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PubMed1999

Pituitary lactotroph adenomas develop after prolonged lactotroph hyperplasia in dopamine D2 receptor-deficient mice.

Tuberoinfundibular dopamine tonically inhibits PRL expression and secretion from the pituitary gland by the activation of dopamine D2 receptors (D2R) localized on lactotrophs. Mutant female mice that lack D2Rs have persistent hyperprolactinemia but also develop extensive hyperplasia of pituitary lactotrophs and peliosis of the adenohypophysis at 9 to 12 months of age, while age-matched male D2R-deficient mice have no morphologic adenohypophysial lesion. We now report that both female and male D2R-deficient mice 17 to 20 months of age develop pituitary lactotroph adenomas. Of 12 aged female mice examined, all developed monohormonal PRL-immunoreactive neoplasms that had a characteristic juxtanuclear Golgi pattern of PRL staining and loss of the reticulin fiber network. Several of these adenomas were 50-fold larger than normal glands with marked suprasellar extension and invasion of brain but no gross evidence of distant metastases. They also had striking peliosis that was more marked than the lesion seen in the hyperplastic pituitaries of the younger females. These findings demonstrate that a chronic loss of neurohormonal dopamine inhibition promotes the hyperplasia-neoplasia sequence in adenohypophysial lactotrophs. Our results are analogous to previous data indicating that protracted stimulation of adenohypophysial cells by hormones or growth factors results in proliferation with initial hyperplasia followed by the development of neoplasia. Six aged male D2R-deficient mice had slightly enlarged anterior pituitaries similar in size to normal female glands. However, each case exhibited multifocal, microscopic lactotroph adenomas with strong nuclear immunoreactivity for estrogen receptors and Pit-1 transcription factor. The unexpected development of adenomas in males without preexisting or concomitant hyperplasia suggests that prolonged loss of dopamine inhibition may also cause neoplasia by distinct cellular mechanisms in male and female animals.

Adrenocorticotropic Hormone↗

PubMed1995

Targeting of transforming growth factor-alpha expression to pituitary lactotrophs in transgenic mice results in selective lactotroph proliferation and adenomas.

The PRL-secreting cells of the pituitary gland normally express transforming growth factor-alpha (TGF alpha). To determine the effect of increasing TGF alpha expression in the pituitary, a transgenic mouse model was created in which overexpression of human TGF alpha was directed to the pituitary lactotrophs using the rat PRL promoter. Of the four gene-positive mouse lines, two expressed the messenger RNA corresponding to the transgenic in the pituitary glands. However, in both these lines, expression could only be detected in the female animals. Expression of the transgenic could be detected as early as 1 month of age, but no pathology or developmental abnormalities were detected until the animals reached 6 months, at which time, hyperplasia of the lactotrophs. By the age of 12 months, all of the homozygous transgenic females had developed pituitary adenomas that were immunopositive for PRL. The other hormone-producing cells of the pituitary showed no obvious pathology. The male transgenics developed neither hyperplasia nor adenomas, nor did the gene-positive transgenic lines that did not express the transgene. In no case was an aggressive pituitary tumor seen. This transgenic mouse model indicates that TGF alpha overexpression by lactotrophs stimulates the growth of these pituitary cells. Furthermore, TGF alpha has a highly localized action in the pituitary gland, resulting only in lactotroph hyperplasia and prolactinomas. These observations suggest that TGF alpha might play a role in the development of prolactinomas.

Animals↗

PubMed2001

Reversible transdifferentiation: interconversion of somatotrophs and lactotrophs in pituitary hyperplasia.

Previous studies conclusively demonstrated transformation of somatotrophs into bihormonal mammosomatotrophs in gestational lactotroph hyperplasia during pregnancy. Similar transdifferentiation of somatotrophs into thyrotrophs through bihormonal intermediate thryrosomatotrophs was documented during thyrotroph hyperplasia in both rodent and human pituitaries in hypothyroidism. The cessation of the stimulation resulted in reversal of the process in both conditions. The conversion of lactotrophs into somatotrophs was suggested but not documented previously in the human gland. The present study was undertaken to investigate cases of somatotroph hyperplasia by transmission electron microscopy, immunoelectron microscopy using double immunogold labeling for growth hormone and prolactin, as well as combined immunocytochemistry and in situ hybridization. Adenohypophysial tissue was removed from a 38-year-old man and a 29-year-old woman with long-standing acromegaly due to ectopic overproduction of growth hormone-releasing hormone (GRH) by bronchial carcinoid tumors. For comparison, two pituitary biopsies were studied: one from a 38-year old woman with idiopathic lactotroph hyperplasia and one from a 14-year-old boy with secondary lactotroph hyperplasia due to a suprasellar craniopharyngioma. In the patients with somatotroph hyperplasia, the prevailing cell type was the hyperplastic somatotroph joined by mammosomatotroph deriving from lactotrophs, whereas monohormonal lactotrophs were rare. The predominance of mammosomatotrophs and active lactotrophs was documented in the patient with idiopathic lactotroph hyperplasia, whereas the case of the patient with secondary lactotroph hyperplasia was characterized by monohormonal lactotrophs and somatotrophs, but mammosomatotrophs were rare. That finding in the pituitary of the boy suggests that participation of mammosomatotrophs in lactotroph hyperplasia is not unconditional Our findings conclusively demonstrate conversion of lactotrophs into mammosomatotrophs during somatotroph hyperplasia, providing further evidence for the potential of reversible transdifferentiation between somatotrophs and lactotrophs in response to functional demand.

Acromegaly↗

PubMed1997

Heterogeneity of pituitary lactotrophs: immunocytochemical identification of functional subtypes.

The existence of functional lactotroph subpopulations was confirmed in primary pituitary cell cultures of female rats submitted to estrogen treatment and stimulation with thyrotrophin releasing hormone (TRH) and angiotensin II (A-II). In cell cultures of pituitary tissue, prolactin (PRL) producing cells represent about 50% of the total cell count, most of which (90%) correspond to a typical lactotroph subpopulation characterized by large secretory granules, 500-900 nm in diameter, and well developed rough endoplasmic reticulum (RER) and Golgi complex. Few atypical lactotrophs were detected with a quiescent appearance and containing smaller secretory granules, often indistinguishable from granular content of other pituitary cells. Depletion of endogenous estrogen caused by ovariectomy (OVX) decreased the pituitary lactotroph population about 34%, with a relative increase of atypical forms (56%). Replacement therapy with benzoate estradiol (EB) to OVX rats did not reverse the proportion of typical and atypical lactotrophs gauged in control pituitary glands. The predominant lactotroph population of OVX rat was an atypical PRL producing cell which displayed a quiescent appearance compatible with a reduced secretory activity. By contrast, estrogen administration to OVX rats caused a striking development of the RER, a hypertrophy of the Golgi complex and an increased storage of mature and immature secretory granules in the majority of lactotrophs. These features are compatible with a reactivated protein synthesis. Estrogen also enhanced significantly (p < 0.05) the responsiveness of lactotrophs to A-II and the PRL secretion in both intact and OVX + EB treated rats increased by 40% and 30% respectively. By contrast, A-II did not produce any statistically significant response of lactotrophs from OVX female rats. At variance to this observation, in all models tested TRH increased significantly the PRL secretion (p < 0.05). The correlation of PRL secretion and morphology of different lactotroph subtypes authenticates the existence of a lactotroph subpopulation unresponsive to A-II in pituitary cell cultures from rats depleted of estrogen.

Angiotensin II↗

PubMed1992

Lactotrophs secreting small amounts of prolactin reveal great responsiveness to thyrotropin-releasing hormone: analysis by the sequential cell immunoblot assay.

The effects of TRH on PRL secretion from individual lactotrophs of female rats were investigated by using a sequential cell immunoblot assay. The same pituitary cells cultured on coverslips were first incubated to determine basal secretion of PRL and subsequently challenged by one of various concentrations of TRH. The PRL secreted from the single lactotrophs was absorbed on protein-blotting transfer membranes, immunostained, and quantified by microscopic image analysis. When no TRH was added to the medium used in the second incubation (controls), the amount of PRL secreted from individual lactotrophs was 93% of that secreted in the first incubation. Treatment with 3 x 10(-10)-10(-7) M TRH in the second incubation increased in a dose-dependent manner the proportion of lactotrophs whose PRL secretion was significantly greater than confidence limits for PRL secretion in the controls. However, the percentage of TRH-responsive lactotrophs remained less than 50% even at a maximally effective concentration of TRH. Proportions of the TRH-responsive lactotrophs were significantly greater in cells that secreted small amounts of PRL under basal conditions than in those that secreted large amounts. Furthermore, the small, but not the large, secretors showed a significant increase in mean absolute amounts of PRL secreted by 10(-7) M TRH, which represented no less than 45% of all PRL secreted from the lactotroph population by the TRH treatment. These results indicate that 1) there is a heterogeneity with respect to lactotroph responsiveness to TRH and that 2) a population of lactotrophs that secrete small amounts of PRL under basal conditions contains a much larger proportion of TRH-responsive lactotrophs than does a population of lactotrophs that secrete large amounts of PRL.

Animals↗

PubMed1995

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.

Anesthesia↗

PubMed2003

Apoptotic cell death of oestrogen activated lactotrophs induced by tamoxifen.

Stimulation and inhibition of lactotroph cells cause remarkable morphological and functional changes. In keeping with these changes, the size of the lactotroph cell population undergoes striking alterations due to proliferation or cell death. Factors involved in the induction of apoptosis of pituitary cells are not well established. We demonstrated earlier that oestrogens prevent lactotroph cells of female rats to die by apoptosis induced by bromocryptine treatment, a fact that can be reversed in ovariectomised rats. In this study, we developed experimental models for in vivo and in vitro studies to gain further insight on the survival effect of oestrogens on lactotrophs. In rats pretreated with oestrogens, tamoxifen generates a massive cell death by apoptosis as validated by the TUNEL technique and DNA electrophoresis of pituitary gland. On electron microscope observations, numerous lactotrophs exhibited progressive morphological changes in the nuclei compatible with the apoptotic process. The cells remaining intact also exhibit signs of inhibition due to a significant transformation of regular lactotrophs in atypical subtypes. In pituitary cell cultures exposed to tamoxifen and oestrogen simultaneously, most of the lactotrophs displayed features of apoptosis in the nucleus. The present reports gathered new evidences on the apoptogenic potential of tamoxifen on lactotroph cells, and corroborates the contribution of oestrogens to sustain both a balanced population of lactotrophs and a competent secretory activity. The concept that opposed activities, such as inhibition and stimulation, can activate apoptosis is also strengthen by these observations.

Animals↗

PubMed1981

Enhanced responsiveness of lactotrophs in ectopic pituitaries to bromocryptine and estrone acetate.

Intrasellar and transplanted pituitaries removed from the same rats were studied using light microscopy, immunocytology, electron microscopy and ultrastructural morphometry following treatment with bromocryptine and/or estrone acetate. Ectopic lactotrophs of rats treated with bromocryptine showed an increase in storage granule size and number, which was not observed in the lactotrophs of corresponding intrasellar pituitaries. In lactotrophs of intrasellar and ectopic pituitaries, treatment with estrone acetate caused a decrease of storage granule size, while rough endoplasmic reticulum (RER) and Golgi region volume density increased. When rats were treated with a combination of bromocryptine and estrone acetate, intrasellar lactotrophs exhibited increased volume density and diameter size in forming granules as well as increased RER volume density. In ectopic lactotrophs, combined treatment led to a decrease in RER, volume densities of Golgi region and forming granules, as well as increased storage granule size. It can be concluded that ectopic lactotrophs were more sensitive to the inhibiting effects of bromocryptine treatment than intrasellar lactotrophs. Intrasellar lactotrophs were more susceptible to estrone acetate than bromocryptine treatment. As a result, the increased responsiveness of ectopic lactotrophs to estrone acetate was less conspicuous.

Animals↗

PubMed2004

Evidence that lactotrophs do not differentiate directly from somatotrophs during chick embryonic development.

It is generally accepted that, in mammals, lactotrophs differentiate from somatotrophs through an intermediate cell type, the mammosomatotroph. However, little information exists about mammosomatotrophs and their relationship with lactotroph development in non-mammalian vertebrates. We reported previously that corticosterone (CORT) can induce both somatotroph and lactotroph differentiation in cultures of chicken embryonic pituitary cells. Our current objectives were to determine the abundance of mammosomatotrophs during chicken pituitary development, to identify mammosomatotrophs during CORT induction of lactotrophs, and to explore whether lactotrophs induced by CORT are derived from somatotrophs. Cells that produced prolactin (PRL) only, growth hormone (GH) only or both hormones simultaneously were detected by three approaches - dual immunofluorescence, a combination of immunofluorescence and immunocytochemistry (ICC), and by ICC using combinations of antibodies to GH and PRL. Mammosomatotrophs were not detected between embryonic day (E) 16 and E20, even though lactotrophs increased from nearly absent to greater than 10% of all pituitary cells during this period. CORT induced more than 10% of all E13 pituitary cells to produce PRL, while the percentage of mammosomatotrophs remained at less than 1% of all cells. When cells from the cephalic and caudal lobes of the anterior pituitary were treated separately, CORT increased GH cells in cultures from the caudal lobe. No PRL cells were found in the caudal lobe. In the cephalic lobe, CORT increased lactotrophs, while GH cells were barely detected. In summary, mammosomatotrophs are rare during chicken pituitary development, and CORT does not induce lactotrophs from somatotrophs. These findings indicate that, unlike in mammals, lactotrophs do not differentiate from somatotrophs during chicken embryonic development.

Animals↗

PubMed2000

Gonadotroph-lactotroph associations and expression of prolactin receptors in the equine pituitary gland throughout the seasonal reproductive cycle.

An interaction between gonadotroph and lactotroph cells of the pituitary gland has long been recognized in several species. The current study was conducted to investigate whether an association between gonadotrophs and lactotrophs occurs in mares and whether prolactin receptors are expressed within the pituitary gland of this species. The effects of both reproductive state and season on these variables were examined in pituitary glands obtained from sexually active mares in July (breeding season), sexually active mares in November (non-breeding season) and anoestrous mares in November. Pituitaries were dissected out immediately after death and immunofluorescent staining was carried out on 6 micrometer sections using specific antibodies to the LHbeta subunit, FSHbeta subunit, prolactin and prolactin receptor. Gonadotrophs were observed in both the pars distalis and pars tuberalis; although they appeared mostly as isolated cells, small groups of gonadotrophs were also identified in the pars distalis. In contrast, lactotrophs were observed only as clusters of cells exclusively in the pars distalis of sexually active and anoestrous mares in November and in most of the sexually active mares in July. A specific gonadotroph-lactotroph association was identified only between large isolated gonadotrophs and lactotroph clusters. Double immunofluorescent staining for FSHbeta and prolactin revealed a similar gonadotroph-lactotroph association to the one detected for LH gonadotrophs. No statistical difference in the gonadotroph:lactotroph ratio was observed as a result of changes in reproductive status or season. However, a tendency for a simultaneous decrease in the number of gonadotrophs and an increase in the number of lactotrophs was detected in anoestrous animals. Prolactin receptor immunoreactivity was found in the pars distalis, but not in the pars tuberalis, of sexually active (July and November) and anoestrous animals for both long and short forms of the receptor. No prolactin receptor co-localization for either form of the receptor was observed in LH or FSH gonadotrophs in either of the reproductive states examined during both summer and winter seasons. Furthermore, no significant difference was apparent in the proportion of cells expressing prolactin receptors between mares of different reproductive state or season. The specific anatomical association between gonadotroph and lactotroph cells and the expression of prolactin receptors in the equine pituitary gland indicate a potential role of prolactin in the regulation of gonadotrophin secretion. However, the absence of evidence for co-localization of prolactin receptors in LH or FSH cells does not support the hypothesis of a direct effect of prolactin on the gonadotroph as reported in a short day breeder. The results raise the possibility that, in horses, an intermediate regulatory cell may mediate the action of prolactin on gonadotroph function.

Animals↗

PubMed1994

Distribution of lactotroph subpopulations in different regions of the rat pituitary.

In this study, we examined the distribution of lactotrophs in different regions of pituitaries of ovariectomized (OVX) rats either untreated or treated with estradiol, progesterone or a combination of estradiol and progesterone. Anterior pituitaries were cut into inner and outer zones. Each of these regions was enzymatically dispersed and the resulting cells subjected to density sedimentation through a discontinuous Percoll gradient. The light and heavy cell subpopulations obtained were compared with cells not subjected to Percoll (unseparated cells). Cell numbers were determined and prolactin positive cells were assessed by immunocytochemistry. In OVX rats, the percentage of lactotrophs in the unseparated cell fraction of the outer zone was significantly (P < 0.05) lower than that in the inner zone. Estradiol increased the percentage of PRL cells in all cell populations, but the effect on inner zone light cells was significantly less than on any other type of cells. Progesterone given alone did not affect the percentage of lactotrophs in pituitary compared to untreated OVX rats nor did it alter the effects of estradiol. When the number of lactotrophs was calculated, the unseparated cells of inner and outer zone were equivalent except in the untreated OVX group where there was a significantly greater number of lactotrophs in the outer zone. In untreated OVX rats there was an equal distribution of lactotrophs between light and heavy cells in both inner and outer zones. Estradiol significantly increased the number of PRL cells in both zones and the effect was greater in the heavy cell fractions especially in the outer zone. In contrast, progesterone decreased the number of PRL positive cells in both zones and across cell types, but this effect was most pronounced in the outer zone. Progesterone also decreased the total pituitary cell number and this effect was greater than could be accounted for by the decrease in lactotroph numbers. We conclude that, except in untreated OVX rats, the numbers of lactotrophs in inner and outer zones are similar. The results also indicate that estradiol and progesterone can significantly alter the proportion and/or numbers of PRL positive cells within pituitary zones and may also affect cells that are not identified as PRL positive.

Animals↗

PubMed1990

Correlation study of serum prolactin levels, pituitary weights, number and ultrastructure of pituitary lactotrophs in female Long-Evans rats.

Twenty-five female, 23-month-old Long-Evans rats were sacrificed for investigation of correlations between serum prolactin levels, pituitary weights, numbers and ultrastructural features of pituitary lactotrophs. Serum prolactin levels measured by radioimmunoassay varied from 7.1 ng/ml to 1,534.0 ng/ml. Pituitary weights ranged from 16.0 mg to 255.0 mg. Serum prolactin levels were increased when pituitary weights were high; statistical analysis revealed a correlation between the two. No significant correlation was evident between serum prolactin levels and lactotroph percentage and ultrastructure. Light microscopy revealed a large number of lactotrophs in almost every pituitary. Values for nuclear, cell and cytoplasmic areas, nuclear/cytoplasmic ratios and nucleolar diameters remained similar in the lactotrophs of all animals. Electron microscopy disclosed no lactotroph damage or vascular injury. Ultrastructural morphometry of lactotrophs in the pituitaries studied showed no major differences in cytoplasmic volume densities of endoplasmic reticulum, Golgi complex, mitochondria, secretory granules and lysosomes as well as secretory granule diameters. It is reasonable to conclude that elevations of serum prolactin levels are due to an increase in pituitary mass, resulting from accumulation of lactotrophs. Thus hyperprolactinemia appears to be secondary to an increase in the number of lactotrophs and not hyperactivity of individual cells.

Animals↗

PubMed1997

Different behavior of lactotroph cell subpopulations in response to angiotensin II and thyrotrophin-releasing hormone.

1. In the present investigation we have extended the study of lactotroph subpopulations in primary pituitary cell cultures. Male rats with or without previous estrogenization followed by A-II or TRH treatments were selected as experimental models. 2. The TRH increased up to 50% the PRL released in both whole and OROX+EB rats (P < 0.05). In contrast, A-II treatment introduced no changes in PRL secretion from cell cultures derived from whole male rats but attained a significant augmentation (about 75%) of PRL secreted by ORQX+EB pituitary cells. 3. The addition of TRH and A-II to cultures of ORQX+EB-derived lactotrophs induced cytological changes compatible with a high secretory activity. In estrogen-treated rats the prevailing lactotroph subpopulation is type I. In cell cultures from control and A-II treated whole male pituitaries, the majority of lactotrophs consists of atypical subpopulations of II and III cells, with smaller secretory granules (between 150 and 300 nm in diameter). 4. Morphometry of immunostained lactotrophs performed on light microscopic preparations revealed that about 30-36% of the total cell count were lactotrophs. This percentage was fixed and did not change significantly after TRH and A-II treatments. 5. The present results confirm the presence of morphological and functional subtypes of lactotroph cells in rat pituitary. Typical PRL cell population shows the highest responsiveness to angiotensin II and TRH action. This functional heterogeneity of lactotroph subtypes may reflect an important and scarcely explored factor in the regulatory process of prolactin secretion.

Angiotensin II↗

PubMed2005

The Intermediate lactotroph: a morphologically distinct, ghrelin-responsive pituitary cell in the dwarf (dw/dw) rat.

Profound somatotroph hypoplasia in the dwarf (dw/dw) rat is accompanied by an estrogen-dependent induction of prolactin secretion by the GH secretagogue, GHRP-6. Using electron microscopy, we demonstrated that the reduction in the somatotroph population in the dw/dw pituitary is accompanied by the presence of a morphologically distinct lactotroph subpopulation. In these cells, which did not coexpress GH, the size, shape, and number of the secretory granules were between those of the type I and type II lactotrophs. We therefore called these cells intermediate lactotrophs. The intermediate lactotrophs accounted for up to 30% of the total prolactin-positive cell population in dw/dw males and up to 12% in females. Using tannic acid to quantify the fusion of secretory granules, we have shown that the intermediate lactotrophs are unresponsive to either GH-releasing factor (GRF) or TRH but exhibit a sexually dimorphic secretory response to acute ghrelin treatment, granular fusions being 4-fold higher in females. No cell matching the morphology of the novel lactotroph subpopulation was observed in the pituitary of the GRF-insensitive lit/lit mouse. However, ablation of GRF neurons with neonatal monosodium glutamate treatment had no effect on the population of intermediate lactotrophs in the dw/dw rat. Thus, the presence of the intermediate lactotrophs in the dw/dw pituitary appears to be independent of the function of the GRF neurons.

Aging↗

PubMed1994

Increase in Pit-1 mRNA is not required for the estrogen-induced expression of prolactin gene and lactotroph proliferation.

Estrogen has been shown to stimulate lactotroph proliferation and expression of the prolactin (PRL) gene. Recently it has been established that Pit-1, a pituitary-specific transcription factor, is required for lactotroph proliferation. Furthermore, in vitro studies showed that an increase in the PRL promoter activity caused by estrogen was dependent of the amount of cotransfected Pit-1-expressing plasmid. These findings led us to examine whether the induction of Pit-1 mRNA is required for the estrogen-increased PRL gene expression in the rat anterior pituitary in vivo. Short term estrogen treatment was achieved by means of a single intramuscular injection of estradiol dipropionate. DNA synthesis, the levels of PRL and Pit-1 messenger RNAs in the anterior pituitary were determined. Estradiol dipropionate resulted in a significant increase in DNA synthesis 24 h after administration and in PRL mRNA after 48 h. In contrast, the Pit-1 mRNA level was not altered. Since Pit-1 is expressed not only in lactotroph but also in somatotroph and thyrotroph, and the lactotroph cell population has been reported to be less than 10% in the pituitary, the change in the Pit-1 mRNA level in lactotrophs was not seen following only short term estrogen treatment. An increase in the lactotroph cell population was therefore achieved by chronic estrogen treatment (subcutaneous implantation of a silastic tube containing 17 beta-estradiol powder for 30 days). This treatment resulted in the marked proliferation of lactotrophs and a 3-fold increase in PRL mRNA. However, no alteration in Pit-1 mRNA was observed. These results suggest that the increase in Pit-1 mRNA is not required for the estrogen-induced lactotroph proliferation or PRL gene expression.

Animals↗

PubMed1986

Regression of redundant lactotrophs in rat pituitary gland after cessation of lactation.

Regressive changes occurring in the pituitary gland of the rat after removal of litters were studied. Pituitary glands of lactating rats were characterized by the presence of numerous hypertrophied lactotrophs. Interruption of lactation caused a blockade of prolactin synthesis and secretion, followed by degeneration of lactotrophs. Morphometric analysis of pituitary glands revealed that lactotrophs accounted for about 50% of the total hypophysial cell count in lactating rats. This percentage decreased progressively and reached pre-pregnant levels 7 days after removal of litters; the decrease was inversely correlated with an increase in the number of degenerating lactotrophs which comprised 30% of all lactotrophs 72 h after removal of litters. The morphological changes found in lactotrophs were closely related to changes in the prolactin content of serum and the pituitary gland. Regression of lactotrophs appeared to be the most important cause inducing the reversal of hypophysial lactotrophic activity to pre-pregnant conditions.

Animals↗

PubMed1991

Selectivity of juxtaposition between cup-shaped lactotrophs and gonadotrophs from rat anterior pituitary in culture.

Semi-thin sections of three-dimensional reaggregates from adult female rat pituitary, cultured in serum-free defined medium, were stained for prolactin, gonadotropin, thyrotropin, growth hormone and S-100, using the double immunolabelling technique. The frequency of juxtaposition between lactotrophs and gonadotrophs was enumerated and compared with the expected frequency at random distribution of polygonal cell profiles in a hexagonal configuration. The proportions of lactotrophs and gonadotrophs in the aggregate sections were determined using stereometrical analysis. The observed frequency of juxtaposition did not differ significantly from the expected frequency. Hence, no reason was found to assume a selective adhesion between lactotrophs and gonadotrophs in adult female rat pituitary reaggregates. A constant proportion of lactotrophs was found to meet the criteria of a cup-shaped morphology, and 70% +/- 9% (mean +/- S.D.) of these so-called cup-shaped lactotrophs were found to be juxtaposed at their concave side to gonadotrophs. Administration of 0.01 nM 17 beta-oestradiol to the culture medium resulted in a significant reduction of the proportion of cup-shaped lactotrophs but did not affect the selectivity of juxtaposition to gonadotrophs. The selectivity of juxtaposition between cup-shaped lactotrophs and gonadotrophs may be the morphological correlate of the functional relationship between these cells, which are known to be involved in an intra-pituitary paracrine communication system.

Animals↗

PubMed2004

Immunolocalization of Pit-1 in gonadotroph nuclei is indicative of the transdifferentiation of gonadotroph to lactotroph cells in prolactinomas induced by estrogen.

The pituitary protein transcription factor (Pit-1) regulates the differentiation and proliferation of somatotrophs, lactotrophs, and thyrotrophs and the c-Myc oncoprotein plays a critical role in somatotroph and lactotroph differentiation. Both were involved in the genesis of pituitary tumors. The combined analysis of Pit-1 and c-Myc expression and the morphometric and biochemical parameters of the lactotroph population after treatment with estrogen for 7, 20, and 60 days provided new information on molecular mechanisms implicated in the formation of prolactinomas. Estrogen treatment for 7 days caused a significant proliferation of lactotrophs (70%) and this increase reached an additional 55% at 60 days. The proliferation of lactotrophs was concurrent with higher serum and pituitary prolactin levels. An augmentation of Pit-1 and c-Myc expression in both cytoplasmic and nuclear extracts after estrogen can be associated with lactotroph proliferation. Moreover, the multistep correlation analysis revealed that the expression of nuclear Pit-1 was the strongest predictor of prolactinoma development. Also the Pit-1 immunolocalization in nuclei of gonadotrophs suggests the activation of genes involved in transdifferentiation of gonadotroph to lactotroph. Therefore, the understanding of the Pit-1 function may help in the design of strategies to control the secretion and proliferation of pituitary tumors of the somatomammotrope lineage.

Animals↗