• hippocampus;
  • olfactory system;
  • heart;
  • bladder;
  • somatotrophs


  1. Top of page
  2. Abstract
  3. Influence of GnRH in the central nervous system
  4. GnRH affects pituitary cells other than gonadotrophs
  5. Effects of GnRH outside the pituitary and brain
  6. Conclusions
  7. Acknowledgements
  8. References

Gonadotrophin-releasing hormone (GnRH) is a hypothalamic decapeptide with an undisputed role as a primary regulator of gonadal function. It exerts this regulation by controlling the release of gonadotrophins. However, it is becoming apparent that GnRH may have a variety of other vital roles in normal physiology. A reconsideration of the potential widespread action that this traditional reproductive hormone exerts may lead to the generation of novel therapies and provide insight into seemingly incongruent outcomes from current treatments using GnRH analogues to combat diseases such as prostate cancer.

Gonadotrophin-releasing hormone (GnRH) was among an array of hypothalamic-releasing factors discovered almost four decades ago by the laboratories of Schally and Guillemin (1). Confirmation that GnRH was released into hypophyseal portal blood (2, 3) cemented the contention that this decapeptide was unique to the reproductive hypothalamic-pituitary axis. However, there are occasional reports that GnRH has unexpected effects or is present in nonreproductive tissues, forcing us to reconsider this restricted reproduction-only view. For example, GnRH has activity on the sympathetic ganglia of the frog (4), GnRH receptor expression is present in the cerebellum (5) and bladder (6), and GnRH is released in significant concentrations into cerebrospinal fluid (CSF) (7), to potentially act outside the hypothalamus through volume transmission (8). Indeed, GnRH may have evolved with functions extraneous to reproduction. Studies on octopi provide evidence that GnRH has potent cardiovascular roles (9).

More than 40 different GnRH precursors have been identified (10, 11). Most of the evidence available in mammals indicates that GnRH I and chicken GnRH II have been conserved in this class, although GnRH II has not been retained in all species (12). In mammals, two GnRH receptors have been identified, type I and type II, but the type II GnRH receptor has been silenced in several species (10, 12). It is possible that the functions of GnRH II and the type II GnRH receptor have been assumed by GnRH I and/or the type I GnRH receptor. Except for an evolutionary context, this review focuses on GnRH I and the type I GnRH receptor.

There is compelling evidence that GnRH and its receptor may perform fundamental roles in cancer cells (13) but it is arguable that these tumour effects do not occur in ‘normal’ physiology. There are also several studies showing local GnRH and GnRH receptor production in extrapituitary reproductive tissues: endometrium (14), ovary (15, 16), placenta (17–19), testis (20, 21) and prostate (22). Thus, the purpose of this short review is to summarise evidence that, in addition to its well-established reproductive roles, GnRH may affect multiple tissues that are not directly associated with the reproductive axis or cancer. Table 1 summarises the putative nonreproductive sites of action of GnRH in mammals. This review will address areas in which studies have attempted to address the physiological significance of GnRH effects.

Table 1.   Sites Outside the Hypothalamic-Pituitary-Reproductive Axis that are Potential Gonadotrophin-Releasing Hormone Targets (GnRH).
 Evidence of GnRH receptorsSpeciesReferences
  1. a, binding of a GnRH ligand (e.g. radioactive, biotinylated); b, GnRH receptor mRNA; c, immunoreactive GnRH receptors; d, cellular responses (e.g. cell signalling, electrophysiological, secretory). *There are several other central nervous system sites that have been identified. A more complete list is provided elsewhere (37, 39).

Nervous tissue*
 Retinaa, b, cMouse, rat, vole(88, 99, 141)
 Olfactory bulba, cMouse, rat(37, 39, 89)
 Cortex, especially Piriforma, cMouse, rat(37, 39, 140)
 Lateral septuma, b, cMouse, rat(34, 37, 39)
 Preoptic areab, c, dMouse, sheep(31, 32, 39, 82)
 Arcuate nucleusb, c, dMouse, sheep(25, 26, 39, 82)
 Hippocampusa, cMouse, rat, sheep(37, 39)
 Amygdalaa, cMouse, rat, sheep(37, 39)
 Central greya, cMouse, rat, sheep(39, 129)
 Cerebellumb, c, dMouse, rat(5, 88, 95)
 Spinal cordbSheep(180)
 Growth hormonea, dRat, human(107, 118, 122–127, 181)
 ProlactindRat, human(118, 182, 183)
 Thyroid-stimulating hormone, adrenocorticotrophic hormonedRat(118)
 Kidneya, b, dMouse, rat, human(19, 131, 139–142, 145, 175, 184, 185)
 Livera, bMouse, rat, human(19, 89, 139–142, 145, 175, 185)
 Hearta, b, c, dMouse, human(19, 89, 139–143, 145, 159)
 Bladdera, bMouse, dog, human(6, 139, 171, 172)
 Toothb, cMouse(186, 187)
 Adrenala, bMouse, rat, human, cow(17, 139, 141, 142, 145, 162–164, 185)
 Skina, bMouse, rat, dog(139, 142, 173)
 Skeletal musclebRat, human(19, 139, 141, 145)
 Spleena, dMouse, rat(89, 140, 141, 145, 188, 189)
 Lymphocytesa, b, dMouse, rat, human(89, 174, 189, 190)

Influence of GnRH in the central nervous system

  1. Top of page
  2. Abstract
  3. Influence of GnRH in the central nervous system
  4. GnRH affects pituitary cells other than gonadotrophs
  5. Effects of GnRH outside the pituitary and brain
  6. Conclusions
  7. Acknowledgements
  8. References

It has been known for nearly three decades that GnRH can affect the central nervous system. Not only can GnRH depolarise sympathetic ganglion neurones in the frog (4, 23, 24), but also GnRH has been shown to affect hypothalamic (25, 26), hippocampal (27–29), cerebellar (30), preoptic (31, 32) and cortical (30, 33) neurones in the rat. Indeed, there is evidence that GnRH may influence neurones in numerous other locations (34–39). Although GnRH projections may be widespread in the brain (40–44), the discovery that GnRH is released by the median eminence in large quantities into third ventricle CSF (Fig. 1a) (7, 45–48) frees this decapeptide from the constraints of synaptic transmission expanding its potential sphere of influence. As shown in Table 1, several areas within the central nervous system have been reported to express GnRH receptors.


Figure 1.  (a) Oestrogen induced luteinising hormone (LH) surge in the jugular blood and commensurate gonadotrophin-releasing hormone (GnRH) surges in the hypophyseal portal system and cerebrospinal fluid (CSF) of an ewe. Details of CSF harvesting are provided elsewhere (179). (b) GnRH receptor-immunoreactive neurones in the murine hippocampus. Details of immunocytochemistry are provided elsewhere (39). (c) Lipopolysaccharide (LPS), but not GnRH, induced temperature changes on the skin of the ewe ear. (d) Effect of growth hormone-releasing hormone (GHRH) and GnRH on GH secretion from an ovariectomised, progesterone treated ewe.

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The hippocampus consistently expresses high levels of GnRH receptors. In the human hippocampus, pyramidal neurones were recently found to express immunoreactive GnRH receptors (49). Similarly, GnRH receptor-immunoreactive neurones were found almost exclusively within the pyramidal cell layer, dentate gyrus, and indusium griseum of the mouse and sheep (Fig. 1b) (39). Hippocampal pyramidal neurones in the rat take up I125-buserilin when it is injected into the lateral ventricle (37) but it should be noted that endogenous GnRH is not detectable in the lateral ventricle (48). There is evidence from the rat that the indusium griseum receives GnRH projections (40) and GnRH has been detected in human hippocampus extractions (50). GnRH alters the electrical properties of rat hippocampal pyramidal cells (27–29) and stimulates increased IP3 production within these cells (51). Both these effects are modified by oestrogen in the rat (27). In sheep, hippocampal GnRH receptor-expressing neurones co-express ERβ (39). Because GnRH is likely to be elevated post-menopause due to the loss of oestrogen negative feedback (52), the effect of GnRH on these neurones may constitute a component of the neurodegenerative pathology that accompanies Alzheimer’s disease (53). It is notable that hippocampal spinophilin, a reliable dendritic spine marker, is significantly decreased in response to high doses of GnRH (54).

Olfactory system

GnRH receptor expressing neurones are evident throughout the olfactory system in the rodent (36, 39, 55). These structures include the mitral cell layers of the olfactory and accessory olfactory bulbs, piriform cortex, tenia tecta and amygdala. GnRH has been detected in the hamster accessory olfactory bulb (42) and in the rat piriform cortex (55). The tenia tecta contain a discrete population of testosterone sensitive GnRH-immunoreactive neurones in the hamster (43, 56). GnRH has also been reported within the terminal nerve, which projects to several olfactory regions (57) and is a structure associated with reproductive behaviour in hamsters (58, 59). It is noteworthy that olfactory bulbectomy eliminates mating behaviour in hamsters (60), mice (61) and shrews (62). GnRH has been proposed to alter the detection of specific odours relevant to reproduction via a neuromodulatory effect (57). Such modulation may be the cause of variations in smell perception across the menstrual cycle (63, 64). GnRH receptor-expressing neurones were distributed throughout the amygdala (39). Although some studies (37) have reported a limited distribution of GnRH binding sites in the rat amygdala, others have detected a high density of potential GnRH receptor expressing neurones in this region of the mouse (34) and rat (65). GnRH may access these receptors through neurones that project directly to the amygdala (66). Lesions of the amygdala decrease lordotic behaviour in the rat (67) and prevent ovulation (66).

Central grey and sexual behaviour sites

GnRH receptors have been reported within the central grey of the rat (37), mouse (39) and sheep (39). Importantly, GnRH injections into the rat central grey potentiated lordosis (68, 69). GnRH immunoreactive fibres have been identified within the rat central grey (41) and significant amounts of GnRH have been extracted from midbrain preparations in this species (70). Additionally, the intimate association between the central grey, the fourth ventricle and cerebral aqueduct allows potential access for CSF-borne GnRH. We have shown in sheep that, during the luteinising hormone (LH) surge, GnRH concentrations will be elevated in this vicinity (48).

Cerebral cortex

GnRH binds to cerebral cortex neurones (37), which express immunoreactive GnRH receptors (39, 71). Indeed, GnRH receptor-immunoreactive neurones in the cerebral cortex are widespread, suggesting that GnRH may act as common neuromodulatory peptide. In the rat, GnRH depresses the activity of cortical neurones (30, 33) and has been shown to affect neurite outgrowth and neurofilament protein expression in cultured cortical neurones (72). We are unaware of GnRH immunoreactive fibres being reported in cortical regions. We have already noted the presence of GnRH in the piriform cortex (55). Low levels of GnRH have been reported in the human cortex (50). In addition, the splicing intermediate of mature GnRH mRNA, which still contains intron A, has also been detected in the rat cortex (73, 74). It is possible that third ventricle CSF-GnRH accesses these cortical GnRH receptor-expressing neurones, especially during the GnRH surge because this lasts for more than 40 h. In support of this conjecture, Chauhan et al. (75) injected trypan blue into the third ventricle of the mouse and, after 24 h, this trypan blue was detected in the dorsal cortex. Similarly, when the 40-kDa plant glycoprotein, horseradish peroxidase, is injected into the lateral ventricle, it distributes widely and is evident in cortical areas within 4 h (76). There is evidence in women that chronic GnRH agonist administration affects cortical functioning (77, 78) but these studies cannot discriminate between direct GnRH effects or the induced hypo-oestrogenic environment. However, it is noteworthy that exogenous GnRH can access the brain (48).

Lateral septum, preoptic area and arcuate nucleus

GnRH receptor-expressing neurones in the lateral septum (34, 39) provide neuroanatomical support explaining why GnRH administered to this region affects thermoregulatory activity in the rat (79, 80). It is noteworthy that dysregulation of the GnRH system has been suggested as a causative factor in hot flashes (80, 81). However, in a preliminary study in sheep (Fig. 1c), we found no effect of 1 mg GnRH i.v. on peripheral thermoregulatory events. This 1-mg dose elevates CSF-GnRH into the physiological range (48). The presence of GnRH receptor-expressing neurones in the preoptic area and arcuate nucleus (39, 82) is in keeping with the findings of electrophysiological studies (25, 26, 31, 32). Because these regions have a surfeit of GnRH in their vicinity, the potential source of ligand is not a conundrum. It has been hypothesised that GnRH may modulate its own release through an ultrashortloop feedback system (83, 84). This hypothesis is supported by evidence that some GnRH neurones are electrophysiologically responsive to GnRH (31, 32) and also express GnRH receptors (85). However, we found that physiological infusions of exogenous GnRH into the third ventricle did not perturb endogenous GnRH release (86). GnRH neurones receive input from far more neurones than previously thought (87) and thus it is possible that any effects of this exogenous GnRH (86) on endogenous GnRH release may have been countered by input from these neurones.

Cerebellum and motor control sites

GnRH receptor expression within the superior colliculus (39), red nucleus (39) and cerebellum (5, 88, 89) suggests that GnRH may modulate motor control. Previous studies have reported GnRH binding within the superior colliculus (90). The red nucleus has been implicated in movement, possesses cerebellar connections, and projects to the olivary nucleus (91, 92). It is noteworthy that the red nucleus contains an abundance of dopamine neurones and low levels of immunoreactive GnRH have been reported in the human red nucleus (50). Because GnRH inhibits the synthesis of dopamine (93), it may act within the red nucleus to regulate dopamine production. The cerebellum plays complex roles in motor behaviour and cognition. Cerebellar Purkinje cells are GABAergic and provide inhibitory output from the cerebellum, whereas cerebellar granule cells act to modulate the actions of the Purkinje cells through excitatory glutamatergic input (94). Centrally-administered GnRH significantly affects both cerebellar glutamate and GABA content (95). The source of GnRH for these cerebellar and other motor control sites is unclear but GnRH immunoreactivity has been reported in Purkinje cells (89) and low levels of GnRH have been detected in extracts of the middle lobe of the human cerebellum (50). There is also evidence that antibodies administered into the third ventricle have access to the cerebellum (75). Thus, CSF-GnRH may affect this part of the brain.

Cerebellar GnRH activity may provide a correlative link between seemingly different symptoms associated with at least two genetic disorders, Gordon Holmes’ syndrome (GHS) and Boucher–Neuhauser syndrome. GHS is characterised by cerebellar ataxia and gonadal insufficiency. The gonadotrophin deficiency is not reversed with GnRH treatment, suggesting gonadotroph insensitivity (96). GHS is attributed to an autosomal recessive genetic defect (97) but there is no evidence that the GnRH receptor gene is mutated (96). This does not eliminate problems with GnRH and its receptor as potential key players in GHS pathology because mutation of possible downstream targets would cause problems with activation of the receptor, such as G-protein coupling, glycosylation or second messenger systems. Boucher–Neuhauser syndrome is characterised by the same symptoms as GHS but with the addition of chorioretinal atrophy (98). GnRH and the GnRH receptor have been reported in the retina of mammals (88, 99) and fish (100); GnRH may play a role in normal ocular development in the zebrafish (101). Testing the hypothesis that GnRH has a physiological role in the mammalian cerebellum may be technologically challenging. Of interest, Minakata et al. (102) reported that administering GnRH into the octopus cerebellum has profound effects on motor activity, providing some preliminary support for this hypothesis.

Thus, there is compelling evidence that GnRH may act on several sites throughout the brain. However, apart from the strong evidence that GnRH plays a role in sexual behaviour, unequivocal data supporting physiologically functional roles for these other GnRH receptor expressing sites in the mammalian central nervous system are lacking.

GnRH affects pituitary cells other than gonadotrophs

  1. Top of page
  2. Abstract
  3. Influence of GnRH in the central nervous system
  4. GnRH affects pituitary cells other than gonadotrophs
  5. Effects of GnRH outside the pituitary and brain
  6. Conclusions
  7. Acknowledgements
  8. References

Hypothalamic factors, although named according to their first discovered function, are known to stimulate the release of pituitary hormones that are not associated with their name. For example, thyrotrophin-releasing hormone has been shown to stimulate growth hormone (GH) and prolactin release (103, 104). On the other hand, the recently discovered prolactin-releasing factor has no effect on prolactin release in vivo (105, 106). GnRH has been shown to stimulate prolactin release in the rat (107) but this effect is thought to be mediated through paracrine modulation of lactotrophs by gonadotrophs (108). It is notable that in mammals [rat (109), mouse (110), monkey (111), sheep (112)], a proportion of gonadotrophs express GH (or somatotrophs express LH). We (113) and others (114, 115) have also observed in sheep that, at the time of the oestradiol-induced LH surge, there is a concomitant GH surge. In fish, GnRH is a potent stimulator of GH release (116) and a significant proportion of chicken somatotrophs respond to GnRH (117). Villalobos et al. (118) showed that all cell types (GH, adrenocorticotrophic hormone, thyroid-stimulating hormone, prolactin) in the rat pituitary responded to GnRH with both an increase in intracellular Ca2+ and in hormone release. Although it is maintained that, in higher vertebrates, GnRH does not stimulate GH release (119), few studies have been conducted. GnRH-induced GH release has been reported in some (120), but not all (121), normal males, and many studies have observed an effect of GnRH on GH release in individuals with disorders: anorexia (122), schizophrenia (123), acromegaly (124), diabetes (125) and Klinefelter’s syndrome (126). GnRH-induced GH secretion was observed in vitro in the rat, but only in the early post-natal period (107, 127). Our preliminary studies in ovariectomised ewes (Fig. 1d) suggest that a physiological dose of GnRH is able to elicit an increase in GH release. One putative role of this GnRH-induced GH secretion may be in luteogenesis after the pre-ovulatory LH surge. LH and GH are the primary luteotropic hormones that support the development and function of the corpus luteum in domestic ruminants (128).

Taken together, these studies suggest that, although GnRH plays a fundamental role in pituitary gonadotrophin regulation, GnRH may also affect the secretion of other pituitary hormones. The relative physiological importance of these nongonadotropic effects may be species dependent. Thus, in lower vertebrates and mammals, GnRH-induced GH secretion may be critical, whereas in others, such as humans, these effects may have become vestigial and only invoked during disease.

Effects of GnRH outside the pituitary and brain

  1. Top of page
  2. Abstract
  3. Influence of GnRH in the central nervous system
  4. GnRH affects pituitary cells other than gonadotrophs
  5. Effects of GnRH outside the pituitary and brain
  6. Conclusions
  7. Acknowledgements
  8. References

GnRH binding has been detected in multiple extra-central nervous system sites (19, 129) but only the presence of GnRH receptors on tumors has attracted considerable attention due to the therapeutic potential of co-opting their use to target the delivery of toxic substances to cancer cells (130, 131). Apart from the noted reproductive tissues that express GnRH receptors (14–18, 20–22), there are several other sites expressing GnRH receptors that warrant further study.


It is noteworthy that the presence of GnRH and GnRH receptors in the heart of lower vertebrates, especially fish, is well established (132–137). In an elegant study knocking down GnRH by blocking GnRH mRNA translation, cardiac development in the zebrafish was significantly impaired (138). Studies injecting biotinylated GnRH (89), radioactive GnRH (139, 140) or GnRH agonists (141–143) have consistently reported GnRH binding in the rodent heart. GnRH receptor mRNA has also been detected in the human heart (19). Immunoreactive GnRH receptors have also been noted in the human heart, with the highest GnRH receptor levels being evident in the infarcted heart (144). Moreover, for cetrorelix, a GnRH agonist, the total amount of cetrorelix bound to the rat heart was almost 50% of the amount bound to the pituitary gland (145). GnRH has been reported in the rat heart (89, 146, 147) and GnRH mRNA is measurable in the human (19) and mouse (148) heart.

Men who are chemically castrated are at a significantly increased risk of a serious cardiovascular event (149, 150). This may be due to the loss of testicular androgens: androgens are known to affect cardiac contractility (151, 152) and low circulating androgen levels are linked to cardiovascular disease (153). However, a recent epidemiological study on 73 000 men, which compared chemically versus surgically castrated men, strongly supports the hypothesis that the increased risk of cardiovascular disease is not due to the loss of androgens (154). Subsequent studies (155–158) have confirmed this seminal investigation. Our preliminary in vitro investigations demonstrate a direct effect of GnRH, as low as 1 pg/ml, on the contractility of murine cardiomyocytes in serum-free, and thus androgen-free, media (159). Studies in the chemically castrated rat using the GnRH agonist, Zoladex, suggest this may translate into impaired cardiac function in vivo (160, 161). It was not established whether this impaired cardiac function was due to the GnRH agonist per se rather than the loss of testosterone.


In several species, including humans, binding of GnRH analogues or GnRH receptor mRNA have been reported in the mammalian adrenal (17, 142, 145, 162–164). Administration of a GnRH analogue, Surfagon, induced morphological changes in the adrenal cortex of the male mouse and, importantly, these effects persisted in castrated animals (165). In castrate or ovariectomised ferrets, the GnRH agonist deslorelin significantly improved adrenocortical disease (166). Treating female rats for 3 months with the GnRH antagonist, Detirelix, caused a significant reduction in the adrenal/body weight ratio (167). However, whether these affects are directly on the adrenal gland or indirectly through modulation of gonadotrophin release has not been established.


The human bladder epithelium produces both GnRH and GnRH receptor (6). After 3H-GnRH injection, significant accumulation of radioactivity was reported in the mouse bladder (139). The putative function of this paracrine GnRH system has been investigated in the dog (168–172). Ovariectomy causes incontinence in dogs. Treatment with the GnRH agonist, deslorelin, restored continence to all ovariectomised incontinent animals (169). With the loss of ovarian steroids and an absence of a relationship between gonadotrophin levels and urodynamic function, the effect was considered to be directly due to GnRH (168) and confirmation of the GnRH receptor in the bladder of this species (171, 172) supports this hypothesis. It is not known how GnRH affects bladder function but urethral closure pressure is unaffected by GnRH (170).

There are other GnRH target sites that have received scant attention to date, such as the skin (142, 173), lymphocytes (174), kidney (131, 140, 142, 175) and liver (140, 142, 175). Several studies have shown that GnRH binding may occur in the liver and kidney (142, 175) but consideration of these data has suggested that these sites are involved in peptide degradation, despite evidence that GnRH is undetectable in jugular blood (176). Clearly, future work will be required to address the functional relevance, if any, of these novel putative GnRH targets.


  1. Top of page
  2. Abstract
  3. Influence of GnRH in the central nervous system
  4. GnRH affects pituitary cells other than gonadotrophs
  5. Effects of GnRH outside the pituitary and brain
  6. Conclusions
  7. Acknowledgements
  8. References

GnRH is not just a reproductive hormone. Indeed, one of the first functions of GnRH in evolution may have been cardioactive, as shown powerfully in the octopus (9). The diverse location of GnRH receptors and/or ligand suggests that GnRH may be a major modulator of multiple physiological systems in addition to reproduction. Recent studies suggest that, although GnRH may act through a common receptor at the pituitary and these novel sites, the intracellular signalling pathways employed may be different (13, 177). Certainly, the presence of a receptor on a particular target does not establish that site as biologically important (e.g. olfactory receptors are expressed in the heart) (178). Nevertheless, reconsideration of the potential widespread action that this traditional reproductive hormone may exert, could lead to the generation of novel therapies and encourage due caution when investigating the potential targets of current GnRH therapies (e.g. prostate cancer, endometriosis).


  1. Top of page
  2. Abstract
  3. Influence of GnRH in the central nervous system
  4. GnRH affects pituitary cells other than gonadotrophs
  5. Effects of GnRH outside the pituitary and brain
  6. Conclusions
  7. Acknowledgements
  8. References

This publication was made possible by Grants RR15553 and RR15640 from the National Center for Research Resources, a component of the NIH. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NCRR or NIH. AJA and HT were funded, in part, by grants from NSF #EPS-9983278 and #EPS-0447681, respectively. QW was supported by a grant from the Wyoming NASA Space Grant Consortium, #NNG05G165H.


  1. Top of page
  2. Abstract
  3. Influence of GnRH in the central nervous system
  4. GnRH affects pituitary cells other than gonadotrophs
  5. Effects of GnRH outside the pituitary and brain
  6. Conclusions
  7. Acknowledgements
  8. References
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