Can Vaginal Estrogen Trigger HPV for Women in Menopause?

Ask Dr. Jen

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A reader of The Vajenda asked if there could be a link between starting vaginal estrogen in menopause and a new appearance of HPV (human papilloma virus) on their cervical cancer screen. (HPV is the virus that causes over 99% of cervical cancers). Could vaginal estrogen cause HPV that was dormant to reactivate?

It’s an interesting question, so let’s take a look.

Estrogen and HPV–What we know

Birth control pills are associated with an increased risk of cervical cancer (they also significantly lower the risk of ovarian and endometrial cancers, for perspective). The risk is pretty low for less than 5 years of use (<10%), but increases with longer use, and may be increased by 60% for those who have taken the pill for 5 to 9 years. This associated between the pill and cervical cancer supports a hypothesis that estrogen and/or a progestogen could play a role in facilitating or enhancing an HPV infection. There are a variety of theories as to how this might occur. The estrogen in the pill could change the microenvironment in the cervix in such a way that facilitates HPV acquisition. There is also data that suggests estrogen can cause genomic instability, which is when a cell's DNA becomes more prone to damage and errors over time, and these mistakes build up and lead to cancer if the cell can't repair them properly–these changes might make it easier for HPV to damage the cell’s DNA. Cells affected by HPV that have begun to show precancerous changes can express more estrogen receptors, meaning HPV could facilitates a change in the cells that could make them vulnerable to negative effects of estrogen. And while we’re talking about hormones. progesterone can enhance the ability of HPV to transform cells infected with the virus.

There are two important caveats to consider. The first is that people taking hormonal contraception or MHT may be having more sex than people not using any contraception, so sexual activity needs to be considered as a confounder, as this obviously increases the risk of exposure to HPV, and hence a new infection. The second is just because estrogen can be shown in the lab or even in human tissue to facilitate DNA damage, the body has many checks and balances, so people shouldn’t start panicking.

This is a good time to put in a plug for the HPV vaccine, which will dramatically reduce if not eliminate the risk of cervical cancer. I wrote about getting the HPV vaccine over the age limit here. If someone doesn’t get HPV, then hormonal contraception cannot increase their risk of cervical cancer.

Also, for all the “see, hormone contraception is toxic” folks out there, pregnancy also significantly increases the risk of reactivation of HPV. Still waiting for those folks to label pregnancy as a “toxin” (I know, it’ll be a long wait).

Estrogen, HPV, and Menopause

The link between hormonal contraception and cervical cancer suggests a potential connection between estrogen and HPV, so what do we know about menopause hormone therapy (MHT) and HPV?

The Women’s Health Initiative (WHI) combined arm where women took Premarin plus a progestin, showed a 40% higher incidence of abnormal Pap smears versus placebo, but there was no difference in the rate of pre-cancer or cancer (which is what really matters). There was no testing for HPV in the WHI.

Several observational studies have looked at MHT, HPV, and cervical cancer and the results are conflicting. For example, one study found that while short-term use of MHT was not linked with an increased risk of HPV, longer use of MHT was. Another study found no link between MHT and HPV. And, a large data base study found MHT was associated with a reduced risk of cervical cancer. None of these studies are randomized trials or long term, so they can’t be definitive about supporting or ruling out a link between MHT and HPV. There are a lot of confounders that were not considered in these studies. For example, women using MHT may be more likely to have sex or to have more partners than women not using MHT, and of course, MHT is a market for having access to health care.

Vaginal Estrogen and HPV/Precancer of the Cervix

While the MHT data can’t tell us much, as there is a link between oral contraception and HPV and there is lab data that shows estrogen can have negative effects on HPV infected cells, we do need to consider if vaginal estrogen could have some role. However, it’s important to remember that just because estrogen taken orally as contraception can have a negative effect, that doesn’t mean that it will have that same effect when administered in the vagina. Remember, systemic MHT doesn’t protect against bladder infections, but vagina; estrogen does.

With menopause, vaginal tissues become fragile, there is a decrease in protective mucus, and decreased blood flow to the tissues. This creates a situation where microtrauma is more common and healing may be delayed, which could make it easier for HPV to enter cells and establish an infection. We also know that changes in the vaginal microbiome and the elevated vaginal pH of menopause increase the risk of acquiring HIV if exposed, so it’s plausible that this increased risk could also be seen with other viruses, like HPV. Supporting this theory is a relatively large study that identified an elevated vaginal pH (a surrogate for low levels of vaginal estrogen) as a risk factor for being HPV positive and for having low grade abnormalities related to HPV for women age 65 and older. This last study is probably the most relevant to a discussion about vaginal estrogen and HPV. Meaning, vaginal estrogen may have a protective effect.

We also often give vaginal estrogen to women in menopause who are newly HPV positive before they have a colposcopy, to make the procedure easier. While admittedly this is short term exposure, if this increased the risk of abnormalities, we’d likely know.

Increases in HPV and Perimenopause and Menopause

For women, the first peak in HPV infection of the cervix is in their early 20'‘s, and there is a second peak that starts around ages 45-50 years.

What is the reason for this second peak?

People can appear to clear HPV they acquired earlier in life, meaning their PCR tests become negative but in reality they have a low-level persistent infection where before there just wasn’t enough virus that could be detected. Years later this virus can start to multiple again, and the test is once again positive. This is likely due to changes in the immune system with aging, but it’s also possible that changes in estrogen and/or progesterone levels may play a role.

It’s always important to consider that a new HPV positive test for a woman over age 45 could be a new infection from a new partner. Various studies have tried to determine what percentage are new infections for women over age 40, and I’ve seen anywhere from 10% to almost 25% quoted. It’s also important to remember that a new HPV infection can be acquired from a long standing partner who has a reactivation of a dormant HPV infection (the scenario described above) and so now is able to transmit the infection. People can also lose their immunity to an HPV type altogether, so they may have had HPV 16 when they were 24 years old (for example), they may have since cleared it and completely lost their immunity, and can now get reinfected with the same type of virus years later.

What Can We Tell Someone Who Now Has HPV on Cervical Cancer Screening That Appeared Shortly After Starting Vaginal Estrogen?

We do not have clinical trials where women are prescribed estrogen or a placebo and then followed over time, so being definitive is not possible, especially as women who are using vaginal estrogen are more likely to be sexually active than those not using it.

We do know that time when women are most likely to start vaginal estrogen coincides with the second peak of HPV, so what seems like cause and effect may well be coincidence. Considering HPV testing is typically every 3-5 years, it’s not possible to know exactly when someone previously was negative and then turned positive. For example, if someone started vaginal estrogen at age 50 and had a positive HPV test 6 months later, they may have had that infection for one or two years before they started vaginal estrogen.

While it’s biologically plausible that vaginal estrogen could impact HPV expression or activation, based on the study that suggests it’s a higher vaginal pH that is more likely to be linked with HPV or HPV-related changes in the cervix, it seems that the sum of the effects of vaginal estrogen is beneficial or at least neutral as far as HPV is concerned. While we don’t have clinical trials, based on what we know, the likelihood that a new HPV positive test result is related to starting vaginal estrogen in a cause and effect manner seems unlikely.

Do you have any questions you’d like answered? Drop them below.

As always, none of the information here is direct medical advice.

References

Smith JS, Green J, Berrington de Gonzalez A, et al. Cervical cancer and use of hormonal contraceptives: A systematic review. Lancet 2003; 361(9364):1159–1167.

International Collaboration of Epidemiological Studies of Cervical Cancer, Appleby P, Beral V, et al. Cervical cancer and hormonal contraceptives: Collaborative reanalysis of individual data for 16,573 women with cervical cancer and 35,509 women without cervical cancer from 24 epidemiological studies. Lancet 2007; 370(9599):1609–1621.

Roura E, Travier N, Waterboer T, et al. The influence of hormonal factors on the risk of developing cervical cancer and pre-cancer: Results from the EPIC Cohort. PLoS One 2016; 11(1):e0147029.

Iversen L, Sivasubramaniam S, Lee AJ, Fielding S, Hannaford PC. Lifetime cancer risk and combined oral contraceptives: The Royal College of General Practitioners' Oral Contraception Study. American Journal of Obstetrics and Gynecology 2017; 216(6):580.e1–580.e9. [PubMed Abstract]

Minori Ogawa, Kae Hashimoto, Saki Kitano, Saya Yamashita, Aska Toda, Koji Nakamura, Yasuto Kinose, Michiko Kodama, Kenjiro Sawada, Tadashi Kimura,

Estrogen induces genomic instability in high-risk HPV-infected cervix and promotes the carcinogenesis of cervical adenocarcinoma. Biochemical and Biophysical Research Communications 2023;659: 80-90 https://doi.org/10.1016/j.bbrc.2023.04.009.

M.E. Spurgeon,J.A. den Boon,M. Horswill,S. Barthakur,O. Forouzan,J.S. Rader,D.J. Beebe,A. Roopra,P. Ahlquist,& P.F. Lambert, Human papillomavirus oncogenes reprogram the cervical cancer microenvironment independently of and synergistically with estrogen, Proc. Natl. Acad. Sci. U.S.A. 114 (43) E9076-E9085, https://doi.org/10.1073/pnas.1712018114 (2017).

Clarke, M.A., Rodriguez, A.C., Gage, J.C. et al. A large, population-based study of age-related associations between vaginal pH and human papillomavirus infection. BMC Infect Dis 12, 33 (2012). https://doi.org/10.1186/1471-2334-12-33

Yasmeen S et al., Incidence of cervical cytological abnormalities with aging in the Women's Health Initiative, Obstetrics & Gynecology, 2006, 108(2):410–419.

Elaine M Smith, Justine M Ritchie, Barcey T Levy, Wei Zhang, Donghong Wang, Thomas H Haugen, Lubomir P Turek. Prevalence and persistence of human papillomavirus in postmenopausal age women. Cancer Detection and Prevention 2003;27: 472-480,

ISSN 0361-090X,

https://doi.org/10.1016/S0361-090X(03)00104-1.

Roura E, Travier N, Waterboer T, et. al. The Influence of Hormonal Factors on the Risk of Developing Cervical Cancer and Pre-Cancer: Results from the EPIC Cohort. PLoS One. 2016 Jan 25;11(1):e0147029. doi: 10.1371/journal.pone.0147029. Erratum in: PLoS One. 2016 Mar 08;11(3):e0151427. doi: 10.1371/journal.pone.0151427. PMID: 26808155; PMCID: PMC4726518.

Brake T, Lambert PF. Estrogen contributes to the onset, persistence, and malignant progression of cervical cancer in a human papillomavirus-transgenic mouse model. Proc Natl Acad Sci U S A. 2005 Feb 15;102(7):2490-5. doi: 10.1073/pnas.0409883102. Epub 2005 Feb 7. PMID: 15699322; PMCID: PMC548999.

Smith EM, Levy BT, Ritchie JM, Jia J, Wang D, Haugen TH, Turek LP. Is use of hormone replacement therapy associated with increased detection of human papillomavirus and potential risk of HPV-related genital cancers? Eur J Cancer Prev. 2002 Jun;11(3):295-305. doi: 10.1097/00008469-200206000-00013. PMID: 12131663.

Althoff KN, Paul P, Burke AE, Viscidi R, Sangaramoorthy M, Gravitt PE. Correlates of cervicovaginal human papillomavirus detection in perimenopausal women. J Womens Health (Larchmt). 2009 Sep;18(9):1341-6. doi: 10.1089/jwh.2008.1223. PMID: 19702476; PMCID: PMC2825723.

Lindau ST, Dude A, Gavrilova N, Hoffmann JN, Schumm LP, McClintock MK. Prevalence and correlates of vaginal estrogenization in postmenopausal women in the United States. Menopause. 2017 May;24(5):536-545. doi: 10.1097/GME.0000000000000787. PMID: 27898651; PMCID: PMC5403603.

Liaw KL, Glass AG, Manos MM, Greer CE, Scott DR, Sherman M, Burk RD, Kurman RJ, Wacholder S, Rush BB, Cadell DM, Lawler P, Tabor D, Schiffman M. Detection of human papillomavirus DNA in cytologically normal women and subsequent cervical squamous intraepithelial lesions. J Natl Cancer Inst. 1999 Jun 2;91(11):954-60. doi: 10.1093/jnci/91.11.954. PMID: 10359548.

Lindau ST, Dude A, Gavrilova N, Hoffmann JN, Schumm LP, McClintock MK. Prevalence and correlates of vaginal estrogenization in postmenopausal women in the United States. Menopause. 2017 May;24(5):536-545. doi: 10.1097/GME.0000000000000787. PMID: 27898651; PMCID: PMC5403603.

Gravitt PE, Rositch AF, Silver MI, Marks MA, Chang K, Burke AE, Viscidi RP. A cohort effect of the sexual revolution may be masking an increase in human papillomavirus detection at menopause in the United States. J Infect Dis. 2013 Jan 15;207(2):272-80. doi: 10.1093/infdis/jis660. Epub 2012 Dec 12. PMID: 23242540; PMCID: PMC3532829.