New insights of the role of β-NGF in the ovulation mechanism of induced ovulating species

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  • 1 Department of Animal Science, Universidad Austral de Chile, Valdivia, Chile
  • | 2 Faculty of Natural Resources, Universidad Católica de Temuco, Temuco, Chile
  • | 3 Department of Veterinary Biomedical Sciences, WCVM, Saskatoon, Canada

Correspondence should be addressed to M H Ratto; Email: marceloratto@uach.cl
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The type of stimuli triggering GnRH secretion has been used to classify mammalian species into two categories: spontaneous or induced ovulators. In the former, ovarian steroids produced by a mature follicle elicit the release of GnRH from the hypothalamus, but in the latter, GnRH secretion requires coital stimulation. However, the mechanism responsible for eliciting the preovulatory LH surge in induced ovulators is still not well understood and seems to vary among species. The main goal of this review is to offer new information regarding the mechanism that regulates coitus-induced ovulation. Analysis of several studies documenting the discovery of β-NGF in seminal plasma and its role in the control of ovulation in the llama and rabbit will be described. We also propose a working hypothesis regarding the sites of action of β-NGF in the llama hypothalamus. Finally, we described the presence of β-NGF in the semen of species categorized as spontaneous ovulators, mainly cattle, and its potential role in ovarian function. The discovery of this seminal molecule and its ovulatory effect in induced ovulators challenges previous concepts about the neuroendocrinology of reflex ovulation and has provided a new opportunity to examine the mechanism(s) involved in the cascade of events leading to ovulation. The presence of the factor in the semen of induced as well as spontaneous ovulators highlights the importance of understanding its signaling pathways and mechanism of action and may have broad implications in mammalian fertility.

Abstract

The type of stimuli triggering GnRH secretion has been used to classify mammalian species into two categories: spontaneous or induced ovulators. In the former, ovarian steroids produced by a mature follicle elicit the release of GnRH from the hypothalamus, but in the latter, GnRH secretion requires coital stimulation. However, the mechanism responsible for eliciting the preovulatory LH surge in induced ovulators is still not well understood and seems to vary among species. The main goal of this review is to offer new information regarding the mechanism that regulates coitus-induced ovulation. Analysis of several studies documenting the discovery of β-NGF in seminal plasma and its role in the control of ovulation in the llama and rabbit will be described. We also propose a working hypothesis regarding the sites of action of β-NGF in the llama hypothalamus. Finally, we described the presence of β-NGF in the semen of species categorized as spontaneous ovulators, mainly cattle, and its potential role in ovarian function. The discovery of this seminal molecule and its ovulatory effect in induced ovulators challenges previous concepts about the neuroendocrinology of reflex ovulation and has provided a new opportunity to examine the mechanism(s) involved in the cascade of events leading to ovulation. The presence of the factor in the semen of induced as well as spontaneous ovulators highlights the importance of understanding its signaling pathways and mechanism of action and may have broad implications in mammalian fertility.

Introduction

Ovulation in mammals involves the release of GnRH from the hypothalamus into the hypophyseal portal system followed by the release of LH from the pituitary gland into the systemic circulation (Karsch 1987, Karsch et al. 1997). Mammals have been classified as either spontaneous or induced (reflex) ovulators. In spontaneously ovulating females (e.g., woman, sheep, cow, mare, sow), increasing systemic concentrations of estradiol, under basal levels of progesterone, induces release of GnRH from the hypothalamus (Jaffe & Keys 1974, Knobil 1980, Kelly et al. 1988, Turzillo & Nett 1999). Hence, a luteal phase in these species is induced spontaneously and ovulation occurs at regular intervals. By contrast, in induced ovulators (e.g., rabbits, ferrets, cats, camelids), copulation is responsible for triggering GnRH secretion from the hypothalamus, followed by a pre-ovulatory release of LH from the pituitary (Bakker & Baum 2000). Therefore, females from these species do not display an estrous cycle per se, as observed in spontaneous ovulators.

Reasons for the evolution of a species-specific mechanism of ovulation among mammals remain unknown. Current concepts of phylogeny do not explain the presence of one type of ovulatory mechanism over the other, and the evolutionary drive toward an induced or spontaneous ovulation mechanism may be associated with social or environmental cues for a given species. Although the LH surge is a mandatory event for triggering ovulation in both types of ovulators, the specific signaling pathway to elicit the GnRH/LH surge is still poorly understood in induced ovulators.

The main goal of this review is to offer new information regarding the mechanism that regulates coitus-induced ovulation. Analysis of several studies documenting the discovery of β-NGF in seminal plasma and its role in the ovulatory mechanism in the llama and rabbit will be described. We also propose a working hypothesis regarding the site of action of β-NGF in the llama hypothalamus. Undoubtedly, gaps remain in our understanding of the role of β-NGF in the ovulation mechanism, but the results of recent research on the presence and effect of this seminal factor in both spontaneous and induced ovulators are exciting and may have a profound impact on fertility management in domestic animals and humans.

General aspects of ovulation induction in induced ovulatory species

The first evidence of coitus-induced ovulation was documented more than 100 years ago by Heape (1905) who described the phenomenon in rabbits. In some induced ovulators, ovulation is triggered by penile intromission (mink and ferret; Carroll et al. 1985, Sundquist et al. 1988), mounting with or without copulation (rabbit; Ramirez & Soufi 1994), single copulation (camelids; Fernandez-Baca et al. 1970, England et al. 1971, Marie & Anouassi 1986) or multiple copulations (cat; Concannon et al. 1980). Although circulating estradiol concentration was positively correlated with increasing size of the dominant ovarian follicle in llamas and alpacas, the physiological increase did not result in ovulation in these species (Bravo et al. 1990a,b, 1991, 1992). Similarly, neither endogenous nor exogenous estradiol induced LH secretion in rabbits or ferrets (Sawyer & Markee 1959, Baum et al. 1990). However, estradiol in induced ovulators was reported to act on the female hypothalamus to induce the behaviors characteristic of the proceptive and receptive sexual stages (Baum & Schretlen 1978).

The rabbit is the only induced ovulator in which GnRH has been measured and was found to be released in a pulsatile manner using the push–pull perfusion technique (Pau et al. 1986, Ramirez et al. 1986). Coitus was associated with a dramatic increase in GnRH pulse-frequency from the medial basal hypothalamus (MBH) followed by an increase in circulating LH concentrations within 20–60 min (Pau et al. 1986, Ramirez et al. 1986). Neurotransmitter and peptidergic systems have been shown to affect GnRH secretion and ovulation in mammalian females (reviewed in McEwen & Parsons 1982). An increase in norepinephrine after coitus was deemed responsible for regulating GnRH secretion and subsequent ovulation in rabbits (reviewed in Kauffman & Rissman 2006). Norepinephrine neurons, A1, A2, A5 and A6 groups are located in several loci of the brainstem, including the medulla oblongata, solitary tract, lateral tegumentum of the pons and the locus coeruleus. The effects of neuropeptide Y and acetylcholine have also been reported to modulate ovulation in the rabbit (Ramirez & Soufi 1994).

Recent findings in camelids (llamas, alpacas, camels) offer new insight into the mechanism of induced ovulation (reviewed in Adams & Ratto 2013, Adams et al. 2016). An ovulation-inducing factor (OIF) in the seminal plasma of camelids has been isolated and identified as nerve growth factor (β-NGF, Kershaw-Young et al. 2012, Ratto et al. 2012, Kumar et al. 2013). Moreover, we have developed a llama model to document that genital-somatosensory stimuli of copulation is not the principal ovulation-inducing signal in this species (Berland et al. 2016). Whether or not the same mechanism is present in other species of induced ovulators is yet unknown.

The discovery of β-NGF in the semen of camelids and its role in ovulation induction

Seminal plasma is produced by the male accessory sex glands and its composition may vary among species according to the type of glands present. Seminal plasma has been considered primarily a vehicle for sperm transport; however, it contains proteins, growth factors, hormones and cytokines that may regulate important functions in the spermatozoa and in the female reproductive system (Bromfield 2016).

The first study to document a direct role of semen on the ovulatory mechanism was reported by Chen et al. (1985) where ovulation was observed after intra-vaginal semen deposition in Bactrian camels without any physical contact with the male. Also, seminal plasma was found to stimulate LH secretion from rat pituitary cells cultured in vitro (Paolicchi et al. 1999). The first study to document the association between systemic seminal plasma administration and LH secretion and ovulation in alpacas and llamas was reported by Adams et al. (2005); results demonstrated the presence of an ovulation inducing-factor (OIF) in the seminal plasma of both species. Intramuscular administration of seminal plasma induced ovulation in >90% of females by eliciting a sustained preovulatory LH surge.

The effect of seminal plasma on ovulation may not be unique to induced ovulatory species. For instance, the preovulatory LH surge was advanced in cattle when mating was conducted within the first 6–8 h of behavioral estrus (Jochle 1975). Similarly, intrauterine infusion of boar seminal plasma accelerated ovulation in gilts (Waberski et al. 1995). Also, studies in humans suggested the presence of molecules with GnRH-like activity in semen (Izumi et al. 1985, Sokol et al. 1985).

Aside from the potent ovulatory effect of llama β-NGF, this molecule has a marked luteotrophic effect after intramuscular or intrauterine infusion in llamas and alpacas (Adams et al. 2005, Ratto et al. 2006). The CL that developed after ovulations induced by seminal plasma treatment tended to be larger and regress later than the CL resulting from GnRH treatment, and progesterone secretion was higher than that in GnRH-treated females (Adams et al. 2005). The magnitude of LH release and subsequent CL function in female llamas treated with seminal plasma suggest that the luteotrophic effect of β-NGF is mediated by LH. In this regard, the luteotrophic effects of seminal plasma has been confirmed in other studies using purified NGF from the seminal plasma of llamas (Ratto et al. 2011, Silva et al. 2011a,b, 2014, Tanco et al. 2012). Moreover, an increase in the vascular area of the CL was highly correlated to progesterone production in females treated with β-NGF compared to the GnRH-treated group (Ulloa-Leal et al. 2014).

Potential mechanism of seminal plasma β-NGF in ovulation induction in llamas

The circuits and basic mechanisms of stimulation and signaling for GnRH release and LH discharge have not been intensively investigated in induced ovulators. Although different stimuli such as olfactory, tactile, visual and auditory have been indicated as facilitators or modulators of ovulation in reflex ovulators, penile intromission during copulation has been considered the main factor associated with the preovulatory discharge of LH and subsequent ovulation in these species (Bakker & Baum 2000, Kauffman & Rissman 2006). However, more recent studies in llamas and alpacas have provided important and conclusive evidence to challenge the notion that physical stimulation of the genital tract is a necessary requirement to induce ovulation in these species (Adams & Ratto 2013, Adams et al. 2016, Berland et al. 2016).

Systemic administration of purified NGF from llama seminal plasma stimulates secretion of LH in both intact and ovariectomized llamas, and the magnitude of LH secretion was modulated by estradiol (Silva et al. 2012). In addition, the effect of OIF on LH secretion was inhibited in llamas pretreated with a GnRH antagonist (Silva et al. 2011a). Results document that NGF elicits a preovulatory LH surge by a direct or indirect action on GnRH neurons.

In a recent study (Berland et al. 2016), an urethrostomized male was used to discriminate between the effects of seminal plasma NGF and penile stimulation as the main stimulus to induce ovulation in llamas. Females mated with the urethrostomized male did not ovulate (0/6), but ovulation was observed in females mated with an intact male (6/7) or those given an intrauterine infusion of seminal plasma (5/6). Results indicated that intrauterine administration of seminal plasma was sufficient to elicit an LH surge and that circulating LH concentrations were positively correlated with a rapid systemic increase in β-NGF observed during the first hour after treatment. The results of this and previous studies (Ratto et al. 2005, Silva et al. 2011a, 2012, Berland et al. 2016) suggest that β-NGF from the seminal plasma is absorbed from the endometrium after copulation and enters systemic circulation to elicit GnRH secretion from the hypothalamus. However, the signaling pathway by which β-NGF elicits GnRH secretion remains unknown.

How then does β-NGF gain access at the central level to trigger GnRH secretion? What are the potential sites of action or binding of NGF in the hypothalamus? Is it necessary for NGF to cross the blood–brain barrier to reach the hypothalamus? Does NGF act directly or indirectly on GnRH neurons? There are still many questions to answer.

Gonadotrophin-releasing hormone is produced by hypothalamic neurons and transported to the terminal axons located at the median eminence (ME; Fink 1988). In mammals, GnRH nerve fibers are concentrated mainly in the lateral and medial post-infundibular regions, where their axon terminals are housed in the pericapillary space of the hypophyseal portal system in the ME (Baker et al. 1975, Barry & Dubois 1976, Rodríguez et al. 2010). As well, GnRH fibers located in the floor of the third ventricle are closely associated with highly specialized glial cells, the tanycytes, which have also been ascribed a role in the direct release of GnRH into the hypophyseal portal system (reviewed in Ojeda et al. 2008, 2010, Rodríguez et al. 2010).

In a recent study (Carrasco et al. 2018a), GnRH neurons in llamas were not equally distributed among hypothalamic areas and were not aggregated in hypothalamic nuclei, but rather had a more diffuse distribution. A high number of GnRH neurons were located in the medio-basal hypothalamus, twice as many as the second most-populated region, the anterior hypothalamus. A lower population of GnRH neurons was located in the diagonal band of Brocca and the arcuate and periventricular nuclei (Carrasco et al. 2018a).

Another component of the cellular network of GnRH release includes the neurons that produce Kisspeptin. In rodents, kisspeptin has been described as the most potent activator of LH secretion and the majority of GnRH neurons express receptors for kisspeptin (GPR54 or KISS1R; Herbison 2015). In rodents, the neurons that synthesize kisspeptin form clusters and are distributed in close association with GnRH neurons in the preoptic area and basal hypothalamus (Herbison 2015). Associations among GnRH neurons, kisspeptin neurons and hypothalamic tanycytes have been implicated in the preovulatory LH surge (Clarkson et al. 2010, Ojeda et al. 2010, Rodríguez et al. 2010).

The entry of peripheral peptides/proteins into the brain is regulated by the blood–brain barrier, a unique uninterrupted barrier that is located at the level of the endothelial cells of the cerebral capillaries (Rodríguez et al. 2010). However, this barrier is displaced at the circumventricular organs to specialized ependymal cells (Hawkins & Davis 2005, Rodríguez et al. 2010). The circumventricular organs have been described as windows that allow neural cells to sense the blood and exchange certain substances between blood and nerve tissue, which cannot otherwise cross due to the presence of the blood–brain barrier (reviewed in Prevot et al. 2010, Rodríguez et al. 2010, Spuch & Navarro 2010).

Recent immunocytochemical studies of nerve tissue from llamas treated with seminal plasma (Berland 2017) revealed strong immunoreactivity for trkA (high-affinity receptor) and its ligand β-NGF in the choroid plexus at the roof of the third ventricle (Fig. 1). An interesting aspect of this finding is that the expression of the receptor in the choroid plexus has not been described in any species previously. In rats, Timmusk et al. (1995) reported the presence of NGF, NT-4, NT-3 and BDNF mRNAs in the choroid plexus, as well as high mRNA levels for trkB, undetectable levels of trkA and trkC mRNA. Although the presence of β-NGF and its specific receptor in the choroid plexus does not necessarily indicate that β-NGF is transported from circulation to the CSF by this route, this feature may represent a unique particularity associated with induced ovulating species. Transport of other growth factors, peptides, neurotrophins and hormones through their corresponding specific receptors at the choroid plexus have been demonstrated (Redzic & Segal 2004, Rodríguez et al. 2010), suggesting that this route may be a potential window for NGF to access the brain via cerebrospinal fluid.

Figure 1
Figure 1

Immunostaining of trkA receptor (A) and β-NGF (B) in the choroid plexus of the llama encephalon. (A) Shows granular immunolabeling of trkA receptor in the cytoplasm of the epithelial cells in the choroid plexus at the roof of the third ventricle. (B) Shows immunolabeling of β-NGF in the choroid plexus. Immunlabelling of controls for trkA and β-NGF is presented in the Supplementary Figure 1 (see section on Supplementary data given at the end of the article). Scale bars = 10 µm. bv, blood vessels. Arrow heads show immunolabeling. Specific antibodies: β-NGF, sc-548 and sc-118 polyclonal, from Santa Cruz Biotechnology.

Citation: Reproduction 157, 5; 10.1530/REP-18-0305

We have also identified β-NGF immunoreactivity in the tanycytes of the median eminence in llamas (Fig. 2), where GnRH nerve terminals are concentrated. Tanycytes in the median eminence contribute to the development of an anatomical link between ventricular CSF and portal blood (Rodríguez et al. 2005). This anatomical arrangement allows bidirectional passage of macromolecules between the portal blood and CSF (Rodríguez et al. 2005, 2010, Prevot et al. 2010) potentially providing signals to the GnRH or kisspeptin neurons. In rats, removal of tanycytes prevented GnRH release into the portal blood, the peak of luteinizing hormone and ovulation in rats (Rodríguez et al. 1979). The mechanism of tanycyte in leptin transport from the portal blood into the ventricular CSF has been demonstrated (Balland et al. 2014). In addition, a greater relative abundance of kisspeptin fibers was detected in association with GnRH fibers in the median eminence region (Fig. 3).

Figure 2
Figure 2

Immunostaining of β-NGF labeling of β2 tanycyte processes in the median eminence. Negative control for immunostaining of β-NGF is presented in Supplementary Figure 2. Scale bars = 50 µm. bv, blood vessels; PT, pars tuberalis. Specific antibodies: β-NGF sc-548, rabbit polyclonal from Santa Cruz Biotechnology.

Citation: Reproduction 157, 5; 10.1530/REP-18-0305

Figure 3
Figure 3

Immunolabeling of GnRH and kisspeptin neuronal fibers in median eminence of coronal sections of the llama hypothalamus. Low magnification of the llama median eminence where abundant fibers of GnRH (A) and kisspeptin (B) neurons are observed. Immunostaining of negative controls for GnRH and Kisspeptin are presented in Supplementary figure 3. 3V, third ventricle; ME, median eminence; RI, infundibular recess. Specific antibodies: GnRH mouse polyclonal, contributed by Dr S Ojeda; kisspeptin AB9754 are rabbit polyclonal, Millipore.

Citation: Reproduction 157, 5; 10.1530/REP-18-0305

Therefore, we propose two potential pathways by which β-NGF from seminal plasma may signal at the level of the hypothalamic region (Fig. 4): (1) by entering into the cerebrospinal fluid of the third ventricle through the choroid plexus or via tanycyte transport from portal capillaries at the median eminence or (2) by acting directly or indirectly on GnRH neurons present at the level of median eminence without entering into the third ventricle.

Figure 4
Figure 4

Proposed model for the potential access and signaling pathways of β-NGF for triggering ovulation in llamas. Seminal plasma β-NGF is absorbed from the uterus and transported through the circulation to the hypothalamic region, where it may (1) enter into the cerebrospinal fluid of the third ventricle through the choroid plexus or via tanycyte-transport from the portal capillaries at the median eminence, or (2) act directly or indirectly on GnRH neurons at the median eminence. Additionally, ovarian actions of β-NGF are described for rabbit, cattle and llama. 3V, third ventricle; AN, arcuate nucleus; β1, β2, tanycyte; CSF, cerebrospinal fluid; CP, choroid plexus; FSH, follicle-stimulating hormone; LH, luteinizing hormone; ME, median eminence; PG, pituitary gland; pbv, portal blood vessels; trk-A, β-NGF receptor; VMN, ventromedial nucleus.

Citation: Reproduction 157, 5; 10.1530/REP-18-0305

In this context, another potential site of signaling of NGF for GnRH release, may be the organum vasculosum laminae terminalis (OVLT), a structure where a significant population of GnRH neurons have been found in rodents (Silverman et al. 1994, Herbison 2006, Herde et al. 2011). Although it is not yet known if neurons of the OVLT are involved in the control of the hypothalamic–hypophyseal axis, we cannot rule out that systemic β-NGF may transduce its signal at this site to initiate the ovulatory cascade in llamas. Herde et al. (2011) showed that GnRH neurons at the OVLT have dendritic terminals that can be activated by local administration of kisspeptin, and thereby stimulate LH secretion without crossing the blood–brain barrier (Messager et al. 2005, Navarro et al. 2005). These results are particularly interesting light of a study in which exogenous administration of kisspeptin induced ovulation in the Musk shrew (an induced ovulator; Inoue et al. 2011).

According to a recent llama study (Carrasco et al. 2018b), an indirect effect of β-NGF on GnRH neurons was postulated since only a 2.5% of GnRH neurons expressed the high-affinity receptor trkA, and no immunoreactivity was detected for the low affinity receptor p75.

Potential mechanism of seminal plasma β-NGF on ovulation induction in rabbits

Similar to camelids, the presence of a factor capable of inducing ovulation in the seminal plasma of rabbits was also suggested nearly a decade ago (Niño 2010, Silva et al. 2011b). Niño (2010) documented the expression of β-NGF in rabbit semen by western blot, and when female llamas were used in an in vivo bioassay, intramuscular administration of rabbit seminal plasma induced and LH surge and ovulation (Silva et al. 2011b). Curiously, however, neither the administration of rabbit nor the administration of llama seminal plasma induced LH release or ovulation in rabbits (Silva et al. 2011b, Cervantes et al. 2015), suggesting that a species-specific response exists between these two induced ovulators.

Recently, several studies (Maranesi et al. 2015, Casares-Crespo et al. 2016, García-García et al. 2017, Maranesi et al. 2018) have confirmed the presence of NGF in rabbit semen. The molecule was found at relatively high concentrations in rabbit seminal plasma (about 1894 ± 277 pg/mL and 151.9 ± 9.25 μg/mL; Maranesi et al. 2015, 2018); however, concentrations were lower than those described in camelids (Tanco et al. 2012). Moreover, different authors have suggested that the prostate gland is the main source of this neurotrophin in rabbit semen (Maranesi et al. 2015, García-García et al. 2017), similar to reports in llamas (Bogle et al. 2013, 2018).

Despite the abundance of NGF in rabbit semen, the ovulatory responses after treatment with seminal plasma or NGF have not been as consistent as in camelids. A recent study (García-García et al. 2017) reported that only 1 of 6 female rabbits treated intramuscularly with 24 μg of murine β-NGF, ovulated, and no preovulatory elevation in LH was detected. In the same study, mechanical stimulation of the vagina increased the ovulation rate to 2/4 in β-NGF-treated females (García-García et al. 2017), suggesting that physical stimulation may be required to complement the effect of ovulation-inducing factor in this species. In contrast, Rebollar et al. (2012) reported 75% ovulation rate in rabbits does artificially inseminated with raw semen delivered by intravaginal deposition, but again, no increase in plasma LH concentration was observed. In the same study, the use of lumbar anesthesia blocked ovulation in the inseminated female rabbits. Similarly, Maranesi et al. (2018) reported ovulation rates of 67% (4/6) and 17% (1/6) in female rabbits inseminated with raw semen in non-anesthetized and lumbar-anesthetized females, respectively, and ovulations were preceded by an increase in plasma LH concentration during the 2 h after artificial insemination. These last studies highlight the role of efferent nervous pathways in the induction of ovulation in rabbits.

Strikingly similar ovulation rates and changes in blood concentrations of β-NGF and LH were described in a recent report in rabbits (Maranesi et al. 2018) as in an earlier report in llamas (Berland et al. 2016) after natural mating or artificial insemination with raw semen. However, in rabbits, administration of lumbar anesthesia or COX inhibitors before artificial insemination blocked the increase in plasma LH concentration, attenuated the systemic rise of β-NGF and reduced the ovulation rate. Based on these findings, the authors proposed that in rabbits (a) semen-derived NGF stimulates de novo synthesis of NGF in the uterine wall, (b) both seminal NGF and uterine NGF are absorbed into the bloodstream and act directly on the ovary rather than on the pituitary or hypothalamus and (c) semen-derived and locally synthesized NGF stimulate uterine/cervix sensory neurons which trigger GnRH neurons in the hypothalamus.

The local effect of NGF in the rabbit ovary was based on immunodetection of NGF and its high- (trkA) and low- (p75) affinity receptors in the oocyte, and the granulosa and theca cells of ovarian follicles at different stages of development (Maranesi et al. 2018). Interestingly, in rabbits, i.m. treatment with homologous seminal plasma (Silva et al. 2011b) or with murine β-NGF (García-García et al. 2017) resulted in a significant increase in the number of large hemorrhagic anovulatory follicles. Similar hemorrhagic follicles have been observed after superovulation of does with eCG (García-Ximénez & Vicente 1990, Mehaisen et al. 2005) or treatment with high doses of hCG (Bomsel-Helmreich et al. 1989), suggesting a direct local effect of these molecules with LH-like action on LH receptors at the follicular wall. Whether the formation of large hemorrhagic follicles observed after treatment with seminal plasma (Silva et al. 2011b) or NGF (García-García et al. 2017) is due to a direct action of NGF on its own receptors or by means of an indirect action through LH receptors at the follicular wall remains to be investigated.

Taken together, results of recent studies of the effects of seminal plasma lead us to re-evaluate the mechanism of reflex ovulation stated many years ago. For instance, β-NGF in camelid semen is the main driver of ovulation, and mechanical stimulation of the female genitalia appears to have little or no role in this species. Conversely, although the presence of β-NGF may be involved in the ovulatory mechanism in rabbits, it appears that physical stimulation is required to induce a high rate of ovulation.

Potential mechanism of seminal plasma β-NGF in spontaneous ovulators

Several studies confirmed the presence of β-NGF in seminal plasma of spontaneous ovulators (e.g., bovine, equine and porcine; Ratto et al. 2012, Bogle et al. 2018). It was also documented that the administration of llama seminal plasma or purified β-NGF influenced ovarian function in spontaneous ovulators. For instance, llama seminal plasma induced ovulation in a pre-pubertal mouse model (Bogle et al. 2011), and systemic administration of purified β-NGF from llama seminal plasma altered ovarian follicular growth and had a luteotrophic effect in cattle (Tanco et al. 2012). In the last study, intramuscular administration of 4–5 mg/animal of purified β-NGF induced neither a preovulatory LH surge nor ovulation in prepubertal heifers, but increased FSH secretion and hastened the emergence of the next follicular wave. Also, the same authors found that llama β-NGF treatment induced a greater growth of the CL resulting in higher plasma progesterone concentration compared to GnRH-treated post-pubertal heifers. The high-affinity NGF receptor, trkA, has also been detected in bovine granulosa cells of preovulatory follicles and in luteal cells of bovine CL (Carrasco et al. 2016), and the preovulatory LH surge seems to upregulate the expression of trkA receptor in these cells. In a further study, the administration of bovine seminal plasma in heifers pre-treated with LH induced a more synchronous interval from treatment to ovulation than in non-pretreated heifers, and plasma progesterone concentrations tended to be higher than those of the control group, reinforcing the notion of a potential luteotrophic effect of NGF in cattle (Tribulo et al. 2015). In a recent bovine study (Stewart et al. 2018a), administration of purified β-NGF from bovine seminal plasma intramuscularly at the time of artificial insemination increased pregnancy rate up to 16%. Treated females displayed a greater plasma progesterone concentration, improving conceptus development and ultimately conception rate. In addition, concentration of NGF in bovine seminal plasma has been correlated with fertility in dairy and beef bulls (Stewart et al. 2018b).

Conclusions

Among induced ovulators, there appears to be a differential species-specific mechanism that, contrary to the established notion that mechanical stimulation from copulation is the pivotal stimulus to trigger ovulation, relies on the presence of seminal factors that chemically induce endocrine changes that ultimately induce the ovulatory response. The discovery of β-NGF in the seminal plasma of camelids, and recently in rabbits, and its central role as the main chemical compound inducing ovulation in these species without the need of copulation, allow us to challenge the notion that reflex ovulation depends merely upon physical stimulation of the female genital tract. Surprisingly, β-NGF appears to act on different target tissues in these two species, suggesting different evolutionary adaptations to arrive as present-day induced ovulators. Evidence documented in cattle suggests that β-NGF may have a role as a luteotrophic factor in spontaneous ovulators.

Supplementary data

This is linked to the online version of the paper at https://doi.org/10.1530/REP-18-0305.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

Several studies that have been cited in the present review have received funding from the Chilean National Research Council of Science and Technology (CONICYT, Fondecyt 11080141, 1120518, 1160934 and 11140396), Fondequip (EQM 120131) and the Natural Sciences and Engineering Research Council of Canada.

Acknowledgements

The authors mention a special thanks to all their under and graduate students of the Faculty of Veterinary Sciences at the Universidad Austral de Chile, Valdivia, Chile in the development of several research studies. In addition, they thank Dr Alexander Orloff, Universidad Catolica de Temuco, for his assistance in the preparation of Fig. 4 and Dr Alfredo Ramirez, Universidad Austral de Chile, for his assistance in the preparation of the Supplementary Fig. 3.

References

  • Adams GP & Ratto MH 2013 Ovulation-inducing factor in seminal plasma: a review. Animal Reproduction Science 136 148156. (https://doi.org/10.1016/j.anireprosci.2012.10.004)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Adams GP, Ratto MH, Huanca W & Singh J 2005 Ovulation-inducing factor in the seminal plasma of alpacas and llamas. Biology of Reproduction 73 452457. (https://doi.org/10.1095/biolreprod.105.040097)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Adams GP, Ratto MH, Silva ME & Carrasco RA 2016 Ovulation-inducing factor (OIF/NGF) in seminal plasma: a review and update. Reproduction in Domestic Animals 51 417. (https://doi.org/10.1111/rda.12795)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Baker BL, Dermody WC & Reel JR 1975 Distribution of gonadotropin releasing hormone in the rat brain as observed with immunocytochemistry. Endocrinology 97 125135. (https://doi.org/10.1210/endo-97-1-125)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bakker J & Baum MJ 2000 Neuroendocrine regulation of GnRH release in induced ovulators. Frontiers in Neuroendocrinology 21 220262. (https://doi.org/10.1006/frne.2000.0198)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Balland E, Dam J, Langlet F, Caron E, Steculorum S, Messina A, Rasika S, Falluel-Morel A, Anouar Y & Dehouck B et al. 2014 Hypothalamic tanycytes are an ERK-gated conduit for leptin into the brain. Cell Metabolism 19 293301. (https://doi.org/10.1016/j.cmet.2013.12.015)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Barry L & Dubois MP 1976 Immunoreactive LRF neurosecretory pathways in mammals. Acta Anatomica 94 497503. (https://doi.org/10.1159/000144582)

  • Baum MJ & Schretlen PJM 1978 Oestrogenic induction of sexual behavior in ovartectomised ferrets housed under short or long photoperiods. Journal of Endocrinology 78 295296. (https://doi.org/10.1677/joe.0.0780295)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Baum MJ, Carroll RS, Cherry JA & Tobe SA 1990 Steroidal control of behavioral, neuroendocrine and brain sexual differentiation: studies in a carnivore, the ferret. Journal of Neuroendocrinology 2 401418. (https://doi.org/10.1111/j.1365-2826.1990.tb00425.x)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Berland MA 2017 Acción central del factor inductor de ovulación (OIF/NGF) presente en el plasma seminal de llamas. Thesis, Doctorate on Veterinary Sciences, Faculty of Veterinary Sciences, Universidad Austral de Chile, Valdivia, Chile.

    • Search Google Scholar
    • Export Citation
  • Berland MA, Ulloa-Leal C, Barría M, Wright H, Dissen GA, Silva ME, Ojeda SR & Ratto MH 2016 Seminal plasma induces ovulation in llamas in the absence of a copulatory stimulus: role of nerve growth factor as an ovulation-inducing factor. Endocrinology 157 32243232. (https://doi.org/10.1210/en.2016-1310)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bogle OA, Ratto MH & Adams GP 2011 Evidence for the conservation of biological activity of ovulation-inducing factor (OIF) in the seminal plasma. Reproduction 142 277283. (https://doi.org/10.1530/REP-11-0042)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bogle OA, Singh J & Adams GP 2013 Distribution of ovulation-inducing factor in male reproductive tissues of llamas. Reproduction, Fertility and Development 25 272 (abstract). (https://doi.org/10.1071/RDv25n1Ab248)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Bogle OA, Carrasco RA, Ratto MH, Singh J & Adams GP 2018 Source and localization of ovulation-inducing factor/nerve growth factor in male reproductive tissues among mammalian species. Biology of Reproduction 99 11941204: doi:10.1093/biolre/ioy149.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bomsel-Helmreich O, Huyen LVN & Durand-Gasselin I 1989 Effects of varying doses of HCG on the evolution of preovulatory rabbit follicles and oocytes. Human Reproduction 4 636642. (https://doi.org/10.1093/oxfordjournals.humrep.a136957)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Bravo PW, Fowler ME, Stabenfeldt GH & Lasley BL 1990a Ovarian follicular dynamics in the llama. Biology of Reproduction 43 579585. (https://doi.org/10.1095/biolreprod43.4.579)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Bravo PW, Fowler ME, Stabenfeldt GH & Lasley B 1990b Endocrine response in the llama to copulation. Theriogenology 33 891899. (https://doi.org/10.1016/0093-691X(90)90824-D)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Bravo PW, Stabenfeldt GH, Lasley BL & Fowler ME 1991 The effect of ovarian follicle size on pituitary and ovarian responses to copulation in domesticated south american camelids. Biology of Reproduction 45 553559. (https://doi.org/10.1095/biolreprod45.4.553)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bravo PW, Stabenfeldt GH, Fowler ME & Lasley BL 1992 Pituitary response to repeated copulation and/or gonadotropin-releasing hormone administration in llamas and alpacas. Biology of Reproduction 47 884888. (https://doi.org/10.1095/biolreprod47.5.884)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bromfield JJ 2016 A role for seminal plasma in modulating pregnancy outcomes in domestic species. Reproduction 152 R223R232. (https://doi.org/10.1530/REP-16-0313)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Carrasco R, Singh J & Adams GP 2016 The dynamics of trkA expression in the bovine ovary are associated with a luteotrophic effect of ovulation-inducing factor/nerve growth factor (OIF/NGF). Reproductive Biology and Endocrinology 14 4757. (https://doi.org/10.1186/s12958-016-0182-9)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Carrasco RA, Singh J & Adams GP 2018a The relationship between gonadotrophin releasing hormone and ovulation inducing factor/nerve growth factor receptors in the hypothalamus of the llama. Reproductive Biology and Endocrinology 16 8392. (https://doi.org/10.1186/s12958-018-0402-6)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Carrasco RA, Singh J & Adams GP 2018b Distribution and morphology of gonadotrophin releasing hormone neurons in the hypothalamus of an inducing ovulator – the llama (Lama glama). General and Comparative Endocrinology 263 4350. (https://doi.org/10.1016/j.ygcen.2018.04.011)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Carroll RS, Erskine MS, Doherty PC, Lundell LA & Baum MJ 1985 Coital stimuli controlling luteinizing hormone secretion and ovulation in the female ferret. Biology of Reproduction 32 925933. (https://doi.org/10.1095/biolreprod32.4.925)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Casares-Crespo L, Talaván AM & Viudes-de-Castro MP 2016 Can the genetic origin affect rabbit seminal plasma protein profile along the year? Reproduction in Domestic Animals 51 294300. (https://doi.org/10.1111/rda.12680)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Cervantes MP, Palomino JM & Adams GP 2015 In vivo imaging in the rabbit as a model for the study of ovulation-inducing factors. Laboratory Animals 49 19. (https://doi.org/10.1177/0023677214547406)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Chen BX, Yuen ZX & Pan GW 1985 Semen induced ovulation in the Bactrian camel (Camelus bactrianus). Journal of Reproduction and Fertility 73 335339. (https://doi.org/10.1530/jrf.0.0740335)

    • Search Google Scholar
    • Export Citation
  • Clarkson J, Han S, Liu X, Lee K & Herbison AE 2010 Neurobiological mechanisms underlying kisspeptin activation of gonadotropin-releasing hormone (GnRH) neurons at puberty. Molecular and Cellular Endocrinology 324 4550. (https://doi.org/10.1016/j.mce.2010.01.026)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Concannon P, Hodgson B & Lein D 1980 Reflex LH release in estrous cats following single and multiple copulations. Biology of Reproduction 23 111117. (https://doi.org/10.1095/biolreprod23.1.111)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • England BG, Foot WC, Cardozo AG, Matthews DH & Riera S 1971 Oestrus and mating behaviour in the llama (Lama glama). Animal Behaviour 19 722726. (https://doi.org/10.1016/S0003-3472(71)80176-8)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Fernandez-Baca S, Madden DHL & Novoa C 1970 Effect of different mating stimuli on induction of ovulation in the alpaca. Reproduction 22 261267. (https://doi.org/10.1530/jrf.0.0220261)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Fink G 1988 Gonadotropin secretion and its control. In The Physiology of Reproduction, 3rd ed, pp 13491377. Eds Knobil E & Neill JD. New York: Raven Press.

    • Search Google Scholar
    • Export Citation
  • García-García RM, Masdeu M, Sánchez-Rodriguez A, Millán P, Arias-Alvarez M, Sakr OG, Bautista JM, Castellini C, Lorenzo PL & García-Rebollar P 2017 β-Nerve growth factor identification in male rabbit genital tract and seminal plasma and its role in ovulation induction in rabbit does. Italian Journal of Animal Science 17 442453.

    • Search Google Scholar
    • Export Citation
  • García-Ximénez F & Vicente JS 1990 Effect of PMSG treatment to mating interval in the superovulatory response of primiparous rabbits. Journal of Applied Rabbit Research 13 7173.

    • Search Google Scholar
    • Export Citation
  • Hawkins BT & Davis TP 2005 The blood-brain barrier/neurovascular unit in health and disease. Pharmacological Reviews 57 173185. (https://doi.org/10.1124/pr.57.2.4)

  • Heape W 1905 Ovulation and degeneration of ova in the rabbit. Proceedings of the Royal Society B 76 260268. (https://doi.org/10.1098/rspb.1905.0019)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Herbison AE 2006 Physiology of the GnRH neuronal network. In The Physiology of Reproduction, 3rd ed, pp 14151482. Ed Neill JD. San Diego: Elsevier Academic Press.

    • Search Google Scholar
    • Export Citation
  • Herbison AE 2015 Physiology of the adult gonadotropin-releasing hormone neuronal network. In The Physiology of Reproduction, 4th ed, pp 399467. Eds Plant TM & Zeleznik AJ. San Diego: Elsevier Academic Press.

    • Search Google Scholar
    • Export Citation
  • Herde MK, Geist K, Campbell RE & Herbison AE 2011 Gonadotropin-releasing hormone neurons extend complex highly branches dendritic trees outside the blood-brain barrier. Endocrinology 152 38323841. (https://doi.org/10.1210/en.2011-1228)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Inoue N, Sasagawa K, Ikai K, Sasaki Y, Tomikawa J, Oishi S, Fujii N, Uenoyama Y, Ohmori Y & Yamamoto N et al. 2011 Kisspeptin neurons mediate reflex ovulation in the musk shrew (Suncus murinus). PNAS 108 1752717532. (https://doi.org/10.1073/pnas.1113035108)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Izumi S, Makino T & Iizuka R 1985 Immunoreactive luteinizing hormone-releasing hormone in the seminal plasma and human semen parameters. Fertility and Sterility 43 617620. (https://doi.org/10.1016/S0015-0282(16)48506-7)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jaffe RB, Keys WR & Jr 1974 Estradiol augmentation of pituitary responsiveness to gonadotropin-releasing hormone in women. Journal of Clinical Endocrinology and Metabolism 39 850855. (https://doi.org/10.1210/jcem-39-5-850)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Jochle W 1975 Current research in coitus-induced ovulation: a review. Journal of Reproduction and Fertility Supplement 22 165207.

  • Karsch FJ 1987 Central actions of ovarian steroids in the feedback regulation of pulsatile secretion of luteinizing hormone. Annual Review of Physiology 49 365382. (https://doi.org/10.1146/annurev.ph.49.030187.002053)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Karsch FJ, Bowen JM, Caraty A, Evans NP & Moenter SM 1997 Gonadotropin-releasing hormone requirements for ovulation. Biology of Reproduction 56 303309. (https://doi.org/10.1095/biolreprod56.2.303)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kauffman AS & Rissman EF 2006 Neuroendocrine control of mating-induced ovulation. In The Physiology of Reproduction, 3rd ed, pp 22832326. Ed Neill JD. San Diego: Elsevier Academic Press.

    • Search Google Scholar
    • Export Citation
  • Kelly CR, Socha TE & Zimmerman DR 1988 Characterization of gonadotrophic and ovarian steroids hormones during the periovulatory period in high ovulating select and control line gilts. Journal of Animal Science 66 14621474. (https://doi.org/10.2527/jas1988.6661462x)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Kershaw-Young CM, Druart X, Vaughan J & Maxwell WMC 2012 β-Nerve growth factor is a major component of alpaca seminal plasma and induces ovulation in female alpacas. Reproduction, Fertility and Development 24 10931097. (https://doi.org/10.1071/RD12039)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Knobil E 1980 The neuroendocrine control of the menstrual cycle. Recent Progress in Hormone Research 36 5388.

  • Kumar S, Kumar-Sharma V, Singh S, Hariprasad GR, Mal G, Srinivasan A & Yadav S 2013 Proteomic identification of camel seminal plasma: purification of β-nerve growth factor. Animal Reproduction Science 136 284295.

    • Search Google Scholar
    • Export Citation
  • Maranesi M, Zerani M, Leonardi L, Pistilli A, Arruda-Alencar J, Stabile AM, Rende M, Castellini C, Petrucci L & Parillo F et al. 2015 Gene expression and localization of NGF and its cognate receptors NTRK1 and NGFR in the sex organs of male rabbits. Reproduction in Domestic Animals 50 918925. (https://doi.org/10.1111/rda.12609)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Maranesi M, Petrucci L, Leonardi L, Piro F, García-Rebollar PG, Millán P, Cocci P, Vullo C, Parrillo F & Moura A et al. 2018 New insights on a NGF-mediated pathway to induce ovulation in rabbits (Oryctolagus cuniculus). Biology of Reproduction 98 634643. (https://doi.org/10.1093/biolre/ioy041)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Marie M & Anouassi A 1986 Mating induced luteinizing hormone surge and ovulation in the female camel (Camelus dromedarius). Biology of Reproduction 35 792798. (https://doi.org/10.1095/biolreprod35.4.792)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • McEwen BS & Parsons B 1982 Gonadal steroid action on the brain: neurochemistry and neuropharmacology. Annual Review of Pharmacology and Toxicology 22 555598. (https://doi.org/10.1146/annurev.pa.22.040182.003011)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Mehaisen GMK, Vicente JS, Lavara R & Viuedes-de-Castro MP 2005 Effect of eCG dose and ovulation induction treatments on embryo recovery and in vitro development post-vitrification in two selected lines of rabbit does. Animal Reproduction Science 90 175184. (https://doi.org/10.1016/j.anireprosci.2005.01.015)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Messager S, Chatzidaki EE, Ma D, Hendrick AG, Zahn D, Dixon J, Thresher RR, Malinge I, Lomet D & Carlton MBL et al. 2005 Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. PNAS 102 17611766. (https://doi.org/10.1073/pnas.0409330102)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Navarro VM, Castellano JM, Fernández-Fernández R, Tovar S, Roa J, Mayen A, Nogueiras R, Vazquez MJ, Barreiro ML & Magni P et al. 2005 Characterization of the potent luteinizing hormone-releasing activity of KiSS-1 peptide, the natural ligand of GPR54. Endocrinology 146 156163. (https://doi.org/10.1210/en.2004-0836)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Niño A 2010 Determinación de la presencia de un factor inductor de ovulación en el plasma seminal de conejo. Thesis, Master in Clinical Sciences, Faculty of Veterinary Sciences, Universidad Austral de Chile, Valdivia, Chile.

    • Search Google Scholar
    • Export Citation
  • Ojeda SR, Lomniczi A & Sandau US 2008 Glial–gonadotrophin hormone (GnRH) neurone interactions in the median eminence and the control of GnRH secretion. Journal of Neuroendocrinology 20 732742. (https://doi.org/10.1111/j.1365-2826.2008.01712.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ojeda SR, Lomniczi A & Sandau US 2010 Contribution of glial–neuronal interactions to the neuroendocrine control of female puberty. European Journal of Neuroscience 32 20032010. (https://doi.org/10.1111/j.1460-9568.2010.07515.x)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Paolicchi F, Urquieta B, Del Valle L & Bustos-Obregon E 1999 Biological activity of the seminal plasma of alpacas: stimulus for the production of LH by pituitary cells. Animal Reproduction Science 54 203210. (https://doi.org/10.1016/S0378-4320(98)00150-X)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Pau KYF, Orstead KM, Hess DL & Spies HG 1986 Feedback effects of ovarian steroids on the hypothalamic-hypophyseal axis in the rabbit. Biology of Reproduction 35 10091023. (https://doi.org/10.1095/biolreprod35.4.1009)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Prevot V, Hanchate NK, Bellefontaine N, Sharif A, Parkash J, Estrella C, Allet C, de Seranno S, Campagne C & d’Anglemont de Tassigny X et al. 2010 Function-related structural plasticity of the GnRH system. Frontiers in Neuroendocrinology 31 241258. (https://doi.org/10.1016/j.yfrne.2010.05.003)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ramirez VD & Soufi W 1994 The neuroendocrine control of the rabbit ovarian cycle. In The Physiology of Reproduction, 2nd ed, pp 585611. Eds Knobil E & Neill JD. New York: Raven Press Ltd.

    • Search Google Scholar
    • Export Citation
  • Ramirez VD, Ramirez AD, Slamet W & Nduka E 1986 Functional characteristics of the luteinizing hormone-releasing hormone pulse generator in conscious unrestrained female rabbits: activation by norepinephrine. Endocrinology 118 23312339. (https://doi.org/10.1210/endo-118-6-2331)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ratto MH, Huanca W, Singh J & Adams GP 2005 Local versus systemic effect of ovulation-inducing factor in seminal plasma of alpacas. Reproductive Biology and Endocrinology 3 29. (https://doi.org/10.1186/1477-7827-3-29)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Ratto MH, Huanca W, Singh J & Adams GP 2006 Comparison of the effect of ovulation-inducing factor (OIF) in seminal plasma of llamas, alpacas, and bulls. Theriogenology 66 11021106. (https://doi.org/10.1016/j.theriogenology.2006.02.050)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ratto MH, Delbaere LTJ, Leduc YA, Pierson RA & Adams GP 2011 Biochemical isolation and purification of ovulation-inducing factor (OIF) in seminal plasma of llamas. Reproductive Biology and Endocrinology 9 24. (https://doi.org/10.1186/1477-7827-9-24)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Ratto MH, Leduc YA, Valderrama XP, van Straaten KE, Delbaere LTJ, Pierson RA & Adams GP 2012 The nerve of ovulation inducing factor. PNAS 109 1504215047. (https://doi.org/10.1073/pnas.1206273109)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rebollar PG, Dal Bosco A, Millán P, Cardinali R, Brecchia G, Sylla L, Lorenzo PL & Castellini C 2012 Ovulating induction methods in rabbit does: the pituitary and ovarian responses. Theriogenology 77 292298. (https://doi.org/10.1016/j.theriogenology.2011.07.041)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Redzic ZB & Segal MB 2004 The structure of the choroid plexus and the physiology of the choroid plexus epithelium. Advanced Drug Delivery Reviews 56 16951716.

  • Rodríguez EM, González CB & Delannoy L 1979 Cellular organization of the lateral and postinfundibular regions of the median eminence in the rat. Cell and Tissue Research 201 377408.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rodríguez EM, Blázquez JL, Pastor FE, Peláez B, Peña P, Peruzzo B & Amat P 2005 Hypothalamic tanycytes: a key component of brain–endocrine interaction. International Review of Cytology 247 89164. (https://doi.org/10.1016/S0074-7696(05)47003-5)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rodríguez EM, Blázquez JL & Guerra M 2010 The design of barriers in the hypothalamus allows the median eminence and the arcuate nucleus to enjoy private milieus: the former opens to the portal blood and the latter to the cerebrospinal fluid. Peptides 31 757776. (https://doi.org/10.1016/j.peptides.2010.01.003)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sawyer CH & Markee JE 1959 Estrogen facilitation of release of pituitary ovulating hormone in the rabbit in response to vaginal stimulation. Endocrinology 65 614621. (https://doi.org/10.1210/endo-65-4-614)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Silva M, Smulders JP, Guerra M, Valderrama XP, Letelier C, Adams GP & Ratto MH 2011a Cetrorelix suppresses the preovulatory LH surge and ovulation induced by ovulation-inducing factor (OIF) present in llama seminal plasma. Reproductive Biology and Endocrinology 9 74.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Silva M, Niño A, Guerra M, Letelier C, Valderrama XP, Adams GP & Ratto MH 2011b Is an ovulation-inducing factor (OIF) present in the seminal plasma of rabbits? Animal Reproduction Science 127 213221. (https://doi.org/10.1016/j.anireprosci.2011.08.004)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Silva ME, Recabarren MP, Recabarrren SE, Adams GP & Ratto MH 2012 Ovarian estradiol modulates the stimulatory effect of ovulation-inducing factor (OIF) on pituitary LH secretion in llamas. Theriogenology 77 18731882. (https://doi.org/10.1016/j.theriogenology.2012.01.004)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Silva M, Ulloa-Leal C, Norambuena C, Fernández A, Adams GP & Ratto MH 2014 Ovulation-inducing factor (OIF/NGF) from seminal plasma origin enhances corpus luteum function in llamas regardless the preovulatory follicle diameter. Animal Reproduction Science 148 221227. (https://doi.org/10.1016/j.anireprosci.2014.05.012)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Silverman A, Livne I & Witkin JW 1994 The gonadotrophin-releasing hormone (GnRH), neuronal systems: immunocytochemistry and in situ hybriditization. In The Physiology of Reproduction, 2nd ed, pp 16831706. Eds Knobil E & Neill JD. New York: Raven.

    • Search Google Scholar
    • Export Citation
  • Sokol RZ, Peterson M, Heber D & Swerdlof RS 1985 Identification and partial characterization of gonadotropin-releasing hormone-like factors in human seminal plasma. Biology of Reproduction 33 370374. (https://doi.org/10.1095/biolreprod33.2.370)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Spuch C & Navarro C 2010 Transport mechanisms at the blood-cerebrospinal-fluid barrier: role of megalin (LRP2). Recent Patents on Endocrine, Metabolic and Immune Drug Discovery 4 190205. (https://doi.org/10.2174/1872214811004030190)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Stewart JL, Canisso IF, Ellerbrock RE, Mercadante VRG & Lima FS 2018a Nerve growth factor β production in the bull: gene expression, immunolocalization, seminal plasma constitution, and association with sire conception rates. Animal Reproduction Science 197 335342. (https://doi.org/10.1016/j.anireprosci.2018.09.006)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Stewart JL, Mercadante VRG, Diaz NW, Canisso IF, Yau P, Imai B & Lima FS 2018b Nerve growth factor-beta, purified from bull seminal plasma, enhances corpus luteum formation and conceptus development in Bos taurus cows. Theriogenology 106 3038. (https://doi.org/10.1016/j.theriogenology.2017.10.007)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Sundquist C, Ellis LC & Bartke A 1988 Reproductive endocrinology of the mink (Mustela vison). Endocrine Reviews 9 247266. (https://doi.org/10.1210/edrv-9-2-247)

  • Tanco VM, Van Steelandt MD, Ratto MH & Adams GP 2012 Effect of purified llama ovulation-inducing factor (OIF) on ovarian function in cattle. Theriogenology 78 10301039. (https://doi.org/10.1016/j.theriogenology.2012.03.036)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Timmusk T, Mudò G, Metsis M & Belluardo N 1995 Expression of mRNAs for neurotrophins and their receptors in the rat choroid plexus and dura mater. NeuroReport 6 19972000. (https://doi.org/10.1097/00001756-199510010-00011)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Tribulo P, Bogle O, Mapletoft RJ & Adams GP 2015 Bioactivity of ovulation inducing factor (or nerve growth factor) in bovine seminal plasma and its effects on ovarian function in cattle. Theriogenology 83 13941401. (https://doi.org/10.1016/j.theriogenology.2014.12.014)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Turzillo AM & Nett TM 1999 Regulations of the GnRH receptor gene expression in sheep and cattle. Journal of Reproduction and Fertility Supplement 54 7586.

    • Search Google Scholar
    • Export Citation
  • Ulloa-Leal C, Bogle OA, Adams GP & Ratto MH 2014 Luteotrophic effect of ovulation-inducing factor/nerve growth factor present in the seminal plasma of llamas. Theriogenology 81 11011107.e1. (https://doi.org/10.1016/j.theriogenology.2014.01.038)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Waberski D, Sudhoff H, Hahn T, Jungblut PW, Kallweit E, Calvete JJ, Ensslin M, Hoppen HO, Wintergalen N & Weitze KF 1995 Advanced ovulation in gilts by the intrauterine application of a low-molecular mass pronase-sensitive fraction of boar seminal plasma. Journal of Reproduction and Fertility 105 247252. (https://doi.org/10.1530/jrf.0.1050247)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

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    Immunostaining of trkA receptor (A) and β-NGF (B) in the choroid plexus of the llama encephalon. (A) Shows granular immunolabeling of trkA receptor in the cytoplasm of the epithelial cells in the choroid plexus at the roof of the third ventricle. (B) Shows immunolabeling of β-NGF in the choroid plexus. Immunlabelling of controls for trkA and β-NGF is presented in the Supplementary Figure 1 (see section on Supplementary data given at the end of the article). Scale bars = 10 µm. bv, blood vessels. Arrow heads show immunolabeling. Specific antibodies: β-NGF, sc-548 and sc-118 polyclonal, from Santa Cruz Biotechnology.

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    Immunostaining of β-NGF labeling of β2 tanycyte processes in the median eminence. Negative control for immunostaining of β-NGF is presented in Supplementary Figure 2. Scale bars = 50 µm. bv, blood vessels; PT, pars tuberalis. Specific antibodies: β-NGF sc-548, rabbit polyclonal from Santa Cruz Biotechnology.

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    Immunolabeling of GnRH and kisspeptin neuronal fibers in median eminence of coronal sections of the llama hypothalamus. Low magnification of the llama median eminence where abundant fibers of GnRH (A) and kisspeptin (B) neurons are observed. Immunostaining of negative controls for GnRH and Kisspeptin are presented in Supplementary figure 3. 3V, third ventricle; ME, median eminence; RI, infundibular recess. Specific antibodies: GnRH mouse polyclonal, contributed by Dr S Ojeda; kisspeptin AB9754 are rabbit polyclonal, Millipore.

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    Proposed model for the potential access and signaling pathways of β-NGF for triggering ovulation in llamas. Seminal plasma β-NGF is absorbed from the uterus and transported through the circulation to the hypothalamic region, where it may (1) enter into the cerebrospinal fluid of the third ventricle through the choroid plexus or via tanycyte-transport from the portal capillaries at the median eminence, or (2) act directly or indirectly on GnRH neurons at the median eminence. Additionally, ovarian actions of β-NGF are described for rabbit, cattle and llama. 3V, third ventricle; AN, arcuate nucleus; β1, β2, tanycyte; CSF, cerebrospinal fluid; CP, choroid plexus; FSH, follicle-stimulating hormone; LH, luteinizing hormone; ME, median eminence; PG, pituitary gland; pbv, portal blood vessels; trk-A, β-NGF receptor; VMN, ventromedial nucleus.