**8. References**


Estrogens in the Control of Growth Hormone Actions in Live**r** 65

Fisher B, Gunduz N, Saffer EA and Zheng S (1984) Relation of estrogen and its receptor to

Flores-Morales A, Fernandez L, Rico-Bautista E, Umana A, Negrin C, Zhang JG and

Flores-Morales A, Greenhalgh CJ, Norstedt G and Rico-Bautista E (2006) Negative regulation of growth hormone receptor signaling. *Mol Endocrinol*20:241-253. Flores-Morales A, Stahlberg N, Tollet-Egnell P, Lundeberg J, Malek RL, Quackenbush J, Lee

Foryst-Ludwig A and Kintscher U (2010) Metabolic impact of estrogen signalling through

Greenhalgh CJ and Alexander WS (2004) Suppressors of cytokine signalling and regulation

Gustavsson C, Yassin K, Wahlstrom E, Cheung L, Lindberg J, Brismar K, Ostenson CG,

Heldring N, Pike A, Andersson S, Matthews J, Cheng G, Hartman J, Tujague M, Strom A,

Ho KK, O'Sullivan AJ, Weissberger AJ and Kelly JJ (1996) Sex steroid regulation of growth

Holst B and Schwartz TW (2006) Ghrelin receptor mutations--too little height and too much

Horvat S and Medrano JF (2001) Lack of Socs2 expression causes the high-growth

Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, Hamelin M,

Huang DS and O'Sullivan AJ (2009) Short-term oral oestrogen therapy dissociates the

Kaplan SA and Cohen P (2007) The somatomedin hypothesis 2007: 50 years later. *J Clin* 

Kelly PA, Djiane J, Postel-Vinay MC and Edery M (1991) The prolactin/growth hormone

metabolism in premenopausal women. *Growth Horm IGF Res*19:162-167. Jansson JO, Eden S and Isaksson O (1985) Sexual dimorphism in the control of growth

Hreniuk DL, Palyha OC, Anderson J, Paress PS, Diaz C, Chou M, Liu KK, McKee KK, Pong SS, Chaung LY, Elbrecht A, Dashkevicz M, Heavens R, Rigby M, Sirinathsinghji DJ, Dean DC, Melillo DG, Patchett AA, Nargund R, Griffin PR, DeMartino JA, Gupta SK, Schaeffer JM, Smith RG and Van der Ploeg LH (1996) A receptor in pituitary and hypothalamus that functions in growth hormone release.

growth hormone/insulin-like growth factor-I axis without altering energy

rat liver growth and regeneration. *Cancer Res*44:2410-2415.

ERalpha and ERbeta. *J Steroid Biochem Mol Biol*122:74-81.

signal and what are their targets. *Physiol Rev*87:905-931.

hormone secretion and action. *Horm Res*45:67-73.

of growth hormone action. *Growth Horm IGF Res*14:200-206.

pathway. *Mol Endocrinol*15:1471-1483.

glucose output in rats. *BMC Biochem*11:38.

hunger. *J Clin Invest*116:637-641.

*Science*273:974-977.

phenotype in mice. *Genomics*72:209-212.

hormone secretion. *Endocr Rev*6:128-150.

receptor family. *Endocr Rev*12:235-251.

*Endocrinol Metab*92:4529-4535.

*Endocrinology*142:3163-3176.

1824.

pathway requires protein synthesis and phospholipase C. *Endocrinology*139:1815-

Norstedt G (2001a) Endoplasmic reticulum stress prolongs GH-induced Janus kinase (JAK2)/signal transducer and activator of transcription (STAT5) signaling

NH and Norstedt G (2001b) Microarray analysis of the in vivo effects of hypophysectomy and growth hormone treatment on gene expression in the rat.

Norstedt G and Tollet-Egnell P (2010) Sex-different hepaticglycogen content and

Treuter E, Warner M and Gustafsson JA (2007) Estrogen receptors: how do they


Carro E, Senaris R, Considine RV, Casanueva FF and Dieguez C (1997) Regulation of in vivo

Cho Y, Ariga M, Uchijima Y, Kimura K, Rho JY, Furuhata Y, Hakuno F, Yamanouchi K,

Colao A, Merola B, Ferone D and Lombardi G (1997) Acromegaly. *J Clin Endocrinol* 

Corpas E, Harman SM and Blackman MR (1993) Human growth hormone and human

Cui Y, Hosui A, Sun R, Shen K, Gavrilova O, Chen W, Cam MC, Gao B, Robinson GW and

Dahlman-Wright K, Cavailles V, Fuqua SA, Jordan VC, Katzenellenbogen JA, Korach KS,

Dominici FP and Turyn D (2002) Growth hormone-induced alterations in the insulin-

Elam MB, Simkevich CP, Solomon SS, Wilcox HG and Heimberg M (1988) Stimulation of in

Engblom D, Kornfeld JW, Schwake L, Tronche F, Reimann A, Beug H, Hennighausen L,

Fan Y, Menon RK, Cohen P, Hwang D, Clemens T, DiGirolamo DJ, Kopchick JJ, Le Roith D,

Faulds MH, Pettersson K, Gustafsson JA and Haldosen LA (2001) Cross-talk between ERs

Faulds MH, Zhao C, Dahlman-Wright K and Gustafsson JA (2011) Regulation of metabolism

Fernandez L, Flores-Morales A, Lahuna O, Sliva D, Norstedt G, Haldosen LA, Mode A and

two functionally separate mechanisms. *Mol Endocrinol*15:1929-1940.

signaling system. *Exp Biol Med (Maywood)*227:149-157.

vivo. *Endocrinology*122:1397-1402.

metabolism. *J Biol Chem*284:19937-19944.

by estrogen signaling. *J Endocrinol*.

*Dev*21:1157-1162.

of Pharmacology. LXIV. Estrogen receptors. *Pharmacol Rev*58:773-781. Della Torre S, Rando G, Meda C, Stell A, Chambon P, Krust A, Ibarra C, Magni P, Ciana P

Nishihara M and Takahashi S (2006) The novel roles of liver for compensation of insulin resistance in human growth hormone transgenic rats.

Hennighausen L (2007) Loss of signal transducer and activator of transcription 5 leads to hepatosteatosis and impaired liver regeneration. *Hepatology*46:504-513. D'Eon TM, Souza SC, Aronovitz M, Obin MS, Fried SK and Greenberg AS (2005) Estrogen

regulation of adiposity and fuel partitioning. Evidence of genomic and nongenomic regulation of lipogenic and oxidative pathways. *J Biol Chem*280:35983-

Maggi A, Muramatsu M, Parker MG and Gustafsson JA (2006) International Union

and Maggi A (2011) Amino acid-dependent activation of liver estrogen receptor alpha integrates metabolic and reproductive functions via IGF-1. *Cell Metab*13:205-

vitro triglyceride synthesis in the rat hepatocyte by growth hormone treatment in

Moriggl R and Schutz G (2007) Direct glucocorticoid receptor-Stat5 interaction in hepatocytes controls body size and maturation-related gene expression. *Genes* 

Trucco M and Sperling MA (2009) Liver-specific deletion of the growth hormone receptor reveals essential role of growth hormone signaling in hepatic lipid

and signal transducer and activator of transcription 5 is E2 dependent and involves

Gustafsson JA (1998) Desensitization of the growth hormone-induced Janus kinase 2 (Jak 2)/signal transducer and activator of transcription 5 (Stat5)-signaling

growth hormone secretion by leptin. *Endocrinology*138:2203-2206.

*Endocrinology*147:5374-5384.

aging. *Endocr Rev*14:20-39.

*Metab*82:2777-2781.

35991.

214.

pathway requires protein synthesis and phospholipase C. *Endocrinology*139:1815- 1824.


Estrogens in the Control of Growth Hormone Actions in Live**r** 67

Mode A, Ahlgren R, Lahuna O and Gustafsson JA (1998) Gender differences in rat hepatic

Mode A and Gustafsson JA (2006) Sex and the liver - a journey through five decades. *Drug* 

Morales O, Faulds MH, Lindgren UJ and Haldosen LA (2002) 1Alpha,25-dihydroxyvitamin

Olsson B, Bohlooly YM, Brusehed O, Isaksson OG, Ahren B, Olofsson SO, Oscarsson J and

Ribas V, Nguyen MT, Henstridge DC, Nguyen AK, Beaven SW, Watt MJ and Hevener AL

Rico-Bautista E, Negrin-Martinez C, Novoa-Mogollon J, Fernandez-Perez L and Flores-

Rogol AD (2010) Sex steroids, growth hormone, leptin and the pubertal growth spurt.

Rowland JE, Lichanska AM, Kerr LM, White M, d'Aniello EM, Maher SL, Brown R, Teasdale

Santana-Farre R, Flores-Morale A, Fernández-Pérez L (2008) Growth Hormone, Thyroid

Schwartzbauer G and Menon RK (1998) Regulation of growth hormone receptor gene

Segerlantz M, Bramnert M, Manhem P, Laurila E and Groop LC (2001) Inhibition of the rise

signaling domains and their associated transcripts. *Mol Cell Biol*25:66-77. Sampath H and Ntambi JM (2005) Polyunsaturated fatty acid regulation of genes of lipid

women and men. *J Clin Endocrinol Metab*94:3833-3841.

intact actin cytoskeleton. *Exp Cell Res*294:269-280.

metabolism. *Annu Rev Nutr*25:317-340.

expression. *Mol Genet Metab*63:243-253.

deficient adults. *J Clin Endocrinol Metab*86:5813-5818.

S.r.l., Rio de Janeiro (Brazil).

Suppl B:61-67.

*Metab Rev*38:197-207.

*Science*307:1625-1630.

*Rev*17:431-439.

*Endocr Dev*17:77-85.

CYP2C gene expression--regulation by growth hormone. *Growth Horm IGF Res*8

D3 inhibits GH-induced expression of SOCS-3 and CIS and prolongs growth hormone signaling via the Janus kinase (JAK2)/signal transducers and activators of transcription (STAT5) system in osteoblast-like cells. *J Biol Chem*277:34879-34884. Munzer T, Harman SM, Sorkin JD and Blackman MR (2009) Growth hormone and sex

steroid effects on serum glucose, insulin, and lipid concentrations in healthy older

Tornell J (2003) Bovine growth hormone-transgenic mice have major alterations in hepatic expression of metabolic genes. *Am J Physiol Endocrinol Metab*285:E504-511. Revankar CM, Cimino DF, Sklar LA, Arterburn JB and Prossnitz ER (2005) A

transmembrane intracellular estrogen receptor mediates rapid cell signaling.

(2010) Impaired oxidative metabolism and inflammation are associated with insulin resistance in ERalpha-deficient mice. *Am J Physiol Endocrinol Metab*298:E304-319. Rico-Bautista E, Flores-Morales A and Fernandez-Perez L (2006) Suppressor of cytokine

signaling (SOCS) 2, a protein with multiple functions. *Cytokine Growth Factor* 

Morales A (2004) Downregulation of the growth hormone-induced Janus kinase 2/signal transducer and activator of transcription 5 signaling pathway requires an

RD, Noakes PG and Waters MJ (2005) In vivo analysis of growth hormone receptor

Hormones and Estradiol interplay in vivo to regulate gene expression of Suppressors of Cytokine Signalling (SOCS), in *International Proceedings 13th International Congress of Endocrinology* (A. Godoy-Matos JW ed) pp 8-12, Medimond,

in FFA by Acipimox partially prevents GH-induced insulin resistance in GH-


Kerrigan JR and Rogol AD (1992) The impact of gonadal steroid hormone action on growth hormone secretion during childhood and adolescence. *Endocr Rev*13:281-298. Kharitonenkov A, Chen Z, Sures I, Wang H, Schilling J and Ullrich A (1997) A family of

Klover P and Hennighausen L (2007) Postnatal body growth is dependent on the

Kopchick JJ, Bellush LL and Coschigano KT (1999) Transgenic models of growth hormone

Kovacs P and Stumvoll M (2005) Fatty acids and insulin resistance in muscle and liver. *Best* 

Lanning NJ and Carter-Su C (2006) Recent advances in growth hormone signaling. *Rev* 

Laron Z, Ginsberg S, Lilos P, Arbiv M and Vaisman N (2006) Body composition in untreated

Le Roith D, Bondy C, Yakar S, Liu JL and Butler A (2001) The somatomedin hypothesis:

LeRoith D and Yakar S (2007) Mechanisms of disease: metabolic effects of growth hormone and insulin-like growth factor 1. *Nat Clin Pract Endocrinol Metab*3:302-310. Leung KC, Johannsson G, Leong GM and Ho KK (2004) Estrogen regulation of growth

Lichanska AM and Waters MJ (2008) How growth hormone controls growth, obesity and

Lundholm L, Bryzgalova G, Gao H, Portwood N, Falt S, Berndt KD, Dicker A, Galuska D,

Maher AC, Akhtar M, Vockley J and Tarnopolsky MA (2010b) Women have higher protein content of beta-oxidation enzymes in skeletal muscle than men. *PLoS One*5:e12025. Meinhardt UJ and Ho KK (2006) Modulation of growth hormone action by sex steroids. *Clin* 

Miller ME, Michaylira CZ, Simmons JG, Ney DM, Dahly EM, Heath JK and Lund PK (2004)

intestinal epithelial cell proliferation. *Gastroenterology*127:570-581.

Zierath JR, Gustafsson JA, Efendic S, Dahlman-Wright K and Khan A (2008) The estrogen receptor {alpha}-selective agonist propyl pyrazole triol improves glucose tolerance in ob/ob mice; potential molecular mechanisms. *J Endocrinol*199:275-286. Lupu F, Terwilliger JD, Lee K, Segre GV and Efstratiadis A (2001) Roles of growth hormone and insulin-like growth factor 1 in mouse postnatal growth. *Dev Biol*229:141-162. Maher AC, Akhtar M and Tarnopolsky MA (2010a) Men supplemented with 17beta-

estradiol have increased beta-oxidation capacity in skeletal muscle. *Physiol* 

Suppressor of cytokine signaling-2: a growth hormone-inducible inhibitor of

LeRoith D (2009) Gender differences in metabolic disorders. *Gend Med*6 Suppl 1:1-3. Leroith D and Nissley P (2005) Knock your SOCS off! *J Clin Invest*115:233-236.

adult patients with Laron syndrome (primary GH insensitivity). *Clin Endocrinol* 

186.

*Endocrinology*148:1489-1497.

action. *Annu Rev Nutr*19:437-461.

*Endocr Metab Disord*7:225-235.

2001. *Endocr Rev*22:53-74.

*Genomics*42:342-347.

*Endocrinol (Oxf)*65:413-422.

*(Oxf)*65:114-117.

*Pract Res Clin Endocrinol Metab*19:625-635.

hormone action. *Endocr Rev*25:693-721.

sexual dimorphism. *Trends Genet*24:41-47.

proteins that inhibit signalling through tyrosine kinase receptors. *Nature*386:181-

transcription factors signal transducers and activators of transcription 5a/b in muscle: a role for autocrine/paracrine insulin-like growth factor I.


Estrogens in the Control of Growth Hormone Actions in Live**r** 69

Vidal O, Lindberg MK, Hollberg K, Baylink DJ, Andersson G, Lubahn DB, Mohan S,

Vidal OM, Merino R, Rico-Bautista E, Fernandez-Perez L, Chia DJ, Woelfle J, Ono M,

Vidarsdottir S, Walenkamp MJ, Pereira AM, Karperien M, van Doorn J, van Duyvenvoorde

Wang L, Zhang X, Farrar WL and Yang X (2004) Transcriptional crosstalk between nuclear

Wang Y and Cheng CH (2004) ERalpha and STAT5a cross-talk: interaction through C-

Wang Z, Masternak MM, Al-Regaiey KA and Bartke A (2007) Adipocytokines and the

Waters MJ, Shang CA, Behncken SN, Tam SP, Li H, Shen B and Lobie PE (1999) Growth

Wauthier V, Sugathan A, Meyer RD, Dombkowski AA and Waxman DJ (2010) Intrinsic sex

Waxman DJ and Holloway MG (2009) Sex differences in the expression of hepatic drug

Waxman DJ and O'Connor C (2006) Growth hormone regulation of sex-dependent liver

Waxman DJ, Ram PA, Park SH and Choi HK (1995) Intermittent plasma growth hormone

Wehrenberg WB and Giustina A (1992) Basic counterpoint: mechanisms and pathways of gonadal steroid modulation of growth hormone secretion. *Endocr Rev*13:299-308. Wiwi CA and Waxman DJ (2004) Role of hepatocyte nuclear factors in growth hormone-

Woelfle J, Chia DJ and Rotwein P (2003) Mechanisms of growth hormone (GH) action.

male-specific liver gene transcription. *J Biol Chem*270:13262-13270.

like growth factor-I gene activation. *J Biol Chem*278:51261-51266.

translocation and DNA-binding. *FEBS Lett*572:238-244.

hormone as a cytokine. *Clin Exp Pharmacol Physiol*26:760-764.

5479.

7.

*Endocrinol*21:293-311.

*Immunol*1:416-424.

*Factors*22:79-88.

mice. *Endocrinology*148:2845-2853.

mouse liver. *Mol Endocrinol*24:667-678.

metabolizing enzymes. *Mol Pharmacol*76:215-228.

gene expression. *Mol Endocrinol*20:2613-2629.

Gustafsson JA and Ohlsson C (2000) Estrogen receptor specificity in the regulation of skeletal growth and maturation in male mice. *Proc Natl Acad Sci U S A*97:5474-

Lenhard B, Norstedt G, Rotwein P and Flores-Morales A (2007) In vivo transcript profiling and phylogenetic analysis identifies suppressor of cytokine signaling 2 as a direct signal transducer and activator of transcription 5b target in liver. *Mol* 

HA, White S, Breuning MH, Roelfsema F, Kruithof MF, van Dissel J, Janssen R, Wit JM and Romijn JA (2006) Clinical and biochemical characteristics of a male patient with a novel homozygous STAT5b mutation. *J Clin Endocrinol Metab*91:3482-3485. Vijayakumar A, Novosyadlyy R, Wu Y, Yakar S and LeRoith D (2010) Biological effects of

growth hormone on carbohydrate and lipid metabolism. *Growth Horm IGF Res*20:1-

receptors and cytokine signal transduction pathways in immunity. *Cell Mol* 

terminal portions of the proteins decreases STAT5a phosphorylation, nuclear

regulation of lipid metabolism in growth hormone transgenic and calorie-restricted

differences in the early growth hormone responsiveness of sex-specific genes in

triggers tyrosine phosphorylation and nuclear translocation of a liver-expressed, Stat 5-related DNA binding protein. Proposed role as an intracellular regulator of

regulated, sexually dimorphic expression of liver cytochromes P450. *Growth* 

Identification of conserved Stat5 binding sites that mediate GH-induced insulin-


Simpson ER, Misso M, Hewitt KN, Hill RA, Boon WC, Jones ME, Kovacic A, Zhou J and

Sjoberg A, Oscarsson J, Boren J, Eden S and Olofsson SO (1996) Mode of growth hormone

B-containing lipoproteins in cultured rat hepatocytes. *J Lipid Res*37:275-289. Sos BC, Harris C, Nordstrom SM, Tran JL, Balazs M, Caplazi P, Febbraio M, Applegate MA,

Stahlberg N, Merino R, Hernandez LH, Fernandez-Perez L, Sandelin A, Engstrom P, Tollet-

actions using a compilation of gene expression profiles. *BMC Physiol*5:8. Stahlberg N, Rico-Bautista E, Fisher RM, Wu X, Cheung L, Flores-Morales A, Tybring G,

translocase/CD36 in rat and human liver. *Endocrinology*145:1972-1979. Stofega MR, Wang H, Ullrich A and Carter-Su C (1998) Growth hormone regulation of SIRP and SHP-2 tyrosyl phosphorylation and association. *J Biol Chem*273:7112-7117. Svensson J, Lonn L, Jansson JO, Murphy G, Wyss D, Krupa D, Cerchio K, Polvino W, Gertz

*Rev*26:322-330.

1423.

Clyne CD (2005) Estrogen--the good, the bad, and the unexpected. *Endocr* 

administration influences triacylglycerol synthesis and assembly of apolipoprotein

Wagner KU and Weiss EJ (2011) Abrogation of growth hormone secretion rescues fatty liver in mice with hepatocyte-specific deletion of JAK2. *J Clin Invest*121:1412-

Egnell P, Lenhard B and Flores-Morales A (2005) Exploring hepatic hormone

Norstedt G and Tollet-Egnell P (2004) Female-predominant expression of fatty acid

B, Boseaus I, Sjostrom L and Bengtsson BA (1998) Two-month treatment of obese subjects with the oral growth hormone (GH) secretagogue MK-677 increases GH secretion, fat-free mass, and energy expenditure. *J Clin Endocrinol Metab*83:362-369. Takahashi J, Furuhata Y, Ikeda A, Takahashi M, Iwata H, Kazusaka A and Fujita S (1999)

Characterization of hepatic cytochrome P450 isozyme composition in the transgenic

the sexually dimorphic spontaneous GH secretory profiles and hepatic STAT5

Bodner S, Grosveld G and Ihle JN (1998) Stat5a and Stat5b proteins have essential

Differential cloning of growth hormone-regulated hepatic transcripts in the aged

Gene expression profile of the aging process in rat liver: normalizing effects of

and Norstedt G (2004) Growth hormone-mediated alteration of fuel metabolism in the aged rat as determined from transcript profiles. *Physiol Genomics*16:261-267. Udy GB, Towers RP, Snell RG, Wilkins RJ, Park SH, Ram PA, Waxman DJ and Davey HW

(1997) Requirement of STAT5b for sexual dimorphism of body growth rates and

Aromatase inhibition impairs skeletal modeling and decreases bone mineral

rat expressing low level human growth hormone. *Xenobiotica*29:1203-1212. Tannenbaum GS, Choi HK, Gurd W and Waxman DJ (2001) Temporal relationship between

Teglund S, McKay C, Schuetz E, van Deursen JM, Stravopodis D, Wang D, Brown M,

and nonessential, or redundant, roles in cytokine responses. *Cell*93:841-850. Tollet-Egnell P, Flores-Morales A, Odeberg J, Lundeberg J and Norstedt G (2000)

Tollet-Egnell P, Flores-Morales A, Stahlberg N, Malek RL, Lee N and Norstedt G (2001)

Tollet-Egnell P, Parini P, Stahlberg N, Lonnstedt I, Lee NH, Rudling M, Flores-Morales A

Vanderschueren D, van Herck E, Nijs J, Ederveen AG, De Coster R and Bouillon R (1997)

growth hormone replacement. *Mol Endocrinol*15:308-318.

liver gene expression. *Proc Natl Acad Sci U S A*94:7239-7244.

density in growing male rats. *Endocrinology*138:2301-2307.

activity. *Endocrinology*142:4599-4606.

rat. *Endocrinology*141:910-921.


**4** 

**Somatostatin in the Periventricular** 

**Effects of Estrogen and Onset of** 

*Human and Animal Physiology Group, Dept. Animal Sciences,* 

Eline M. Van der Beek, Harmke H. Van Vugt,

**Reproductive Aging** 

*Wageningen University & Research Centre* 

*The Netherlands* 

**Nucleus of the Female Rat: Age Specific** 

Annelieke N. Schepens-Franke and Bert J.M. Van de Heijning

The functioning of the growth hormone (GH) and reproductive axis is known to be closely related: both GH overexpression and GH-deficiency are associated with dramatic decreases in fertility (Bartke, 1999; Bartke et al, 1999; 2002; Naar et al, 1991). Also, aging results in

In the rat, GH secretion patterns are clearly sexually dimorphic (Clark et al, 1987; Eden et al, 1979; Gatford et al, 1998). This has been suggested to result mainly from differences in somatostatin (SOM) release patterns from the median eminence (ME) (Gillies, 1997; Muller et al, 1999; Tannenbaum et al, 1990). SOM is synthesized in the periventricular nucleus of the hypothalamus (PeVN) and controls in concert with GH-releasing hormone (GHRH) the GH release from the pituitary (Gillies, 1987; Tannenbaum et al, 1990; Terry and Martin, 1981; Zeitler et al, 1991). An altered GH status is reflected in changes in the hypothalamic SOM system. For instance, the number of SOM cells (Sasaki et al, 1997) and pre-pro SOM mRNA levels (Hurley and Phelps, 1992) in the PeVN were elevated in animals overexpressing GH. Several observations suggest that SOM may also affect reproductive function directly at the level of the hypothalamus. SOM synthesis in the hypothalamus and its release from the ME fluctuate over the estrous cycle. (Estupina et al, 1996, Zorrila et al, , 1991). Central injections with SOM or a SOM analog (octreotide) decreased the number of gonadotropic cells in the pituitary (Lovren et al, 1998; Nestorovic et al 2002; 2003). Also, we previously showed that a single central injection with octreotide significantly attenuated the E2-induced Luteinizing Hormone (LH) surge and significantly decreased the activation of Gonadotropin Releasing

significant changes in functionality of both axes within a similar time frame.

Hormone (GnRH) cells in the hypothalamus of female rats (van Vugt et al, 2004).

Age-related changes in fertility and fecundity are associated with selective changes at the level of the ovary and uterus (Meredith and Butcher, 1985; Nass et al, 1984; te Velde et al, 1998; Wise, 1982), pituitary gland (Brito et al, 1994; DePaolo et al, 1986; Krieg et al, 1995; Nass et al, 1984; Wise, 1982), and hypothalamus (Rubin et al, 1994; Wise, 1982; Wise et al, 2002*).* Reproductive aging is characterized by changes in the length of the reproductive

**1. Introduction** 

