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Biol Reprod 2004, 10.1095/biolreprod.104.027201
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BIOLOGY OF REPRODUCTION 71, 1412–1418 (2004)
DOI: 10.1095/biolreprod.104.027201
© 2004 by the Society for the Study of Reproduction, Inc.

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Extragonadal Luteinizing Hormone Receptors in the Reproductive Tract of Domestic Animals1

Michael J. Fields2,3, and Mordechai Shemesh4

Department of Animal Sciences,3 University of Florida, Gainesville, Florida 32611 Department of Hormone Research,4 Kimron Veterinary Institute and Koret Veterinary School, Hebrew University, Bet Dagan POB 12, Israel 50250


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 OVIDUCT
 ENDOMETRIUM
 MYOMETRIUM
 CERVIX
 MOUSE LHR KNOCKOUT
 CONCLUSIONS
 REFERENCES
 
Binding sites for LH/hCG and/or its mRNA are found in the uterus of several species, including human, primate, pig, cow, and turkey. Activation of LH receptors around Day 15 of the estrous cycle is associated with increased prostaglandin F2{alpha} production in the bovine, porcine, and ovine uterus. Activation of uterine LH receptors is also associated with increased levels of prostaglandins in human and primate. The presence of gonadotropin receptors with a dynamic pattern in the oviduct, endometrium, myometrium, and cervix of different species provides evidence that gonadotropins play a substantial role in molecular autocrine-paracrine regulation of the estrous cycle and implantation.

cervix, female reproductive tract, luteinizing hormone, oviduct, uterus


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
OVIDUCT
 ENDOMETRIUM
 MYOMETRIUM
 CERVIX
 MOUSE LHR KNOCKOUT
 CONCLUSIONS
 REFERENCES
 
The pituitary gonadotropins, LH and FSH, as well as hCG, belong to the family of glycoprotein hormones consisting of two dissimilar, noncovalently bound {alpha} and ß subunits [1]. The receptors for LH (LHR), FSH (FSHR), and thyroid-stimulating hormone (TSH) belong to a G protein-coupled associated seven transmembrane domain-receptor superfamily [2]. Both LH and hCG share a common receptor, with hCG binding having a somewhat higher affinity [3].

The luteotropic activity of both hCG and LH are widely recognized. Human chorionic gonadotropin is a luteotropic agent that maintains function in the corpus luteum until approximately the ninth week of pregnancy, at which time the placenta becomes the primary site of progesterone synthesis [4]. It has become evident over the last decade that organs other than "traditional" gonadal target sites are affected by FSH and LH. Receptors for these gonadotropins have been found throughout the reproductive tract: in the oviduct, endometrium, myometrium, cervix, and uterine vessels. Various models have been proposed for the function of these receptors, considering that their expression is dynamic and changing during the estrous cycle.

The objective of the present review is to summarize the current knowledge of extragonadal LHRs in the reproductive tract. Suggestions as to the physiological functions of these receptors also will be offered. The most comprehensively studied reproductive tracts (bovine, ovine, porcine, and turkey) will be the focus, though comparisons will be made with pertinent published studies involving other species.


   OVIDUCT
TOP
 ABSTRACT
 INTRODUCTION
 OVIDUCT
ENDOMETRIUM
 MYOMETRIUM
 CERVIX
 MOUSE LHR KNOCKOUT
 CONCLUSIONS
 REFERENCES
 
Luteinizing hormone receptors have been demonstrated in human [5, 6], bovine [7, 8], porcine [9–12], turkey (infundibulum) [13], and mouse [14] fallopian tubes (Table 1). Lei et al. [5] demonstrated that the human oviduct contains a 4.4-kilobase LHR mRNA transcript and an 80-kDa immunoreactive protein. Derecka et al. [9] detected the LHR transcript in pig oviduct during the early luteal and follicular phase of the estrous cycle. Subsequent studies revealed that the pig oviduct possesses immunoreactive and functional LHR [11, 12]. Immunohistochemical studies showed that LHR is present in the epithelium of tubal mucosa, smooth muscle cells, and blood vessel endothelium. The most noticeable immunostaining was seen in the mucosal epithelium, and staining of the epithelium of the ampulla was more intense for LHR than in the epithelium of the isthmus. Staining of the myosalpinx was less intense than that of the mucosal layer. A similar distribution of LHR was found in women [5]. Moreover, the intensity of the immunohistochemical reaction in the porcine oviduct was shown to depend on the hormonal status of the animals. Oviductal sections from ovariectomized pigs reveal only minor LHR immunostaining compared with sections of estradiol-treated, ovariectomized animals. Estradiol benzoate increased the number of LH-binding sites in oviduct 24– 72 h after injection compared to control gilts treated with corn oil [10]. A direct influence of estradiol on the LHR was shown when the LHR was up-regulated by estradiol in cultured human oviductal epithelial cells [6]. Tubal-receptor concentrations vary during the menstrual cycle in women, and the fallopian tubes contain more LHR during the secretory phase than during the proliferative phase [5]. The presence of LHR in various cells of the oviduct and the changes in receptor quantity depend on the hormonal status of the animal, indicating that LH might directly regulate tubal function.


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  		TABLE 1. Distribution of LHRs and their function in nongonadal tissues

In vitro, LH could modulate spontaneous contraction of the porcine oviduct, causing its relaxation, especially during the preovulatory stage of the estrous cycle [10]. Furthermore, LH treatment affected oviductal contractility of pigs treated with estradiol and progesterone combined, but not the oviductal motility of progesterone-, estradiol-, or corn oil-treated animals. It is interesting that in all cases, a gradual inhibition of spontaneous contractions takes place within 10 min after addition of LH. The mechanism of LH action on the oviduct is possibly through locally released factors (e.g., cAMP and/or prostaglandins [PGs]).

Oviducts are organs that support gamete transport, maturation, fertilization, early embryonic growth, and development as well as their timely transport for implantation in the uterus [15]. They are regulated by a wide variety of agents, including locally synthesized molecules working in an additive, synergistic, or antagonistic manner to regulate different oviductal functions. Luteinizing hormone is among the circulating hormones that can potentially regulate oviductal function. The presence of oviductal LHR and/ or activation by LH has been demonstrated in several species. The LHR activation resulted in up-regulation of PG endoperoxidase H synthase (PGHS)-1 and -2 [5, 6], synthesis of PGE2 and PGF2{alpha} [5, 6, 16, 17], 5-lipoxygenase [5], oviductal glycoprotein [7, 8], and endothelin-1 [16, 17], which have been shown to play an important role in various oviductal functions.

Activation of the bovine oviductal LHR results in an increased synthesis of oviductal glycoprotein [7, 8], which binds embryos to increase their development [18]. The hCG treatment of oviductal epithelial cells cocultured with 2-cell embryos resulted in increased embryonic development to the blastocyst stage [9]. Furthermore, hCG was shown to bind directly to the bovine oocyte, embryo, and blastocyst. The effect of this binding is unknown, but a common theme in LH action outside the gonads across all species is the up-regulation of PG synthesis.


   ENDOMETRIUM
TOP
 ABSTRACT
 INTRODUCTION
 OVIDUCT
 ENDOMETRIUM
MYOMETRIUM
 CERVIX
 MOUSE LHR KNOCKOUT
 CONCLUSIONS
 REFERENCES
 
Evidence for the presence of LHR in endometrium was found in the crude membrane fractions of bovine [19] and porcine endometrium [20] collected from the luteal phase of the estrous cycle, as determined by radioreceptor assay. Western blot analysis revealed the presence of 75- and 93-kDa immunoreactive proteins in the bovine endometrium [21] and 75-kDa protein in the porcine endometrium [22]. Recently, we have shown via immunohistochemistry that LHR is localized to the luminal and glandular epithelium of the bovine endometrium (Fig. 1). Furthermore, LH was shown to increase the in vitro expression of its own receptor in the luteal phase endometrium (Fig. 2A). At higher doses of LH, the LHR was down-regulated [21]. In addition, LH induced the Gs({alpha}) protein (Fig. 2B) and hydrolysis of inositol phosphate (Fig. 3), indicating not only the presence of the LHR but that LH activates both the cAMP and phospholipase C pathways [21]. Besides in cow [21], messenger RNA encoding LHR was found in the reproductive tract of pigs [9], humans [24, 25], turkeys [13], and rodents [14, 26].



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  		FIG. 1. Localization of immunoreactive LHR in endometrial epithelium of a cow on Day 14 of the estrous cycle. The Vector Elite ABC IHC kit (Vector Laboratories, Burlingame, CA) was used with a polyclonal anti-rat LHR antibody, LHRO2, prepared against affinity- and SDS-purified rat ovarian LHR [23]. Antibody was donated by Dr. D. Segaloff (University of Iowa). Tissues were counterstained with hematoxylin. Shown are (A) Control in which tissue sections stained with diluent without the primary antibody was negative as well as (B) luminal epithelium and (C) glandular epithelium stained with LHR antibody (1:50). Luminal epithelium stained consistently, whereas not all glands stained



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  		FIG. 2. A) Induction of LHR by LH in the endometrium of luteal-phase cows (Days 12–16). Endometrial minces were incubated with LH (0, 10, and 20 ng/ml) for 180 min (n = 6 cows). Blots were treated with an anti-rat LHR antibody, LHRO2, donated by Dr. D. Segaloff (University of Iowa). B) Induction of Gs({alpha}) protein by LH in bovine endometrium of luteal-phase cows. Endometrial minces were incubated with LH, and blots were treated with an antibody for bovine Gs({alpha}). (From Shemesh et al. [21]; with permission)



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  		FIG. 3. Effect of LH or oxytocin on the hydrolysis of labeled myo-inositol to inositol phosphate in the endometrium of luteal phase cows (Days 12– 16). Endometrial minces were incubated with LH (0 and 10 ng/ml) or oxytocin (0 or 10 ng/ml) for 90 min (n = 4 cows) at each stage of the cycle. (From Shemesh et al. [21]; with permission)

Physiological Role of Endometrial LHR

In ruminants, uterine production of PGs plays a central role in regulation of the estrous cycle, pregnancy recognition, pregnancy, and parturition. The product of endometrial PG is mainly governed by the rate-limiting enzyme PG endoperoxidase H synthase (PGHS)-2, also known as cyclooxygenase-2. Because PGHS-1 is not found in bovine endometrium [27], PGHS-2 is responsible for the conversion of arachidonic acid into PG, the common precursor of the various forms of PGs, including PGF2{alpha} and PGE2 [27]. The downstream enzymes, PGE2 synthase and PGF2{alpha} synthase, catalyze the conversions of PGH2 to PGE2 and PGF2{alpha}, respectively. The expression and regulation of PGHS-2 is tissue specific. Luteinizing hormone regulates PGHS-2, but not PGHS-1, in all uterine tissues (endometrium, myometrium, cervix, and oviduct) that are modulated by activation of both inositol phosphate and adenyl cylase [22].

The endometrial LHR reaches its highest concentration during the luteal phase. This elevation of LHR before the preovulatory LH peak indicates that other unique intracellular factors may be involved in regulation of the cycle in ruminants. A direct chronological relationship of the increased concentration of LHR and the initiation of PGHS-2 and PGF2{alpha} production in endometrial epithelial cells [19, 21, 28–30] implies a role for LH in the commencement of bovine and porcine luteolysis. Evidence indicates that PGF2{alpha} may deplete endometrial gonadotropin-binding sites at the follicular stage of the estrous cycle following the start of luteolytic endometrial PGF2{alpha} secretion, producing a decline in the number of LHR sites. Studies supporting this hypothesis show that injection of PGF2{alpha} induced rapid inhibition of bovine corpus luteal progesterone production, followed by a decrease in the concentration of luteal LH/hCG-binding sites [31]. This effect can be achieved through blood flow [28] as well as by feedback mechanism or enhancement of LHR internalization. Rahe et al. [32] have shown pulses of LH in the luteal phase, which would indicate that the extragonadal actions of LH do not correspond to preovulatory LH. This would further indicate that the peripheral plasma concentration of LH is of less importance than the increased expression of the LHR in the uterus.

Traditionally, LH is known to increase progesterone synthesis by the corpus luteum. However, in the endometrium, it apparently is involved in uterine PGF2{alpha} synthesis at a time when a potential role of endometrial LH in luteal regression is associated with luteolysis, but this is yet to be confirmed.

The stimulatory effect of LH on uterine PGHS-2 and its associated product, PGF2{alpha}, observed in vitro was also demonstrated in vivo using hCG [21, 33]. When cows were injected with 3000 U of hCG on Day 15 of the estrous cycle, the concentration of the PGF2{alpha} metabolite 13,14-dihydro-15-keto-PGF2{alpha} (PGFM) was greater than that in cows injected with either saline or oxytocin (Fig. 4). Similar results were found in ovariectomized cows implanted with progesterone.



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  		FIG. 4. Effect of hCG injection via the jugular vein on peripheral plasma concentrations of PGFM in cows on Day 15 of the estrous cycle. Cows were pretreated with 3 mg of estradiol-17ß, followed by either 3000 (n = 6 cows) or 1000 U (n = 3 cows) of hCG or by 100 U of oxytocin (n = 6 cows, positive control) or saline (n = 5 cows, estradiol control). Blood samples were taken from the jugular vein at 15 min intervals. Regression analysis and orthogonal contrasts showed that the group receiving 3000 U of hCG was different (P < 0.01) from that receiving 1000 U of hCG or saline. (From Shemesh et al. [21]; with permission)

In the pig, Ziecik et al. [34] found that the concentration of peripheral plasma PGFM was increased after hCG infusion during the luteal phase of the porcine estrous cycle. Moreover, they observed a close relationship between plasma LH and PGFM in pigs around the time of luteolysis. The stimulatory effect of LH on uterine PGHS-2 and its associated product was also shown in pig [29] and ovine endometrium [35]. These data indicate that LH involvement during the elevation of endometrial PGF2{alpha} secretion in the bovine, ovine, and porcine uterus is associated with induction of luteolysis. Luteinizing hormone and its extragonadal receptors may have an expanded role toward the end of the cycle. This may result in secretion of PGF2{alpha} before the elevation in LH that leads to ovulation, starting the cycle anew. Aside from LH initiating the cycle and, possibly, playing a role in its demise, LH may also have a positive role in early pregnancy, as reported by Weems et al. [35] working with the ewe and by Ziecik et al. [36, 37] working with the pig. Both groups showed that the responsiveness of the endometrium to LH changed from the production of PGF2{alpha} during the cycle to PGE2 during early pregnancy. In nonpregnant women, endometrial epithelial cells responded to LH by up-regulating PGHS-2 and secretion of PGE2 [38]. Similar results were reported for baboon epithelial cells [39].


   MYOMETRIUM
TOP
 ABSTRACT
 INTRODUCTION
 OVIDUCT
 ENDOMETRIUM
 MYOMETRIUM
CERVIX
 MOUSE LHR KNOCKOUT
 CONCLUSIONS
 REFERENCES
 
Specific high-affinity, low-capacity binding sites for LH/ hCG were first reported in pig myometrium [20, 40–42]. The LHR is also present in uterus of rats [43, 44] and rabbits [44, 45] and in myometrial muscle of women [46, 47] and cows [48]. In all of the species studied, expression of LHR is dependent on the stage of the cycle. Expression of LHR mRNA is high during the luteal phase, but LHR mRNA is expressed only weakly during the follicular phase. Both the cAMP and phospholipase C pathways are activated by LH, and the effect of LH on both pathways at each stage of the cycle is correlated with the amount of LHR in the tissue. Activation of these signal pathways is associated with an increase in the expression of PGHS-2 in the bovine myometrium (for review, see [49]).

The LHR may have a role in the hyperplastic hypertrophy of the uterus and uterine motility (for review, see [40]), consistent with a decrease of intracellular calcium concentration in human myometrial smooth muscle cells after hCG treatment [50]. Myometrial growth and uterine relaxation seen during early pregnancy may be regulated, in part, by trophoblastic hCG in women or pituitary LH in pigs and other nonprimates. High concentrations of LHR induced by estradiol allow a relaxing effect on the pig myometrium, which is not seen in the absence of LHR [51, 52]. Therefore, regulation of LHR results in increased binding of LH and an increase in cAMP, which may serve to maintain the quiescence of the uterus during the luteal phase.

LHRs of Uterine Blood Vessels

Receptors for LH were found in both the arteries and veins of the porcine broad ligament [53]. Both the ovarian artery and the ovarian vein contained higher concentrations of LHR during the follicular than the luteal phase of the estrous cycle. In all cases, the vein contained a higher concentration of LHR than that in the artery. The relaxing effect of hCG on smooth muscle and blood vessels of the porcine uterus is associated with increased uterine blood flow [53, 54]. Injection of hCG to pigs during the luteal phase of the estrous cycle and to ovariectomized animals treated with estrogen and progesterone produced an increased uterine blood flow that was biphasic [54]. The first phase occurred within 1 h after the injection of hCG and is believed to be a direct effect on uterine blood flow. The delayed, second-phase increase, however, may be a response to estradiol secretion that has been shown previously to increase uterine blood flow in pigs [55].

Lacroix and Kann [56] suggested that in the ewe, PGs produced by the vascular tissue could contribute to the well-documented increase in uterine vein PGF2{alpha} during proestrus. This elevation in uterine vein PGF2{alpha} coincided with a lower production by the endometrium on Days 16–17 than on Day 14. Similar observations have been made in the cow, with higher uterine vein PGF2{alpha} during proestrus [57], concomitant with a lower endometrial PGHS-2 expression [28, 58] and PGF2{alpha} synthesis [59], than seen during the late luteal phase.

Concurrent with bovine uterine vein PGF2{alpha} secretion during estrus was the expression of uterine vein LHR mRNA and LHR protein [60]. Low to nondetectable expression of the LHR mRNA was found in uterine veins from other stages of the estrous cycle and from arteries at any stage of the cycle. The 93-kDa LHR protein was found in abundance in uterine vein extracts from cows in estrus, whereas very little was observed in uterine vein extracts from the luteal and postovulatory phase [60]. Binding of labeled hCG has also been reported in the vasculature of the bovine corpus luteum [61].

A direct effect of LH on induction of bovine uterine vein PGHS-2 was shown using endothelial layer minces from uterine veins. After 3 h of incubation, LH induced a greater than 100% increase in PGHS-2, whereas no effect of LH was observed on uterine arterial minces [60]. An increase in PGHS-2 induced by exogenous LH was associated with increased PGF2{alpha} and PGE2 production by the veins. When the uterine vein from estrous cows was incubated with LH, a significant increase was observed in both PGF2{alpha} and PGE2 synthesis. This is in contrast with the bovine endometrium, where LH induced PGF2{alpha} but not PGE2 [19, 21, 30]. No effect of LH on PG synthesis was seen when incubations were done with the uterine artery.

In contrast to cow uterine arteries, expression of LHR mRNA and LHR protein have been reported for human uterine arteries [62, 63]. Furthermore, those authors reported that exogenous hCG can increase PGHS-2 and the formation of vasoactive eicosanoids in the human uterine artery. One of the earliest reported effects of LH was the induced hyperemia of ovarian blood vessels [64, 65]. Recently, Zygmunt et al. [66] reported that hCG may be involved in early pregnancy as an angiogenic factor. They showed that hCG induced in vitro capillary formation and migration of endothelial cells. Furthermore, in the chicken chorioallantoic membrane assay, hCG induced neovascularization comparable to the effect seen with vascular endothelial growth factor.

The concentration of PGHS-2 and synthesis of PGF2{alpha} in the bovine endometrium at estrus is low [19]. However, the plasma concentration of PGF2{alpha} in the uterine vein ranges from 1–3 ng/ml in the cow [57] to 6–7 ng/ml in the ewe [67, 68]. Because LH increases PGHS-2 and synthesis of PGF2{alpha} and PGE2 by the uterine vein during estrus, the uterine vein may be a significant contributor to the circulating PG during the latter stages of the estrous cycle.

The increased PG secretion during proestrus and estrus could contribute to luteolysis by PGE2 inducing an increased blood flow in the countercurrent plexus between the uterine and ovarian vasculature, resulting in delivery of increasing amounts of the luteolytic agent PGF2{alpha} to the corpus luteum. Furthermore, the uterine venous PGE2 could contribute to the softening of the cervix at estrus and to initiation of the preovulatory development of antral follicles. The action of LH in a coordinated way on both the endometrium and uterine vasculature confined to a specific stage of the estrous cycle may prove to be important in understanding the mechanisms involved with regulation of the cycle and signaling during early pregnancy [35–37].


   CERVIX
TOP
 ABSTRACT
 INTRODUCTION
 OVIDUCT
 ENDOMETRIUM
 MYOMETRIUM
 CERVIX
MOUSE LHR KNOCKOUT
 CONCLUSIONS
 REFERENCES
 
The bovine cervix has high levels of LHR mRNA and protein at the luteal phase of the cycle, similar to the time seen for elevation of the receptor in the endometrium. The LHR is a member of the protein coupled-receptor family that mediates cAMP and phosphotidylinositol signaling responses. The receptor coupling to the PG synthase leads to cervical synthesis of PGE2 [69]. Similar findings were reported for FSHRs and their activation in the bovine cervix [48]. In the cervix of the pig, LHR mRNA and protein have been reported [22] to be present throughout the estrous cycle and not to be elevated in the luteal phase, as reported for the cow. Both the LHR mRNA and protein were also reported in the human cervix, with localization to the epithelial layer [70]. Treatment of human cervical tissue minces with hCG resulted in a significant increase in cAMP levels, with a concomitant decline in PGHS-2 protein. It is interesting that in the human, LH induces PGHS-2 in the oviduct [6] and uterus [42] but inhibits PGHS-2 in the cervix [70]. The PGHS-2 response to LH in the human cervix was opposite that reported for the cow cervix [69], which may reflect a species difference in the role of LH in cervical functions.

The cervix undergoes constriction and relaxation depending on the underlying biochemical and structural changes in connective tissue. The LH has been shown to regulate collagen turnover via the collagenases in the extracellular matrix [71]. Prostaglandin E2, a product of LH stimulation, has been found to cause softening of the cervix in the ewe [72, 73] and cow [74, 75] and in clinical obstetrics when the induction of labor is medically indicated [76, 77]. However, because both stimulatory and inhibitory subtypes of PGE2 receptor are present in the reproductive tract, PGE2 could cause the contraction or relaxation of cervical muscle, depending on the subtype of the receptor [78]. The preovulatory rise in plasma LH also may play an important role in influencing cervical secretions and facilitating sperm transport across the cervical canal. An additional and seemingly contradictory role for hCG in the human for sustaining pregnancy may be the prevention of premature cervical ripening [79, 80]. In vitro, LH regulates the expression of LHR in both the gonads as well as uterine tissue. The level of LHR in the endometrium and myometrium is maximal during the luteal phase, however, whereas in the uterine vein and oviduct, LHR is maximally expressed during the follicular phase. These differences are related to local autocrine-paracrine regulation by local factors (e.g., calcium, estrogen, and PGs), which might regulate the number of receptors.


   MOUSE LHR KNOCKOUT
TOP
 ABSTRACT
 INTRODUCTION
 OVIDUCT
 ENDOMETRIUM
 MYOMETRIUM
 CERVIX
 MOUSE LHR KNOCKOUT
CONCLUSIONS
 REFERENCES
 
Knockout of the LHR in the mouse resulted in infertile males and females with markedly atrophied external and internal genitalia [81–83]. This is expected given the dependence of the reproductive system on the steroid hormones testosterone, progesterone, and estrogen. The question relevant to the present review concerns direct effects of LH that are independent of the steroid hormones. Testosterone replacement therapy initiated immediately after birth was successful in restoring fertility in the male. In the female, steroid replacement therapy did not substitute for direct LH signaling, which has been shown previously to be necessary for development of the antral follicle. In an evaluation of the uterus, steroid replacement therapy failed to completely restore the endometrium to a similar morphology as the wild type (i.e., incomplete decidual changes and uterine gland numbers remained depressed) [83]. To determine if the uterus could sustain a pregnancy, donor blastocysts from wild-type mice were implanted into the uterus of the steroid-treated, LHR-null mouse. These blastocysts failed to implant. One cannot completely rule out that the steroid regimen was inadequate; however, if that is the case, why then the need for expression of uterine LHR? Further work in this area, particularly concerning reported differences in gene expression between the wild-type, null-type, and the steroid-treated, null-type mice, will no doubt contribute to our understanding of the role of extragonadal LHR. We agree with the authors of the LHR knockout studies that LHR is playing a definitive role in uterine function. It would not be unexpected for this role to vary across species and, in particular, between mice and domestic animals.


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 OVIDUCT
 ENDOMETRIUM
 MYOMETRIUM
 CERVIX
 MOUSE LHR KNOCKOUT
 CONCLUSIONS
REFERENCES
 
The present review describes the novel observations that gonadotropins are involved in the regulation of uterine PGHS-2 and its products. The actions of LH were evident in the entire uterus: oviducts, myometrium, endometrium, cervix, and blood vessels. The presence of LHR has been demonstrated in several species, including cows, pigs, humans, primates, rodents, and turkeys. The stimulatory effect of LH on bovine uterine PG production has been well documented [17, 19, 21, 30, 33]. We are unaware of any work concerning the extragonadal LHR expression in the ewe, but the effect of LH on uterine PGF2{alpha} and PGE2 was recently reported [35]. This increase in PG synthesis in nonbred ewes indicates a role for LH in luteolysis. Good evidence suggests a role of LH in luteolysis in the cow and sow as well. It appears that in addition to its well-established role as a luteotropic agent, LH has an oxytocin-like effect in the luteolytic process. The possibility of a role for LHR also exists in early pregnancy-stimulated PGE2 [35–37]. Although LHR is found in the uterine tract of humans, primates, rats, mice, rabbits, and turkeys, it is probably more important in the domestic ruminant, where luteolysis is regulated by the uterus and autocrine-paracrine regulation of the uterine environment is an essential part of luteolysis. The finding across a wide range of species, including salmon [84] and catfish [85], that LHR is distributed and functional in tissues other than the gonads indicates that LHR evolved in nongonadal tissues early during the evolutionary process.


   FOOTNOTES
 
1 Supported by Florida Agriculture Experiment Station Journal Series No. R-10378 Back

2 Correspondence. FAX: 352-392-7652; fields{at}animal.ufl.edu Back

Received: 6 January 2004.

First decision: 28 January 2004.

Accepted: 15 June 2004.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 OVIDUCT
 ENDOMETRIUM
 MYOMETRIUM
 CERVIX
 MOUSE LHR KNOCKOUT
 CONCLUSIONS
 REFERENCES
 

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