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The underlying cause of cervical cancer in oral contraceptive users may be related to cervical mucus changes
Medical Hypotheses (2007) 69, 550–552
http://intl.elsevierhealth.com/journals/mehy
The underlying cause of cervical cancer in oral contraceptive users may be related to cervical mucus changes Suleyman Guven a,*, Cavit Kart b, Emine Seda Guvendag Guven c, G. Serdar Gunalp b a
Department of Obstetrics and Gynecology, Karadeniz Technical University, School of Medicine, Trabzon, Turkey b Department of Obstetrics and Gynecology, Hacettepe University School of Medicine, Ankara, Turkey c Department of Obstetrics and Gynecology, Etlik Women’s Health and Maternity Teaching Hospital, Ankara, Turkey Received 25 December 2006; accepted 3 January 2007
Summary Oral contraceptives (OCs) remain among the most effective reversible methods of birth control available today, providing almost 100% effectiveness with an impressively high margin of safety and other important health benefits. However, concerns have been raised about the role that the hormones in OCs might play in the pathogenesis of cervical cancer. Evidence shows that long-term use of OCs (five or more years) may be associated with an increased risk of cancer of the cervix. The mechanism of increased risk of cervical cancer in OCs users has long been debated, and remains uncertain. Our hypothesis is that scanty, thick, and highly viscous cervical mucus obtained in OCs users intimately involved in the pathogenesis of cervical cancer. Possibly, this architecture of cervical mucus may modulate and prolong the effect of carcinogenic agents, which have been carried by coitus and stored in posterior vaginal fornix, on squamocolumnar junction of cervix by not permitting them to be removed because of its highly viscous pattern. The role of cervical mucus changes by means of specific mucin protein changes on the pathophysiology of cervical cancer in OCs users should be investigated. c 2007 Elsevier Ltd. All rights reserved.
Introduction Oral contraceptives (OCs) remain among the most effective reversible methods of birth control avail* Corresponding author. Address: Mahmut Esat Bozkurt Caddesi No: 69/2, Oncebeci 06660, Ankara, Turkey. Tel.: +90 312 419 49 16; fax: +90 312 432 24 15. E-mail address: [email protected] (S. Guven).
able today, providing almost 100% effectiveness with an impressively high margin of safety and other important health benefits [1]. However, concerns have been raised about the role that the hormones in OCs might play in a number of cancers, and how hormone-based OCs contribute to their development. The risk of endometrial and ovarian cancers is reduced with the use of OCs, while the risk of breast and cervical cancers is increased [2].
0306-9877/$ - see front matter c 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2007.01.051
Oral contraceptives and cancer Evidence shows that long-term use of OCs (five or more years) may be associated with an increased risk of cancer of the cervix [3]. Moreover, a 2003 analysis by the International Agency for Research on Cancer (IARC) found an increased risk of cervical cancer with longer use of OCs. Researchers analyzed data from 28 studies that included 12,531 women with cervical cancer. The data suggested that the risk of cervical cancer may decrease after OC use stops [4]. In another IARC report, data from eight studies were combined to assess the effect of OC use on cervical cancer risk in HPV-positive women. Researchers found a fourfold increase in risk among women who had used OCs for longer than five years. Risk was also increased among women who began using OCs before age 20 and women who had used OCs within the past five years [5]. The mechanism of increased risk of cervical cancer in OCs users has long been debated, and remains uncertain. The most popular mechanism is the mechanism which expressed the relationship between oral contraceptives and human papilloma virus (HPV), since HPV is recognized as the major cause of this disease and approximately 14 types of HPV have been identified as having the potential to cause cancer, and HPVs have been found in 99% of cervical cancer biopsy specimens worldwide [3]. Steroid contraception has been postulated to be one mechanism whereby HPV exerts its tumorogenic effect on cervical tissue. Steroids are thought to bind to specific DNA sequences within transcriptional regulatory regions on the HPV DNA, either to increase or suppress the transcription of various genes. The regulatory region of the HPV type 16 viral genome indicates transcriptional control of the HPV genome and is thought to contain enhancer elements that are activated by steroid hormones [6]. Considering these findings, it appears logical to suspect a role for local factors in cervical cancer development. In women using combined oral contraceptives, the cervical mucus remains scanty, thick, and highly viscous [7]. The role of cervical mucus changes on the pathophysiology of cervical cancer development in OC users has not been well described.
The hypothesis Our hypothesis is that scanty, thick, and highly viscous cervical mucus obtained in OCs users intimately involved in the pathogenesis of cervical cancer. Possibly, this architecture of cervical mucus may modulate and prolong the effect of carcinogenic agents, which have been carried by coitus and stored in posterior vaginal fornix, on squamo-
551 columnar junction of cervix by not permitting them to be removed because of its highly viscous pattern. The macroscopic and microscopic changes in cervical mucus may be related to the changes in the ratio of cervical mucins and other proteins, which may predispose to cervical cancer.
Evaluation of hypothesis The mucus covering on the surfaces of the female reproductive tract is important in its defense and reproductive function. The mucus gel, secreted primarily by the endocervical epithelium, provides a barrier to sperm and pathogen penetrance into the endometrium and a protective covering for the vaginal and cervical epithelium [8,9]. The major structural components of the mucus gel are mucins—highly glycosylated proteins, the major mass of which are O-linked carbohydrates. At least nine distinct mucin genes have been cloned and designated, in order of discovery, as MUCs 1,2, 3, 4, 5AC, 5B, 6, 7, and 8 [10]. Progestogens alter the cervical mucus to prevent sperm penetration and subsequent migration into the uterus.The cervical mucus quality is assessed by the characteristics of arborization, spinnbarkeit, and viscosity. For most of the menstrual cycle, the cervical mucus is thick and viscous, becoming thin and more liquefied around the time of ovulation. During treatment with OCs, the arborization, quantity, viscosity, and spinnbarkeit of the cervical mucus approximate the preovulatory phase of an untreated cycle, and sperm penetration is negligible, and it always becomes thick and highly viscous [11]. This effect may suggest the idae that the architecture of such mucus may also prevent the penetration and removal of other pathogens or carcinogens. Mucins contribute to all-important physiologic event in menstrual cycle. mRNA levels of the gelforming mucin MUC5B, the major gel-forming mucin expressed by the endocervical epithelium, peak before midcycle. Message levels for MUC4, a major membrane-spanning mucin of the endocervix, peak at midcycle. Message for each mucin diminishes dramatically as progesterone levels increase in the blood. Perhaps, through its hydrophilicity, the MUC5B mucin holds water in place at the endocervical canal surface at midcycle, keeping the canal patent for sperm motility. In addition pathogens and other seminal fluid components may be excluded from entering the uterus by mucin trapping [10,12]. In OC users the major mucin in thick viscous cervical mucus may be expected to be MUC5B. Furthermore, MUC5B may be put the pathogens (such
552 as HPV) inside through its hydrophilicity and modulate and prolong the interaction of HPV and cervix in OC users.
How to test this hypothesis? Measuring mucin protein levels of a specific mucin in samples containing multiple mucin gene products has proven difficult. This is partly attributable to difficulty in identifying specific gene products, because there have been relatively few well-characterized specific antibodies based on molecular characterization of the molecules, and because individual mucins have not been purified [12]. An extensive CsCl density centrifugation purification of the mucins followed by direct measurement of the protein in the isolated fractions by mucin-specific antibodies may be used [13]. Measurement of mucins within mucus secretions by using antibodies to isolates of mucin in combination with enzyme-linked immunosorbent assay (ELISA) is another choice [14]. An alternative method is the use of antibodies specific to a synthetic peptide that mimics a unique nonglycosylated region of the D4 domain of MUC5B in an ELISA-based assay, to determine relative amounts of a specific mucin protein in a mixed sample [12]. A new study designed to compare the composition of mucins in cervical mucus in OC users and non-OC users would bring a new insight to the current literature about the pathogenesis of cervical cancer in OC users.
Consequences of the hypothesis When an epithelium undergoes malignant transformation, the mucin genes can undergo aberrant expression causing reduced production of an expected mucin and/or production of a structurally different and unexpected mucin within the transformed epithelium [12,15]. The current hypothesis may also contribute to the current literature about early detection of cervical cancer, may be by examining the mucin composition of cervical mucus in Ocs users. Studies to determine the mechanism of hormonal regulation of mucins and the composition of mucins in patients with OC users as well as the function of individual mucins are needed.
Guven et al.
References [1] Hedon B. The evolution of oral contraceptives. Maximizing efficacy, minimizing risks. Acta Obstet Gynecol Scand Suppl 1990;152:7–12. [2] Burkman R, Schlesselman JJ, Zieman M. Safety concerns and health benefits associated with oral contraception. Am J Obstet Gynecol 2004;190:S5–S22. [3] Franceschi S. The IARC commitment to cancer prevention: the example of papillomavirus and cervical cancer. Recent Results Cancer Res 2005;166:277–97. [4] Smith JS, Green J, Berrington de Gonzalez A, Appleby P, Peto J, Plummer M, et al. Cervical cancer and use of hormonal contraceptives: a systematic review. Lancet 2003;361:1159–67. [5] Moreno V, Bosch FX, Munoz N, Meijer CJ, Shah KV, Walboomers JM, et al. Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: the IARC multicentric e-control study. Lancet 2002;359:1085–92. [6] Moodley M, Moodley J, Chetty R, Herrington CS. The role of steroid contraceptive hormones in the pathogenesis of invasive cervical cancer: a review. Int J Gynecol Cancer 2003;13:103–10. [7] Rivera R, Yacobson I, Grimes D. The mechanism of action of hormonal contraceptives and intrauterine contraceptive devices. Am J Obstet Gynecol 1999;181:1263–9. [8] Morales P, Roco M, Vigil P. Human cervical mucus: relationship between biochemical characteristics and ability to allow migration of spermatozoa. Hum Reprod 1993;8:78–83. [9] Gipson IK, Spurr-Michaud S, Moccia R, Zhan Q, Toribara N, Ho SB, et al. MUC4 and MUC5B transcripts are the prevalent mucin messenger ribonucleic acids of the human endocervix. Biol Reprod 1999;60:58–64. [10] Gipson IK. Mucins of the human endocervix. Front Biosci 2001;6:D1245–55. [11] Lammers P, Blumenthal PD, Huggins GR. Developments in contraception: a comprehensive review of Desogen (desogestrel and ethinyl estradiol). Contraception 1998;57:1S–27S. [12] Gipson IK, Moccia R, Spurr-Michaud S, Argueso P, Gargiulo AR, Hill 3rd JA, et al. The amount of MUC5B mucin in cervical mucus peaks at midcycle. J Clin Endocrinol Metab 2001;86:594–600. [13] Wickstrom C, Davies JR, Eriksen GV, Veerman EC, Carlstedt I. MUC5B is a major gel-forming, oligomeric mucin from human salivary gland, respiratory tract and endocervix: identification of glycoforms and C-terminal cleavage. Biochem J 1998;334(Pt 3):685–93. [14] Steiger D, Fahy J, Boushey H, Finkbeiner WE, Basbaum C. Use of mucin antibodies and cDNA probes to quantify hypersecretion in vivo in human airways. Am J Respir Cell Mol Biol 1994;10:538–45. [15] Baker AC, Eltoum I, Curry RO, Stockard CR, Manne U, Grizzle WE, et al. Mucinous expression in benign and neoplastic glandular lesions of the uterine cervix. Arch Pathol Lab Med 2006;130:1510–5.
http://intl.elsevierhealth.com/journals/mehy
The underlying cause of cervical cancer in oral contraceptive users may be related to cervical mucus changes Suleyman Guven a,*, Cavit Kart b, Emine Seda Guvendag Guven c, G. Serdar Gunalp b a
Department of Obstetrics and Gynecology, Karadeniz Technical University, School of Medicine, Trabzon, Turkey b Department of Obstetrics and Gynecology, Hacettepe University School of Medicine, Ankara, Turkey c Department of Obstetrics and Gynecology, Etlik Women’s Health and Maternity Teaching Hospital, Ankara, Turkey Received 25 December 2006; accepted 3 January 2007
Summary Oral contraceptives (OCs) remain among the most effective reversible methods of birth control available today, providing almost 100% effectiveness with an impressively high margin of safety and other important health benefits. However, concerns have been raised about the role that the hormones in OCs might play in the pathogenesis of cervical cancer. Evidence shows that long-term use of OCs (five or more years) may be associated with an increased risk of cancer of the cervix. The mechanism of increased risk of cervical cancer in OCs users has long been debated, and remains uncertain. Our hypothesis is that scanty, thick, and highly viscous cervical mucus obtained in OCs users intimately involved in the pathogenesis of cervical cancer. Possibly, this architecture of cervical mucus may modulate and prolong the effect of carcinogenic agents, which have been carried by coitus and stored in posterior vaginal fornix, on squamocolumnar junction of cervix by not permitting them to be removed because of its highly viscous pattern. The role of cervical mucus changes by means of specific mucin protein changes on the pathophysiology of cervical cancer in OCs users should be investigated. c 2007 Elsevier Ltd. All rights reserved.
Introduction Oral contraceptives (OCs) remain among the most effective reversible methods of birth control avail* Corresponding author. Address: Mahmut Esat Bozkurt Caddesi No: 69/2, Oncebeci 06660, Ankara, Turkey. Tel.: +90 312 419 49 16; fax: +90 312 432 24 15. E-mail address: [email protected] (S. Guven).
able today, providing almost 100% effectiveness with an impressively high margin of safety and other important health benefits [1]. However, concerns have been raised about the role that the hormones in OCs might play in a number of cancers, and how hormone-based OCs contribute to their development. The risk of endometrial and ovarian cancers is reduced with the use of OCs, while the risk of breast and cervical cancers is increased [2].
0306-9877/$ - see front matter c 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2007.01.051
Oral contraceptives and cancer Evidence shows that long-term use of OCs (five or more years) may be associated with an increased risk of cancer of the cervix [3]. Moreover, a 2003 analysis by the International Agency for Research on Cancer (IARC) found an increased risk of cervical cancer with longer use of OCs. Researchers analyzed data from 28 studies that included 12,531 women with cervical cancer. The data suggested that the risk of cervical cancer may decrease after OC use stops [4]. In another IARC report, data from eight studies were combined to assess the effect of OC use on cervical cancer risk in HPV-positive women. Researchers found a fourfold increase in risk among women who had used OCs for longer than five years. Risk was also increased among women who began using OCs before age 20 and women who had used OCs within the past five years [5]. The mechanism of increased risk of cervical cancer in OCs users has long been debated, and remains uncertain. The most popular mechanism is the mechanism which expressed the relationship between oral contraceptives and human papilloma virus (HPV), since HPV is recognized as the major cause of this disease and approximately 14 types of HPV have been identified as having the potential to cause cancer, and HPVs have been found in 99% of cervical cancer biopsy specimens worldwide [3]. Steroid contraception has been postulated to be one mechanism whereby HPV exerts its tumorogenic effect on cervical tissue. Steroids are thought to bind to specific DNA sequences within transcriptional regulatory regions on the HPV DNA, either to increase or suppress the transcription of various genes. The regulatory region of the HPV type 16 viral genome indicates transcriptional control of the HPV genome and is thought to contain enhancer elements that are activated by steroid hormones [6]. Considering these findings, it appears logical to suspect a role for local factors in cervical cancer development. In women using combined oral contraceptives, the cervical mucus remains scanty, thick, and highly viscous [7]. The role of cervical mucus changes on the pathophysiology of cervical cancer development in OC users has not been well described.
The hypothesis Our hypothesis is that scanty, thick, and highly viscous cervical mucus obtained in OCs users intimately involved in the pathogenesis of cervical cancer. Possibly, this architecture of cervical mucus may modulate and prolong the effect of carcinogenic agents, which have been carried by coitus and stored in posterior vaginal fornix, on squamo-
551 columnar junction of cervix by not permitting them to be removed because of its highly viscous pattern. The macroscopic and microscopic changes in cervical mucus may be related to the changes in the ratio of cervical mucins and other proteins, which may predispose to cervical cancer.
Evaluation of hypothesis The mucus covering on the surfaces of the female reproductive tract is important in its defense and reproductive function. The mucus gel, secreted primarily by the endocervical epithelium, provides a barrier to sperm and pathogen penetrance into the endometrium and a protective covering for the vaginal and cervical epithelium [8,9]. The major structural components of the mucus gel are mucins—highly glycosylated proteins, the major mass of which are O-linked carbohydrates. At least nine distinct mucin genes have been cloned and designated, in order of discovery, as MUCs 1,2, 3, 4, 5AC, 5B, 6, 7, and 8 [10]. Progestogens alter the cervical mucus to prevent sperm penetration and subsequent migration into the uterus.The cervical mucus quality is assessed by the characteristics of arborization, spinnbarkeit, and viscosity. For most of the menstrual cycle, the cervical mucus is thick and viscous, becoming thin and more liquefied around the time of ovulation. During treatment with OCs, the arborization, quantity, viscosity, and spinnbarkeit of the cervical mucus approximate the preovulatory phase of an untreated cycle, and sperm penetration is negligible, and it always becomes thick and highly viscous [11]. This effect may suggest the idae that the architecture of such mucus may also prevent the penetration and removal of other pathogens or carcinogens. Mucins contribute to all-important physiologic event in menstrual cycle. mRNA levels of the gelforming mucin MUC5B, the major gel-forming mucin expressed by the endocervical epithelium, peak before midcycle. Message levels for MUC4, a major membrane-spanning mucin of the endocervix, peak at midcycle. Message for each mucin diminishes dramatically as progesterone levels increase in the blood. Perhaps, through its hydrophilicity, the MUC5B mucin holds water in place at the endocervical canal surface at midcycle, keeping the canal patent for sperm motility. In addition pathogens and other seminal fluid components may be excluded from entering the uterus by mucin trapping [10,12]. In OC users the major mucin in thick viscous cervical mucus may be expected to be MUC5B. Furthermore, MUC5B may be put the pathogens (such
552 as HPV) inside through its hydrophilicity and modulate and prolong the interaction of HPV and cervix in OC users.
How to test this hypothesis? Measuring mucin protein levels of a specific mucin in samples containing multiple mucin gene products has proven difficult. This is partly attributable to difficulty in identifying specific gene products, because there have been relatively few well-characterized specific antibodies based on molecular characterization of the molecules, and because individual mucins have not been purified [12]. An extensive CsCl density centrifugation purification of the mucins followed by direct measurement of the protein in the isolated fractions by mucin-specific antibodies may be used [13]. Measurement of mucins within mucus secretions by using antibodies to isolates of mucin in combination with enzyme-linked immunosorbent assay (ELISA) is another choice [14]. An alternative method is the use of antibodies specific to a synthetic peptide that mimics a unique nonglycosylated region of the D4 domain of MUC5B in an ELISA-based assay, to determine relative amounts of a specific mucin protein in a mixed sample [12]. A new study designed to compare the composition of mucins in cervical mucus in OC users and non-OC users would bring a new insight to the current literature about the pathogenesis of cervical cancer in OC users.
Consequences of the hypothesis When an epithelium undergoes malignant transformation, the mucin genes can undergo aberrant expression causing reduced production of an expected mucin and/or production of a structurally different and unexpected mucin within the transformed epithelium [12,15]. The current hypothesis may also contribute to the current literature about early detection of cervical cancer, may be by examining the mucin composition of cervical mucus in Ocs users. Studies to determine the mechanism of hormonal regulation of mucins and the composition of mucins in patients with OC users as well as the function of individual mucins are needed.
Guven et al.
References [1] Hedon B. The evolution of oral contraceptives. Maximizing efficacy, minimizing risks. Acta Obstet Gynecol Scand Suppl 1990;152:7–12. [2] Burkman R, Schlesselman JJ, Zieman M. Safety concerns and health benefits associated with oral contraception. Am J Obstet Gynecol 2004;190:S5–S22. [3] Franceschi S. The IARC commitment to cancer prevention: the example of papillomavirus and cervical cancer. Recent Results Cancer Res 2005;166:277–97. [4] Smith JS, Green J, Berrington de Gonzalez A, Appleby P, Peto J, Plummer M, et al. Cervical cancer and use of hormonal contraceptives: a systematic review. Lancet 2003;361:1159–67. [5] Moreno V, Bosch FX, Munoz N, Meijer CJ, Shah KV, Walboomers JM, et al. Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: the IARC multicentric e-control study. Lancet 2002;359:1085–92. [6] Moodley M, Moodley J, Chetty R, Herrington CS. The role of steroid contraceptive hormones in the pathogenesis of invasive cervical cancer: a review. Int J Gynecol Cancer 2003;13:103–10. [7] Rivera R, Yacobson I, Grimes D. The mechanism of action of hormonal contraceptives and intrauterine contraceptive devices. Am J Obstet Gynecol 1999;181:1263–9. [8] Morales P, Roco M, Vigil P. Human cervical mucus: relationship between biochemical characteristics and ability to allow migration of spermatozoa. Hum Reprod 1993;8:78–83. [9] Gipson IK, Spurr-Michaud S, Moccia R, Zhan Q, Toribara N, Ho SB, et al. MUC4 and MUC5B transcripts are the prevalent mucin messenger ribonucleic acids of the human endocervix. Biol Reprod 1999;60:58–64. [10] Gipson IK. Mucins of the human endocervix. Front Biosci 2001;6:D1245–55. [11] Lammers P, Blumenthal PD, Huggins GR. Developments in contraception: a comprehensive review of Desogen (desogestrel and ethinyl estradiol). Contraception 1998;57:1S–27S. [12] Gipson IK, Moccia R, Spurr-Michaud S, Argueso P, Gargiulo AR, Hill 3rd JA, et al. The amount of MUC5B mucin in cervical mucus peaks at midcycle. J Clin Endocrinol Metab 2001;86:594–600. [13] Wickstrom C, Davies JR, Eriksen GV, Veerman EC, Carlstedt I. MUC5B is a major gel-forming, oligomeric mucin from human salivary gland, respiratory tract and endocervix: identification of glycoforms and C-terminal cleavage. Biochem J 1998;334(Pt 3):685–93. [14] Steiger D, Fahy J, Boushey H, Finkbeiner WE, Basbaum C. Use of mucin antibodies and cDNA probes to quantify hypersecretion in vivo in human airways. Am J Respir Cell Mol Biol 1994;10:538–45. [15] Baker AC, Eltoum I, Curry RO, Stockard CR, Manne U, Grizzle WE, et al. Mucinous expression in benign and neoplastic glandular lesions of the uterine cervix. Arch Pathol Lab Med 2006;130:1510–5.