scholarly journals IGF-I inhibits apoptosis through the activation of the phosphatidylinositol 3-kinase/Akt pathway in pituitary cells

2004 ◽  
Vol 33 (1) ◽  
pp. 155-163 ◽  
Author(s):  
M Fernandez ◽  
F Sanchez-Franco ◽  
N Palacios ◽  
I Sanchez ◽  
C Fernandez ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Kinase Inhibitor ◽  
Cell Types ◽  
Pi3 Kinase ◽  
Pituitary Cell ◽  
Male Rat ◽  
Pituitary Cells ◽  
Signaling Transduction Pathway ◽  
Igf I ◽  
Rat Pituitary Cells

In previous studies we demonstrated that IGF-I induces proliferation of pituitary lactotrophs. In addition to its mitotrophic actions, IGF-I is known to prevent apoptosis induced by diverse stimuli in several cell types. In this study, we investigated the action of IGF-I on pituitary cell survival and the intracellular signaling transduction pathway implicated in this effect. Treatment of cultured male rat pituitary cells with IGF-I (10(-7) M) for 24 h prevented pituitary cell death induced by serum deprivation. The protective effect of IGF-I was blocked by phosphoinositide 3-kinase (PI3-kinase) inhibitor, LY294002, but was unaffected by PD98059, which inhibits MAP/ERK kinase (MEK1). IGF-I activation of PI3-kinase induced the phosphorylation and activation of the serine/threonine kinase Akt. Moreover, IGF-I increased the phosphorylation of the pro-apoptotic factor Bad and the levels of the anti-apoptotic protein Bcl-2 through the PI3-kinase pathway in primary pituitary cells.

scholarly journals Cell Type-Specific Metabolism of Peptidylglycineα -Amidating Monooxygenase in Anterior Pituitary*

Endocrinology ◽  
2000 ◽  
Vol 141 (8) ◽  
pp. 3020-3034 ◽  
Author(s):  
Rajaa El Meskini ◽  
Richard E. Mains ◽  
Betty A. Eipper
Keyword(s):  
Anterior Pituitary ◽  
Secretory Granules ◽  
Primary Cultures ◽  
Cell Types ◽  
Pituitary Cell ◽  
Male Rat ◽  
Pituitary Cells ◽  
Cell Type ◽  
Cell Content ◽  
Monooxygenase Activity

Peptidylglycine α-amidating monooxygenase (PAM) is a bifunctional enzyme expressed in each major anterior pituitary cell type. We used primary cultures of adult male rat anterior pituitary to examine PAM expression, processing, and secretion in the different pituitary cell types and to compare these patterns to those observed in transfected AtT-20 corticotrope tumor cells. Immunostaining and subcellular fractionation identified PAM in pituitary secretory granules and additional vesicular compartments; in contrast, in AtT-20 cells, transfected PAM was primarily localized to the trans-Golgi network. PAM expression was highest in gonadotropes, with moderate levels in somatotropes and thyrotropes and lower levels in corticotropes and lactotropes. Under basal conditions, less than 1% of the cell content of monooxygenase activity was secreted per h, a rate comparable to the basal rate of release of individual pituitary hormones. General secretagogues stimulated PAM secretion 3- to 5-fold. Stimulation with specific hypothalamic releasing hormones demonstrated that different pituitary cell types secrete characteristic sets of PAM proteins. Gonadotropes and thyrotropes release primarily monofunctional monooxygenase. Somatotropes secrete primarily bifunctional PAM, whereas corticotropes secrete a mixture of mono- and bifunctional proteins. As observed in transfected AtT-20 cells, pituitary cells rapidly internalize the PAM/PAM-antibody complex from the cell surface. The distinctly different steady-state localizations of endogenous PAM in primary pituitary cells and transfected PAM in AtT-20 cell lines may simply reflect the increased storage capacity of primary pituitary cells.

scholarly journals Quantification of in Vivo 3H-Estrogen Uptake by Individual Anterior Pituitary Cell Types of Male Rat:

1981 ◽  
Vol 29 (1A_suppl) ◽  
pp. 167-174 ◽  
Author(s):  
Donald A. Keefer
Keyword(s):  
Anterior Pituitary ◽  
Cell Types ◽  
Pituitary Cell ◽  
Male Rats ◽  
Male Rat ◽  
Pituitary Cells ◽  
Cell Tissue ◽  
Reliable Quantification ◽  
Refined Version

A refined version of the combined dry-mount auto-radiographic-immunocytochemical technique (Keefer DA, Stumpf WE, Petrusz P: Cell Tissue Res 166:25, 1976) is described in detail. In vivo nuclear estrogen uptake is measured by silver grain counting in immunocytochemically stained gonadotropes (G), somatotropes (S), lactotropes (L), corticotropes (C), and thyrotropes (T) of male rats. In rats 1 day after orchidectomy and adrenalectomy, the order of nuclear estrogen uptake was S = L G = C T, with T concentrating less than half as much radioactivity as L or S. Fifteen percent of anterior pituitary cells neither concentrated estrogen nor stained immunocytochemically. Estrogen uptake was examined in gonadotropes 1, 14, and 50 days after orchidectomy and was found to be identical at all three times. Estrogen uptake in gonadotropes of rats 14 days following orchidectomy and treatment with progesterone was reduced significantly. Guidelines for reliable quantification of the autoradiographic data is discussed.

Control of secretion in anterior pituitary cells--linking ion channels, messengers and exocytosis

1988 ◽  
Vol 139 (1) ◽  
pp. 287-316
Author(s):  
W. T. Mason ◽  
S. R. Rawlings ◽  
P. Cobbett ◽  
S. K. Sikdar ◽  
R. Zorec ◽  
...  
Keyword(s):  
Ion Channels ◽  
Intracellular Calcium ◽  
Anterior Pituitary ◽  
Hormone Secretion ◽  
Cell Types ◽  
Pituitary Cell ◽  
Pituitary Cells ◽  
Calcium Activity ◽  
Anterior Pituitary Cells ◽  
Voltage Dependent

Normal anterior pituitary cells, in their diversity and heterogeneity, provide a rich source of models for secretory function. However, until recently they have largely been neglected in favour of neoplastic, clonal tumour cell lines of pituitary origin, which have enabled a number of studies on supposedly homogeneous cell types. Because many of these lines appear to lack key peptide and neurotransmitter receptors, as well as being degranulated with accompanying abnormal levels of secretion, we have developed a range of normal primary anterior pituitary cell cultures using dispersion and enrichment techniques. By studying lactotrophs, somatotrophs and gonadotrophs we have revealed a number of possible transduction mechanisms by which receptors for hypothalamic peptides and neurotransmitters may control secretion. In particular, the transduction events controlling secretion from pituitary cells may differ fundamentally from those found in other cell types. Patch-clamp recordings in these various pituitary cell preparations have revealed substantial populations of voltage-dependent Na+, Ca2+ and K+ channels which may support action potentials in these cells. Although activation of these channels may gate Ca2+ entry to the cells under some conditions, our evidence taken with that of other laboratories suggests that peptide-receptor interactions leading to hormone secretion occur independently of significant membrane depolarization. Rather, secretion of hormone and rises in intracellular calcium measured with new probes for intracellular calcium activity, can occur in response to hypothalamic peptide activation in the absence of substantial changes in membrane potential. These changes in intracellular calcium activity almost certainly depend on both intracellular and extracellular calcium sources. In addition, strong evidence of a role for multiple intracellular receptors and modulators in the secretory event suggests we should consider the plasma membrane channels important for regulation of hormone secretion to be predominantly agonist-activated, rather than of the more conventional voltage-dependent type. Likewise, evidence from new methods for recording single ion channels suggests the existence of intracellular sites for channel modulation, implying they too may play an important role in secretory regulation. We shall consider new data and new technology which we hope will provide key answers to the many intriguing questions surrounding the control of pituitary hormone secretion. We shall highlight our work with recordings of single ion channels activated by peptides, and recent experiments using imaging of intracellular ionized free calcium.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals IGFs stimulate zebrafish cell proliferation by activating MAP kinase and PI3-kinase-signaling pathways

2001 ◽  
Vol 280 (4) ◽  
pp. R1230-R1239 ◽  
Author(s):  
Kasiani C. Pozios ◽  
Jun Ding ◽  
Brian Degger ◽  
Zee Upton ◽  
Cunming Duan
Keyword(s):  
Cell Proliferation ◽  
Protein Kinase ◽  
Dna Synthesis ◽  
Signaling Pathways ◽  
Kinase Inhibitor ◽  
Pi3 Kinase ◽  
Dependent Manner ◽  
Embryonic Cells ◽  
Kinase Signaling ◽  
Igf I

Insulin-like growth factor (IGF)-I and -II have been cloned from a number of teleost species, but their cellular actions in fish are poorly defined. In this study, we show that both IGF-I and -II stimulated zebrafish embryonic cell proliferation and DNA synthesis in a concentration-dependent manner, whereas insulin had little mitogenic activity. Affinity cross-linking and immunoblotting studies revealed the presence of IGF receptors with the characteristics of the mammalian type I IGF receptor. Competitive binding assay results indicated that the binding affinities of the zebrafish IGF-I receptors to IGF-I, IGF-II, and insulin are 1.9, 2.6, and >190 nM, indicating that IGF-I and -II bind to the IGF-I receptor(s) with approximately equal high affinity. To further investigate the cellular mechanism of IGF actions, we have studied the effects of IGFs on two major signal transduction pathways: mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3 kinase). IGFs activated MAPK in zebrafish embryonic cells in a dose-dependent manner. This activation occurred within 5 min of IGF-I stimulation and disappeared after 1 h. IGF-I also caused a concentration-dependent activation of protein kinase B, a downstream target of PI3 kinase, this activation being sustained for several hours. Inhibition of MAPK activation by the MAPK kinase inhibitor PD-98059 inhibited the IGF-I-stimulated DNA synthesis. Similarly, use of the PI3 kinase inhibitor LY-294002 also inhibited IGF-I-stimulated DNA synthesis. When both the MAPK and PI3 kinase pathways were inhibited using a combination of these compounds, the IGF-I-stimulated DNA synthesis was completely negated. These results indicate that both IGF-I and -II are potent mitogens for zebrafish embryonic cells and that activation of both the MAPK and PI3 kinase-signaling pathways is required for the mitogenic action of IGFs in zebrafish embryonic cells.

scholarly journals SAT-298 Integrative Single-Cell Transcriptomic and Epigenomic Landscape of Mouse Anterior Pituitary Cell Types

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Frederique Murielle Ruf-Zamojski ◽  
Michel A Zamojski ◽  
German Nudelman ◽  
Yongchao Ge ◽  
Natalia Mendelev ◽  
...  
Keyword(s):  
Single Cell ◽  
Cell Line ◽  
Anterior Pituitary ◽  
Cell Types ◽  
Chromatin Accessibility ◽  
Pituitary Cell ◽  
Integrated Analysis ◽  
Pituitary Cells ◽  
Rna Seq ◽  
Cell Type

Abstract The pituitary gland is a critical regulator of the neuroendocrine system. To further our understanding of the classification, cellular heterogeneity, and regulatory landscape of pituitary cell types, we performed and computationally integrated single cell (SC)/single nucleus (SN) resolution experiments capturing RNA expression, chromatin accessibility, and DNA methylation state from mouse dissociated whole pituitaries. Both SC and SN transcriptome analysis and promoter accessibility identified the five classical hormone-producing cell types (somatotropes, gonadotropes (GT), lactotropes, thyrotropes, and corticotropes). GT cells distinctively expressed transcripts for Cga, Fshb, Lhb, Nr5a1, and Gnrhr in SC RNA-seq and SN RNA-seq. This was matched in SN ATAC-seq with GTs specifically showing open chromatin at the promoter regions for the same genes. Similarly, the other classically defined anterior pituitary cells displayed transcript expression and chromatin accessibility patterns characteristic of their own cell type. This integrated analysis identified additional cell-types, such as a stem cell cluster expressing transcripts for Sox2, Sox9, Mia, and Rbpms, and a broadly accessible chromatin state. In addition, we performed bulk ATAC-seq in the LβT2b gonadotrope-like cell line. While the FSHB promoter region was closed in the cell line, we identified a region upstream of Fshb that became accessible by the synergistic actions of GnRH and activin A, and that corresponded to a conserved region identified by a polycystic ovary syndrome (PCOS) single nucleotide polymorphism (SNP). Although this locus appears closed in deep sequencing bulk ATAC-seq of dissociated mouse pituitary cells, SN ATAC-seq of the same preparation showed that this site was specifically open in mouse GT, but closed in 14 other pituitary cell type clusters. This discrepancy highlighted the detection limit of a bulk ATAC-seq experiment in a subpopulation, as GT represented ~5% of this dissociated anterior pituitary sample. These results identified this locus as a candidate for explaining the dual dependence of Fshb expression on GnRH and activin/TGFβ signaling, and potential new evidence for upstream regulation of Fshb. The pituitary epigenetic landscape provides a resource for improved cell type identification and for the investigation of the regulatory mechanisms driving cell-to-cell heterogeneity. Additional authors not listed due to abstract submission restrictions: N. Seenarine, M. Amper, N. Jain (ISMMS).

scholarly journals Direct Stimulatory Effects of Oxytocin in Female Rat Gonadotrophs and Somatotrophs In Vitro: Comparison With Lactotrophs

Endocrinology ◽  
2014 ◽  
Vol 156 (2) ◽  
pp. 600-612 ◽  
Author(s):  
Arturo E. Gonzalez-Iglesias ◽  
Patrick A. Fletcher ◽  
José A. Arias-Cristancho ◽  
Ruth Cristancho-Gordo ◽  
Cleyde V. Helena ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Cell Types ◽  
Pituitary Hormones ◽  
Prolactin Secretion ◽  
Female Rats ◽  
Pituitary Cells ◽  
Female Rat ◽  
Dependent Manner ◽  
Rat Pituitary Cells

The peptide oxytocin (OT) is secreted by hypothalamic neurons and exerts numerous actions related to reproduction. OT stimulation of prolactin secretion in female rats is important during the estrous cycle, pregnancy, and lactation. Here we report that OT also stimulates transients of intracellular Ca2+ concentration in somatotrophs and gonadotrophs as well as the release of GH and LH in a dose-dependent manner with EC50 values that closely correspond to the ligand affinity of the OT receptor (OTR). Remarkably, the hormone-releasing effect of OT in these two cell types is 2 orders of magnitude more sensitive than that in lactotrophs. The specific OTR agonist [Thr4,Gly7]-oxytocin acutely stimulated the release of LH, GH, and prolactin from female rat pituitary cells in primary culture and increased intracellular Ca2+ concentration in gonadotrophs, somatotrophs, and lactotrophs. In these three cell types, the effects on hormone release and intracellular Ca2+ of both OT and [Thr4,Gly7]oxytocin were abolished by the specific OT receptor antagonist desGly-NH2-d(CH2)5[D-Tyr2,Thr4]OVT but not by the highly selective vasopressin V1a receptor antagonist, d(CH2)5[Tyr(Me)2,Dab5]AVP. Furthermore, 10 nM arginine vasopressin stimulated LH and GH release comparably with a dose of OT that was at least 10 times lower. Finally, the presence of the OTR-like immunoreactivity could be observed in all three cell types. Taken together, these results show that OT directly stimulates gonadotrophs, somatotrophs, and lactotrophs through OT receptors and suggest that OT signaling may serve to coordinate the release of different pituitary hormones during specific physiological conditions.

scholarly journals Melatonin Regulates Somatotrope and Lactotrope Function Through Common and Distinct Signaling Pathways in Cultured Primary Pituitary Cells From Female Primates

Endocrinology ◽  
2015 ◽  
Vol 156 (3) ◽  
pp. 1100-1110 ◽  
Author(s):  
Alejandro Ibáñez-Costa ◽  
José Córdoba-Chacón ◽  
Manuel D. Gahete ◽  
Rhonda D. Kineman ◽  
Justo P. Castaño ◽  
...  
Keyword(s):  
Calcium Channels ◽  
Signaling Pathways ◽  
Somatostatin Receptors ◽  
Cell Types ◽  
Pituitary Hormones ◽  
Pituitary Cell ◽  
Pituitary Cells ◽  
Primate Model ◽  
Direct Role ◽  
Precise Relationship

Abstract Melatonin (MT) is secreted by the pineal gland and exhibits a striking circadian rhythm in its release. Depending on the species studied, some pituitary hormones also display marked circadian/seasonal patterns and rhythms of secretion. However, the precise relationship between MT and pituitary function remains controversial, and studies focusing on the direct role of MT in normal pituitary cells are limited to nonprimate species. Here, adult normal primate (baboons) primary pituitary cell cultures were used to determine the direct impact of MT on the functioning of all pituitary cell types from the pars distalis. MT increased GH and prolactin (PRL) expression/release in a dose- and time-dependent fashion, a response that was blocked by somatostatin. However, MT did not significantly affect ACTH, FSH, LH, or TSH expression/release. MT did not alter GHRH- or ghrelin-induced GH and/or PRL secretions, suggesting that MT may activate similar signaling pathways as ghrelin/GHRH. The effects of MT on GH/PRL release, which are likely mediated through MT1 receptor, involve both common (adenylyl cyclase/protein kinase A/extracellular calcium-channels) and distinct (phospholipase C/intracellular calcium-channels) signaling pathways. Actions of MT on pituitary cells also included regulation of the expression of other key components for the control of somatotrope/lactotrope function (GHRH, ghrelin, and somatostatin receptors). These results show, for the first time in a primate model, that MT directly regulates somatotrope/lactotrope function, thereby lending support to the notion that the actions of MT on these cells might substantially contribute to the define daily patterns of GH and PRL observed in primates and perhaps in humans.

scholarly journals Estrogen Actions on Lactotroph Proliferation Are Independent of a Paracrine Interaction with Other Pituitary Cell Types: A Study Using Lactotroph-Enriched Cells

Endocrinology ◽  
2007 ◽  
Vol 148 (7) ◽  
pp. 3131-3139 ◽  
Author(s):  
Maho Ishida ◽  
Wakaba Takahashi ◽  
Susumu Itoh ◽  
Shigetaka Shimodaira ◽  
Shuichiro Maeda ◽  
...  
Keyword(s):  
Fluorescent Protein ◽  
Cell Types ◽  
Cell Interaction ◽  
Pituitary Cell ◽  
Pituitary Cells ◽  
Dependent Manner ◽  
Paracrine Factor ◽  
Mitogenic Action ◽  
Estrogen Receptor Positive ◽  
Green Fluorescent

The mitogenic action of estrogen on estrogen-responsive tissues is suggested to be mediated by paracrine growth factors secreted from neighboring estrogen receptor-positive cells. Using pituitary lactotrophs in primary culture, on which estrogen exerts both mitogenic and antimitogenic actions in a cell context-dependent manner, we investigated whether a paracrine cell-to-cell interaction with other pituitary cell types was required for estrogen action. In pituitary cells, enriched for lactotrophs by 85% using differential sedimentation on a discontinuous Percoll gradient, 17β-estradiol (E2) showed an antimitogenic action on lactotrophs in the presence of IGF-I, which was similar to that in control unenriched cells. Mitogenic actions were also seen in lactotroph-enriched cells when E2 was administered alone, in combination with serum, or in combination with the adenylate cyclase activator forskolin. Similar results were obtained in 90% lactotroph-enriched cells collected by fluorescence-activated cell sorting from transgenic rats expressing enhanced green fluorescent protein under the control of the prolactin promoter. The putative role of basic fibroblast growth factor (bFGF) as a paracrine factor mediating the mitogenic action of estrogen was not supported by the results that: 1) bFGF inhibited lactotroph proliferation; 2) immunoneutralization of bFGF failed to block E2-induced proliferation; and 3) cellular bFGF levels were not altered by E2 treatment. These results suggest that the antimitogenic and mitogenic actions of estrogen on lactotrophs do not require paracrine signals from other pituitary cell types and that estrogen directly influences lactotroph proliferation.

scholarly journals Transcriptomic heterogeneity of Sox2-expressing pituitary cells

2021 ◽  
Author(s):  
Patrick A. Fletcher ◽  
Rafael M. Prévide ◽  
Kosara Smiljanic ◽  
Arthur Sherman ◽  
Steven L. Coon ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Types ◽  
Stem Cell Marker ◽  
Marker Genes ◽  
Pituitary Cells ◽  
Posterior Lobe ◽  
Female Rat ◽  
Stem Cell Pluripotency ◽  
Cell Niche ◽  
Rat Pituitary Cells

AbstractThe mammalian pituitary gland is a complex organ consisting of hormone-producing cells (HPC), nonhormonal folliculostellate cells (FSC) and pituicytes, vascular pericytes and endothelial cells, and putative Sox2-expressing stem cells. Here, we used scRNAseq analysis of adult female rat pituitary cells to study the heterogeneity of pituitary cells with a focus on evaluating the transcriptomic profile of the Sox2-expressing population. Samples containing whole pituitary and separated anterior and posterior lobe cells allowed the identification of all expected pituitary resident cell types and lobe-specific subpopulations of vascular cells. Sox2 was expressed uniformly in all FSC, pituicytes, and a fraction of HPC. FSC comprised two subclusters; FSC1 contained more cells but expressed less genetic diversity compared to FSC2. The latter contained proliferative cells, expressed genes consistent with stem cell niche formation, including tight junctions, and shared genes with HPC. The FSC2 transcriptome profile was also consistent with the activity of pathways regulating cell proliferation and stem cell pluripotency, including the Hippo and Wnt pathways. The expression of other stem cell marker genes was common for FSC and pituicytes (Sox9, Cd9, Hes1, Vim, S100b) or cell type-specific (FSC: Prop1, Prrx1, Pitx1, Pitx2, Lhx3; pituicytes: Fgf10, Tbx3, Lhx2, Nkx2-1, Rax). FSC and pituicytes also expressed other astroglial marker genes, some common and other distinct, consistent with their identities as astroglial cells of the pituitary. These data suggest functional heterogeneity of FSC, with a larger fraction representing classical FSC, and a smaller fraction containing active stem-like cells and HPC-committed progenitors.

scholarly journals Physical and Functional Interaction of Growth Hormone and Insulin-Like Growth Factor-I Signaling Elements

2004 ◽  
Vol 18 (6) ◽  
pp. 1471-1485 ◽  
Author(s):  
Yao Huang ◽  
Sung-Oh Kim ◽  
Ning Yang ◽  
Jing Jiang ◽  
Stuart J. Frank
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Intracellular Signaling ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Janus Kinase ◽  
Intact Cells ◽  
Igf I

Abstract GH and IGF-I are critical regulators of growth and metabolism. GH interacts with the GH receptor (GHR), a cytokine superfamily receptor, to activate the cytoplasmic tyrosine kinase, Janus kinase 2 (JAK2), and initiate intracellular signaling cascades. IGF-I, produced in part in response to GH, binds to the heterotetrameric IGF-I receptor (IGF-IR), which is an intrinsic tyrosine kinase growth factor receptor that triggers proliferation, antiapoptosis, and other biological actions. Previous in vitro and overexpression studies have suggested that JAKs may interact with IGF-IR and that IGF-I stimulation may activate JAKs. In this study, we explore interactions between GHR-JAK2 and IGF-IR signaling pathway elements utilizing the GH and IGF-I-responsive 3T3-F442A and 3T3-L1 preadipocyte cell lines, which endogenously express both the GHR and IGF-IR. We find that GH induces formation of a complex that includes GHR, JAK2, and IGF-IR in these preadipocytes. The assembly of this complex in intact cells is rapid, GH concentration dependent, and can be prevented by a GH antagonist, G120K. However, it is not inhibited by the kinase inhibitor, staurosporine, which markedly inhibits GHR tyrosine phosphorylation. Moreover, complex formation does not appear dependent on GH-induced activation of the ERK or phosphatidylinositol 3-kinase signaling pathways or on the tyrosine phosphorylation of GHR, JAK2, or IGF-IR. These results suggest that GH-induced formation of the GHR-JAK2-IGF-IR complex is governed instead by GH-dependent conformational change(s) in the GHR and/or JAK2. We further demonstrate that GH and IGF-I can synergize in acute aspects of signaling and that IGF-I enhances GH-induced assembly of conformationally active GHRs. These findings suggest the existence of previously unappreciated relationships between these two hormones.

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