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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 7 3409-3414
Copyright © 2003 by The Endocrine Society

Human Cervix Contains Functional Luteinizing Hormone/Human Chorionic Gonadotropin Receptors

P. C. Lin, X. Li, Z. M. Lei and Ch. V. Rao

Division of Research, Department of Obstetrics, Gynecology, and Women’s Health, University of Louisville Health Sciences Center, Louisville, Kentucky 40292

Address all correspondence and requests for reprints to: Dr. Ch. V. Rao, Department of Obstetrics, Gynecology, and Women’s Health, University of Louisville Health Sciences Center, Louisville, Kentucky 40292. E-mail: cvrao001{at}gwise.louisville.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The upper genital tract of women contains functional LH/human chorionic gonadotropin (hCG) receptors. Whether the cervix, an anatomical continuum of the uterus and fallopian tubes, also contains these receptors has never been investigated. Multiple receptor detection techniques revealed their presence with higher levels in endocervix than in ectocervix. The receptor positive cells include stratified squamous luminal epithelium of the ectocervix, columnar epithelium, glands, blood vessels, and smooth muscle in the endocervix. Treatment of cervical tissue minces with hCG resulted in a significant increase in cAMP levels and a decrease in cyclooxygenase-2 protein levels in endocervix, but not in ectocervix. In summary, human cervix contains functional LH/hCG receptors, which suggests that LH during the menstrual cycle and hCG during pregnancy may regulate cervical functions.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
LH AND HUMAN chorionic gonadotropin (hCG) are structural and functional homologs that bind to the same receptors (1). The receptors are transmembrane glycoproteins that belong to the G protein-coupled receptor superfamily (2, 3). They consist of equal size exo- and endo- domains (2, 3). The exodomain contains hormone binding sites and the endodomain contains seven transmembrane regions and a short cytoplasmic tail that is coupled to signal transduction pathways (2, 3). Studies from around the world in the last 15 yr have firmly established that a number of nongonadal tissues, including human uterus and fallopian tubes, also contain LH/hCG receptors (4, 5, 6, 7, 8, 9). In vitro and in vivo human studies have demonstrated that activation of uterine and fallopian tube LH/hCG receptors resulted in numerous changes that generally fall into those that are required for pregnancy initiation (10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22), those that are required for pregnancy maintenance (11, 12, 15, 16, 17, 18, 19, 20, 21, 23, 24, 25, 26, 27), and finally those that allow parturition to occur in a timely manner (28). The LH and hCG actions in fallopian tubes and uterus require their receptors as inhibition of receptor synthesis by treatment with antisense phosphorothioate oligodeoxynucleotides resulted in a loss of actions (16, 22). The hCG and LH actions in uterus are beginning to form a basis for novel therapeutic uses of hCG in the treatment of miscarriages (19), preterm labor (28B ), etc.

The cervix is an anatomical continuation of fallopian tubes and uterus and is derived from the same Müllerian duct system. It plays an important role in sperm transport into the upper genital tract, keeping the fetus inside the uterus until the end of pregnancy and then allowing safe passage to the outside world, and in local mucosal immune defense mechanisms (29, 30, 31, 32, 33). Although hormonal control of cervical functions has not been investigated in as great a detail as in the case of uterus and fallopian tubes, it seems that the same hormones that regulate the uterus and fallopian tube functions may also regulate cervical functions (34, 35, 36, 37, 38, 39, 40). Because the uterus and fallopian tubes contain functional LH/hCG receptors (4, 5, 6, 7, 8), we tested the hypothesis that the cervix may also contain them.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Materials

The following were purchased: monoclonal antihuman cyclooxygenase (COX-2) antibody and cAMP immunoassay kit from Cayman Chemical Co. (Ann Arbor, MI); chemiluminescence Western blot detection kit from Amersham Life Sciences (Arlington Heights, IL), and peroxidase-antiperoxidase immunostaining kits from Vector Laboratories (Burlingame, CA). The following were obtained: polyclonal LH/hCG receptor antibody raised against the synthetic N terminus 15–38 amino acid sequence from Dr. Patrick Roche at the Mayo Clinic (Rochester, MN), a HindIII-AspH1 200-1029 bp cDNA fragment encoding human LH/hCG receptor in pBSK-SK+ plasmid from Dr. Aaron Hseuh at Stanford University Medical Center (Palo Alto, CA), and highly purified hCG (CR-127, 14,900 IU/mg) from NIDDK’s National Hormone and Pituitary Program and Dr. A. F. Parlow (Torrance, CA).

Tissues

Cervical specimens were collected from uteri removed for benign gynecological conditions such as dysfunctional uterine bleeding, pelvic pain, pelvic adhesive disease, leiomyomata, endometriosis, and benign serous cystadenoma. Specimens with cancer or cervical dysplasia were excluded. There was no evidence of endometriosis in cervix in patients who had endometriosis. The specimens were kept intraoperatively at room temperature and soaked in normal saline. Either a senior author or a pathologist dissected cervix from uterus. Briefly, uteri were bihalved in a sagittal plane, cervix was identified, and longitudinal specimen was cut from the endocervical canal. A separate cut was then made of the ectocervix some distance from its border with the vagina. A total of 34 specimens were collected. Twenty-two of them came from premenopausal, 8 from perimenopausal, and 4 from postmenopausal women. According to histopathologic examination, 18 premenopausal specimens were in the proliferative phase, 11 in the secretory phase, and 5 were atrophic. Patient ages ranged from 30–81 yr. The study was reviewed by the University of Louisville Human Studies Committee and felt that it was exempt from requiring patient consent because discarded specimens were being used and the information that could identify patients was not recorded. All of the tissues were immediately brought to the laboratory, and unless indicated otherwise, frozen at -70 C for later analysis.

In situ hybridization

Eight specimens were thawed, fixed in 10% formalin, embedded in paraffin, and 5-µm-thick sections cut. A nonradioactive method with fluorescein uridine triphosphate-labeled antisense or sense riboprobes transcribed from human LH/hCG receptor cDNA was used. Briefly, the sections were treated for 30 min at 37C with 5 µg/ml proteinase K in 50 mM Tris-HCl, 5 mM EDTA (pH 7.5), prehybridized for 3 h at 62 C in humidified chambers in a mixture containing 50% formamide, 5x SSC, 1x Denhardt’s solution, 1 mg/ml yeast tRNA, 100 µg/ml heparin, and 5 mM EDTA. Hybridization was then carried out overnight in the same mixture containing riboprobes. After hybridization, the sections were washed twice at 62 C for 30 min each with 1 x SSC and 0.2 x SSC. Hybridization signals were detected by using an antifluorescein alkaline phosphatase conjugate and nitro blue tetrazolium/5-bromo-4-chloro-3-indolyyl phosphate, which gives a blue color.

Immunocytochemistry

Eighteen specimens, which included 8 from in situ hybridization studies, were thawed, fixed in Bouin’s solution, and processed by an avidin-biotin immunoperoxidase method (4, 6). Briefly, the tissues were embedded in paraffin, and 5-µm-thick sections were cut and treated with hydrogen peroxide before overnight exposure at 4 C to a 1:300 dilution of LH/hCG receptor antibody. Preabsorption of the receptor antibody with excess receptor peptide or its substitution with nonspecific IgG were used for procedural controls.

Western blotting

For the detection of LH/hCG receptor protein, six fresh endocervical and ectocervical specimens were separately processed by immediately placing them in ice-cold 25 mM HEPES (pH 7.4) containing 120 mM NaCl, 1 mM EDTA, 1% Triton X-100, 10 µg/ml phenylmethylsufonylfluoride, 5 µg/ml aprotinin, and 5 µg/ml leupeptin. They were then homogenized and protein concentrations were determined by the Bradford method using the commercial kit. Sixty-microgram protein aliquots were separated by discontinuous 10% SDS-PAGE under reducing conditions and electroblotted to Immobilon P membranes (41, 42). Receptors were detected by using a 1:2000 dilution of LH/hCG receptor antibody and an enhanced chemiluminescence detection system. The receptor antibody preabsorbed with the receptor peptide was used in the procedural control.

To determine COX-2 response, four endocervical and ectocervical minces were separately incubated for 4 h at 37 C in the presence or absence of increasing concentrations of hCG. They were then processed the same as in the above paragraph by separating 20- to 30-µg protein aliquots in 10% discontinuous SDS-PAGE under reducing conditions and electroblotting to Immobilon P membranes. COX-2 protein was detected by using a 1:1000 dilution of a COX-2 antibody and an enhanced chemiluminescence detection system.

The molecular sizes of proteins were determined by comparing with standard marker proteins run in an adjacent lane. ß-Actin was used for a loading control. The optical density of the bands was quantified using the Z-gel scanning system (Zaxis Inc., Hudson, OH).

Ligand blotting

This procedure was performed by separating homogenate proteins by 10% SDS-PAGE under nonreducing conditions and then electroblotting to immobilon P membranes (43). The receptor binding was detected by incubating with 1 x 106 cpm/ml of 125I-hCG in the presence or absence of 4 µg unlabeled hCG (43). The molecular size of the receptor protein was determined by running molecular weight standards in an adjacent time.

cAMP measurement

Six endocervical and ectocervical tissue minces were separately incubated for 30 min at 37 C in the presence or absence of increasing concentrations of hCG. Spent culture media were then recovered and stored at -70 C until cAMP was measured using an enzyme immunoassay kit. The kit instructions were followed in the measurement. The antibody specificity was 100% for acetylated cAMP, 0.3% for cAMP, 0.05% for cGMP, and less than 0.01% for others. The intraassay and interassay coefficients of variations were less than 10%. The detection limit of the assay was 1.1 pmol/ml.

Statistical analysis

The data from all the experiments were pooled for the calculation of means and their SEs. One-way ANOVA with the Tukey or Games-Howell test were used for determining the significant differences between the control and treatments (44).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
LH/hCG receptors in human cervix

A nonradioactive method of in situ hybridization, which gives blue hybridization signals, was used to investigate the presence of LH/hCG receptor mRNA in human cervix. It demonstrated that these signals were abundant in stratified squamous epithelium of the ectocervix (Fig. 1AGo), columnar epithelium, blood vessels, smooth muscle, and glands in the endocervix (Fig. 1BGo). The hybridization signals were not detected when the sense riboprobe was used for the procedural control (Fig. 1CGo).



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  		FIG. 1. In situ hybridization for LH/hCG receptors in the human cervix. Antisense riboprobe was used in A and B, and sense riboprobe was used in C. A, Red arrow indicates stratified squamous epithelium of ectocervix. B, Black arrow indicates columnar epithelium, blue arrow indicates smooth muscle, green arrow indicates blood vessel, and red arrow indicates gland in endocervix. Magnification, x300.

 
Immunocytochemistry demonstrated the presence of receptor immunostaining in the same cells that are positive for receptor mRNA, i.e. stratified squamous epithelium of the ectocervix (Fig. 2AGo), columnar epithelium (Fig. 2BGo), blood vessels, smooth muscle (Fig. 2CGo), and glands (Fig. 2DGo) in the endocervix. The receptor immunostaining was not detected when nonspecific IgG was used (Fig. 2EGo), and it dramatically decreased when receptor antibody preabsorbed with the receptor peptide was used (Fig. 2FGo).



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  		FIG. 2. Immunocytochemistry for LH/hCG receptors in the human cervix. Unabsorbed receptor antibody was used in A–D and preabsorbed receptor antibody was used in F. E, Another immunostaining control in which nonspecific IgG was used in place of receptor antibody. Arrow in A indicates stratified squamous luminal epithelium of ectocervix; arrow in B indicates columnar epithelium of endocervix, blue arrow indicates smooth muscle and pink arrows indicate blood vessels in C and red arrows in D indicate endocervical glands. Magnification, x300.

 
Western blotting detected the presence of a 66-kDa receptor protein with significantly higher levels in the endocervix than in the ectocervix (P < 0.05, Fig. 3Go). Ligand blotting demonstrated that 66-kDa protein in endo and ecto cervix can bind 125I-hCG and this binding was completely inhibited by coincubation with excess unlabeled hCG (Fig. 4Go).



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  		FIG. 3. Western blotting for LH/hCG receptors in the human cervix. *, P < 0.05 compared with ectocervix.

 


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  		FIG. 4. Ligand blotting for LH/hCG receptors in the human cervix.

 
hCG effects on human cervical cAMP and COX-2 levels

Previous studies demonstrated that activation of uterine and fallopian tube LH/hCG receptors resulted in an increase in media cAMP and tissue COX-2 levels (12, 13, 16, 26, 45). These two hCG responses were chosen to evaluate whether cervical LH/hCG receptors are functional. Figure 5Go shows that treatment of endocervical minces with increasing concentrations of hCG resulted in a significant increase in media cAMP levels (P < 0.05). The response was modest, variable, and seen between 10 and 100 ng/ml hCG. This contrasted with an inconsistent or no significant change in media cAMP levels from ectocervical minces incubated under the same conditions and at the same time with hCG (data not shown).



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  		FIG. 5. The effect of hCG on media cAMP levels in the human endocervix. *, P < 0.05 compared with the control, which was considered 100%.

 
The hCG treatment of human endocervical minces resulted in a significant decrease in tissue COX-2 protein levels (P < 0.05, Fig. 6Go). The decreases were seen with 10 and 100 ng/ml hCG with no significant difference between the doses.



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  		FIG. 6. The hCG effect on human endocervical COX-2 protein levels. *, P < 0.05 compared with the control, which was considered 100%.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Uterine cervix is a dynamic organ (29, 30, 31, 32, 33). Even though it is an anatomical continuation, it is histologically and functionally quite distinct from uterus and fallopian tubes (29, 30, 31, 32, 33). The cervix is made up of mainly fibrous connective tissue containing collagen and glycosaminoglycans, which give it rigidity (29, 30, 31, 32, 33). The interplay between molecules, along with the contributions from other cell types, determines its physiological responses (29, 30, 31, 32, 33). The responses include allowing sperm transport into the upper genital tract and acting at the same time as a barrier against ascending infections (29, 30, 31, 32, 33). During most of the pregnancy, the cervix acts as a barrier to retain the fetus in the uterus, and at delivery, it softens and dilates to allow safe fetal passage through its canal (29, 30, 31, 32, 33). These opposing cervical functions require numerous morphological and biochemical changes, which are likely to be controlled by circulating hormones and locally made molecules. These include steroid hormones, protein hormones, prostaglandins, cytokines, and nitric oxide (34, 35, 36, 37, 38, 39, 40). Whether LH during the menstrual cycle and hCG during pregnancy are among the circulating hormones that control cervical functions has not been suspected until it became known that human uterus and fallopian tubes contain LH/hCG receptors (4, 5, 6, 7, 8), and their activation results in numerous changes that help initiate and maintain pregnancy and hCG influence may have to decrease for parturition to occur in a timely manner (10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28). Pregnancy maintenance and delivery require cooperative functions of the cervix. Although there are far fewer studies on cervix than those on fallopian tubes and uterus, the regulatory factors are likely to be similar for all three organs. These findings led us to test the hypothesis that the cervix may also contain LH/hCG receptors.

Various receptor detection techniques systematically demonstrated the presence of LH/hCG receptor transcripts, receptor protein, and 125I-hCG binding in human cervical tissue. The receptor levels are higher in the endocervix than in the ectocervix. The results on whether cervical LH/hCG receptors vary with menopausal status or menstrual cycle phase are inconclusive. The receptor activation resulted in an increase in media cAMP levels and a decrease in tissue COX-2 levels in the endocervix but not in the ectocervix. The significance of the differential receptor distribution and response differences between two parts of the cervix is not known, but it could be important. It is of interest to note that the cervical cAMP response is similar, whereas the COX-2 response was opposite to that seen in the uterus and fallopian tubes (12, 13, 16, 26, 45).

Although the cervix contains functional LH/hCG receptors, it does not necessarily mean that LH and hCG regulate cervical functions. However, it is likely considering the cellular distribution of receptors and the hCG effects on cAMP and COX-2. It is possible that the elevated circulatory periovulatory LH levels, besides inducing ovulation, may also activate receptors in endocervical glands and surface epithelial cells to influence cervical secretions and facilitate sperm transport through the cervical canal. These LH actions could be synergtic with estrogens. Because LH receptors are also found in blood vessels and smooth muscle, it is also likely that LH may also regulate cervical blood flow and motility.

The hCG actions to promote pregnancy maintenance may include cervical actions to prevent its premature ripening. Consistent with this possibility, hCG treatment decreased COX-2 levels and this decrease could cause a reduction in prostaglandin (PG)E2, which promotes cervical ripening (46, 47). Thus, decreased PGE2 prevents cervical ripening. hCG could very well prevent cervical ripening until the end of pregnancy and then a waning hCG influence may allow the cervix to respond to other signals that stimulate its ripening. The ability of hCG to inhibit myometrial activity along with its potential role in preventing premature cervical ripening makes it an attractive therapeutic reagent to prevent premature birth. In fact, in a mouse model, hCG was effective in preventing preterm birth (48). Moreover, human studies (28B ) demonstrate that hCG treatment works in preventing preterm delivery. Finally, it is possible that LH and hCG actions could have a relevance to cervical cancer and its mucosal immune defense mechanisms.

The presence of LH receptors that are functionally coupled to increasing cAMP, inositol phosphate production, COX, and PGE2 levels in cow cervix has been reported (49). Although the COX isoform being measured was not specified, the COX response was opposite from human cervix, which may reflect a species difference on the role of LH in cervical functions.

In summary, this is the first study, to our knowledge, to demonstrate the presence of functional LH /hCG receptors in human uterine cervix. This finding may suggest that elevated periovulatory serum LH levels may also play an important role in influencing cervical secretions and facilitating sperm transport across the cervical canal and high hCG levels during pregnancy may prevent premature cervical ripening. Thus, hCG actions not only in uterus, but also in the cervix could be essential for pregnancy inositol phosphate maintenance.


   Footnotes
 
P.C.L.’s present address: Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, Washington 98105.

Abbreviations: COX-2, Cyclooxygenase-2; hCG, human chorionic gonadotropin; PGE2, prostaglandin E2.

Received December 13, 2002.

Accepted March 31, 2003.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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