Growth Hormone Prolactin Research Articles

12568 “Unusual Presentation Of Pituitary Macroadenoma: Co-secretion Of GH And Prolactin With Prozone Phenomenon"

Abstract Disclosure: F. Lopez Maldonado: None. A. Rodriguez Gonzalez: None. A. Mayorga Leon: None. E. Leon Milan: None. Background: Plurihormonal pituitary adenomas (10-15% cases) are linked to acromegaly, especially in young patients. ∼8% are associated with MEN1. They produce growth hormone (GH), prolactin (PRL), and sometimes thyroid-stimulating hormone (TSH), causing clinical effects from GH and excess PRL. Most are large and invasive in ∼50% of cases. Case Report: A 37-year-old male with no significant medical history, exhibited monthly right temporal headaches, ipsilateral eye pain, nausea, and vomiting, that responded to analgesics and antibiotics. Two years later he presented increased headaches, fainting, and decreased vision in the right eye. Over the next four years, his headaches worsened, leading to complete vision loss in the right eye and compromised vision in the left eye. Evaluation by Internal Medicine revealed bradylalia, recent memory changes, a prominent supraorbital arch, pale optic disc with centered vessels in the right eye. Additionally, macroglossia, prognathism, and acromegaly-like changes in extremities were noted. Campimetry revealed left temporal hemianopsia. Hormonal profile: LH 0.04 mIU/mL (1.24 - 8.6 mIU/mL), FSH 0.21 mIU/mL (1.27 - 19.2 mIU/mL), TSH 4.78 mIU/mL (1.24 - 19.2 mIU/mL), Total T4 2.04 mcg/dL (4.5 - 10.9 mcg/dL), PRL 1.1 ng/mL (2.8 - 13.13 ng/mL) (at dilution 1:100) >20,000 ng/mL, Cortisol 0.903 mcg/dL (3.7 - 19.4 mcg/dL), IGF-1 1001 ng/mL (41 - 246 ng/mL), GH 12 ng/mL (0.03 - 2.47 ng/mL), Total Testosterone 0.13 ng/mL (1.6 - 8.7 ng/mL) MRI report: Invasive macroadenoma measuring 49x43x48 mm with partial inclusion of the right cavernous sinus and complete inclusion of the left cavernous sinus, bilateral carotid involvement with left predominance, involvement over the optic chiasm, pituitary stalk, floor of the sella turcica with migration towards the sphenoidal sinus. Diagnosis: Co-secreting PRL and GH pituitary macroadenoma, Secondary Hypogonadotropic Hypogonadism, Secondary Hypothyroidism, Secondary Adrenal Insufficiency. Treatment: Prednisone 5 mg PO QD, Cabergoline 0.5 mg PO QD 5/7 (MWFSS), Levothyroxine 100 mcg PO QD, Sostenon 240 mg/mL IM every 3 weeks. One week post-treatment initiation, the patient reported improvement.Follow-up labs showed normalized hormone levels. MRI revealed a 37x34x28 mm pituitary macroadenoma with bleeding and cystic changes. Surgery was deferred due to the favorable response to medical treatment. An annual MRI was performed, which showed a decrease in tumor size. By the seventh year, the tumor had reduced by 98% under the same treatment. Conclusion: Macroprolactinomas pose diagnostic challenges due to the prozone effect, requiring sample dilution for accurate diagnosis. Reflecting on the unexpected, this tumor co-secretes GH, which is uncommon; however, it responded effectively to medical treatment. Presentation: 6/3/2024

Prolactin response to growth hormone stimulation tests

BackgroundDespite many similarities between the structure, receptors, proliferative and growth promoting actions, the relationship between Prolactin (PRL) and Growth Hormone (GH) in clinical conditions has received little attention. ObjectiveTo determine the PRL response to GH stimulation tests. SubjectsPrepubertal and early pubertal boys (n = 581) and girls (n = 502) with idiopathic, non-syndromatic short stature. DesignData was retrieved from the computerized records of the Endocrine Laboratory, Schneider Children's Medical Center. Peak GH and PRL levels during GH stimulation tests with glucagon (Gluc), Clonidine (Clon) and Clonidine with arginine (Clon+Arg), were compared. Both PRL and GH were determined by radioimmunoassay. ResultsWhereas Gluc stimulated both GH and PRL to similar levels, Clon alone or combined with Arg suppressed the PRL secretion (p < 0.0001). It is also evident that in both boys and girls Clon alone and Clon±Arg are superior to Gluc in GH stimulation. The higher GH levels during Clon+Arg than with Clon alone are attributed to the pubertal stage. ConclusionThis study provides further information on the Prolactin-Growth hormone relationship in children.

Plurihormonal pituitary macroadenoma:\xa0 a case report

BackgroundPlurihormonal pituitary adenomas are a unique type of pituitary adenomas that secrete two or more pituitary hormones normally associated with separate cell types that have different immunocytochemical and ultrastructural features. Although they represent 10–15% of all pituitary tumors, only a small fraction of plurihormonal pituitary adenomas clinically secrete multiple hormones. The most common hormone combinations secreted by plurihormonal pituitary adenomas are growth hormone, prolactin, and one or more glycoprotein hormones. The most common hormonal symptom is acromegaly (50%). The aim of this case report is to bring awareness about this rare type of pituitary adenomas and to describe the unique presentation of our patient, even though plurihormonal pituitary adenomas are known mostly as a clinically silent tumors.Case presentationHerein, we describe an unusual case of plurihormonal pituitary adenoma with triple-positive staining for adrenocorticotropic hormone, growth hormone, and prolactin. The patient is a 65-year-old Egyptian woman who presented with mass effect symptoms of the pituitary tumor, which primarily manifested as severe headache and visual field defects. She also presented with some cushingoid features, and further analysis confirmed Cushing’s disease; slightly high prolactin and normal growth hormone levels were observed. She underwent transsphenoidal surgery and has been in remission thus far. Only a few cases have been reported in the literature, but none has exhibited silent acromegaly or mass effect symptoms as the initial presentation.ConclusionThis case highlights an unusual plurihormonal pituitary adenoma case with a rare combination of secreted hormones; mass effect symptoms were dominant, as were uncommon visual field defects. Our case further proves that immunohistochemical analyses of all pituitary hormones are needed to ensure correct diagnosis and to alert clinicians to the need for more rigorous follow-up due to the higher morbidity of these patients. Our case report approval number Federal Wide Assurance NIH, USA is FWA00018774 IRB registration number with OHRP/NIH is IRB00010471.

Interactions of amino acids and hormones regulate the balance between growth and milk protein synthesis in lactating rats fed diets differing in protein content.

Insulin-like growth factor-I (IGF-I), growth hormone (GH), and prolactin (PRL) play important roles in milk protein synthesis, and their plasma concentrations were reported to be affected by dietary protein intake. To investigate the relationship between circulating amino acid (AA) and concentrations of these hormones, 18 Wistar rats aged 14 wk were assigned to a low (LP; 9% protein), standard (SP; 21% protein), or high-protein (HP; 35% protein) diet from parturition through day 15 of lactation. Plasma, liver, pituitary gland, skeletal muscle, and mammary gland samples were collected at the end of treatment. Circulating and hepatic IGF-I concentrations increased linearly with elevated dietary protein concentrations (P < 0.0001). Rats receiving the HP diet had higher circulating GH (P < 0.01) and pituitary PRL concentrations (P < 0.0001) but lower pituitary GH concentration (P < 0.0001) relative to those in rats receiving the LP and SP diets. Pearson correlation test performed on composed data across treatments showed that several circulating AAs were correlated with circulating and tissue concentrations of IGF-I, GH, and PRL. Multiple linear regression analyses identified Leu, Gln, Ala, Gly, and Arg as the main AAs associated with hormone responses (R2 = 0.37 ~ 0.80; P < 0.05). Rats fed the LP and HP diets had greater Igf1 and Ghr gene expression in skeletal muscle than those fed the SP diets (P < 0.01). However, LP treatment decreased Prlr mRNA abundance in mammary glands as compared with the SP and HP treatments (P < 0.05). The HP diets increased AA transporter expression (P < 0.01) but decreased mammalian target of rapamycin (P < 0.05) and 70 kDa ribosomal protein S6 kinase 1 (P < 0.01) phosphorylation in mammary glands as compared with the LP and SP diets. The results of the present study suggested that several circulating AAs mediated the effects of dietary protein supply on concentrations of IGF-I, GH, and PRL, which in turn altered the metabolism status in peripheral tissues including the lactating mammary glands.

The Role of Placental Hormones in Mediating Maternal Adaptations to Support Pregnancy and Lactation

During pregnancy, the mother must adapt her body systems to support nutrient and oxygen supply for growth of the baby in utero and during the subsequent lactation. These include changes in the cardiovascular, pulmonary, immune and metabolic systems of the mother. Failure to appropriately adjust maternal physiology to the pregnant state may result in pregnancy complications, including gestational diabetes and abnormal birth weight, which can further lead to a range of medically significant complications for the mother and baby. The placenta, which forms the functional interface separating the maternal and fetal circulations, is important for mediating adaptations in maternal physiology. It secretes a plethora of hormones into the maternal circulation which modulate her physiology and transfers the oxygen and nutrients available to the fetus for growth. Among these placental hormones, the prolactin-growth hormone family, steroids and neuropeptides play critical roles in driving maternal physiological adaptations during pregnancy. This review examines the changes that occur in maternal physiology in response to pregnancy and the significance of placental hormone production in mediating such changes.

Over-Expression of GH/GHR in Breast Cancer and Oncosuppressor Role of Somatostatin as a Physiological Inhibitor

Background: The interaction between pituitary hormones (Growth Hormone-Prolactin), ovarian hormones (Estradiol) and growth factors forms the basis of the mechanisms underlying the growth of tumors of the breast. The literature contains reports of the increased expression of the mitogenic GH (Growth Hormone)/IGF1 (Insulin-Like Growth Factor) axis in tumor tissues compared to healthy tissues, with a directly proportional dose-dependent relationship between GH/IGF1, proliferative index and invasive ability in numerous types of tumors. Methods and Findings: We carried out this experimental research on the mitogenic role of GH and consequently on the rationale of the anticancer use of its inhibition. The levels of expression of several genes, GH and GHR, were evaluated in 39 cases of breast cancer, divided according to different risk levels on the basis of immunohistochemical and histological tests with nuclear grade. Conclusion: Research showed that breast cancers with a high and intermediate risk of recurrence are characterized by over-expression of GH and of its receptor (GHR). The expression was limited in cases with a low risk. The overexpression of GH-GHR in breast cancer with a ratio proportional to the level of aggressiveness is a rationale that can encourage a therapeutic intervention with inhibition of the mitogenic GH-IGF1-PRL axis and estrogen.

Exploration of Molecular Network Variations in Different Subtypes of Human Non-functional Pituitary Adenomas.

Exploration of Molecular Network Variations in Different Subtypes of Human Non-functional Pituitary Adenomas.

Growth hormone granulation pattern and somatostatin receptor subtype 2A correlate with postoperative somatostatin receptor ligand response in acromegaly: a large single center experience

Acromegaly is associated with serious morbidity and mortality, if not well controlled. Approved somatostatin receptor ligands (SRLs) are a mainstay of medical therapy and exhibit preferential affinity for somatostatin receptor (SSTR) subtype 2. Our objective was to assess whether characteristic features of individual growth hormone (GH)-secreting adenomas at diagnosis, correlated with SRL sensitivity, using defined tumor markers. A retrospective review of 86 consecutive acromegaly surgeries (70 patients) performed between January 2006 and December 2011 was undertaken. Patients with any preoperative medical treatment were excluded. Response to SRL therapy was defined as normalization of insulin-like growth factor 1 (IGF1) and random GH < 1.0 ng/dl. Immunohistochemical staining pattern: sparsely granulated, densely granulated, mixed growth hormone-prolactin (GH/PRL) and SSRT2 positivity (+) were correlated with clinicopathologic features, adenoma recurrence, and SRL treatment response. Two-tailed t test, univariate ANOVA, Kruskal-Wallis and bivariate correlation were performed using PAWS 18. The cohort eligible for analysis comprised 59 patients (41 female and 18 male). Based on pre-surgery adenoma imaging dimensions, 81.3% (48) were macroadenomas and average maximum tumor diameter was 18.1 ± 9.9 mm. Patients on SRLs were followed for 13.4 ± 15.8 (mean ± SD) months. Sparsely granulated adenomas were significantly larger at diagnosis, exhibited lower SSTR2 positivity and had a lower rate of biochemical normalization to SRLs. Densely granulated adenomas were highly responsive to SRLs. Overall, patients with SSTR2A+ adenomas responded more favorably to SRL treatment than those with SSTR2A- adenomas. Eighty-one percent of patients with SSTR2A+ adenomas were biochemically controlled (both GH and IGF1) on SRL treatment, e.g. a much higher normalization rate than that reported in the unselected acromegaly population (20-30%). Detailed knowledge of adenoma GH granularity and the immunohistochemical SSTR2A+ status is a predictor of SRL response. These immunoreactive markers should be assessed routinely on surgical specimens to assess subsequent SRL responsiveness and potential need for adjunctive therapy after surgery.

Downregulation of HMGA-targeting microRNAs has a critical role in human pituitary tumorigenesis

Previous studies have demonstrated that high mobility group A proteins have a critical role on the onset of human pituitary adenomas. Indeed, both high mobility group A (HMGA) genes are overexpressed in pituitary adenomas, and consistently transgenic mice overexpressing either the Hmga1 or the Hmga2 gene develop mixed growth hormone/prolactin (GH-PRL)-secreting pituitary adenomas. Trisomy of chromosome 12, where HMGA2 is located, and/or amplification of the HMGA2 gene locus account for the HMGA2 overexpression in most human prolactinomas. Conversely, HMGA1 overexpression is not associated to any rearrangement or amplification of the HMGA1 locus. We have first identified micro RNAs (miRNAs) able to target both HMGA1 and HMGA2 messenger RNAs. Then, all of these miRNAs have been found downregulated in pituitary adenomas of different histotypes, compared with normal pituitary. Interestingly, their downregulation was also observed in nonfunctioning pituitary adenomas where HMGA2 overexpression is not associated to any alteration of the HMGA2 locus. Functional studies show that all these HMGA-targeting miRNAs inhibit the proliferation of the rat pituitary adenoma cell line GH3. Therefore, these results indicate that the downregulation of the miRNAs able to target the HMGA genes could contribute to increase HMGA protein levels in human pituitary adenomas, and then to pituitary tumorigenesis.

Reassessment of the role of human placental lactogen in physiological non-pregnant and pathological conditions.

The recent demonstration of ectopic production of human placental lactogen (PL) in the human testis and ovary prompted us to reassess its role under non-pregnant physiological and pathological conditions. Possible physiological hPL concentrations and potential age-related changes in the sera of healthy young and elderly individuals (n = 75) selected according to the SENIEUR-protocol were investigated by a highly sensitive (detection limit: 2 pg/ml) and specific (cross-reactivity with prolactin and human growth hormone (hGH) of less than 0.001% and 0.0001%, respectively) monoclonal antibody-based time-resolved fluoroimmunoassay (IFMA) established in our laboratory. All individuals, even the aged probands (mean age: 72 +/- 3a), had hPL-levels below 20 pg/ml, in contrast to glycoprotein hormones, such as luteinizing hormone or human chorionic gonadotropin (hCG). To determine the significance of hPL as a tumour marker, serum samples of 12 testicular cancer patients with highly elevated levels of holo-hCG (mean: 42.490 ng/ml) at diagnosis were followed over 6-12 months and analysed with the hPL-IFMA. Elevation of hPL was seen in 10 patients, but the respective levels were 2-3 orders of magnitude smaller than those of holo-hCG and returned earlier to undetectable values. These in vivo data were compared to the hPL secretion pattern of the choriocarcinoma cell lines JAR and BeWo in vitro. In tissue culture supernatants of the two cell lines hPL was detected only in JAR cells, whereas both cell lines secreted holo-hCG. In conclusion, the fact that hPL is not physiologically present in peripheral blood but is produced ectopically in the human testis and ovary suggest auto/paracrine functions of this molecule. The significance of hPL as a tumour marker for patients with testicular cancer is limited as it provides no additional information to holo-hCG.

Development of a novel ligand that activates JAK2/STAT5 signaling through a heterodimer of prolactin receptor and growth hormone receptor

The objective of this study was to determine if a functional heterodimer of prolactin receptor (PRLR) and growth hormone receptor (GHR) can be formed in humans. A novel ligand was designed that is composed of a GHR antagonist (B2036) and a PRLR antagonist (G129R) fused in tandem (B2036-G129R). Because both B2036 and G129R are binding site 2 inactive antagonists, the B2036-G129R fusion protein, in theory contains only two functional binding site 1s: one for GHR and one for PRLR. We examined the behavior of this chimeric ligand in cell lines known to express GHR, PRLR, or both receptors. The data presented show that B2036-G129R is inactive in IM-9 cells that express only GHR or Nb2 cells that express PRLR. In T-47D cells that coexpress PRLR and GHR, B2036-G129R activates JAK2/STAT5 signaling. These findings provide evidence that B2036-G129R is able to activate signal transduction through a heterodimer of PRLR and GHR in humans.

Evolution of the Growth Hormone–Prolactin–Somatolactin System in Relation to Vertebrate Tetraploidizations

Gene sequences from several species representing major vertebrate groups were used to create phylogenetic trees for the growth hormone family of peptide hormones as well as the growth hormone receptor family. These analyses show that both the peptide and receptor families were formed through local duplications in early vertebrate evolution and chromosome duplications.

Prolactin/growth hormone–derived antiangiogenic peptides highlight a potential role of tilted peptides in angiogenesis

Angiogenesis is a crucial step in many pathologies, including tumor growth and metastasis. Here, we show that tilted peptides exert antiangiogenic activity. Tilted (or oblique-oriented) peptides are short peptides known to destabilize membranes and lipid cores and characterized by an asymmetric distribution of hydrophobic residues along the axis when helical. We have previously shown that 16-kDa fragments of the human prolactin/growth hormone (PRL/GH) family members are potent angiogenesis inhibitors. Here, we demonstrate that all these fragments possess a 14-aa sequence having the characteristics of a tilted peptide. The tilted peptides of human prolactin and human growth hormone induce endothelial cell apoptosis, inhibit endothelial cell proliferation, and inhibit capillary formation both in vitro and in vivo. These antiangiogenic effects are abolished when the peptides' hydrophobicity gradient is altered by mutation. We further demonstrate that the well known tilted peptides of simian immunodeficiency virus gp32 and Alzheimer's beta-amyloid peptide are also angiogenesis inhibitors. Taken together, these results point to a potential new role for tilted peptides in regulating angiogenesis.

Cloning and expression of two new prolactin-related proteins, prolactin-related protein-VIII and -IX, in bovine placenta

BackgroundProlactin-related proteins (PRPs) are specific proteins of the growth hormone/prolactin (GH/PRL) family in bovine placenta. This study reports the identification and sequencing of a full-length cDNA for two new members of bovine PRPs, bPRP-VIII and -IX, and their localization and quantitative expression in bovine placenta.MethodsNew bPRP-VIII and -IX were identified from bovine placentome. Localization and quantitative gene expression in the placenta were respectively investigated by in situ hybridization and real-time RT-PCR methods. Recombinant proteins of these genes were produced by a mammalian HEK293 cell expression system.ResultsFull-length bPRP-VIII and -IX cDNA were respectively cloned with 909 and 910 nucleotide open-reading-frames corresponding to proteins of 236 and 238 amino acids. The predicted bPRP-VIII amino acid sequence shared about 40 to 70% homology with other bPRPs, and bPRP-IX had about 50 to 80 % homology of others. The two new bPRPs were detected only in the placenta by RT-PCR. mRNA was primarily expressed in the cotyledon and intercotyledonary tissues throughout gestation. An in situ hybridization analysis revealed the presence of bPRP-VIII and -IX mRNA in the trophoblastic binucleate and/or trinucleate cells. bPRP-VIII mRNA was observed in the extra-embryonic membrane on Day 27 of gestation, however, no bPRP-IX mRNA was observed in the extra-embryonic membrane in the same stage of pregnancy by quantitative real-time RT-PCR analysis. Both new bPRP genes were possible to translate a mature protein in a mammalian cell expression system with approximately 28 kDa in bPRP-VIII and 38 kDa in bPRP-IX.ConclusionWe identified the new members of bovine prolactin-related protein, bPRP-VIII and -IX. Localization and quantitative expression were confirmed in bovine placenta by in situ hybridization or real-time PCR. Their different temporal and spatial expressions suggest a different role for these genes in bovine placenta during gestation.

Distribution of immunoreactive adenohypophysial cell types in the pituitaries of the Atlantic and the Pacific hagfish, Myxine glutinosa and Eptatretus burgeri

The hagfish is considered the most primitive vertebrate known, living or extinct. It remains an enigma whether adenohypophysial hormones similar to those of more advanced vertebrates are present in the hagfish pituitary gland or not. The present study aimed to detect immunoreactive adenohypophysial hormones in the hagfish pituitary gland, using antisera to tetrapod and fish adenohypophysial hormones as immunohistochemical probes. For this purpose, two species of hagfish, the Atlantic hagfish, Myxine glutinosa, and the Pacific hagfish, Eptatretus burgeri, were used. In both species, three different types of immunoreactive cells were detected in the adenohypophysis. (1) The first type of cells was gonadotropin (GTH)-like cells which were stained by antisera to LH-related GTHs, such as ovine LHβ, human LHβ, bullfrog LH, salmon LHβ and sturgeon LHβ in both species of hagfish. (2) The second type of cells that were detected was growth hormone (GH)/prolactin (PRL)-like cells. In M. glutinosa the cells were stained by antisera to salmon GH, salmon PRL, sturgeon GH, sturgeon PRL, blue shark GH, and lamprey GH. In E. burgeri the cells were only stained by anti-human GH and anti-sturgeon PRL. (3) The last type of cells was adrenocorticotropin (ACTH)-like cells. These cells were stained by antisera to lamprey ACTH and human β-endorphin. In both species of hagfish, GTH-like cells were relatively abundant, and were distributed throughout the adenohypophysis, whereas GH/PRL-like and ACTH-like cells were few in number in the adenohypophysis. Based on these findings, we suggest that hagfish may have retained ancestral characteristics of key anterior pituitary hormones.

Suppressor of Cytokine Signaling 7 Inhibits Prolactin, Growth Hormone, and Leptin Signaling by Interacting with STAT5 or STAT3 and Attenuating Their Nuclear Translocation

We report here the role of one of the less studied members of the family of suppressors of cytokine signaling (SOCS), namely SOCS-7, in cytokine signaling. We demonstrate that SOCS-7 inhibits prolactin (PRL), growth hormone (GH), or leptin (LEP) signaling mediated through STAT3 and STAT5 in a dose-dependent manner. SOCS-7 also attenuated STAT3 and STAT5 signaling induced by overexpression of JH1, the catalytic subdomain of JAK2. Since SOCS-7 interacted with phosphorylated STAT3 or STAT5, we assumed that SOCS-7 acts at the level of STAT proteins. Indeed, we showed that SOCS-7 inhibits PRL- and leptin-induced STAT5 and STAT3 phosphorylation and prevented the nuclear translocation of activated STAT3. Taken together, our results indicate that SOCS-7 is a physiological dysregulator of PRL, leptin, and probably also GH signaling and that its mode of action is a novel variation of SOCS protein inhibition of cytokine-inducible STAT-mediated signal transduction.

Genomic Structure and Functional Analysis of Promoter Region of Somatolactin Gene of Sea Bream (Sparus aurata)

Somatolactin (SL) is a pituitary hormone belonging to the growth hormone-prolactin family and is produced in the intermediate lobe of teleosts. The SL gene was isolated from a sea bream genomic library and found to be composed of 5 exons distributed within a 9-kb length of DNA. Sequence analysis of the proximal promoter region showed the presence of a classical TATA box located 59 bp upstream from the initial start ATG codon, 5 consensus sequences corresponding to the Pit-1 binding element, and a putative CREB site. In CHO cells cotransfected with the DNA from 2 plasmids, one encoding sea bream Pit-1 under Rous sarcoma virus long terminal repeat regulation and one encoding the SL promoter driving the expression of luciferase, Pit-1 was found to enhance the expression of luciferase. Only one Pit-1 binding site was necessary for enhancement. Analysis by immunoblots of in vitro culture of pituitaries of Sparus aurata showed that several agents, including estradiol, verapamil, and phorbol myristate acetate, had different inhibitory effects on SL and growth hormone released to the culture medium.

Ontogeny and nutritional manipulation of the hepatic prolactin–growth hormone–insulin-like growth factor axis in the ovine fetus and in neonate and juvenile sheep

The somatotrophic axis is the main endocrine system regulating postnatal growth; however, prenatal growth is independent of growth hormone (GH). Fetal development relies on the coordinated actions of a range of hormones, including insulin-like growth factors (IGF), and prolactin (PRL), in the control of differentiation, growth and maturation. In the sheep the abundance peaks for liver IGF-II and PRL receptors occur during late gestation while that for IGF-I receptor occurs at birth. All receptors, with the exception of GH receptor subsequently decrease by age 6 months. It has been proposed that maternal undernutrition during gestation regulates the maturation of the fetal hypothalmic-pituitary-adrenal axis and endocrine sensitivity. Critically, the timing of the nutritional insult may affect the magnitude of reprogramming. Maternal malnutrition during early to mid-gestation (3.2-3.8 MJ/d (60% total metabolisable energy requirements) v. 8.7-9.9 MJ/d (150% total metabolisable energy requirements) between 28 and 80 d of gestation) had no effect on body or liver weight. Nutrient-restricted (NR) fetuses sampled at 80 d (mid-gestation) showed up-regulation of hepatic PRL receptor, but following refeeding the normal gestational rise in PRL and GH receptors did not occur. Hepatic IGF-II receptor was down regulated in NR fetuses at both mid- and late gestation. Conversely, 6-month-old offspring showed no difference in the abundance of either GH receptor or PRL receptor, while IGF-II mRNA was increased. Offspring of ewes malnourished during late gestation (9.1 MJ/d (60% total metabolisable energy requirements) v. 12.7 MJ/d (100% total metabolisable energy requirements) from 110 d of gestation to term) showed reduced abundance of hepatic GH and PRL receptor mRNA. In conclusion, maternal undernutrition during the various stages of gestation reprogrammed the PRL-GH-IGF axis. Nutritional regulation of cytokine receptors may contribute to altered liver function following the onset of GH-dependent growth, which may be important in regulating endocrine adaptations during subsequent periods of nutritional deprivation.

Identification of mammosomatotropes, growth hormone cells and prolactin cells in the pituitary gland of the gilthead sea bream (Sparus aurata L., Teleostei) using light immunocytochemical methods: an ontogenetic study.

Growth hormone (GH) and prolactin (PRL) immunoreactivities in the adenohypophysis of Sparus aurata specimens from newly hatched until 48-months-old were detected using the peroxidase-antiperoxidase method. GH cells and PRL cells, and cells that were immunoreactive to both GH and PRL antisera, called mammosomatotropes (MS cells), were found. This is the first report on the identification of MS cells in fish, which were found in newly hatched and older larvae and juvenile specimens. GH and PRL cells appeared from two days after hatching. MS cells were first located in the central region of the adenohypophysis and afterwards in the rostral pars distalis. The GH cells were first identified in the dorsal and ventral areas of the middle-posterior part, and the PRL cells in the ventral region of the middle-anterior part. Later, during development, the sequence of appearance of the GH cells was proximal pars distalis, pars intermedia and rostral pars distalis, while for the PRL cells sequence was rostral pars distalis, proximal pars distalis and pars intermedia. This expansion pattern could be due to a GH- and PRL-cell migration although independent cell differentiation may occur in each region. The present results suggest that GH and PRL cells arise from MS cells at the outset of pituitary development, while MS cells proceed from PRL cells in old larvae and juveniles.

Cytokine Receptor Heterodimerization

The mechanism of signal initiation by placental lactogens (PLs) has been unclear. In heterologous systems, ruminant PLs can bind to both prolactin receptors (PRLRs) and growth hormone receptors (GHRs) from other species. In homologous systems (i.e., ovine PL binding to ovine PRLR or ovine GHR), ovine PL can act as antagonist for the ovine GHR in transfected cells, and the affinity of PL for the homodimeric receptors does not correlate with physiological activity. One possible explanation for the unusual characteristics of PL activity is that PL would induce heterodimerization of GHRs and PRLRs. Herman et al . demonstrate by gel filtration and surface plasmon resonance that ovine PL can induce heterodimers between the extracellular domains of ovine GHRs and bovine PRLRs. Heterodimers appeared to be functional, on the basis of cotransfection assays in which cotransfection of the ovine PRLR and GHR resulted in enhanced response to ovine PL. Further evidence for functional interaction of the GHR cytoplasmic domain with the PRLR cytoplasmic domain came from activation of signal transduction through chimeras between the extracellular domain of the α or β subunit of granulocyte and macrophage colony-stimulating factor receptor and the intracellular domain of GHR or PRLR. The data provide evidence for a mechanism of generating cytokine-signaling diversity through receptor heterodimerization. Herman, A., Bignon, C., Daniel, N., Grosclaude, J., Gertler, A., and Dijane, J. (2000) Functional heterodimerization of prolactin and growth hormone receptors by ovine placental lactogen. J. Biol. Chem. 275 : 6295-6301. [Abstract] [Full Text]