PRL-secreting Pituitary Tumors Research Articles

SAT-312 Beta-Arrestin 2 Is Required for Dopamine Receptor Type 2 Inhibitory Effects on Akt Phosphorylation and Cell Proliferation in Pituitary Tumors

Dopamine receptor type 2 (DRD2) agonists are the first-choice treatment for PRL-secreting pituitary tumors but are poorly effective in non-functioning pituitary neuroendocrine tumors (NF-PitNETs). DRD2 reduces AKT phosphorylation in lactotrophs, but no data are available in NF-PitNETs. DRD2 effects on AKT are mediated by a β-arrestin 2-dependent mechanism in mouse striatum.The aim of this study was to investigate DRD2 effects on AKT phosphorylation and cell proliferation in human primary cultured NF-PitNET cells and in rat tumoral lactotroph cells MMQ, and to test β-arrestin 2 involvement.We found that DRD2 agonist BIM53097 induced a reduction of p- AKT /total-AKT ratio in MMQ (-32.8±17.6%, p<0.001 vs basal) and in a subset (n=15/41,36.6%) of NF-PitNETs (subgroup 1). In the remaining NF-PitNETs (subgroup 2), BIM53097 induced an increase of p- AKT. The ability of BIM53097 to reduce p-AKT correlated to its antimitotic effect, since the majority of subgroup 1 NF-PitNETs was responsive to BIM53097 and nearly all subgroup 2 NF-PitNETs were resistant. β-arrestin2 was expressed in MMQ and in 80% of subgroup 1 NF-PitNETs, whereas it was undetectable in 77% of subgroup 2 NF-PitNETs.In MMQ, β-arrestin 2 silencing prevented DRD2 inhibitory effects on p-AKT and cell proliferation. Accordingly, β-arrestin 2 transfection in subgroup 2 NF-PitNETs conferred to BIM53097 the ability to inhibit both p-AKT and cell growth.In conclusion, we demonstrated that β-arrestin 2 is required for DRD2 inhibitory effects on AKT phosphorylation and cell proliferation in MMQ and NF-PitNETs, paving the way for a potential role of β-arrestin 2 as a biomarker predicting NF-PitNETs responsiveness to treatment with dopamine agonists.

Differences between rat strains in the development of PRL-secreting pituitary tumors with long-term estrogen treatment: &lt;i&gt;In vitro&lt;/i&gt; insulin-like growth factor-1-induced lactotroph proliferation and gene expression are affected in Wistar-Kyoto rats with low estrogen-susceptibility

There are differences in the susceptibility of rat strains to pituitary growth and lactotroph proliferation caused by long-term treatment with estrogens. To investigate the pituitary mechanism for this strain difference in estrogen-induced lactotroph proliferation, we compared the abilities of 17-β estradiol (E2) and insulin-like growth factor-1 (IGF-1) to modulate lactotroph proliferation and gene expression in vitro in Wistar and Wistar-Kyoto (WKY) rats. These two strains of rats have a high and very low susceptibility to estrogen, respectively. Long-term in vivo treatment with E2 was confirmed to markedly increase pituitary weight and lactotroph proliferation in ovariectomized Wistar, but not in WKY rats. Pituitary lactotrophs in primary cultures showed similar proliferative responsiveness to the culture condition-dependent, stimulatory and inhibitory actions of E2 in both strains. The only difference in lactotroph proliferation in vitro was a lower response to IGF-1 in WKY cells compared with Wistar cells. This difference in proliferation was associated with strain differences in IGF-1-induced gene expression in Wistar and WKY cultured cells. Of the genes tested, IGF-1-induced expression of the Wnt4, Stc1, Mybl1, and Myc genes was attenuated or abolished in WKY cells. These results suggest that the proliferative response to estrogen in lactotrophs in primary culture does not reflect the proliferative response to long-term estrogen treatment observed in vivo in Wistar and WKY rats. The strain difference in proliferation and gene expression to IGF-1 may be implicated in the variable degree of susceptibility for lactotroph proliferation observed in different strains of rats following long-term estrogen treatment.

Loss of expression of GADD45 gamma, a growth inhibitory gene, in human pituitary adenomas: implications for tumorigenesis.

The underlying molecular pathogenic mechanisms remain unknown in the majority of human pituitary tumors. GADD45 gamma is a member of a growth arrest and DNA damage-inducible gene family that functions in the negative regulation of cell growth. We have found that the mRNA expression of the GADD45 gamma gene is significantly different between normal human pituitary tissue and clinically nonfunctioning pituitary adenomas using cDNA-representational difference analysis. Although GADD45 gamma mRNA was found in normal human pituitary tissue, it was detectable in only 1 of 18 clinically nonfunctioning pituitary tumors by RT-PCR. Furthermore, this gene was not expressed in the majority of GH- or PRL-secreting pituitary tumors (6 of 8 and 7 of 10, respectively). In colony formation assays, transfection of human GADD45 gamma cDNA into the human pituitary tumor-derived cell line, PDFS, results in a dramatic decrease in cell growth by 88%. GADD45 gamma also reduces colony formation in other pituitary tumor-derived cell lines, AtT20 and GH4, by approximately 60% and 50%, respectively, confirming its function in controlling cell proliferation in the pituitary. These data indicate that GADD45 gamma is a powerful growth suppressor controlling pituitary cell proliferation, and GADD45 gamma represents the first identified gene whose expression is lost in the majority of human pituitary tumors.

Effects of estrogen and dopamine agonists on the expression of argyrophilic nucleolar organizer regions in prolactin cells of rats.

The number of nucleolar organizer regions reflects nuclear and cellular activity, such as the proliferation and differentiation of cells. Prolonged administration of estrogen (E2) induces the hyperplasia of prolactin (PRL) cells and the development of PRL-secreting pituitary tumors in rats. Dopamine agonists are known to reduce the effects of E2 treatment. The purpose of this study was to investigate whether the changes of argyrophilic nucleolar organizer regions (AgNORs) in PRL cells are related to circulating levels of PRL or to the proliferative activity of PRL cells during the administration of stimulatory (E2) or inhibitory (dopamine agonist) treatment in rats. E2 increased the size and number of AgNORs per nuclear profile in PRL cells in rats. Bromocriptine and cabergoline, which are dopamine agonists, each reduced the number and size of AgNORs in PRL cells treated with E2 for 10 weeks. In rats treated with E2 alone or dopamine agonists followed by E2, the number and size of AgNORs were correlated more closely with serum levels of PRL than with the proliferative activity of PRL cells. However, neither the number nor size of AgNORs in PRL cells was related with these parameters in different ages of the control. The number and size of AgNORs may be useful in evaluating the secretory activity of pituitary cells during the administration of stimulatory or inhibitory agents.

Pentobarbital anesthesia during the proestrous afternoon blocks lactotroph proliferation occurring on estrus in female rats.

Estradiol stimulates the synthesis and secretion of PRL and lactotroph proliferation, and its long-term administration induces PRL-secreting pituitary tumors. We examined changes in the number of proliferating lactotrophs throughout the estrous cycle in female rats and the involvement of the brain in the regulation of the lactotroph proliferation by anesthetizing with pentobarbital. Female rats revealing regular 4-day estrous cycles were injected ip with the thymidine analog 5-bromo-2'-deoxyuridine (BrdU) 3 h before decapitation to label DNA-replicating cells. Dispersed anterior pituitary cells obtained from these rats were stained for PRL and BrdU with a double labeling immunofluorescence technique. The rate of lactotroph proliferation was represented by the BrdU-labeling index (BrdU-labeled lactotrophs as a percentage of total lactotrophs counted). Lactotrophs from rats injected with BrdU at 1000 h showed a high BrdU-labeling index of 2.6% on estrus, whereas they showed almost undetectable levels of the BrdU-labeling index during the other stages of the estrous cycle. The anterior pituitary cells other than lactotrophs were scarcely labeled during any stages. The BrdU-labeling index began to rise by the midnight between proestrus and estrus, peaked between 0800 and 1200 h, and returned to undetectable levels by the midnight between estrus and diestrus I. Pentobarbital (35 mg/kg, i.p.) injected at 1345 h on proestrus, which was effective in blocking ovulation on estrus, eliminated completely the increase in the BrdU-labeling index as determined by BrdU injection at 1000 h on estrus. In contrast, the high BrdU-labeling index on estrus was partly suppressed to a level of 1.4% by pentobarbital injection at 0900 or 2100 h on proestrus. The rats injected with pentobarbital at 1345 h on proestrus did not show any increases in the BrdU-labeling index even after BrdU injection was delayed from 1000 to 1400 h on estrus. However, a high BrdU-labeling index of 3.7% was obtained in these animals when BrdU was injected at 1000 h on diestrus I. We conclude that 1) lactotrophs of cycling female rats proliferate selectively on the day of estrus; and 2) the proliferation of lactotrophs on estrus is not due to a direct action on the anterior pituitary of estradiol secreted from the ovaries but triggered by neural events occurring during the proestrous afternoon, which are closely related with the regulation of preovulatory surges of gonadotropin and PRL secretion.

Ras mutations in human prolactinomas and pituitary carcinomas.

Pituitary adenomas have been shown to be clonal in origin, indicating that one or more somatic mutations underlie tumor pathogenesis. Mutated oncogenic forms of ras protein have been identified in a number of human neoplasms, including thyroid adenomas and carcinomas. However, the potential role of activated ras in the development of specific human pituitary tumor phenotypes has not been determined. Although ras mutations were not found in glycoprotein hormone-secreting or somatotroph adenomas, we recently identified a mutation in the H-ras gene (Gly-Val) at codon 12 in a highly invasive prolactinoma. These data raise the possibility that ras mutations might play a role in the pathogenesis of PRL-secreting pituitary tumors and/or may be a marker for tumor invasiveness and malignant transformation. Therefore, we investigated 78 pituitary tumors (59 prolactinomas, 13 invasive prolactinomas, and 6 pituitary carcinomas) for activating point mutation in the three ras genes using oligonucleotide-specific hybridization. In contrast to the relatively high frequency of ras mutations in many different tumor types, no ras mutations were identified in either prolactinomas or pituitary carcinomas. Our data indicate that ras mutations are rare in prolactinomas and pituitary carcinomas.

Transforming DNA Sequences Present in Human Prolactin-Secreting Pituitary Tumors

Five human PRL-secreting pituitary tumors were tested for the presence of DNA-transforming sequences. After calcium phosphate transfection to NIH-3T3 mouse fibroblast cells, DNA samples derived from two prolactinomas induced foci of morphologically transformed cells which subsequently grew in soft agar. After retransfection of transformant DNA, resulting secondary transformants elicited rapidly growing solid tumors in nude mice. Southern analysis of transformant DNA revealed the integration of Alu-positive human DNA sequences into the mouse fibroblast NIH-3T3 cells, as judged by hybridization to a Blur-8 probe. The Alu signal became increasingly more difficult to detect with the multiple passaging (greater than 20) of transformant cells in culture. Alu polymerase chain reaction (PCR) was, therefore, used to selectively amplify human DNA sequences from the NIH-3T3 rodent background. PCR using a human Alu-specific primer resulted in amplification of an Alu-containing DNA region within these transformants. The transformant DNA did not hybridize to human genomic probes for genes known to evoke focus formation in this assay, including H-ras, K-ras, N-ras, trk, ret, ros, or met. Further identification of the Alu-containing region revealed that it contained sequences from the human hst gene, a member of the fibroblast growth factor family. The presence of human hst was demonstrated by strong hybridization to a 40-mer oligonucleotide probe to the second exon of hst, by amplification of this region with human hst-nested amplimers within the first and second introns, and finally by direct sequencing.(ABSTRACT TRUNCATED AT 250 WORDS)

G proteins in normal rat pituitaries and in prolactin-secreting rat pituitary tumors

It is still undetermined which GTP-binding (G) protein is involved in the regulation of prolactin (PRL) release and through which effector. This study shows that, when compared to normal pituitary tissue, the levels of αo protein were very low in dopamine (DA)-resistant, PRL-secreting pituitary tumors 7315a and MtTW15, while αo mRNA was present in the two tumors. In the MtTW15 tumor αil, αi2 and αi3 levels were decreased while those of αs42 and αs47 were increased, and in the 7315a tumor αi2, αi3 and β levels were decreased and those of αs47 increased. In an estrone-induced, DA-sensitive prolactinoma the levels of ι3 were greatly reduced. DA was unable to inhibit basal PRL release by 7315a and MtTW15 and basal cAMP accumulation by adenomatous and MtTW15 cells. Vasoactive intestinal peptide (VIP) increased both cAMP accumulation and PRL release by all cell preparations which could be suppressed by DA with adenomatous and 7315a but not with MtTW15 cells. These and previously published results provide circumstantial evidence that αo, αil and αi3 are all involved in the transduction of the DA inhibitory message while αs47 transduces cAMP activating messages and αs42 is responsible for the constitutive activation of L-type Ca 2+ channels, adenylate cyclase and baseline PRL release.

Enhanced dopamine synthesis and release in vitro in the median eminence of rat hypothalamus are associated with involution of estradiol-induced pituitary tumors.

Changes in the functions of tuberoinfundibular dopaminergic (TIDA) neurons were investigated during the period when the involution of estradiol-induced PRL-secreting pituitary tumors was occurring. Dopamine synthesis and release in vitro by TIDA neurons were determined by 3,4-dihydroxyphenylalanine (DOPA) accumulation in the median eminence and endogenous dopamine release from the median eminence, respectively. Three weeks after a single injection of 2 mg estradiol valerate into ovariectomized rats, there was a marked increase in the weight of anterior pituitaries and the concentration of serum PRL, but a decrease in K+-induced DOPA accumulation in vitro in the median eminence. Twelve weeks after estradiol treatment, by which time pituitary weights and PRL concentrations declined considerably, K+-induced DOPA accumulation in the median eminence rose 5-fold compared to that in control animals. This change in DOPA accumulation persisted for 24 weeks. Increases were observed at 12 weeks in K+-induced as well as basal and (Bu)2cAMP-induced DOPA accumulation in the median eminence. The increases in basal and (Bu2cAMP-induced DOPA accumulation were not altered by Ca2+ removal from medium. In parallel to the changes in DOPA accumulation, basal and K+-induced release in vitro of dopamine from the median eminence into the medium were decreased 3 weeks after estradiol treatment, but increased at 12 and, in part, 24 weeks. The increases in basal and K+-induced dopamine release were observed even after Ca2+ removal from medium. These results suggest that basal, extracellular Ca2+-dependent, and cAMP-dependent dopamine synthesis as well as basal and depolarization-induced dopamine release in TIDA neurons are stimulated during the period of involution of pituitary tumors associated with estradiol withdrawal.

Long term follow-up of women with surgically treated prolactin-secreting pituitary tumors.

To examine the long term effectiveness of transsphenoidal microsurgery for patients with PRL-secreting pituitary tumors, we studied 54 women at yearly intervals after transsphenoidal surgery. Five years after surgery, 19 women (35%) had normal serum PRL concentrations, and 23 (43%) had persistent hyperprolactinemia. Hyperprolactinemia recurred in 12 of 31 patients (39%) who had normal PRL concentration 6 weeks after surgery. None of the patients with recurrent hyperprolactinemia had radiographic evidence of tumor regrowth, and only 3 of 12 had amenorrhea. A serum PRL level below 6 ng/ml 6 weeks after surgery occurred more frequently in cured patients than in those who had a recurrence. PRL responses to TRH were normal in cured patients 1 and 5 yr after surgery and abnormal in those who had recurrent hyperprolactinemia. The PRL responses to chlorpromazine- and insulin-induced hypoglycemia were blunted in patients with normal as well as elevated PRL levels. Patients with recurrent, as well as those with persistent, hyperprolactinemia had no nocturnal rise in serum PRL 5 yr after surgery. The 39% recurrence rate of hyperprolactinemia and persistent abnormalities in pituitary-hypothalamic regulation of PRL secretion after transsphenoidal surgery raise important questions about the choice of primary therapy for patients with PRL-secreting tumors.

Irradiation and Prolactin Effects on Rat Mammary Carcinogenesis: Intrasplenic Pituitary and Estrone Capsule Implants&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;

The implantation of silicone capsules that contained estrone and that were adjacent to grafts of anterior pituitary tissue in the spleens of adrenalectomized glucocorticoid-deficient inbred F344 rats resulted in high circulating prolactin (Prl) levels without the untoward effects of chronic hyperestrogenism or of grafts of Prl-secreting pituitary tumors. All peripheral serum estrone titers were below the titers in sera of proestrous untreated intact rats. Peripheral serum estrone and Prl levels were, however, a function of capsule surface area over the capsule sizes tested (12-74 mm2); the elevated Prl levels persisted for as long as 700 days. In adrenalectomized glucocorticoid-deficient female rats, both 5 Gy gamma-irradiation alone and intrasplenic pituitary-estrone implants alone induced mammary carcinomas; the combination of these treatments induced a greater incidence of first carcinomas and reduced first carcinoma latency. There were, however, no marked differences in tumor incidence or latency due to differences in estrone capsule size. Finally, ovariectomy reduced first carcinoma risk in irradiated, pituitary-estrone-implanted rats but did not change the time of maximum risk. Ovarian secretory activity thus persisted in such rats and ovarian hormones synergized with Prl in mammary carcinoma induction.

Decreased tuberoinfundibular and pituitary dopamine and dihydroxyphenylacetic acid concentrations in rats with estrogen-induced pituitary tumors

The majority of pituitary adenomas are prolactin (PRL)-secreting, but it is still uncertain whether their pathogenesis results from a central nervous system (CNS) disturbance or autonomous lactotroph growth and function. We have measured dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) concentrations in rats bearing estradiol-induced PRL-secreting pituitary tumors. Female rats, injected at 3-week intervals with 2 mg estradiol valerate (EV), had increased plasma prolactin concentrations, up to 3 micrograms/ml, at 31 weeks. Inversely, there was a reduction of DA and DOPAC in the median eminence and arcuate nucleus as well as a decreased DOPAC/DA ratio in the arcuate nucleus. DA-containing nuclei in the other parts of the brain were not affected. Anterior pituitary weight increased while its DA concentration decreased during estradiol treatment. In the neurohypophysis, DA concentrations were unchanged while DOPAC and the ratio DOPAC/DA decreased following the estrogen treatment. Our data suggest that rats with primary estrogen-induced PRL-secreting tumors have a defect in the CNS-DA neurotransmission.

Catecholamines and pituitary function. 2. Prolactin response to different dopamine doses in normal cycling women and patients with prolactin-secreting pituitary tumors, both before and after endogenous catecholamine synthesis inhibition.

The inhibitory effect of various doses of dopamine on serum PRL levels was assessed in both normal cycling women and patients with tumoral hyperprolactinemia before and after endogenous catecholamine synthesis inhibition by alpha-methyl-p-tyrosine, a strong and specific tyrosine-hydroxylase inhibitor. Dopamine infusion induced a significant decrease in the serum PRL levels in both normal cycling and hyperprolactinemic subjects. The mean percent inhibition of baseline PRL induced by the various dopamine infusion rates (0.1, 0.5, 1.0 and 2.0 micrograms/kg/min) was similar in regularly cycling women and in patients with tumoral hyperprolactinemia both before and after endogenous catecholamine synthesis inhibition by alpha-methyl-p-tyrosine. Alpha-methyl-p-tyrosine pretreatment significantly increased serum PRL concentrations in normal women and enhanced their responsiveness to the exogenously administered dopamine. Hyperprolactinemic patients, on the contrary, did not show any significant variation in either basal PRL release or the PRL sensitivity to dopamine infusion after endogenous catecholamine synthesis inhibition. These data indicate that reduced dopamine delivery to the adenomatous lactotroph, either due to a primary hypothalamic abnormality or to a deranged vascular pituitary arrangement, rather than a reduced PRL sensitivity to dopamine inhibition, is the main event accounting for PRL hypersecretion in women with PRL-secreting pituitary tumors.

Dopamine receptors in rat pituitary and estradiol-induced pituitary tumor: Effect of chronic treatment with bromocriptine

We have investigated dopamine (DA) receptors in estradiol-induced PRL-secreting pituitary tumors and intact pituitary tissue. Female rats were injected at 3-week intervals with 2 mg estradiol valerate (EV) or with diluent. After 21 weeks, adenomatous changes in the pituitary gland of EV-treated rats were seen and plasma PRL concentrations reached 2 μg/ml. Bromocriptine (2.5 mg/kg) was then administered for 1 month to half of the control rats and half of the rats bearing tumors. Anterior pituitary weight was increased in EV-treated rats compared to controls while the affinity and the density of DA receptors as assessed by [ 3H]spiperone binding remained unchanged. Bromocriptine (CB-154) induced a 70% decrease in the density of DA receptors without any change in affinity both in normal pituitaries and in tumors. Concurrently, the elevated plasma concentrations of PRL in the tumor bearing rats were decreased to control values following the CB-154 treatment. Our data suggest that rats with primary estrogen-induced PRL secreting tumors have normal pituitary DA receptors.

Demonstration of biological activity of prolactin molecular weight variants in human sera.

Three immunoreactive forms of PRL, separated by Sephadex G-100 column chromatography, were identified in serum samples from 10 normal subjects and 7 patients with PRL-secreting pituitary tumors. Fractions eluted from the column were assayed for bioactivity by using a sensitive bioassay with the Nb2 cell line. Three molecular weight variants of PRL were identified in normal subjects. In samples from 9 of the 10 normal subjects, 80.1 +/- 3.6% (mean +/- SEM) of the total bioactivity eluted in a peak corresponding to a PRL monomer (peak III) with a mol wt of approximately 24,000, 18.3 +/- 3.7% eluted in a peak with a mol wt of approximately 56,000 (peak II), and 1.6 +/- 1.1% of the biological activity was in the void volume (peak I). In the 10th normal sample, 65% of the total bioactivity was in the void volume (peak I), 31% was in peak III, and 4% was in peak II. Samples from the patients had 3.6 +/- 0.7% of the total bioactivity in peak I, 9.3 +/- 1.0% in peak II, and 87.0 +/- 1.1% in peak III, percentages not significantly different from normal. For comparison with bioassay, RIA measurement of PRL was performed on all fractions of six samples (three normal subjects and three tumor patients). Good correlation was found between RIA and bioassay measurements under each of the three peaks identified. We conclude that 1) in sera from normal subjects, three molecular weight variants of PRL have biological activity; 2) in patients with PRL-secreting tumors, secretion of biologically active PRL molecular weight variants is not proportionately different from that in normal subjects; and 3) the results of the Nb2 PRL bioassay correlate well with PRL levels determined by RIA for each of three molecular weight variants identified.

Nomifensine, TRH and insulin-induced hypoglycemia tests in the diagnosis of prolactinomas.

Nomifensine, TRH and insulin-induced hypoglycemia tests were carried out in 37 cases of hyperprolactinemia: 25 were due to PRL-secreting pituitary tumors, 6 cases to GH and PRL-secreting pituitary tumors and 6 to pituitary and suprasellar non secreting tumors. Nomifensine failed to suppress the serum PRL in all subjects and PRL responses to TRH and insulin-induced hypoglycemia were impaired in all patients, irrespective of the origin of hyperprolactinemia. The uniform pattern of PRL response to the above tests in patients with hyperprolactinemia of variable etiology suggests that none of them is specific for prolactinomas.

Chronobiological aspects of headache syndromes due to sellar or pituitary pathology.

A chronobiological study was carried out in headache syndromes due to empty sella or to pituitary G.H.- and PRL-secreting adenomas. In the empty sella syndrome only the chrono-organization of G.H. secretion was disturbed, whereas pl. PRL exhibited the usual circadian pattern. The circadian rhythms of pl. G.H. and pl. PRL were abolished in G.H.- and PRL-secreting pituitary tumors, respectively, and were again detectable when patients were cured by selective transsphenoidal adenomectomy. A normal circadian rhythmicity of pl. cortisol was demonstrable in the empty sella syndrome and in pituitary adenomas, both before and after surgery.

Bone density in amenorrheic women with and without hyperprolactinemia.

To determine whether decreased bone density in patients with PRL-secreting pituitary tumors is specifically related to hyperprolactinemia or is a consequence of disordered pituitary-gonadal function common to all amenorrheic states, we measured the bone mineral content of the radius by photon absorptiometry in normal subjects, in women with amenorrhea and normal serum PRL levels, and in women with PRL-secreting pituitary tumors. The women did not differ significantly in mean age, height, weight, or serum calcium, phosphorous, gonadotropin, testosterone, vitamin D, or PTH concentrations, and all had normal renal and thyroid function. The bone mineral content in women with amenorrhea and normal serum PRL levels (0.91 +/- 0.02 g/cm) was not significantly different from that in control subjects (0.88 +/- 0.01 g/cm). Patients with PRL-secreting tumors studied 2-5 yr after transsphenoidal surgery had significantly diminished bone mineral content whether they were cured (0.82 +/- 0.02 g/cm) or had persistent amenorrhea and hyperprolactinemia (0.81 +/- 0.02 g/cm). Serum estradiol concentrations did not differ significantly in the four groups, and there was no correlation between estradiol concentration and bone mineral content or between PRL concentration and bone mineral content in the amenorrheic women. The presence of decreased bone mineral content in hyperprolactinemic patients suggests that PRL may have a direct effect on bone and may be another indication for early treatment of PRL-secreting pituitary tumors.

Effect of tamoxifen administration on prolactin release by invasive prolactin-secreting pituitary adenomas.

Bromocriptine treatment of patients with invasive prolactin (PRL)-secreting pituitary adenomas does not invariably result in normalization of the plasma PRL levels. We previously showed that the antiestrogenic drug tamoxifen inhibited hormone release from transplantable PRL-secreting pituitary tumors in rats. In 8 patients with invasive PRL-secreting pituitary adenomas with extrasellar extension, the effect of the administration of tamoxifen was investigated on the plasma PRL concentration and on the bromocriptine-mediated inhibition of PRL release. Treatment for 5 days with tamoxifen (20 mg/day) suppressed plasma PRL levels as measured in 5 samples over the day significantly by 20 +/- 3% (means +/- SEM; p less than 0.01). During tamoxifen administration the inhibition of PRL secretion by 2.5 mg bromocriptine was further suppressed by 36 +/- 7%, in comparison with the plasma PRL levels after bromocriptine alone (p less than 0.01). Tamoxifen administration suppressed PRL release in patients with giant invasive PRL-secreting pituitary adenomas, and it had a slight but significant additive or potentiating effect on the bromocriptine-mediated inhibition of PRL secretion. However, despite the simultaneous administration of bromocriptine and tamoxifen, normalization of the circulating PRL levels was not reached in this type of patient.

Comparison of the responses in the nomifensine test with hyperprolactinemia due to prolactin-secreting pituitary tumors and nonprolactin-secreting hypothalamic tumors.

It has recently been proposed that nomifensine (Nom) administration discriminates those patients with PRL-secreting pituitary tumors from those who have hyperprolactinemia due to other causes. In the present study, this test was performed on 12 presumed functional hyperprolactinemic subjects, 9 patients with surgically proved PRL-secreting pituitary adenoma (6 microadenoma and 3 macroadenoma), and 7 patients with surgically proved non-PRL-secreting hypothalamic tumors (3 craniopharyngioma, 3 suprasellar germinoma, and 1 suprasellar ependymoma). The Nom test suppressed the plasma PRL level to below 60% of the basal level in all 12 women with presumed functional hyperprolactinemia, but did not alter plasma PRL levels in the patients with PRL-secreting pituitary adenoma or hypothalamic tumor. This evidence confirms that the test is, at least in part, able to discriminate those individuals with PRL-secreting pituitary adenoma from those without, regardless of the size of the tumor. However, the test is not capable of distinguishing between hyperprolactinemia due to PRL-secreting pituitary tumors and that due to non-PRL-secreting hypothalamic tumors. A lack of response to Nom is not necessarily due to the presence of a PRL-secreting tumor, and may be related to dysfunction to the hypothalamic-pituitary system.