patients. Using [3H]domperidone as ligand, dopaminergic receptors were demonstrated in the membranes of the adenomatous thyrotroph cells. The reason for the paradoxical response of TSH to dopaminergic agents is not known.