The role of steroid contraceptive hormones in the pathogenesis of invasive cervical cancer: A review

Abstract

Invasive cervical cancer remains a leading cause of morbidity and mortality, especially among women in the developing world where screening is either deficient or absent. Of all agents linked to the causation of this disease, high-risk human papillomavirus (HPV) appears to be the strongest factor. However, not all women with HPV develop cervical cancer. Steroid contraception has been postulated to be one mechanism whereby HPV exerts its tumorigenic effect on cervical tissue. Steroids are thought to bind to specific DNA sequences within transcriptional regulatory regions on the HPV DNA to either increase or suppress transcription of various genes. Although some earlier studies were reassuring as no increased incidence of cervical cancer was observed, subsequent research has shown a causative association, especially among long-term users. The role of steroids was further enhanced by the discovery of hormone receptors in cervical tissue. Some earlier studies of oral contraceptive steroids found no increased risk, even after controlling for other risk factors, including smoking and number of partners. However, prospective studies have shown a greater progression of dysplasia to carcinoma-in-situ with more than 6 years of oral steroid contraceptive use. Similar findings were also evident from other work, including the Royal College of General Practitioners Oral Contraception Study. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives showed a relative risk of 1.2 for invasive cancer in users of the long-acting progestational contraceptive, depo-medroxyprogesterone acetate. However, in users of more than 5 years duration, an estimate of 2.4 was reported. The upstream regulatory region (URR) of the HPV type 16 viral genome, mediates transcriptional control of the HPV genome and is thought to contain enhancer elements that are activated by steroid hormones. It has been shown that steroid hormones bind to specific glucorticoid-response elements within HPV-DNA. Experimental evidence has revealed that high–risk type HPV 16 are able to stimulate the development of vaginal and cervical squamous cell carcinomas in transgenic mice exposed to slow-release pellets of 17 β-estradiol in the presence of human keratin-14 promoter. Squamous cell carcinomas developed in a multi-stage pathway only in transgenic mice and not in nontransgenic mice. The E6 oncoprotein of HPV 16 has been shown to bind to the p53 tumor suppressor gene and stimulate its degradation by a ubiquitin-dependent protease system. Steroid hormones are thought to increase the expression of the E6 and E7 HPV 16 oncogenes, which in turn bind to and degrade the p53 gene product, leading to apoptotic failure and carcinogenesis. However, the molecular basis of this remains to be proven.

Prevalence of cervical neoplastic lesions and Human Papilloma Virus infection in Egypt: National Cervical Cancer Screening Project

“…Higher prevalence for high-risk HPV types was significantly associated with cigarette smokers [60]. Steroid contraception has been postulated to be one mechanism whereby HPV exerts its oncogenic effect on cervical tissue especially among long-term users [61], a point concordant with the present study, mostly noted in one half of unskilled workers. The prevalence of HPV in ASM and other abnormal biopsies may be underestimated due to the fact that the HPV probes used in the study do not cover all the high risk types and include some low risk [47].…”

Rate of and Risks for Regression of Cervical Intraepithelial Neoplasia 2 in Adolescents and Young Women

“…This finding is incongruous with the literature that show medroxyprogesterone acetate and combined OC are associated with cancer. (20)…”

Elevated aromatase expression correlates with cervical carcinoma progression

“…In women aged 20 to 39 years, cervical cancer is the second leading cause of cancer deaths, with an estimated 9710 new cases and 3700 deaths from this malignancy [2]. Human papilloma virus (HPV) is a major risk factor for cervical cancer; however, not all HPV positive women develop this malignancy [3,4]. Co-factors like smoking and estrogen are known to contribute to the development of this malignancy [5][6][7][8].…”