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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.

Resume Les etiologies de l'hyperprolactinemie, motif frequent de consultation, sont nombreuses. La demarche diagnostique doit permettre de reconnaitre les causes tumorales au premier rang desquelles on trouve les adenomes a prolactine. L'IRM hypothalamo-hypophysaire est l'examen morphologique de reference. Elle est en pratique clinique, volontiers realisee tres tot, des la mise en evidence d'une augmentation de la concentration plasmatique de PRL. Cette attitude est justifiee si l'elevation de la PRL, en l'absence de traitement hyperprolactinemiant est importante (> 10 fois la norme superieure du dosage) car le diagnostic d'adenome a PRL est alors tres probable. Lorsque l'hyperprolactinemie est moderee, situation la plus frequente en pratique, toutes les etiologies sont possibles et il est important de garder une demarche diagnostique (interrogatoire recherchant d'eventuels traitements hyperprolactinemiants et precisant les antecedents renaux ou hepatiques, recherche d'endocrinopathies parfois associees a une hyperprolactinemie telles que l'hypothyroidie ou le SOPK, confirmation de l'hyperprolactinemie par un deuxieme dosage lorsqu'elle est inferieure a cinq fois la norme superieure du dosage, realisation d'un test de grossesse chez la femme en periode d'activite genitale) dont le but sera d'eliminer les causes non tumorales d'hyperprolactinemie avant de recourir a l'imagerie. L'absence de retentissement de l'hyperprolactinemie sur la fonction gonadique ou l'existence d'une pathologie associee pouvant expliquer les signes cliniques, la mise en evidence de variations importantes des taux de PRL d'un dosage a l'autre chez un meme patient auront conduit a rechercher une macroprolactinemie avant de prescrire l'IRM. Cette situation artefactuelle doit etre egalement evoquee en cas d'IRM normale ou douteuse ou de discordance dans la reponse aux traitements medicaux ou chirurgicaux. Des coupes coronales en acquisition T1 (± injection de gadolinium) et T2 suffisent au diagnostic de microprolactinome. La realisation de tests dynamiques peut etre utile lorsque l'IRM est normale ou douteuse. L'injection de gadolinium et des coupes sagittales voire axiales sont indispensables pour l'etude des lesions volumineuses. Dans ce cas, devant une valeur de PRL peu elevee, il faut evoquer une lesion non lactotrope sans meconnaitre la possibilite d'un effet « crochet ». L'analyse soigneuse des cliches permettra de differencier une lesion tumorale d'une hyperplasie hypophysaire (devant faire rechercher une hypothyroidie peripherique).

Measurements of human growth hormone (hGH) plasma levels using mono or polyclonal antibodies based on kits are often highly variable depending upon the kit used. We compared six kits commercially available: one based on polyclonal antiserum, five based on monoclonal antisera. We measured 695 sera obtained in short stature children (GH deficiency or normal GH secretory) and adults (normal, hypopituitarism or acromegaly). Our results confirm the variability between the assays. The maximal variation was obtained with SBhGH kit which showed mean results 1.7 fold higher than those obtained with hGH Coatria. Using the OMS 80.205 standard with the six kits, we found a good correlation between the six kits indicating that the standard used in each case was not responsible for the observed variations. This suggest that the different antibodies used in these kits may recognize different isoforms of circulating hGH. In addition variations in reagents used in the different kits may also explain these discrepancies. The variations observed using these six commercially available kits may have important clinical repercussion and especially may impede the diagnosis in hGH deficiency in children.

Prolactin (PRL) circadian profiles were analyzed using methods of nonlinear dynamics, directly from the experimental data, by combining in a single time-series (432 measurements), six individual 24-hour PRL profiles (72 measurements per profile, sampling interval = 20 min), obtained from young healthy human volunteers (4 males, 2 females), under basal conditions. Significant autocorrelation exists between any given point of the time series and a limited number of its successors. Fourier analysis showed a dominant frequency of 1 cycle/24 h, without sub-24-hour harmonics. Poincaré section indicated the presence of a fractal attractor and a sketch of the attractor revealed a highly convoluted geometric structure with a conical contour. The box-counting dimension (D0), information dimension (D1) and correlation dimension (D2) of the attractor had low, fractal values, did not differ significantly from each other, and exhibited saturation at an embedding dimension of 2. The evidence taken together suggests that, under basal conditions, the daily changes in the peripheral blood levels of PRL are governed by nonlinear deterministic dynamics, with a dominant rhythm of 1 cycle/day mixed with a higher-frequency, low-amplitude signal.

Twenty one patients with suspected prolactin-secreting microadenoma were evaluated with MRI. MRI is the most sensitive means for detecting focal microadenomas. In these patients who were clinically and endocrinologically considered to harbor a microadenoma, MR detected a focal pituitary signal abnormality in 100% when the patients had not previously taken bromocriptine therapy. On the other hand MR demonstrated a focal abnormality in only 30% of cases when the patients had been on dopamine agonist therapy: the MRI findings in the group of bromocriptine treated patients are not affected by neither the duration and dosage of the therapy or the delay between MR examination and the bromocriptine therapy discontinuation. Among the 9 cases in which MRI did not demonstrate a focal abnormality, MRI was strictly normal in 3 cases only; MR showed a localized expansion of the subarachnoid space in two cases; the pituitary gland was large and round, and had a homogeneous signal in one case; the pituitary gland had a heterogeneous signal in 3 cases. In our study the microadenoma had a high signal intensity on the precontrast T1 weighted sequence in 5 cases. The focal abnormality was not seen on the precontrast MR images in 2 cases. The microadenoma enhanced in 3 cases on the postcontrast three dimensional MR images. This MR technique allows thin section slices (1 mm) and therefore the detection of small focal abnormality of the pituitary gland (2.5 x 3 mm). Thus three points have to the emphasized: a) MRI always detected a microadenoma when the patients had never received a bromocriptine therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

A number of transcription factors evidenced in the pituitary may play a part in the development of this gland, namely Pit-1, Prop-1, P-Lim, Ptx1, Rpx, Dax-1, SF-1. Several of these factors are involved in animal models of hypopituitarism, while up to now only Pit-1 gene alterations have been shown to be responsible for hypopituitarism in man. These factors are briefly presented, and current data on genetically determined uni- or multi-hormonal pituitary deficiencies are reviewed. In particular, data on combined somatotroph, lactotroph and thyrotroph deficiencies due to Pit-1 gene alterations are detailed. Analysis of phenotype-genotype relationships in this syndrome and in other pathological models of multiple pituitary hormone deficiencies will provide useful information on the complex sequence of events that contribute to the development of the pituitary gland and to differentiation and regulation of the different pituitary cell lines.

Besides classical etiologies of hyperprolactinaemia (pregnancy, pharmacological treatments, pituitary or hypothalamic perturbations), another less known cause may explain a spectacular idiopathic elevation of plasma concentrations of prolactin hormone. Macroprolactinaemia is characterized by the presence of a circulating high molecular weight complex of prolactin with an immunoglobulin G. In this article, we report the cases of 3 female patients for whom size exclusion chromatography technique permitted to give a precise biological diagnosis and to avoid heavy, expensive, time consuming and unnecessary clinical investigations or therapeutic actions. Patients with macroprolactinaemia do not exhibit clinical features of classical hyperprolactinaemia, notably as regard to menstrual and fertility disturbances.

Over the last 10 years, important data on pituitary development have been reported using spontaneous or experimental models of gene inactivation. The development pathways of the anterior pituitary lobe include organogenesis resulting in Rathke pouch formation and cell differentiation. Pituitary development is controlled by sequential series of specific signaling molecules and specific transcription factors. In humans, inactivation of Pit-1, Prop-1, Rpx and Ptx2 genes is responsible for pituitary combined deficiency. In this paper, updated data on the embryology of the pituitary gland and the clinical phenotypes of inactivation of pituitary transcription factors are reported.

In the recent years, spontaneous and experimental models of hypopituitarism have underlined the involvement of a number of homeodomain transcription factors in different forms of congenital anterior pituitary hormone deficiencies. Indeed, abnormalities of the transcription factor Pit-1 are responsible for combined deficiencies affecting thyrotroph, somatotroph and lactotroph cell lineages both in dwarf mouse strains (Snell, Jackson) and in human patients. More recently, alterations of the Prop-1 gene have been shown to induce a similar phenotype in the Ames mice, and alterations of the human homolog gene have been evidenced in patients with anterior pituitary deficiencies involving the same three lineages together with the gonadotrophs. Gene knock-out experiments have demonstrated the importance of other transcription factors such as Lhx3 and Lhx4 in the development of the normal pituitary gland. These findings illustrate the potential involvement of anomalies of these and many other factors in the various forms of multiple hypopituitarism.

Over an 8-month period (July 1990-to February 1991), we explored 21 women presenting with a clinical and laboratory profile of prolactin-secreting microadenoma of the pituitary gland. Magnetic resonance imaging (MRI) is undoubtedly the most efficient method to explore microadenomas, especially when carried out in the absence of any treatment. In 8 cases, MRI was performed in the absence of medical treatment and gave a positive result, i.e. always showed a focal lesion. In the remaining 13 cases the patients had been treated before the exploration, and MRI detected a microadenoma in only 4 cases. The duration of treatment and the time elapsed between its withdrawal and the MRI examination did not seem to influence the positivity or negativity of the imaging results. Among the 9 cases where MRI failed to show a focal lesion, the image was normal in 3 cases and displayed an arachnoidocele in 3 cases; the pituitary gland was convex and homogeneous in 1 case and convex and heterogenous in 3 cases, which raised the problem of the effects of bromocriptine on the MRI images. As regards signals, in 5 cases the microadenoma was hyperintense on the spin-echo sequence without contrast injection; it was undetectable on the same sequence in 2 cases. In 4 cases the lesion was contrast-enhanced after gadolinium injection. Using millimetric sections enables small-size adenomas (2.5 x 3 mm) to be visualized.

Brain radiotherapy is a frequent and overlooked cause of pituitary deficiency in adults which may alter patients' health and quality of life. Hormonal consequences have been better studied in children. The onset of hormonal deficiencies depends on the dose delivered to the pituitary-hypothalamic region while their incidence and severity depends on dose fractionating and follow-up duration. Somatotrophic function is the first affected, 90% of patients being GH deficient 10 years after radiotherapy. Other anterior pituitary functions are affected later and less frequently. While initial damage occurs in the hypothalamus, accounting for mild hyperprolactinemia in 30-50% of cases, diabetes insipidus is never observed. Direct pituitary deficiency may occur later. Responses to ACTH or GHRH-arginine tests may be normal for several years though an ACTH and/or GH deficiency has been demonstrated by an insulin tolerance test, which is considered as the gold standard. When the cranio-spinal area--including the neck--has been irradiated, primary thyroid deficiency might occur. Repeated cervical ultrasonographic follow-up is mandatory to exclude radiation-induced thyroid cancer. The gonadotrophic function might be altered after small doses of irradiation causing precocious puberty, while at higher doses delayed puberty or true gonadotrophic deficiencies are more often observed. Combined radio- and chemotherapy might result in mixed central and peripheral deficiencies that might be difficult to diagnose. When radiotherapy is performed in adulthood, GH deficiency is less common, although the sequence of hormonal deficiencies is similar to that observed in children. Prospective longitudinal studies are required to determine the time course and sequence of onset of each deficiency, in order to tailor the monitoring of these patients to their specific needs.

Objective To assess the efficacy and tolerability of monthly injections of the long-acting repeatable bromocriptine in patients with macroprolactinomas. Design Open and prospective trial. Setting This multicenter trial was carried out in seven university hospitals. Patients Forty-two patients with prolactin (PRL)-secreting macroadenomas. Interventions Fifty to 200 mg of the drug were administered intragluteally every 28 days for 6 to 24 months. Main Outcome Measures The efficacy was assessed by repetitive plasma PRL measurements, visual field determinations, and computed tomography scan examinations. Results After the first 50-mg injection, the mean percentage decrease of PRL levels was 71% from baseline on day 14; between days 1 and 28, PRL levels were suppressed to normal in nine cases, and a clear tumor shrinkage was documented in 21% of the patients. Normalization of PRL secretion was obtained in 62%, and a clear-cut reduction in tumor size in 50% of the patients after 6 months of treatment. Conclusions The long-acting repeatable form of bromocriptine was a well tolerated and quickly effective treatment in most of these patients with macroprolactinomas.

Lumbar bone mineral content (BMC) of 33 female patients aged 14-30 years (19 +/- 4.1 (mean +/- SD) with anorexia nervosa (duration 31 +/- 37 months) was studied using dual X-ray absorptiometry. Results were compared with the data obtained in a population of 26 women aged 17-38 years without bone disease. BMC was significantly decreased (0.872 +/- 0.107 g/cm2 hydroxyapatite) in anorectic patients as compared to controls (1.008 +/- 0.098 hydroxyapatite). A single patient had a non traumatic vertebral compression fracture. A statistically significant negative correlation was found between BMC and duration of amenorrhea (r = 0.48; p0.01). There was no significant correlation between BMC and body mass index or daily calorie intake. Ovarian steroid deficiency might thus be a major factor--among other ones--in the development and the degree of bone loss in anorexia nervosa.

Prolactinoma, a benign tumor originating from the lactotroph cells of the anterior pituitary, is responsible for signs and symptoms related to both hypersecretion of prolactin and tumor mass. Hyperprolactinemia frequently causes menstrual cycle disturbances, galactorrhea and infertility in women, sexual disorders in men. Microadenomas, characterized by a largest diameter less than 10 mm, may induce frontal headaches, and macroadenomas (more than 10 mm in diameter) may also impair visual function through chiasma compression. Treatment modalities include dopamine agonist therapy such as bromocriptine which allows normalization of prolactin levels, restoration of gonadal functions and tumor shrinkage in most cases. In microadenomas a definitive cure may be achieved by transsphenoidal total selective adenomectomy.

Among 288 patients with prolactinoma (aged 12-62 years; 242 women), 27 were diagnosed as resistant to bromocriptine as their plasma prolactin (PRL) levels remained elevated despite long-term (3 months or more) treatment at high doses (or = 15 mg daily). These 18 women and 9 men, aged 29 +/- 9 years (mean +/- SD, range 13-50), followed-up for 8 +/- 4 years, had microadenomas (n = 6) or macroadenomas. They were treated by dopamine agonists alone (n = 6) or associated with surgical or radiation therapy. In 8 cases repetitive surgical treatments were necessary. Among the 24 patients who were treated with the nonergot dopamine agonist CV 205-502 after unsuccessful bromocriptine treatment, half of them (9 women, 3 men) resumed normal PRL levels on doses ranging from 0.15 to 0.45 mg/day. Despite daily doses of CV 205-502 from 0.3 to 0.525 mg, the remaining patients were not normalized by this drug which did not prevent tumor growth in 4 of them. Two patients died from invasive cerebral extensions of their tumor and a third had vertebral metastases with positive anti-PRL immunostaining. It is concluded that bromocriptine-resistant prolactinomas represent the most severe aspect of this disease and that a more powerful dopamine agonist like CV 205-502 is effective in only a fraction of these patients.