Proestrous Surge of Gonadotropin-Releasing Hormone Secretion Inhibits Apoptosis of Anterior Pituitary Cells in Cycling Female Rats

Yin, Ping; Ai, Jun

doi:10.1159/000066626

Cited by 25 publications

(36 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…sGC␣ 1 levels and timing of pituitary cell proliferation seem to be correlated. sGC␣ 1 expression raises on estrus and diestrus, while proliferation events are taking place, and remains low on proestrus, when the highest levels of apoptotic cells are detected (6,19,28). Thus the putative role of ␣ 1 in anterior pituitary cell renewal opens a very attractive landscape that is now under investigation.…”

Section: Discussionmentioning

confidence: 99%

Nitric oxide sensitive-guanylyl cyclase subunit expression changes during estrous cycle in anterior pituitary glands

Cabilla¹,

Ronchetti²,

Nudler³

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

Cabilla JP, Ronchetti SA, Nudler SI, Miler EA, Quinteros FA, Duvilanski BH. Nitric oxide sensitive-guanylyl cyclase subunit expression changes during estrous cycle in anterior pituitary glands. Am J Physiol Endocrinol Metab 296: E731-E737, 2009. First published January 13, 2009 doi:10.1152/ajpendo.90795.2008.-17␤-Estradiol (E 2 ) exerts inhibitory actions on the nitric oxide pathway in rat adult pituitary glands. Previously, we reported that in vivo E 2 acute treatment had opposite effects on soluble guanylyl cyclase (sGC) subunits, increasing ␣ 1-and decreasing ␤1-subunit protein and mRNA expression and decreasing sGC activity in immature rats. Here we studied the E 2 effect on sGC protein and mRNA expression in anterior pituitary gland from adult female rats to address whether the maturation of the hypothalamus-pituitary axis influences its effects and to corroborate whether these effects occur in physiological conditions such as during estrous cycle. E 2 administration causes the same effect on sGC as seen in immature rats, and these effects are estrogen receptor dependent. These results suggest that E 2 is the main effector of these changes. Since the sGC ␣-subunit increases while the sGC activity decreases, we studied if other less active isoforms of the sGC ␣-subunit are expressed. Here we show for the first time that sGC␣ 2 and sGC␣2 inhibitory (␣2i) isoforms are expressed in this gland, but only sGC␣ 2i mRNA increased after E2 acute treatment. Finally, to test whether E 2 effects take place under a physiological condition, sGC subunit expression was monitored over estrous cycle. sGC␣ 1, -␤1, and -␣ 2i fluctuate along estrous cycle, and these changes are directly related with E2 level fluctuations rather than to NO level variations. These findings show that E2 physiologically regulates sGC expression and highlight a novel mechanism by which E2 downregulates sGC activity in rat anterior pituitary gland. estrogen; soluble guanylyl cyclase; inhibitory subunit THE MAIN ESTROGENIC HORMONE 17␤-estradiol (E 2 ) plays important regulatory roles in a broad variety of biological processes, acting mainly on reproductive tissues, bone, liver, pituitary, and brain (9, 25).Nitric oxide (NO) is a signaling molecule that freely diffuses across cellular membranes where it binds to its main intracellular receptor, soluble guanylyl cyclase (sGC). This enzyme catalyzes the formation of cGMP from GTP. Subsequently, targets of cGMP such as cGMP-dependent protein kinases, cyclic nucleotide phosphodiesterases, and cyclic nucleotidesensitive ion channels are activated to continue the signal transduction (15,18).sGC is an heterodimeric enzyme and is comprised of two subunits, ␣ and ␤, of which four types exist (␣ 1 , ␣ 2, ␤ 1 , and ␤ 2 ). Both ␣-isoforms form a functional enzyme with the ␤ 1 -subunit, although the ␣ 1 ␤ 1 is the most abundant and widely expressed heterodimer, showing the greater activity (12, 13). The ␣ 2 is expressed in a more restricted pattern: in human tissues, it is present mainly in spleen, placenta, brain, ...

show abstract

Section: Discussionmentioning

confidence: 99%

Nitric oxide sensitive-guanylyl cyclase subunit expression changes during estrous cycle in anterior pituitary glands

Cabilla¹,

Ronchetti²,

Nudler³

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

show abstract

“…Massive release of GnRH is observed during the gonadotropin surge [29,30] and the period of elevated GnRH would be sufficiently long [30] so that GnRH could promote annexin A5 expression. This elevation of GnRH could also produce other cellular responses, including a reduction of a pro-apoptotic gonadotropes [31]. It is of interest to clarify the relationship between annexin A5 expression and gonadotrope-induced apoptosis during the afternoon of proestrus [31].…”

Section: Discussionmentioning

confidence: 99%

“…This elevation of GnRH could also produce other cellular responses, including a reduction of a pro-apoptotic gonadotropes [31]. It is of interest to clarify the relationship between annexin A5 expression and gonadotrope-induced apoptosis during the afternoon of proestrus [31]. On the other hand, GnRH may exert chronic effect in peripheral tissues since GnRH and its receptor are expressed in a wide variety of extra-pituitary tissues [32][33][34].…”

Section: Discussionmentioning

confidence: 99%

Gonadotropin Releasing Hormone (GnRH) Enhances Annexin A5 mRNA Expression through Mitogen Activated Protein Kinase (MAPK) in L.BETA.T2 Pituitary Gonadotrope Cells

et al. 2008

View full text Add to dashboard Cite

Abstract. The mechanism by which GnRH stimulates annexin A5 expression was examined with LβT2 gonadotrope cells. Continuous stimulation with GnRH analog (GnRHa, Des-Gly10 [Pro9]-GnRH ethylamide) transiently elevated LHβ mRNA expression while maintaining annexin A5 mRNA at high levels for 24 h. GnRH antagonist blocked the effect of GnRHa on annexin A5. While 12-O-tetradecanoyl-phorbol-13 acetate, a protein kinase C activator, increased the expression of annexin A5 mRNA, bisindolylmaleimide, an inhibitor of protein kinase C, suppressed GnRHa-stimulated expression of annexin A5 and LHβ mRNA. GnRHa stimulation of LHβ mRNA was inhibited to a greater extent than annexin A5 by a calcium chelator BAPTA/AM. Although a calcium ionophore ionomycin stimulated the expression of both genes, only LHβ was down-regulated. The MAPK kinase inhibitor PD98059 inhibited GnRHa induction of annexin A5 but not LHβ mRNA. EGF stimulated the expression of annexin A5 mRNA but caused only a transient effect on LHβ mRNA expression. These results indicate that GnRH stimulation of signaling pathway for annexin A5 mRNA expression is distinct from that of LHβ mRNA and dependent more on MAPK. GnRH is a hypothalamic neuropeptide that regulates pituitary gonadotropin secretion. GnRH neuron secretes GnRH in a pulsatile fashon at the median eminence of the hypothalamus. Portal blood also shows pulsatile fluctuations of GnRH [1]. The frequency of the GnRH pulses seems to influence the different effects on cell function of the gonadotropes [2][3][4]. Recently, we demonstrated that GnRH stimulates the expression of annexin A5 mRNA in gonadotropes [5][6][7][8]. Because ovariectomy enhanced annexin A5 expression in the gonadotropes and estradiol inhibited it, the expression of pituitary annexin A5 was thought to be physiologically regulated by hypothalamic GnRH [6]. We also demonstrated that annexin A5 participates in GnRH control of gonadotropin secretion. Annexin A5 itself stimulates both LH and FSH release, while an annexin A5 antisense oligonucleotide reduces GnRH stimulation of LH [7]. These findings suggest that intracellular annexin A5 is requisite for GnRH stimulation of gonadotropin secretion.In mammals, the annexin family consists of a group of at least 12 Ca 2+ -dependent phospholipid binding proteins [9,10]. Annexin A1 was first identified as a mediator of the anti-inflammatory activity of glucocorticoids [11]. The identification of other annexins followed, including annexin A5 that was discovered as a protein that inhibits phospholipase A 2 and suppresses blood coagulation [12,13]. These activities are thought to be due to its ability to bind phospholipids, although it is not clear whether these activities are relevant to physiological function. However, as we showed in the gonadotropes, annexin A5 may be at least necessary for an intracellular signaling in some cell types [14][15][16].

show abstract

“…Although we could not detect apoptosis in somatotropes, gonadotropes or corticotropes we cannot rule out that LPS may induce apoptosis in other cell types of the anterior pituitary. It was suggested that rapid degradation of secretory vesicles makes it difficult to identify which cell types in this gland undergo programmed cell death (21,33). Hence, it is possible that any secretory cell at late stages of apoptosis, including lactotropes, could account for nonidentified apoptotic cells.…”

Section: Discussionmentioning

confidence: 99%

Estrogens sensitize anterior pituitary gland to apoptosis

Pisera

Candolfi

Navarra

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

homeostasis results from a balance between cell proliferation and cell death by apoptosis. Estradiol affects proliferation as well as apoptosis in hormone-dependent tissues. In the present study, we investigated the apoptotic response of the anterior pituitary gland to lipopolysaccharide (LPS) in cycling female rats, and the influence of estradiol in this response in ovariectomized (OVX) rats. The OVX rats were chronically estrogenized with implanted Silastic capsules containing 1 mg of 17␤-estradiol (E2). Cycling or OVX and E2-treated rats were injected with LPS (250 g/rat ip). Apoptosis was determined by the terminal deoxynucleotidyl-mediated dUTP nickend labeling (TUNEL) method in sections of the anterior pituitary gland and spleen. Chronic estrogenization induced apoptosis in the anterior pituitary gland. Acute endotoxemia triggered apoptosis of cells in the anterior pituitary gland of E2-treated rats but not of OVX rats. No differences were observed in the apoptotic response to LPS in spleen between OVX and E2-treated rats. The apoptotic response of the anterior pituitary to LPS was variable along the estrous cycle, being higher at proestrus than at estrus or diestrus I. Approximately 75% of the apoptotic cells were identified as lactotropes by immunofluorescence. In conclusion, our results indicate that estradiol induces apoptosis and enables the proapoptotic action of LPS in the anterior pituitary gland. Also, our study suggests that estrogens may be involved in anterior pituitary cell renewal during the estrous cycle, sensitizing lactotropes to proapoptotic stimuli. estrous cycle; estradiol; lactotropes; lipopolysaccharide LIPOPOLYSACCHARIDE (LPS), an endotoxin of gram-negative bacteria, is commonly used to study neuroendocrine-immune interactions. After systemic administration of LPS, the plasma concentrations of several cytokines, such as TNF-␣, IL-1, and IL-6 rise in a temporal-sequential manner (14, 27). Systemic cytokines, as well as those locally released in the central nervous system and pituitary, contribute to the neuroendocrine response to endotoxemia, such as hypothalamic-pituitary-adrenal axis (HPA) activation and hypothalamic-pituitary-gonadal axis inhibition (27,28,29). We have reported that systemic LPS and central TNF-␣ administration exert inhibitory effects on prolactin secretion in male rats by stimulating dopaminergic activity in the hypothalamic-pituitary axis (4), and that LPS (25) and TNF-␣ (26) reduce in vitro prolactin release from anterior pituitary cells of female rats.Gonadal steroid hormones modulate the neuroendocrine response to inflammatory stimuli. It has been reported that endotoxin-induced HPA activation is higher in female than in male rats. This sexual difference is abolished by gonadectomy and restored by administration of estradiol to ovariectomized (OVX) rats (28). We have observed that estradiol stimulates basal and LPS-induced TNF-␣ secretion from anterior pituitary cells of OVX rats (25). Also, TNF-␣ release from anterior pituitary cells varies along the estrous...

show abstract

Proestrous Surge of Gonadotropin-Releasing Hormone Secretion Inhibits Apoptosis of Anterior Pituitary Cells in Cycling Female Rats

Cited by 25 publications

References 41 publications

Nitric oxide sensitive-guanylyl cyclase subunit expression changes during estrous cycle in anterior pituitary glands

Nitric oxide sensitive-guanylyl cyclase subunit expression changes during estrous cycle in anterior pituitary glands

Gonadotropin Releasing Hormone (GnRH) Enhances Annexin A5 mRNA Expression through Mitogen Activated Protein Kinase (MAPK) in L.BETA.T2 Pituitary Gonadotrope Cells

Estrogens sensitize anterior pituitary gland to apoptosis

Contact Info

Product

Resources

About