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International Journal of Health Sciences and Research www.ijhsr.org ISSN: 2249-9571

Review Article

The Effect of on the Hypothalamic-Pituitary Gonadal Axis and

Zewdu Jima Takle1, Tesfaye Girma Legesse2

1Department of , 2Department of , Saint Paul‟s Hospital Millennium Medical College, Addis Ababa, Ethiopia

Corresponding Author: Zewdu Jima Takle

ABSTRACT

Leptin is a secreted by . Many researches done on leptin revealed that leptin plays a key role in regulation of energy, food intake and neuro-. One of the neuro- endocrine axis that expresses the effect of leptin is the i.e. hypothalamic-pituitary gonadal (HPG) axis. As several studies demonstrated, leptin affects HPG axis at different levels. , a center for feeding and endocrine system, is the major target site for expression of the effect of leptin, as this area of the contains leptin receptors. So, these receptors for leptin may mediate endocrine functions and HPG axis is one of them. There are a number of studies done to come across the effect of leptin on HPG axis and all of them evidenced that leptin has direct and indirect effect on HPG axis and releasing hormone (GnRH) is one of the key sites. But there are arguable findings among these researches regarding mechanism of action for leptin. Even though many experiments demonstrated that leptin may directly affects GnRH through its on GnRH, there are some that showed the effect of leptin on GnRH is indirect i.e. through GnRH synapsing neurons. The other target area for leptin is . It is demonstrated that leptin receptors are also found in anterior pituitary and administration of leptin stimulated (LH) and follicle stimulating hormone (FSH) secretion from anterior pituitary. In addition, leptin receptors are located in , injection of leptin to different experimental animals showed reversal of sterility and inhibition of steroidogenesis. On the other hand, many researches done to reveal the correlation between leptin and puberty, the results are controversial. As many findings demonstrated, increase in leptin concentration just before the onset of puberty is seen in humans and rats. On the contrary, some researches evidenced that there is no any correlation between level of leptin and onset of puberty and also there are findings showed the effect of leptin is permissive rather than primary triggering factor for the onset of puberty. Keywords: Anterior pituitary; Follicle stimulating hormone (FSH); Gonadotropin releasing hormone (GnRH); Gonads; Hypothalamic-pituitary Gonadal (HPG) Axis; Hypothalamus; leptin receptors; Leptin; Luteinizing hormone (LH); Steroidogenesis.

INTRODUCTION genetist Jeffery Friedman cloned the ob The obese or ob gene was first gene in mice and its homology in human. discovered in 1950 by a group of Then he purified the ob gene product, a researchers. Since the mutation of this gene hormone he called Leptin. [1] The name caused excessive in the mice, these Leptin is from a Greek root „leptos' meaning mice called ob/ob mice. However, the thin, [2] because it decreased food intake and physiology was yet unknown. But after body weight when administered in mice. [3-5] successive trial, in 1994 a molecular On the other hand, obesity in db/db mice

International Journal of Health Sciences & Research (www.ijhsr.org) 332 Vol.7; Issue: 5; May 2017 Zewdu Jima Takle et al. The Effect of Leptin on the Hypothalamic-Pituitary Gonadal Axis and Puberty was linked to a defect of the the central (CNS) and (LEPR), [6] because the diabetes or db gene peripheral organs. encodes the receptor for the obese (ob) gene product.

Fig.2. A Model for Secondary Structure of Leptin (source: http://www.sciencephoto.com/media/7818)

Leptin is also synthesized in the gastrointestinal tract, , [10-12] and in the brain. [13, 14] As Fig.1. A mouse (left) with a defect in the ob gene that encodes findings demonstrated in humans and ob/ob for leptin comparing to the normal mouse (right). mice, the rate of leptin production is directly (Source: http://newaswire.rockefeller.edu.Leptin /Accessed date: [15] February, 2017) related to mass and leptin mRNA in adipose tissue. [16] Peripheral leptin Leptin secretion concentrations also found decreased in [17] Leptin is an hormone response to . Furthermore in which is a 167 and human females, weight loss resulted in circulates as a 16-kD protein partially bound decrease in leptin level, while to plasma proteins. Human leptin is 84% significantly increased circulating leptin [18,19] identical to mouse leptin and 83% identical concentrations. Leptin secretion is also to rat leptin. [7] In one of these studies, the regulated by other factors (Table 1). proportion of bound leptin was reported to Regarding pattern of leptin secretion be higher in lean (45%) compared with in, humans, it is demonstrated that leptin is obese (20%) individuals. [8] Structural secreted in a circadian and pulsatile manner analysis indicates that leptin is similar to with a nocturnal rise. [20,21] . [9] It signals nutritional status to

Table 1. Factors That Regulate Leptin Expression (Source: Rexford and Jeffrey, 2000) Site Increase Decrease Adipose tissue Overfeeding Fasting Obesity (except ob mutation) Beta-adrenergic (in vitro) Acute infection ? hormone Cytokines (TNF-a, IL-1, LPS) Cold exposure Placenta Insulin Smoking Glucocorticoids Low Hypoxia Skeletal muscle (rat) Glucosamine fundus (rat) Feeding

Leptin receptors and domains; however, only the 'long receptor,' There are six varieties of the Leptin LEPRb, has intracellular motifs necessary receptors (LEPR, OB-R), “a” to “f”, have for activation of the Janus kinase-signal been identified. [22] LEPRa, LEPRb, LEPRc, transducers and activators of transcription LEPRd and LEPRf have transmembrane (JAK-STAT) signal transduction pathway.

International Journal of Health Sciences & Research (www.ijhsr.org) 333 Vol.7; Issue: 5; May 2017 Zewdu Jima Takle et al. The Effect of Leptin on the Hypothalamic-Pituitary Gonadal Axis and Puberty

LEPRe lacks both trans-membrane and extracellular and transmembrane domains as intracellular domains and circulates as a well as the same first 29 intracellular amino 'soluble receptor'. [23] acids. Short-form LEPRs contain exons l-17 Short-form LEPRs (LEPRa, LEPRc, and terminate 3-11 amino acids after the LEPRd, and LEPRf in mice) and the long- splice junction for total intracellular domain form LEPR (LEPRb in mice) contain exons lengths of 32-40 amino acids. [23] 1-17 of LEPR and therefore have identical

Fig.3. Different Leptin Receptor (Ob-R) Isoforms (source: Rexford SA and Jeffrey SF; 2000)

In pigs, long form of leptin receptor, blood brain barrier. [29, 30] In the Ob-Rb, was expressed in the hypothalamus, hypothalamus, the OB-Rb variant is the cerebral cortex, amygdala, , predominant isoform expressed, with high cerebellum and anterior pituitary. In expression noted in the addition, Ob-Rb was expressed in , (ARC), ventromedial nucleus (VMN) and uterine body, testes, , , , paraventricular nucleus (PVN) from studies adrenal , , spleen, lung, intestine, done in rats and mouse, and these areas are marrow, muscle and adipose tissue. known to be involved in the regulation of However, expression was absent in the feeding and [31] also in anterior thyroid, , superior venacava, aorta, pituitary. [32-34] spinal cord and oviduct. In similar experiment in human , Ob-Rb was expressed in brain, intestine, muscle, fat, heart, liver and umbilical cord. [24-27] In addition, In it is found that leptin receptors /LEPR/ are localized in the , ependymal lining, and neurons of the hypothalamic nuclei (arcuate, suprachiasmatic, mamillary, paraventricular, dorsomedial, supraoptic and posterior), inferior olivary nuclei and cerebellar [28] Fig.4. Localization of Leptin Receptors in the Varieties of Purkinje cells. It is suggested that LEPR Hypothalamic Area. ARC, arcuate nucleus; PVN, are localized in the choroid plexus may be paraventricular nucleus; LH, ; VMN, ventromedial nucleus; DMN, dorsomedial nucleus. involved in transport of leptin across the (source: B Beck; 2006)

International Journal of Health Sciences & Research (www.ijhsr.org) 334 Vol.7; Issue: 5; May 2017 Zewdu Jima Takle et al. The Effect of Leptin on the Hypothalamic-Pituitary Gonadal Axis and Puberty

Both leptin and its receptor share evidence for expression of Ob-R mRNA in structural and functional similarities with the gonads of mice, rats, and humans. [46,47] the interleukin-6 family of cytokines. [35] This leptin receptor localization in the Stimulation of the long form activates signal hypothalamic-pituitary gonadal axis has led transducer and activator of transcription to the suggestion that leptin may have an (STAT) proteins both in vivo and in vitro, important reproductive neuro-endocrine whereas the short form is apparently role. incapable of signaling through this pathway. The association between leptin and [36] Works done on signaling pathways for reproduction is mainly derived from leptin implicated that Janus kinase (JAK) researches done on relation of leptin and family members, STAT, as well as mitogen- reproductive . For example, a activated protein kinas (MAPK) pathways study done in healthy cycling women shows in leptin receptor are responsible to mediate there is a positive correlation between leptin signal transduction. [37-39] pulsatility, LH and plasma level. Study on the pathways responsible [48] In addition, findings from studies done for mediating the actions of leptin has on both ob/ob female and male mice shown that STAT-3 induces gene showed the administration of recombinant transcription of the suppressor of leptin significantly affected the reproductive signaling-3 (SOCS-3). [40] Over expression axis and restored in both sexes. [49] of SOCS-3 results in the inhibition of leptin- Besides, it corrected sterility which resulted induced phosphorylation of JAK-2, , pregnancy and parturition in the thus preventing the activation of the female ob/ob mice which further asserts JAK/STAT pathway following the addition leptin has influence on multiple stages of of leptin. [41] reproductive axis. [50] On the other hand, leptin treatment led to pubertal development in leptin deficient children, [51] which further confirms the critical role of leptin in reproduction. The effect of leptin on GnRH The long LEPR, LEPRb, is enriched in the hypothalamus, particularly, in the arcuate, dorsomedial, ventromedial and ventral premamillary nuclei which entail the role of leptin in feeding behavior and hormone regulation. [52] From study done on rats, leptin significantly increases GnRH secretion in vitro from hypothalamic area Fig.5. Cellular Signal Transduction of Leptin [53] (source: Christian and Barbara. 2004) and also FSH and LH secretion. In pigs, existence of Ob-R (Ob-Rb) in the The effect of leptin on HPG axis hypothalamus and pituitary and the fact that Leptin level communicates whether leptin increased LH secretion from pituitary there is sufficient energy available to cells and GnRH release from hypothalamic undertake energy-demanding physiological tissue [54] suggests that leptin acts through functions, including reproduction. the hypothalamic-pituitary axis. Since, in Distribution of Ob-R and its mRNA through dose related manner, leptin has been shown Hypothalamic-pituitary-gonadal axis has to stimulate GnRH secretion from the been examined in several species, including hypothalamus, [55, 56] it has been reported mouse, [42] rat [43,44] and human. [45] The Ob- that leptin may signal GnRH containing R has been found at all points along the neurons directly. HPG axis. Several groups have documented

International Journal of Health Sciences & Research (www.ijhsr.org) 335 Vol.7; Issue: 5; May 2017 Zewdu Jima Takle et al. The Effect of Leptin on the Hypothalamic-Pituitary Gonadal Axis and Puberty

On the contrary, experiments plays a role in feeding and reproduction. performed in rat showed there is little or no NPY has been shown to stimulate GnRH expression of Ob-R in GnRH neurons. [57] release, an action that may be mediated by However, this evidence still shows there synaptic contacts between NPY and GnRH could be a possibility for leptin to affect neurons. [70] NPY neurons in the ARC also GnRH directly. Furthermore, the presence express Ob-R, [71-73] which supports the of long LEPRb different nuclei of the possibility that GnRH modulation by NPY hypothalamus raised an idea that other and the overall effect of leptin on neurons may be intermediaries in the signal reproduction through NPY. On top of this, transduction pathway between leptin and another finding demonstrated that metabolic GnRH release. [58] signals in part are communicated to GnRH neurons via the γ-aminobutyric acid (GABA) neuronal pathway. [74] Over all, even though there are several studies that showed indirect stimulation of GnRH by leptin via different GnRH synapsing neurons, there are also some that revealed the expression of LEPR on GnRH neurons which asserts direct effect of leptin on GnRH.

Fig.6. Leptin-Kiss-1 Regulation of GnRH. (source: Jennifer et al. 2008)

Neurons from these LEPRb- expressing regions project to GnRH neurons and play roles in reproduction, including the ARC, medial (MPOA) and the PMv. One of these neurons is Kiss-l neuron. Leptin regulates expression of hypothalamic -1 (Kiss-l), which regulates GnRH Fig.7. Proposed Model for the Action of Leptin on Neuro- [59,60] endocrine Reproductive Axis. secretion. Cocaine and Amphetamine- (Source: Matthew et al. 1999) Regulated Peptide (CART) is also a facilitator of GnRH expression, and the The effect of leptin on anterior pituitary large population of CART neurons in the /LH and FSH secretion ARC and PMv that project onto GnRH Researches on monkeys ewes neuron-containing regions are key sites of demonstrated that anterior pituitary is also [61-63] direct or indirect leptin regulation. contains Ob-R. [75] It is also demonstrated (POMC) and that leptin stimulates GnRH and Opioid neurons also make direct synaptic gonadotropin release from pigs pituitary. [76] [64- contacts with GnRH-containing neurons, In addition, leptin treatment modulates 66] high expression of Ob-R on POMC GnRH and pulsatile LH frequency in rats. [67] neurons in the ARC is observed in rats [77] In these fasted female rats, both leptin and modulation of reproduction by the concentration and LH pulsatile frequency endogenous opioid 6-endprphin and a- are decreased. Besides, reduction is arrested melanocyte stimulating hormone (a-MSH) by administration of leptin. Another finding [68, 69] also seen. from a research done in rodents, rats [78, 79] Y (NPY) is another and male and female mice [80] also substance that is found in the ARC that

International Journal of Health Sciences & Research (www.ijhsr.org) 336 Vol.7; Issue: 5; May 2017 Zewdu Jima Takle et al. The Effect of Leptin on the Hypothalamic-Pituitary Gonadal Axis and Puberty demonstrated administration of exogenous presence has been demonstrated in rat leptin changed gonadal axis and prevented ovarian granulosa cells. [92] Similarly, in starvation induced delay in ovulation. other experiment, long and short isoforms of In the above experiments, leptin receptors are expressed in leydig cells particularly in the mice, leptin of rats. [93] Thus, granulosa and leydig cells administration (50 microg twice daily, ip) to contain the ability to respond to leptin. In males and females mice increased serum LH vitro experiments performed on theca, and FSH levels. granulosa, and luteinized granulosa cells In addition, fasting in different demonstrated that leptin can have an animals; sheep, [81,82] hamsters [83] monkeys, inhibitory influence on steroidogenesis in [84] rats [85,86] and mice, [87] caused bovine and primate models. [94,95] As these suppression of pulsatile LH secretion. findings indicated, leptin does not inhibit Furthermore, the same result is steroidogenesis directly rather, it does demonstrated in humans [88, 90] following inhibit various mechanisms that stimulate fasting. On the contrary, in female rats, steroidogenesis. As it is proposed, this pulsatile LH secretion is reversed by can be through inhibition of insulin induced refeeding fasted rats. [91] and estradiol production, and insulin induced progesterone and The effect of leptin on gonads production from bovine There are also many researches done granulosa and theca cells, respectively. [95] to understand the presence or absence of On the contrary, in male ob/ob mice, leptin receptors in mammalian gonads. leptin treatment corrected sterility, increased Using reverse transcription polymerase testicular and seminal vesicle weights and chain reaction (RT-PCR), leptin receptor increased production. [96]

Fig.8. Summary for the Role of Leptin in Regulating Reproductive System. Encircled “- -”and dashed line indicates a inhibitory effect; encircled “+” and solid line indicates stimulatory effect. (Source: LeonJ Spicer.2002)

The effect of leptin on puberty boys showed elevation of prepubertal leptin It is known that in humans onset of levels followed by a rise in testosterone but puberty is induced by an increase in leptin level decreased after initiation of pulsatile release of GnRH from the puberty. [97] In addition, an increase in leptin hypothalamus. In addition to those level is also seen in boys and girls children researches revealed the effect of leptin on just before puberty. [98] But, in this study, HPG-axis, there are studies done to discover plasma leptin was higher in girls than boys. the effect of leptin on puberty. A study in In male monkeys [99] and female rats [100] it

International Journal of Health Sciences & Research (www.ijhsr.org) 337 Vol.7; Issue: 5; May 2017 Zewdu Jima Takle et al. The Effect of Leptin on the Hypothalamic-Pituitary Gonadal Axis and Puberty also observed that leptin increased prior to ARC -Arcuate Nucleus the onset of puberty. Besides triggering CNS - puberty, leptin injection also caused earlier CART -Cocaine and Amphetamine-Regulated onset of puberty in normal female mice. [101] Peptide A study done in female mice DMN -Dorsomedial Nucleus FSH -Follicle Stimulating Hormone demonstrated that leptin is not the primary GABA -γ-Aminobutyric Acid signal to initiate onset of puberty rather it [102] GnRH -Gonadotropin Releasing Hormone has permissive function. Moreover, HPG-axis Hypothalamic-Pituitary Gonadal Axis research on male rhesus monkeys evidenced JAK -Janus Kinase that there is no correlation between level of LH -Leuthenazing Hormone leptin and onset of puberty. [103] LEPR /OB-R Leptin Receptor In humans, it is reported that higher MPOA -Medial Preoptic Area serum leptin concentrations is observed NPY - before, during and after puberty in girls than PVN -Paraventricular Nucleus boys also in post pubertal girls than POMC -Proopiomelanocortin prepubertal girls. [104] Regarding the pattern, RT-PCR -Reverse Transcription Polymerase Chain Reaction in both sexes, even though concentration of STAT -Signal Transducers and Activators of leptin increased before and during puberty, Transcription it lowered after puberty in the boys but it [105,106] SOCS-3 -Suppressor of Cytokine Signaling-3 increased in the girls. VMN -Ventromedial Nucleus On the other hand, under nutrition can delay the timing of pubertal onset which REFERENCES is seen in rats. [107] In these rats, earlier onset 1. http://newaswire.rockefeller.edu/2005/0 of puberty and estrus are demonstrated in 4/13/Jeffrey-friedman-discovered-leptin fed on high-fat than low-fat diets. It can also gairdner.Pas- sano-awards / Accessed inhibit reproductive behavior which is on February , 2017 observed in hamsters. [108] In humans, 2. http://en.Wikipedia.org / Leptin. accessed on February, 2017 weight loss in females can cause 3. Campfield LA, Smith FJ, Guisez Y, and can be restored by weight [109] Devos R, Burn P. Recombinant mouse gain. OB protein evidence for a peripheral signal linking adiposity and central CONCLUSION neural networks. Science. 1995; There are thousands of researches 269:546-9 done on the hormone leptin. The effect of 4. Halaas JL, Gajiwala KS, Mafei M leptin on reproduction was one of the target Cohen SI, Chait BTT, Rabinowitz D, et areas of these studies. All findings reviewed al. weight reducing effects of the plasma for this paper evidenced that leptin has protein encoded by the obese gene. effect on HPG axis, even though some of Science. 1995; 269:543-6 5. Pelleymounter MA, Cullen MJ, Baker them are controversial to each other. In MB, Hecht R, Winters D, Boone T, et addition, among researches done on the al. Effect of the obese gene product on effect of leptin on puberty most of them body weight regulation in ob/ob mice. revealed that leptin has effect on puberty. Science. 1995; 269: 540-3 But since there are also studies which stated 6. Lee GH, Proenca R, Montez JM, Carroll that leptin has no significant effect on the KM, Darvishadeh JG, Lee JI, Friedman onset of puberty further studies should be JM. Abnormal splicing of the leptin conducted to clearly identify the effect of receptor in diabetic mice. Nature. leptin on puberty. 1996;379:632-5. 7. Houseknechi KL, Mantzoros CS, List of abbreviations Kuliawat R, Hadro E, Flier JS, Kahn a-MSH α- Melanocyte Stimulating Hormone BB. Evidence for leptin binding to proteins in serum of rodents and

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How to cite this article: Takle ZJ, Legesse TG. The effect of leptin on the hypothalamo-pituitary gonadal axis and puberty. Int J Health Sci Res. 2017; 7(5):332-344.

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International Journal of Health Sciences & Research (www.ijhsr.org) 344 Vol.7; Issue: 5; May 2017