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As obstetricians/gynecologists (ob/gyns),we have seen the proven benefits of cotesting with a Pap test and human papilloma virus (HPV) test for cervical cancer screening in women. Cotesting is widely used and preferred by the majority of ob/gyns. Scientific evidence and professional society guidelines strongly reinforce the value of this screening method, which is why the newly released guidelines from the American Cancer Society (ACS) are concerning.

 The ACS departs from other current medical guidance and advocates for the eventual elimination of Pap testing and cotesting in favor of HPV-alone testing and states that initial cervical cancer screening should begin at age 25 years instead of age 21.

 These new guidelines have prompted questions and concerns from providers like myself who are on the frontlines of patient care. We know the value of the Pap test and what it adds to cervical cancer screening. Before widespread use of the Pap test, cervical cancer was the most common cause of cancer death among women in the United States.

 Today, it is estimated to be the 15th cause, with an estimated 4,290 preventable deaths per year.

 We have made decades of progress toward eliminating this cancer, and taking away the most successful screening tool in history as the ACS recommends would have negative repercussions for women and their health. A close examination of the ACS guidelines reveals several significant concerns that should cause ob/gyns to question this new guidance.

Clinical challenges with HPV-alone testing

The revised ACS guidelines recommend HPV-alone testing over cotesting as the preferred method and move the age at which HPV-alone testing is recommended down to age 25 years. Evidence supporting the long-term reduction of cervical cancer compared to the currently recommended screening options is lacking.

 Worse yet, this proposed change will lead to increased colposcopies and follow-up procedures in women age 25 to 29 years, which pose a risk of serious complications such as loss of a future pregnancy or preterm birth. Other countries that have recently changed from cytology to HPV-alone testing have reported significant increases in follow-up procedures, potentially providing a window into the future for US women. Specifically, the 

implementation of HPV-alone testing in Australia led to a 6-fold increase in colposcopy rates

These concerns are recognized by most US women’s healthcare providers, as shown in a recent survey conducted by the National Association of Nurse Practitioners in Women’s Health (NPWH) and HealthyWomen.

 The survey explored opinions from healthcare providers (ie, ob/gyns, nurse practitioners, primary care physicians) and patients about testingfor cervical cancer.

 Less than 1% of healthcare providers said they screen using HPV-alone testing.

 The survey found that when it comes to HPV-alone testing, healthcare providers fear the possibility of more missed diagnoses (62%), more recommendations for colposcopies (61%), and more positive diagnoses with no treatment options offered to patients (58%).

Removing the Pap test from the screening process also eliminates the ancillary benefit of detecting additional infections, gynecologic malignancies, and other asymptomatic cancers that may not be diagnosed otherwise. This may not be the primary purpose of the Pap test, but it represents additional valuable information that healthcare providers would lose under the proposed guidelines of the ACS. The patient experience of sample collection remains the same whether the lab runs a Pap test and HPV test together or an HPV test alone. Patients and healthcare providers will be better served gathering more information from each visit to better inform follow-up guidance and treatment decisions.

Modeling of cervical cancer screening outcomes represents a major part of the rationale supporting the new ACS guidelines. A review of assumptions, inputs, and predictions to better understand the applicability and representativeness of the model raises a number of questions:

Why does the model exclude endocervical disease when we see increasing rates of adenocarcinoma in the population and know that cotesting provides the best chance of identifying adenocarcinoma and adenocarcinoma in situ?

Why do the model inputs for cytology performance rely predominantly on conventional cytology and data from countries outside the United States?

How can the model predict the identification of more treatable precancer (ie, cervical intraepithelial neoplasia 2 [CIN2], CIN3) using cotesting versus HPV-alone testing, yet at the same time predict a higher incidence and death rate using cotesting?

Why do the modeled scenarios indicate that adding Pap testing will result in higher incidence and death from cervical cancer?

Mathematical models are an important tool to support decision making on best practices, but we have to ensure that the information utilized in making predictions and the outputs generated accurately and appropriately represent what we observe in clinical practice everyday.

The ACS guidelines ignore HPV vaccination realities in the United States. Rarely do healthcare providers have access to complete vaccine records, and it should not be assumed that US women successfully completed the recommended HPV vaccination regimen. The CDC found that less than half of adolescents in this country have completed the HPV vaccination series.

 In the National Immunization Survey-Teen (2017–2018; N = 82,297), 37.1% of participants were unvaccinated and 10.8% had received only one vaccine dose.

 We also need to consider that many women currently at risk for cervical cancer did not receive the HPV vaccination regimen given their age when the vaccine was released in 2006. Although it is vitally important to advocate for greater HPV vaccination compliance, we should be careful not to alter guidelines and current practice based on overly optimistic assumptions.

The ACS guidelines primarily rely on data generated in Europe from randomized clinical trials and the experience of the Kaiser Permanente Northern California (KPNC) regional integrated healthcare system.

 Data from these studies represent best-case scenarios with respect to test utilization and adherence to follow-up and therefore do not represent the experiences of most women across the United States. 

Evaluating evidence from more representative settings in this country may be able to better inform future cervical cancer screening guidelines. 

In fact, data documenting the contribution of the Pap test and HPV test in the detection of cervical disease in routine cervical cancer screening from the University of Pittsburgh Medical Center and Quest Diagnostics have been published and highlight marked differences in outcomes, especially compared to the data reported from the KPNC system.

 These data show a much larger contribution of the Pap test to cotesting in identifying precancer and cancer than previously reported by KPNC.

Real-world evidence is critical to our understanding and direction forward because we lack a nationwide, organized cervical cancer screening program. The aforementioned data sets as well as additional data need to be more carefully evaluated and incorporated into the decision-making process by organizations and societies issuing cervical cancer screening guidelines to ensure that they are representative of all women in the current US healthcare setting.

Diverging from guidelines and preferences 

Increasing the rate of cervical cancer screening among our patients must start with clear, consistent guidelines. Current guidelines from the American College of Obstetricians and Gynecologists (ACOG), Women’s Preventive Services Initiative (WPSI), and the US Preventive Services Task Force (USPSTF) are aligned on the starting age for screening and the continued role of Pap testing alone or in combination with HPV testing depending on a woman’s age (

 The revised ACS guidelines diverge significantly and stand alone as an outlier among these institutions.

 It is important to note on the issuance of the ACS guidelines that ACOG reinforced their position on cotesting, as did other groups such as the American Society of Clinical Pathology. In addition to support for cotesting in guidelines, healthcare providers and women believe in the unequivocal value of cotesting. 

The NPWH and HealthyWomen survey showed that over the past 5 years, there has been an increase in the number of healthcare providers and women who consider using the Pap and HPV tests together as being important to overall health.

 Additionally, 95% of healthcare providers and 90% of women consider the Pap test valuable in screening for cervical cancer.

The survey showed that 89% of healthcare providers believe cotesting is essential for women’s health.

 Unfortunately, even with this broad support, screening rates remain suboptimal and the percentage of screening-eligible women who are up to date with their cervical cancer screening has never reached the 93% threshold set by the Healthy People 2020 initiative. In fact, shockingly, screening rates have been in decline since the early 2000s. Currently, less than 80% of women are up to date with their cervical cancer screenings, with one study putting that percentage at an alarming low total of approximately 65%.

 The NPWH and HealthyWomen survey findings indicate that rather than removing support for cotesting, now is the time to reinforce support for the screening method that is most trusted to help avoid confusion and reduce the decline in screening rates.

Implications for the patient–provider relationship 

By suggesting that women younger than age 25 years do not need cervical cancer screening, I believe the ACS guidelines will open the door to several other negative outcomes. First, any decline in ob/gyn visits from these younger women may cause healthcare providers to lose other important touchpoints with their patients, such as opportunities to screen for sexually transmitted infections (STIs). Testing and education about risk reduction for STIs are part of the care of this young age group and have significant implications for future reproductive health.

Most importantly, while the incidence of cervical cancer in women younger than age 25 years is low, I do not know any ob/gyns willing to accept missing the diagnosis in one of these women and the harm it would cause. 

We should maintain management of these cases rather than giving up on detecting them altogether.

The potential to miss cases and other problematic infections in younger women further demonstrates the unnecessary risks associated with transitioning to HPV- alone testing. We cannot ignore the larger challenges to the patient–provider relationship that would result from the utilization of the ACS guidelines experiment.

Screening guidelines for a condition as serious and preventable as cervical cancer should be developed based on the most rigorous assessment of current technologies applied to a large, heterogeneous, geographically distributed, and socioeconomically diverse population as possible, because such factors represent the conditions under which most care is provided throughout this country.

 It is inadvisable to advocate for a screening strategy for which very little observational data exist in the United States.

The clinical evidence shows that cotesting is the most sensitive and safe approach to cervical cancer screening. With this knowledge, the majority of providers are utilizing this approach to care for their patients today. Future efforts to further reduce cervical cancer incidence and mortality should focus on expanding screening and care to those women who currently do not participate for one reason or another.

Regularly assessing guidelines is important to ensure that patients are receiving the best healthcare available at the time. Changes and attempts to simplify the screening process, however, do not necessarily lead to better patient care or outcomes. None of the evidence I have reviewed suggests that moving to HPV-alone testing every 5 years starting at age 25 years will improve the health of women or lead to an increase in the percentage of women being up to date with their screenings and well-woman visits. In fact, I believe it will have the opposite effect.

Healthcare providers should continue to recommend Pap tests every 3 years starting at age 21 years and cotesting every 3 to 5 years starting at age 30—an approach that continues to be in the best interest, safety, and health of women in the United States.

is in a private obstetrics/gynecology practice in Las Vegas, Nevada. He was previously in Cincinnati, Ohio, where he developed his extensive clinical skills over a 24-year period in private practice and as Residency Director at The Christ Hospital. He received his undergraduate degree in Bio-Medical Engineering at Northwestern University and his medical degree at the Ohio State University College of Medicine. He completed his residency in obstetrics and gynecology at the University of Cincinnati Medical Center in 1993. While in Cincinnati, he cofounded a 50-provider ob/gyn group practice and, as the chair of its quality committee, forged guidelines and developed research protocols regarding PCR technologies useful in the evaluation of vaginal infections.

1. Fontham ETH, Wolf AMD, Church TR, et al. Cervical cancer screening for individuals at average risk: 2020 guideline update from the American Cancer Society. CA Cancer J Clin. 2020 July 30. Online ahead of print.

2. Centers for Disease Control and Prevention. Cervical cancer statistics. June 8, 2020. Available at 

https://www.cdc.gov/cancer/cervical/statistics/index.htm

3. National Institutes of Health. National Cancer Institute. Cancer stat facts: Cervical cancer. Available at 

https://seer.cancer.gov/statfacts/html/cervix.html

4. American Cancer Society. Cancer facts and figures 2020. Available at 

https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2020/cancer-facts-and-figures-2020.pdf

5. Ronco G, Dillner J, Elfström KM, et al; International HPV screening working group. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet. 2014;383(9916):524-532.

6. Sii S, Trivedi A, Wang WC. Analysis of the Peninsula Health colposcopy service data of one year since transitioning to the new cervical screening program. Obstet Gynecol Res. 2019;2(4):88-99.

7. Albright DM, Rawlins S, Wu JS. Cervical cancer today: survey of screening behaviors and attitudes. Women’s Healthcare. 2020;8(3):41-46.

8. Centers for Disease Control and Prevention. Human papillomavirus (HPV). Understanding HPV coverage. Available at 

https://www.cdc.gov/hpv/partners/outreach-hcp/hpv-coverage.html

9. Sonawane K, Zhu Y, Montealegre JR, et al. Parental intent to initiate and complete the human papillomavirus vaccine series in the USA: a nationwide, cross-sectional survey. Lancet Public Health. 2020;5(9):e484-e492.

10. Kaufman HW, Alagia DP, Chen Z, et al. Contributions of liquid-based (Papanicolaou) cytology and human papillomavirus testing in cotesting for detection of cervical cancer and precancer in the United States. Am J Clin Pathol. 2020;154(4):510-516.

11. Austin RM, Onisko A, Zhao C. Enhanced detection of cervical cancer and precancer through use of imaged liquid-based cytology in routine cytology and HPV cotesting. Am J Clin Pathol. 2018;150(5):385-392.

12. American College of Obstetricians and Gynecologists. Cervical cancer screening (update). Available at 

https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2018/08/cervical-cancerscreening-update

13. US Preventive Services Task Force; Curry SJ, Krist AH, Owens DK, et al. Screening for cervical cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2018;320(7):674-686.

14. Women’s Preventive Services Initiative. Screening for cervical cancer. Available at: 

https://www.womenspreventivehealth.org/recommendations/screening-for-cervical-cancer/

Content of this article was sponsored by Hologic. Copyright 2020 and published by MJH Life Sciences. No portion of this program may be reproduced or transmitted in any form, by any means, without the prior written permission of MJH Life Sciences. The views and opinions expressed in this material do not necessarily reflect the views and opinions of MJH Life Sciences, or Contemporary OB/GYN.

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Cervical cancer screening with cotesting is best for women

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Beginning in December 2017, the Australian Government implemented changes in its National Cervical Screening Program (NCSP). These changes came from an assessment of potential screening pathways, tests, and intervals called the Renewal.

 Previously, women between the ages of 18 and 70 years were screened for cervical cancer using a cytologic (Papanicolaou [Pap]) test every 2 years. These changes, however, meant shifting to human papillomavirus (HPV) testing alone every 5 years, including for women as young as age 25 years. A study by Cox and Sneyd to estimate the impact of the changes on cancer prevention predicted an increase in the incidence rate of cervical cancer with primary HPV screening every 5 years compared with prior cytologic screening methodology.

 In addition, the study predicted this Renewal policy would result in cervical cancer overdiagnosis, increase unnecessary colposcopy referrals, and delay reporting results to patients. In this report, we review findings from that study and discuss their relevance to cervical cancer screening strategies in the United States based on recent evidence that shows potential harmful consequences for women derived from the Australian experience.

Renewal policy of the Australian National Cervical Screening Program

The Renewal policy of the Australian NCSP represents a valuable opportunity to assess the true impact of adopting HPV testing alone every 5 years.

 The policy was based on simulation models that do not accurately reflect the impact HPV testing every 5 years may have on public health in Australia.

 The models used detection sensitivity, defined as the probability that a test will detect its target: cervical intraepithelial neoplasia (CIN). The potential for HPV testing to preferentially detect nonprogressive CIN was not assessed, however, and would require measurement of cervical cancer incidence between screening events. The simulation models assumed that HPV testing has greater screening sensitivity than cytology based on the probability that the test detects the subset of disease that will progress to life-threatening invasive cancer when it is present and that reliance on HPV testing will decrease cervical cancer incidence and mortality. Mere HPV detection does not predict the fate of an infection, ie, whether it will spontaneously resolve, cause a cancer lesion, or persist with no clinical consequences. Not distinguishing among these outcomes hinders accurate prediction of the likelihood of cancer.

Risk of increasing cervical cancer incidence

Several clinical studies have compared HPV testing with cytology screening, yielding mixed results.

 A rigorous analysis was conducted to determine the relative impacts of HPV testing and cytology on public health using results from an earlier randomized health services study on cervical cancer screening in Finland.

 This study did not introduce the analytic bias of excluding women previously diagnosed with CIN detected by cytology, which reduces the potential pool of cytology-detectable lesions prior to randomization, thus biasing the comparison against cytologic screening.

Cytologic screening and primary HPV testing were evaluated in the context of well-accepted estimates of the effects of screening frequencies on cervical cancer incidence combined with published age-specific data on the frequency with which women are actually screened. The study showed that women age 30 to 64 years screened under the prior (every 2 years) cytologic protocol would be expected to have a cervical cancer incidence of 7.5% relative to the 100% incidence expected in unscreened women.

 Anticipated reductions in cervical cancer risks with cytology every 2 years and HPV testing every 5 years would be approximately 93% and 84%, respectively (

 Thus, the risk of cervical cancer would increase with the new HPV testing protocol versus the prior cytology screening program.
	
	

Women differ in their adherence to screening protocols. Based on data from the Australian NCSP, 17% of Australian women age 20 years and older had not been screened in the previous 5 years or had never been screened.

 The estimated proportions without screening or with more than 10 years between screening tests varied significantly by age: from 9% to 16% in women age 30 to 54 years and from 21% to 34% in those age 55 to 69 years. When applying the relative protection from screening to the different screening frequencies of different age groups, the cervical cancer risks for women age 30 to 69 years were reduced by only 67% with HPV testing every 5 years versus 76% with cytologic screening every 2 years.

The overall incidence of cervical cancer in women in Australia was predicted to increase by 39% with HPV testing every 5 years versus cytologic screening every 2 years as a result of screening inadequacy.

 This translates to an additional 222 women developing cervical cancer each year for the next 10 years. For relatively screening-compliant women with less than 10 years since their last negative test, the new HPV testing protocol was predicted to increase the annual incidence of cervical cancer in women screened to 121% of that attained with the prior cytologic screening protocol. Even if the new protocol resulted in a 10% increase in the proportion of women screened, the overall incidence of cervical cancer in Australia would be expected to rise 30% due to screening inadequacy. Based on these figures, the transition to the HPV testing protocol would be detrimental to women in the absence of better evidence of at least equivalent public health outcomes.

The Renewal policy includes HPV testing in women age 25 to 69 years and is based on high estimates of detection sensitivity.

 Because the vast majority of HPV infections regress spontaneously within 2 years, the increased sensitivity of HPV testing would amount to overdiagnosis, which in turn would result in overtreatment (ie, use of colposcopies).

 The study findings suggest that this overtreatment would increase the treatment burden on women who would not have ultimately progressed to invasive cancer.

It is important to note that since implementation of the Renewal policy, a colposcopy clinic in Australia reported that the volume of referrals has increased sixfold.

This increase likely stems from increased sensitivity of the HPV test combined with its inability to predict which lesions will progress to cancer. The increased colposcopy volume prolonged the waiting times for women to be seen in the colposcopy clinic to approximately 12 months. Overdiagnosis and unnecessary colposcopies and biopsies could harm a woman’s fertility or ability to carry a child to term.

These findings should prompt additional research to further evaluate the success of various screening protocols at providing protection against cervical cancer. Based on lack of conclusive evidence on the most protective screening program, it would be advisable to implement a cotesting screening protocol, during which time the information lacking to assess the effectiveness of HPV testing on reducing cervical cancer compared with the prior cytologic protocol could be collected. The findings of the study analysis do not support lengthening the cervical cancer screening interval, especially in conjunction with a change in testing method.

Identifying a preferred screening option for cervical cancer

Human papillomavirus testing is often used as an adjunct to cytologic screening, a strategy known as cotesting.

A debate is currently under way as to the best method for cervical cancer screening. Screening with an HPV test alone was shown to be less effective than cotesting in the largest real-world retrospective study, showing that 1 of 5 cases of cervical cancer were missed with HPV screening alone.

Joint guidelines from the American Society for Colposcopy and Cervical Pathology, American Society for Clinical Pathology, and American Cancer Society issued in 2012 recommend cytologic screening every 3 years in women younger than age 30 years and cytologic screening every 3 years or with cotesting every 5 years in women age 30 years and older.

Cotesting is the preferred method, and HPV testing alone every 5 years is discouraged. Subsequent 2016 guidance from the American College of Obstetricians and Gynecologists also recommends cotesting as the preferred screening method.

 More recently in 2018, the US Preventive Services Task Force endorsed cytologic screening every 3 years, HPV testing every 5 years, and cotesting as acceptable options.

The Renewal policy was partially driven by the high HPV vaccine uptake in Australia relative to most countries, including the United States.

 Human papillomavirus testing is most efficacious in screening cohorts with complete HPV vaccine coverage.

HPV infection occurs primarily in young adulthood, however, and vaccination after infection does not reduce risk of cervical cancer. Therefore, vaccination will provide no reduction in risk for most women currently age 30 years or older. Cotesting is the best test method in populations of variable vaccine uptake across all age groups.

 Unvaccinated women who are screened with the HPV test tend to have more “false positives” versus those screened with cotesting.

Despite differences in healthcare programs between the United States and Australia, which has a universal healthcare system, the cervical cancer incidence rates are comparable.

 For Australia, the 2015 age-adjusted incidence rate for cervical cancer was 6.9 cases/100,000 women per year.

 For the United States, the 2012–2017 age-adjusted incidence rate of cervical cancer was 7.3 cases/100,000 women per year.

 These incidence rates suggest that similar factors may influence success in cervical cancer screening between the two countries and that lessons learned from the Australian experiment can provide cautionary guidance.

Other factors that could limit the efficacy of HPV screening should be considered in addition to increased colposcopies and the associated costs demonstrated in the Australian study.

 There is currently a lack of healthcare provider support in the United States for HPV primary screening because the impact on clinical practice has not been rigorously studied. For example, the psychosocial impact of HPV screening on cervical cancer prevention is not understood.

 Changes in clinical practice and screening strategy would require significant investment in patient reeducation and may negatively affect testing compliance, which would contribute to increased cervical cancer incidence.

Based on the study analysis of Australia’s Renewal policy, findings from previous studies, as well as concerning implications for both healthcare providers and patients, adoption of HPV testing alone every 5 years is not advisable in any country, including the United States. The current accepted strategy of cytology for women age 21 to 29 years and cotesting for those age 30 to 65 years should continue to ensure the best possible protection and compliance among both healthcare providers and their patients, and ultimately guarantee what is best for women.

The study on HPV screening, invasive cervical cancer, and screening policy in Australia is not affiliated with Hologic and was conducted independently.

 is a medical epidemiologist and public health physician with specific training in cancer screening and epidemiology. He was also the New Zealand representative to the International Cancer Screening Network of the National Cancer Institute for over 20 years. Dr. Cox was involved in the design and establishment of the National Cervical Screening Program (NCSP). He also established the independent monitoring groups of the national cervical and breast screening programs of New Zealand and was their inaugural chair. Dr. Cox is Director of the Hugh Adam Cancer Epidemiology Unit of the Department of Preventive and Social Medicine of the Dunedin School of Medicine.

 is a Board-Certified Obstetrician and Gynecologist in a private practice in Atlanta, Georgia and on the Medical Staff at Emory Saint Joseph’s Hospital. He earned his Bachelor of Science degree from Emory University in Atlanta and received his Medical degree with research distinction from the University of Miami School of Medicine in Miami, Florida. Dr. Randell is an expert in laparoscopic and robotic gynecologic surgery. His research interests include managing cancer during pregnancy, the effects of barometric pressure changes on the initiation of labor, and the treatment of atypical Pap tests have led to award winning presentations at scientific meetings. Dr. Randell is a Diplomate of the American Board of Obstetrics and Gynecology and the National Board of Medical Examiners. He is also a Fellow of the American College of Obstetricians and Gynecologists.

Department of Health, Australia. National Cervical Screening Program. Available at: 

http://www.cancerscreening.gov.au/internet/screening/publishing.nsf/Content/cervical-screening-1

Cox B, Sneyd MJ. HPV screening, invasive cervical cancer and screening policy in Australia. 

ElfstrÃ¶m KM, Smelov V, Johansson ALV, et al. Long-term duration of protective effect for HPV negative women: follow-up of primary HPV screening randomised controlled trial. 

Kitchener HC, Gilham C, Sargent A, et al. A comparison of HPV DNA testing and liquid based cytology over three rounds of primary cervical screening: extended follow up in the ARTISTIC trial. 

Malila N, Leinonen M, Kotaniemi-Talonen L, et al. The HPV test has similar sensitivity but more overdiagnosis than the Pap test-a randomised health services study on cervical cancer screening in Finland. 

Rijkaart DC, Berkhof J, Rozendaal L, et al. Human papillomavirus testing for the detection of high-grade cervical intraepithelial neoplasia and cancer: final results of the POBASCAM randomised controlled trial. 

Ronco G, Dillner J, ElfstrÃ¶m KM, et al; International HPV Screening Working Group. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. 

Marth C, Landoni F, Mahner S, et al; ESMO Guidelines Committee. Cervical cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. 

Sii S, Trivedi A, Wang WC. Analysis of the Peninsula Health colposcopy service data of one year since transitioning to the new cervical screening program

Flanagan SM, Wilson S, Luesley D, Damery SL, Greenfield SM. Adverse outcomes after colposcopy. 

Blatt AJ, Kennedy R, Luff RD, et al. Comparison of cervical cancer screening results among 256,648 women in multiple clinical practices. [Erratum in 

Saslow D, Solomon D, Lawson HW, et al; ACS-ASCCP-ASCP Cervical Cancer Guideline Committee. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. 

American College of Obstetrics and Gynecology. Committee on Practice Bulletins-Gynecology. Practice Bulletin No. 168: Cervical cancer screening and prevention. 

US Preventive Services Task Force. Final Recommendation Statement. Cervical cancer: Screening. US Preventive Services Task Force website. Available at: 

https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/cervical-cancer-screening2#consider

Bruni L, Diaz M, Barrionuevo-Rosas L, et al. Global estimates of human papillomavirus vaccination coverage by region and income level: a pooled analysis. [Erratum in 

Canfell K, Caruana M, Gebski V, et al. Cervical screening with primary HPV testing or cytology in a population of women in which those aged 33 years or younger had previously been offered HPV vaccination: results of the Compass pilot randomised trial. 

Rebolj M, Pribac I, Frederiksen ME, Lynge E. The problem of false-positive human papillomavirus DNA tests in cervical screening. 

Cervical cancer in Australia statistics. Available at: 

https://cervical-cancer.canceraustralia.gov.au/statistics

NIH. National Cancer Institute. Surveillance, Epidemiology and End Results Program. Cancer Stat Facts: Cervical cancer. Available at: 

Machalek DA, Roberts JM, Garland SM, et al. Routine cervical screening by primary HPV testing: early findings in the renewed National Cervical Screening Program. 

Obermair HM, Dodd RH, Bonner C, et al. ‘It has saved thousands of lives, so why change it?’ Content analysis of objections to cervical screening programme changes in Australia. 

Cervical cancer screening in Australia: A new policy may undermine prevention 

“Most women have used oral contraception at some point in their lives, and they face an increased risk for developing depression,” said principal investigator Michael Winterdahl, PhD, an associate professor of clinical medicine at Aarhus University in Denmark. 

“However, there have been very few studies about the mechanisms by which these pills can affect women's health and mood.”

 that the oxytocin system is of particular interest because it mediates both reproductive physiology and social behavior.

The study comprised 185 young women, whose average age was 21.2 years. Women were divided into two cohorts: oral contraceptive users (n = 71) and non-users (n = 114). 

A blood sample was obtained from all participants to test the plasma levels of oxytocin, adrenocorticotropic hormone (ACTH), estradiol, progesterone and testosterone.

Two datasets were collected as part of two separate studies in different cohorts of participants. The samples obtained in the second cohort were processed using improved methodology that assayed oxytocin from plasma using a RadioImmunoAssay (RIA) kit.

The oxytocin assay also included an extraction step to reduce binding of side products. Samples from the older dataset were also analyzed using a RIA kit; however, without an extraction step.

“Because our methodology for measuring oxytocin had improved between the two data collections, we were unable to pool the data,” Dr. Winterdahl said. “The two methods for measuring oxytocin, however, consistently revealed a significant difference between oral contraceptive users and non-users.”

Both datasets showed highly significant differences between users and non-users, with the former exhibiting elevated basal oxytocin and lower adrenocorticotropic hormone (ACTH), estradiol, progesterone and testosterone.

For instance, in the newer dataset, on average there was a 144 % higher oxytocin concentration in plasma in birth control users compared to non-users, whereas the older dataset only revealed a 24 % higher oxytocin concentration.

“The difference in percentages reflected our improved methodology for measuring oxytocin,” Dr. Winterdahl said.

Plasma hormone levels were also compared to self-reported measures of mood, well-being and depression. Satisfaction With Life Score (SWLS) was significantly higher in OC users than in non-OC users. However, there were no differences in the Beck Depression Score (BDI) and Positive and Negative Affect Schedule (PANES) between the two groups.

“We expected estrogens in birth control to raise oxytocin levels in plasma, and this indeed was the case,” Dr. Winterdahl said.

“But we were surprised that birth control users had higher scores for quality of life. Birth control users who suffer adverse effects tend not to sign up for scientific studies, and our sample consisted of young women in their early 20s, who probably were happy not having to worry about becoming pregnant.

Also, subjects with clinical depression were excluded from the study.”

The lack of information about the duration and the specific OC formulations used by the women were limitations as well. Menstrual cycles may have also affected the results because peripheral oxytocin levels increase during the menstrual cycle until ovulation and then decrease until menstruation begins again.

Despite these caveats, Dr. Winterdahl said changes in oxytocin may explain how birth control can affect mood.

“We anticipate that our research can critically advance our understanding of how changes in sex hormones increase susceptibility for depressive episodes, thus eventually providing novel preventive and therapeutic opportunities,” he said.

Garforth, B., Degnbol, H., Terris, E.T. 

 Elevated plasma oxytocin levels and higher satisfaction with life in young oral contraceptive users. 

https://doi.org/10.1038/s41598-020-64528-w

Plasma oxytocin levels are significantly higher in oral contraceptive (OC) users than in to non-users, according to a study in Scientific Reports. The cross-sectional study of nearly 200 women also found that scores for satisfaction with life were higher among OC users.

Study finds plasma oxytocin levels higher in OC users

Many people ask me how and why I started TherapeuticsMD. The simple answer to why is that, like many of my colleagues, I was frustrated by current therapies in women’s health that were antiquated and by the lack of innovation in commonplace treatments for contraception and menopause. 

Having spent the last 25 years focused on women’s health, I used my personal experience as an obstetrician-gynecologist, along with the collective feedback of my fellow healthcare providers and our patients, to create and bring to market new products like Bijuva (estradiol and progesterone) capsules, Imvexxy (estradiol vaginal inserts), Annovera (segesterone acetate and ethinyl estradiol vaginal system), and our vitaMedMD prenatal vitamins with the goal of answering the needs of our patients with modern solutions that fit their lifestyles.

Practicing in South Florida, I had the opportunity to take care of many menopausal women. Then, in 2002, the initial news from the landmark Women’s Health Initiative (WHI) study suggested that synthetic hormones increased the risk of breast cancer, stroke, heart attack, and blood clots.

This finding was in contrast to what many healthcare providers were recommending to women based on the general belief that hormones were good for their heart, brain, and bones and that they should stay on them indefinitely. Unfortunately, all US Food and Drug Administration (FDA)-approved combination hormone products for postmenopausal conditions contained a synthetic progestin.

After WHI, I observed that most women and healthcare providers shifted to hormone therapy containing bioidentical estradiol and bioidentical progesterone because they believed this was a better alternative.

The lone FDA-approved progesterone, however, was only studied and approved as 200 mg for 12 nights sequentially in combination with 0.625 mg of conjugated estrogen, yet many healthcare providers began prescribing it as 100 mg daily with any amount or form of estrogen.

As an evidence-based practitioner, I was concerned about endometrial safety with this approach, based on the results of small studies that showed endometrial hyperplasia. I struggled with the reality that no combination of estradiol and progesterone, whether oral or transdermal, had been studied in a randomized, placebo-controlled trial and FDA approved to be used together. 

Moreover, I was alarmed that there were no efficacy or safety data supporting compounded bioidentical hormones that had become the standard of care based on prescription volume here in the United States.

The importance of this is significant because the risk to the endometrium represents the greatest risk to a woman when using hormone therapy. The background incidence of endometrial hyperplasia in a non-hormone user is 1% (1/100), which increases significantly when estrogen therapy is not adequately opposed by a progestogen.

Like many of my colleagues, I had a preference for transdermal estrogen because it conveys a small reduction in the venous thromboembolism (VTE) risk from oral estradiol and micronized progesterone (1.5 vs 1.2–3 per 1000 woman-years).

 That, however, was trading a lower risk of VTE for a 10-fold higher risk of endometrial hyperplasia/cancer without robust data for the unapproved regimen of transdermal estradiol with progesterone in women with a uterus.

Moreover, I was frustrated by the confusion among my colleagues and our patients regarding the risks of hormone therapy as these particularly relate to breast cancer and cardiovascular disease, especially after the reanalysis of WHI and subsequent studies. As such, I set out to address these concerns and develop the first and only FDA-approved hormone therapy combination of estradiol and micronized progesterone that would be rigorously studied in a large phase 3, randomized, placebo-controlled trial.

Further, I was troubled by the fact that many of my menopausal patients suffered from symptoms of vulvar and vaginal atrophy, yet too few of them would try or stay on treatment. It is estimated that vulvar and vaginal atrophy occurs in more than 1 out of 2 menopausal women, but only 7% of women are treated with prescription hormone therapy.

I recognized that my patients and fellow healthcare providers were looking for treatments that were easy to use and not messy to administer, and worked quickly in low doses with limited systemic exposure. I then set out to address these concerns and develop an applicator-free, rapidly dissolving softgel vaginal insert containing ultra-low doses of 17β-estradiol. 

I also partnered with the Population Council, a not-for-profit organization founded by John D. Rockefeller, III, with a focus on reproductive health. The Population Council was the initial developer of the world’s long-acting reversible contraceptives, including the 10-year copper intrauterine device (IUD), the original 5-year levonorgestrel IUD, and the contraceptive implant. More than 170 million women worldwide use contraceptive technologies developed by the Population Council. 

The Population Council recognized, however, that despite the importance of long-acting reversible contraception, all too often women declined the options because these required a procedure for insertion and removal. Accordingly, they developed a contraceptive that does not require a procedure for insertion or removal and provides women with long-lasting efficacy for 1 year (13 cycles).

This contraceptive is now part of the TherapeuticsMD product portfolio and supports our commitment to deliver a selection of modern products for women throughout the different stages of their lives. Likewise, to complement these products, I created a line of prescription prenatal vitamins with options for all types of women’s preferences.

Finally, as a community healthcare provider for many years, I understand that affordability is one of the most important considerations for our patients. This has led me to instill within our organization the principle of making certain that cost should not be a barrier to any woman using our products.

Starting a pharmaceutical company is not easy. It takes many years of experimentation and development, millions if not billions of dollars, and a lot of luck. Several clinical trials were conducted all over the United States and throughout the world to support our products. I am fortunate to have had people believe in these opportunities and be willing to invest their money and experience in helping me along the way. 

I truly feel that what we have accomplished is the result of the collective input and experience of my fellow healthcare providers and the women we treat. I am humbled to have played a role in helping to bring more attention and treatment options to women’s health.

For product information and Full Prescribing Information, including BOXED WARNINGS, visit 

Brian A. Bernick, MD, FACOG, is a board-certified obstetrician-gynecologist and co-founder and chief scientific officer of TherapeuticsMD, Inc. He is also a clinical affiliate associate professor at Florida Atlantic University Charles E. Schmidt College of Medicine in Boca Raton.

Rossouw JE, Anderson GL, Prentice RL, et al. Risks
and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-333.

Pinkerton JV, Santoro N. Compounded bioidentical hormone therapy: identifying use trends and knowledge gaps among US women. Menopause. 2015;22(9):926-936.

Mirkin S, Goldstein SR, Archer DF, et al. Endometrial safety and bleeding profile of a 17β-estradiol/progesterone oral softgel capsule (TX-001HR). Menopause. 2020;27(4):410-417.

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