Paternalism in practice: How we create obstacles for sexual, reproductive, and menopausal healthcare despite our best intentions

So was the observational evidence really so wrong?

Not really. Even though a full discussion on MHT is beyond the scope of this commentary, it is important to note that strong observational studies had shown 30% to 50% lower cardiovascular risk in MHT users, with an already known small increase in breast cancer risk.^6,7 As follow-up WHI publications were published over 20 years, the main messaging about the results evolved significantly. Initial concerns in 2002 about “substantial risks for cardiovascular disease and breast cancer”⁸ were followed in 2003 by “the suggestion of a slight overall increase” in the risk of coronary heart disease (CHD),⁹ changed in 2007 to “with no apparent increase in CHD risk for women close to menopause” and “total mortality reduced among women aged 50 to 59 years,”¹⁰ and in 2017 to “no adverse influence on CHD, venous thromboembolism, or all-cause mortality” (for Black postmenopausal women with a hysterectomy).¹¹

The grand finale is that US and European cardiac medical societies, who were often the most concerned about MHT risks, now note the acceptable safety profile in newly menopausal women (defined as women in their 40s and 50s or within a decade of menopause), specifically highlighting the favorable benefits of lower rates of diabetes, insulin resistance, and fracture.^12,13 It is again accepted that the time when MHT is initiated and the type of formulation used can guide whether there is an overall better risk-benefit ratio. Even the WHI authors noted how their own data have been used “inappropriately” in making decisions about treatment for women in their 40s and 50s who have distressing symptoms.¹⁴ MHT is again officially considered an acceptable alternative to prevent fracture in those with low bone density,¹⁵ though it has never come off my list of offered options.

But what about breast cancer risk?

We still see similar “lumping” of MHT fears regarding breast cancer risk, even though the 20-year WHI follow-up clearly shows that individuals using estrogen alone in this trial had a significant reduction in breast cancer incidence and mortality.¹⁶ Though estrogen is not recommended for breast cancer prevention in those at high risk of developing breast cancer, it is notable that the medications used for this purpose, tamoxifen and aromatase inhibitors, have not yet shown a similar reduction in breast cancer mortality. The addition of a progestin to the MHT did indeed increase breast cancer risk after 3 to 5 years in the WHI study,⁷ although other randomized controlled trials (RCTs) and observational studies have not shown similar risk increases.⁶ The increase in breast cancer risk when progestin is used beyond 5 years is within the medical “rare” category of risk (less than 1 of 1,000 cases),^6,7 comparable to the increase in breast cancer risk seen with the consumption of a few alcoholic drinks per week. This degree of risk is considered acceptable to many patients who are carefully counseled in clinic.

No harm in avoiding hormones, right?

Interpreting the MHT data over time has not been easy. Discussions of complex data and concerns of scary diagnoses like heart disease and cancer make these conversations difficult to implement in a busy practice. With clinicians not having either the expertise or the time to address these concerns in clinic, not only were thousands of symptomatic women ill cared for, but also several generations of trainees were without exposure to menopause management with MHT. Most of us in menopausal medicine have noted colleagues making strong recommendations for our mutual patients to discontinue MHT, which had been prescribed after careful weighing of risks and benefits (including those practicing in a completely unrelated medical specialty, often causing a disproportionate degree of alarm for the patient). Given that several RCTs have suggested a 30% reduction in mortality with MHT use,⁶ it is estimated that denial of estrogen-only therapy (with its better safety profile compared with estrogen-progestin therapy) may have led to more than 91,000 women who underwent hysterectomy (who would have needed estrogen alone) dying prematurely between 2002 and 2011.¹⁷

It has been 20 years since the first WHI publication, yet continuity of care in menopause clinics remains problematic, as there are far too few of us trained or certified in menopausal medicine (lists available at menopause.org). Every day, well-intentioned yet overly protective advice continues to unnecessarily limit MHT use in appropriate candidates. Luckily, the tide is turning, and new generations of trainees are being exposed to the most updated information, recognizing that there is an age-related window of opportunity for MHT use. In other words, when patients start therapy in their 40s or 50s, or within a decade of menopause, benefits are optimized, and risks are lower.

Unfortunately, this acceptance has come a little too late, with at least one-third of patients navigating toward unregulated products that can cause supra-physiologic hormone levels. We regularly see women in our clinics with male testosterone levels after compounded use of discouraged treatments such as hormone injections or pellets. It is important to help guide these patients back toward clinicians who are prescribing MHT in a safer, evidence-based approach, with adequate counseling about potential risks. Yet some patients have simply lost faith in “mainstream” medical care. Strong fluctuations in recommendations for or against a therapy over time (with exaggerated discussions of risks, while minimizing potential benefits) breed distrust not only in the clinician but also in the science itself. Most developments in medicine, when interpreted within the context of limitations, typically do not show that we were previously wrong but rather add pieces to a puzzle that make the picture clearer.

The humility lessons learned from the MHT story clearly concede that we are likely to be surprised by how medicine evolves and must acknowledge our patients’ right to have open conversations and consider treatments that deviate from current mainstream thinking. We need to remember that even the most “true” medical recommendations may change with the evidence (aspirin use is a good example). Both risks and benefits of a treatment should be clearly discussed and the individual empowered to make their decision based on their own value system.

But shouldn’t we protect female patients from harm?

Other FDA concerns were related to safety and tolerability. Before approval, there were several unusual stipulations imposed, most notably being subjected to additional studies focused on alcohol interactions with substantial alcohol servings (≥ 5 units). More specifically, individuals were asked to fast overnight, eat a light breakfast, then drink the alcohol equivalent of at least half a bottle of wine (typically within 10 minutes), while taking a dose of flibanserin (though package labeling calls for nighttime dosing). In these initial studies (some which consisted predominantly of men), concerns about orthostasis and hypotension prompted a risk evaluation and mitigation strategy, mandating that only certified prescribers and pharmacies could treat the patient, and that patients sign paperwork promising to avoid any alcohol intake.

I believe that all of this played a role in few pharmacists becoming certified due to unsubstantiated concerns (eg, that this could be used as a “date-rape drug”) based on discussions on pharmacy LISTSERVs. In the postmarketing experience, we understand that alcohol use in real-world situations does not cause any more hypotension than placebo, and flibanserin has a side-effect profile that is comparable to, if not less than, that in women taking antidepressant medications (most common side effects are sedation and nausea).^20,21

Barriers to wider uptake

There have been jokes made about flibanserin use. If it has minimal benefit but is going to make you nauseated and put you to sleep, what’s the point? Yet for a woman distressed by her HSDD, who has chronic insomnia and would like some of the appetite-suppressing effects of the medication (which may lead to ≥ 5% body weight loss),²¹ it can be a great adjunct to her care, alongside traditional biopsychosocial management of sexual dysfunction. Postmarketing safety experience has allowed for the strict alcohol restrictions to be lifted, and package labeling now indicates only the need to space the medication and last drink apart by 2 hours. However, widespread utilization of flibanserin remains limited by cost and ongoing concerns about safety, and the need to avoid all alcohol is still noted within the top results following a quick Internet search.

Lack of awareness of flibanserin has also contributed to low uptake. Part of the FDA approval was contingent on the company agreeing to not run commercial advertisements for 18 months after its approval, with continued strict marketing oversight since that time.²² As we hold this medication to a high standard of advertising ethics (which isn’t a bad thing), my brain is bombarded with images of couples holding hands in adjoining bathtubs, one of the estimated 500 billion US television advertising impressions on erectile dysfunction between 2006 and 2009.²³ These advertisements have been criticized for their explicit content and lack of regulation; further, depending on the venue or timing, they have exposed minors to developmentally inappropriate information approximately 20% of the time—despite recommendations otherwise by the American Academy of Pediatrics.²³ Companies making male erectile dysfunction treatments have been some of the top spenders in direct-to-consumer advertising, leading to widespread use of these medications both clinically and recreationally, and they have even been linked to an increase in birth rates associated with television promotion.²⁴

Holding female and male sexual health products to the same standards

So how is this tied to advocacy? It is important that female and male sexual health products are held to the same standards.

When the initial approval of sildenafil was fast-tracked in 1998, it was known to cause deaths when taken with nitrates, and hypotension when taken with alpha-blockers. However, female products have been subjected to unusually selective protocols and additional safety procedures. We now have a second FDA-approved treatment for HSDD, bremelanotide, self-administered by subcutaneous injection. Although bremelanotide was approved in 2019, insurance coverage remains a major barrier for both treatment options.

In contrast, there are 26 FDA-approved products for male sexual dysfunction. The concern is not simply the difference in number of treatment options between the sexes, but also the struggles of the approval and marketing processes, which have led some sexual health experts to raise concerns about paternalism within the FDA—ie, men get the choice of whether medication risks are worth it, and women need an additional layer of “protection” from harm.²⁵ I hesitate to speak negatively of any processes to ensure safety, but what is clear to me is that the voices of advocacy groups likely had a role in moving the approval process along, so much so that the FDA committee members felt compelled to publish their perspective and defend their processes in the New England Journal of Medicine.¹⁹

The approval process for first-in-class treatments for a new medical indication is clearly challenging. However, it is equally important to note that different sociocultural backgrounds and beliefs can contribute to biases, leading to differences in interpretation of overall treatment risk vs benefit,²⁵ and I suspect biases impact even more so the topic of female sexuality.

We need to advocate for more treatment options for HSDD, several of which are currently being studied. Even though RCTs have consistently shown the benefits and tolerability of testosterone replacement in women (when used at physiologic doses), the FDA has unanimously rejected the request to approve a testosterone patch. Ten US and international professional societies have come to the consensus that testosterone replacement may be tried for female HSDD, with several clinical recommendations on safe use.²⁶ Because there continues to be no FDA-approved way to replace testosterone in women, doing this safely remains a challenge,²⁷ again steering women toward unregulated and potentially harmful treatments such as high-dose pellets. And yes, these products have celebrity endorsements.

Two guiding principles of reproductive care

As a consultant for the contraceptive and hormonal needs of our medically complex patients, I follow 2 guiding principles in managing patient care. First, the contraceptive that the patient prefers is the one she is most likely to use after she leaves my office. Second, no matter what the risks of any contraceptive, the risks of an unintended pregnancy are always far greater. Fortunately, some guidelines do soften language to address necessary variations in practice (eg, newer migraine guidelines since the publication of the CDC eligibility criteria) and emphasize the importance of shared decision-making, as opposed to a universal recommendation to withhold CHCs in those with migraine with aura.^29,31

In the absence of contraindications, clinicians also withhold prescriptions because patients are not up-to-date with health screenings such as Papanicolaou tests or breast examinations. Removing barriers to effective contraception is not only evidence-based, it is also encouraged by guidelines.³² For example, to qualify a patient for CHCs, a prescriber needs only a medical history and a recent blood pressure reading, which can be obtained outside of the office. With excessive restrictions from doctors’ offices, patients have turned to online prescribing companies that use online questionnaires to offer CHCs in an evidence-based way, with an average appointment time of 7.5 minutes, for a total average yearly cost of $313 per prescription, including cost of visit and 1 year of refills.³³ There has been a call for more widespread expansion of over-the-counter contraceptives, which is already a reality in many US states but has had slow uptake. Thus, improving access with virtual visits is encouraged, especially visits during nonbusiness hours.

Fear as an obstacle

The fear of a serious thrombotic complication from a preventive medication in a young healthy woman is understandable. The US medical-legal environment is a hostile one. Between 2008 and 2015, approximately $2 billion in litigation was disputed against the most popular CHC of that time, with ads on social networking platforms soliciting participation in lawsuits directed at the manufacturer, as opposed to individual clinicians.³⁴ (Interestingly, settlements were related to risks clearly outlined in the product package insert.) I suspect that much of the litigation was not related to altruistic concerns about safety, as the evidence is not convincing of a major difference in risk of this CHC compared with others, but was instead attracted by the “deep pockets” of the pharmaceutical company producing the brand-name pill. Not surprisingly, the lawsuits quickly fizzled after the medication became generic.

We cannot let medical-legal fears get in the way of listening to the patient and providing for her contraceptive choices. Flexibility in addressing contraceptive preferences is now even more critical in the setting of limited access to abortion throughout different regions of the country.