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There are two principal types of treatment for pituitary adenomas: fractionated conventional radiation therapy, based on biological selectivity, and radiosurgery, which is delivered in a single dose, based on anatomic selectivity and indicated preferentially for small tumors sufficiently distant from the optic chiasm. Conventional radiation therapy is effective against secretion in 60-80% of cases and radiosurgery in 40-50%, depending on the type of secretion. Maximum antisecretory efficacy is not reached immediately: this delay is longer for conventional radiation therapy (5-10 years) than for radiosurgery (2-3 years). In both cases, antisecretory treatment must be started, while awaiting remission. Radiation therapy and radiosurgery make it possible to stabilize or diminish tumor volume in 70-100% of cases. This is especially useful in the case of an active residue after surgery for non-secreting adenoma, but the long-term side effects of radiation must be borne in mind. The principal side effect is the onset of a pituitary deficiency (in more than 50% of cases after radiation therapy, 20% after radiosurgery). The risk increases with time since treatment. Other very long-term side effects have been described with radiation therapy: radiation-induced tumors, cerebral necrosis, strokes, etc. The role of radiosurgery and radiation therapy is growing ever more limited, because of the increasing efficacy of drug treatments and the excellent surgical results of experienced teams.

Pituitary hormone-producing cells differentiate sequentially from a common epithelial primordium, Rathke's pouch, under the combinatorial action of a subset of tissue- and cell-restricted transcription factors. Some factors have been implicated in early events of pituitary induction and morphogenesis while other factors like Pit-1 and SF-1 have been associated with differentiation of particular lineages. In POMC-expressing cells, Pitx1, NeuroD1 and Tpit were shown to be important for cell specific transcription of the POMC gene. Since Tpit is exclusively expressed in pituitary POMC-expressing lineages, the corticotrophs and melanotrophs, we investigated the TPIT gene coding sequences in 17 patients presenting with congenital isolated ACTH deficiency (IAD). We demonstrated that human TPIT gene mutations cause a neonatal onset form of IAD (8/11), but not juvenile forms of this deficiency (0/6). In the absence of glucocorticoid replacement, IAD can lead to neonatal death by acute adrenal insufficiency. To assess the importance of Tpit in pituitary differentiation and function, we produced Tpit-null mice. Concordant with the human phenotype, Tpit-null mice have IAD : plasma ACTH is greatly reduced in these mice, their plasma corticosterone is undetectable and the adrenals are hypoplastic. Analysis of the pituitary in Tpit-null mice revealed multiple roles of this factor in cell differentiation. First, Tpit is a positive regulator for POMC cell differentiation. Tpit is also a negative regulator of the pituitary gonadotroph fate. Thus, Tpit operates as a molecular switch to orient differentiation of a common precursor towards either POMC or gonadotroph fate. A binary choice model of pituitary cell differentiation is presented.

THE GENETIC ORIGIN INCREASINGLY INCRIMINATED: Congenital pituitary hormone deficiencies represent conditions of hypopituitarism resulting from abnormal pituitary ontogenesis. This group of genetically determined diseases has considerably widened with the development of molecular biology. Many transcription factors playing a role in pituitary development have been identified, and their mutations reported as causes of isolated or multiple pituitary hormone deficiencies. Isolated pituitary hormone deficiencies may affect somatotroph, gonadotroph, and corticotroph lineages. They result from mutations of the genes of hormones (such as growth hormone), of a factor that regulates their synthesis or secretion (such as TPIT for corticotrophics), or of their receptors (GHRH or GnRH receptor genes). Multiple (or combined) pituitary hormone deficiencies result in the concomitant or sequential onset of several anterior pituitary hormone deficiencies. They are due to mutations of transcription factors involved in the early steps of pituitary development (RIEG, HesX1, LHX4, LHX3, Prop1, POU1F1/Pit-1), and are associated with various phenotypes. FOR BETTER MANAGEMENT: Long-term follow-up of these patients and functional studies of the mutations identified in specialized research centers will help to determine phenotype-genotype correlations, hence providing a valuable help to the management of these orphan diseases.

We evaluated serum alpha-subunit concentrations in 72 patients bearing pituitary adenomas. We conclude that: 1) alpha-subunit hypersecretion is found in all patients with TSH secreting pituitary adenoma (n = 10). Two patients have a predominant secretion of alpha-subunit as compared to TSH secretion. 2) As concerns gonadotropin secreting pituitary adenomas (n = 3), all patient have elevated serum alpha-subunit levels with increased FSH and LT concentrations in 2 cases and 1 case respectively. 3) In prolactinomas (n = 14), alpha-subunit concentrations are not significantly different from that of normal subjects. 4) In 11 acromegalic patients, alpha-subunit hypersecretion is found in 2 patients only with GH-alpha and GH-PRL-alpha secreting pituitary adenomas. 5) Among 34 patients with nonsecreting adenomas, 8 have elevated alpha-subunit concentrations (24%). Positive immunocytochemical staining is found in 70% most often with gonadotropins (55%). Only a few pituitary tumors with positive alpha-subunit immunocytochemical staining have elevated serum alpha-subunit levels. At least, the measurement of basal circulating alpha-subunit levels is very useful in the follow-up of patients with nonsecreting adenomas. In our study, medical treatments including bromocriptine and somatostatin analogues have been found effective in patients with alpha-subunit hypersecretion. Further investigations are necessary to prove if such treatments could control tumoral growth and could prevent recurrences.

We studied 7 women with primary hypothyroidism who were suspected to harbor a prolactinoma on the basis of a pituitary gland enlargement associated with hyperprolactinemia. The diagnosis of prolactinoma was confirmed in 1 case only, which was treated surgically. In the remaining 6 patients the serum prolactin levels fell to normal on thyroxine replacement therapy and reduction in size of the pituitary gland was demonstrated by neuroradiological imaging in the 3 documented cases. This study underlines the fact that hyperprolactinemia associated with pituitary hyperplasia is secondary to hypothyroidism and that thyroid function tests should be obtained in all hyperprolactinemic patients even those with pituitary enlargement.

In this prospective multicenter trial, 61 patients presenting with a macroprolactinoma were studied over a 1 month-period following a single 50 mg intragluteal injection of the long-acting repeatable (L.A.R.) form of bromocriptine. The effects of the drug were evaluated mainly by repetitive plasma prolactin measurements on days 1, 3, 7, 14 and 28 after injection, and by repeated visual-field and computed tomography scanning examinations. Normalization of PRL levels was obtained in 23% of patients during the first month following injection. In 6 patients (9.8%), PRL values remained within normal range on day 28 after injection. In these latter patients, PRL levels were significantly lower than in the patients whose PRL values were not normal on day 28 (312 +/- 111 vs 2454 +/- 484 ng/ml [m +/- SEM]). The mean lowest PRL levels were achieved on day 3. The mean percent maximal decrease in PRL levels ranged between 70 and 72% from days 3 to 14 but constantly remained below 50% in 6 patients. An improvement in visual field was observed by day 7 in 45% of patients presenting initially with visual field defects. In particular, in half of the patients with bilateral quadranopsia or hemianopsia, such visual impairments had disappeared after 1 month of treatment. Computed tomography scanning examinations showed in 11% of the patients a more than 20% reduction in tumor mass by day 7 following injection. On day 28, the percent reduction in tumor size was 20-40% in 28% and above 40% in 10% of the patients. Most adverse effects (digestive symptoms, dizziness, postural hypotension) were observed during the first 24 hours of treatment. Local and systemic tolerability was in general good. In macroprolactinoma patients, a single 50 mg injection of bromocriptine LAR was thus able to achieve in the short-term a clear cut reduction in tumor size in 2/5 patients and normalization of PRL levels in 1/10 of patients. A study of the effects of monthly administration of bromocriptine LAR is currently under progress to assess the long-term efficacy of this drug.