 comprised 200 consecutive patients who underwent LSSS between October 2018 and February 2019 at the National Health Insurance Service Ilsan Hospital in Goyang, South Korea.

Patients were alternatively assigned to either the study group, which was 0.25% 10-mL bupivacaine hydrochloride injection at the 1.5-cm umbilical incision site after removal of the wound retractor, or the control group of no injection. In addition, all patients were afforded routine intravenous patient- controlled analgesia (IV-PCA).

The primary outcome was postoperative umbilical pain scores using the visual analog scale (VAS). A trained nurse practitioner blinded to bupivacaine usage collected all the VAS scores.

After adjusting for various confounding variables, differences in postop umbilical pain scores measured at postop 2 to 3 hours, 6 to 10 hours, 1 day and 3 days were non-significant between the two groups. 

However, there were significant differences in clinical characteristics between the bupivacaine injection group and the non-injection group: mean age (49.2 and 44.3, respectively), body mass index (BMI) (25.1 and 23.7 kg/m2, respectively) and menopausal status (31 menopausal patients vs. 19 non-menopausal patients, respectively).

The most frequently performed surgery was hysterectomy, representing 126 cases, of which 102 were performed with LSSS and 24 with robot-assisted LSSS.

Mean operative time was 99.4 minutes in the bupivacaine injection group and 109.2 minutes in the non-injection group. But there were no differences in blood loss during surgery, perioperative complications, hospital stay after surgery or time of flatus between the two groups.

In subanalysis, postoperative pain scores were compared between LSSS (n = 157) and robot-assisted LSSS (n = 43) procedures. 

After adjusting for the confounding variables of patient age, BMI, parity, menopausal status, American Society of Anesthesiologist (ASA) score, comorbidities, type of surgery performed, need for additional trocar usage, and bupivacaine injection, the pain score at the time of return to the ward was significantly higher in the robot-assisted LSSS cases than in the LSSS cases: 4.6 vs. 4.0 (

This difference in pain scores persisted at the evening round on the surgery day: 3.9 for robot-assisted LESS compared to 3.3. for LESS (

“Previous reports on the effectiveness of trocar-site local anesthetic injection in LSSS included only adnexal procedures lasting less than 1 hour, and the role of port-site bupivacaine injection in more complex surgeries with longer operation times accompanied by comparatively higher postoperative VAS scores remains uncertain,” wrote the authors.

As noted, for the current study, the most commonly performed procedure was hysterectomy, not adnexal surgery, and operative time was longer for cases in the current study than in previous studies of adnexal surgeries.

Although bupivacaine hydrochloride is a relatively safe local anesthetic, cardiotoxic and neurotoxic symptoms may occur.

Further studies of various postoperative pain modulators, including liposomal bupivacaine, might help more effectively manage postoperative pain in LSSS. Meanwhile, the authors caution against routine use of postoperative trocar-site bupivacaine injection as a way to reduce postoperative incisional pain.

Seo JW, Lee O, Kim JC, Chung JE. The role of port site local anesthetic injection in laparoendoscopic single site surgery: a prospective randomized study. 

. 2020;63(3):387-394. doi.org/10.5468/ogs.2020.63.3.387

Articles

A South Korean prospective study has concluded that an injection of port-site bupivacaine hydrochloride following gynecologic laparoendoscopic single-site surgery (LSSS) does not provide any additive effect in alleviating postoperative umbilical pain.

Port-site local anesthetic injection for laparoendoscopic surgery

The North American Society for Pediatric and Adolescent Gynecology offers a patient handout on endometriosis at this 

. Endometriosis in adolescents is not as well understood as endometriosis in adults, as covered in the June issue of 

 by Marc Laufer, MD, and Jessica Y. Shim, MD.

In the handout, you will find information for your patients, including an explanation of what endometriosis is, its symptoms, causes and treatments. It also includes an explanation of how a healthcare provider might go about diagnosing the condition.

The North American Society for Pediatric and Adolescent Gynecology offers a patient handout on endometriosis. Continue reading for more. 

Patient handout on adolescent endometriosis

Tuberculosis Screening Options Pros and Cons

This Contemporary OB/GYN® supplement addresses effective screening for and appropriate treatment of tuberculosis (TB) by identifying high-risk subsets both for acquiring an infection and transitioning from latent to active TB, comparing two primary screening methods, and examining treatment regimens for active and latent infections.

Podcasts

Importance of Screening for Tuberculosis Infection in the Ob/Gyn Community

Partner Perspectives allows marketers to connect directly with the Contemporary OBGYN audience by enabling them to share their content. This content does not necessarily reflect the views of Contemporary OBGYN editorial staff or MJH Life Sciences.

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: 

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

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.

Lobo RA, Archer DF, Kagan R, et al. A 17β-estradiol-progesterone oral capsule for vasomotor symptoms in postmenopausal women: a randomized controlled trial. Obstet Gynecol. 2018;132(1):161-170.

Simon JA. What if the Women’s Health Initiative had used transdermal estradiol and oral progesterone instead?Menopause. 2014;21(7):769-783.

American College of Obstetricians and Gynecologists. ACOG committee opinion no. 556: postmenopausal estrogen therapy: route of administration and risk of venous thromboembolism. Obstet Gynecol. 2013;121(4):887-890.

Canonico M, Fournier A, Carcaillon L, et al. Postmenopausal hormone therapy and risk of idiopathic venous thromboembolism: results from the E3N cohort study. Arterioscler Thromb Vasc Biol. 2010;30(2):340-345.

Kingsberg SA, Krychman M, Graham S, et al. The Women’s EMPOWER survey: identifying women’s perceptions on vulvar and vaginal atrophy and its treatment. J Sex Med. 2017;14(3):413-424.

Nelson AL. Comprehensive overview of the recently FDA-approved contraceptive vaginal ring releasing segesterone acetate and ethinylestradiol: a new year-long, patient controlled, reversible birth control method. Expert Rev Clin Pharmacol. 2019;12(10):953-963.

Published as a promotional supplement to Contemporary OB/GYN.

Why I started a pharmaceutical company

2002 Women’s Health Initiative, systemic hormone therapy containing synthetic agents (conjugated equine estrogens, medroxyprogesterone acetate, norethindrone acetate, or drospirenone) decreased by more than 90%.

 At the same time, an increasing number of healthcare providers and menopausal women turned to bioidentical hormone therapies (ie, 17β-estradiol and natural progesterone), described as structurally identical to hormones produced within a woman’s body. 

Compounded estrogen and progesterone prescriptions increased by 865% despite not being approved by the US Food and Drug Administration (FDA).

 The use of two separate bioidentical agents (ie, oral or transdermal estradiol opposed by oral progesterone) also increased, but there is a lack of efficacy and safety data on these two separate compounds when used in combination. 

In fact, the lone FDA-approved progesterone was only studied and approved as 200 mg for 12 nights sequentially in combination with 0.625 mg of conjugated estrogen and not together with oral or transdermal estradiol, whether cyclic or continuous.

Without efficacy or safety data supporting these combinations of bioidentical hormones that had become the standard of care by prescription volume, there was a significant need for an FDA-approved hormone therapy combination of estradiol and micronized progesterone that would be rigorously studied in a large phase 3, randomized, placebo-controlled trial.

Estradiol and progesterone, 1 mg/100 mg capsules for oral use, is the only FDA-approved continuous combined oral product containing bioidentical estradiol and micronized progesterone indicated for the treatment of moderate-to-severe vasomotor symptoms due to menopause.

 The estradiol is solubilized and is combined with suspended micronized progesterone together in a lipid. The estradiol and progesterone are not animal-sourced and are derived from plant-based materials. 

This combination does not contain peanut allergens. It is supplied as a once-a-day single oral capsule, offering the convenience of a single capsule combination of two bioidentical hormones (1 mg of estradiol and 100 mg of micronized progesterone), which may help improve compliance.

Oral versus transdermal hormone therapy–effect on venous thromboembolism/endometrial safety

It is important to understand the differences of oral and transdermal hormone therapy on venous thromboembolism (VTE) risks and endometrial safety in postmenopausal women. 

The preference of transdermal estrogen therapy over an oral estrogen therapy by some healthcare providers is based on a different perceived risk of VTE (1.5 vs 1.2–3 per 1000 woman-years).

 The risk of endometrial hyperplasia, however, in a postmenopausal woman with a uterus is equal to or less than 1 in 100 and increases significantly when estrogen therapy is not adequately opposed by a progestogen.

This risk of endometrial hyperplasia or cancer represents a 10-fold higher risk than the risk of VTE. Therefore, it is critical to provide endometrial protection while prescribing hormone therapy. Stand-alone micronized progesterone has never been adequately studied or approved to be used with transdermal or oral estradiol, and separate estradiol and progesterone products may decrease treatment compliance.

 As such, the use of stand-alone micronized progesterone in combination with oral or transdermal estradiol may expose women to an increased risk of endometrial hyperplasia or cancer.

This is the only estradiol and progesterone combination that has been studied in a randomized, placebo-controlled trial demonstrating relief of vasomotor symptoms with endometrial safety and is FDA approved.

This single daily oral combination of estradiol and progesterone provides a sustained steady state of estradiol over 24 hours (

 It has demonstrated significant improvement in vasomotor symptom frequency and severity.

 It also has shown improvement in menopause-related quality of life and sleep parameters (secondary endpoints).

The safety of this estradiol and progesterone combination was examined in a single 52-week randomized, double-blind, placebo-controlled study. Endometrial biopsy assessments evaluated endometrial safety.

 It was found to be the only bioidentical micronized progesterone combination product to demonstrate endometrial protection.

Furthermore, it demonstrated high rates of amenorrhea that increased with use, so that by 1 year, more than 90% of women were completely amenorrheic.

Adverse reactions were those that would be expected with estradiol and progesterone. The most common adverse reactions reported at a frequency of 3% were breast tenderness (10.4%), headache (3.4%), vaginal bleeding (3.4%), vaginal discharge (3.4%), and pelvic pain (3.1%).

 Most adverse reactions were transient, and no discontinuations were related to breast tenderness.

The continuous combination of solubilized estradiol with suspended micronized progesterone together in a lipid has created a unique product profile. Given the concern for an increased VTE risk with oral estrogens, attention was directed to this estradiol and progesterone combination’s effect on the coagulation factors and its metabolic profile. 

In the 1-year clinical trial, no clinically meaningful changes were found in coagulation factors or lipid and glucose parameters.

 Moreover, there were no VTEs, strokes, or myocardial infarctions (MIs) in the 1-year study.

Other safety analysis—breast, weight, and blood pressure

Other safety analysis showed there was no impact on weight or blood pressure and no clinically meaningful changes in mammograms in the 12-month study.

Women are menopausal for approximately one-third of their lives, during which approximately 80% experience vasomotor symptoms that can negatively impact their quality of life and interfere with their work, sleep, and interpersonal relationships.

The North American Menopause Society concludes that in young, otherwise healthy menopausal women, hormone therapy is the most effective treatment option for bothersome menopausal symptoms.

This bioidentical combination product of estradiol and micronized progesterone is the only one to demonstrate efficacy in the treatment of moderate-to-severe vasomotor symptoms while helping to reduce the risks to the endometrium.

 Its combination of solubilized estradiol and suspended micronized progesterone in a lipid has created a unique profile including high amenorrhea rates, no clinically meaningful changes in coagulation factors, lipid parameters, weight, blood pressure, and with no strokes, MIs, or VTEs in the 1-year trial.

Accordingly, it is the only FDA-approved bioidentical hormone therapy combination of estradiol and micronized progesterone that represents an appropriate option for the treatment of moderate-to-severe vasomotor symptoms in otherwise healthy menopausal women with a uterus and no contraindications.

To learn more about this combination of estradiol and progesterone, visit 

1. Pinkerton JV, Constantine GD. Compounded non-FDA–approved menopausal hormone therapy prescriptions have increased: results of a pharmacy survey. 

2. Symphony Health. FDA-approved synthetic and bio-identical hormones used for the treatment of VMS symptoms. Compounded bio-identical estradiol and progesterone estimated from company survey data on compounding pharmacies and historical trends in the compounding market. Charts are graphical representations of the historical trends of total prescription units of FDA-approved synthetic estrogen and progestin versus the historical trends of total prescription units of the combination of FDA-approved bio-identical estradiol and progesterone and compounded estradiol and progesterone 2001 – 2018 data. Blue Bell, PA: Symphony Health.

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5. Lobo RA, Archer DF, Kagan R, et al. A 17β-estradiol-progesterone oral capsule for vasomotor symptoms in postmenopausal women. 

6. Simon JA. What if the Women’s Health Initiative had used transdermal estradiol and oral progesterone instead? 

7. American College of Obstetricians and Gynecologists. ACOG committee opinion no. 556: postmenopausal estrogen therapy: route of administration and risk of venous thromboembolism. 

8. Canonico M, Fournier A, Carcaillon L, et al. Postmenopausal hormone therapy and risk of idiopathic venous thromboembolism: results from the E3N cohort study. 

9. Reed SD, Newton KM, Clinton WL, et al. Incidence of endometrial hyperplasia. 

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