The American College of Physicians (ACP) released a guideline for treating vasomotor symptoms, a.k.a. hot flashes and night sweats in menopause, entitled, Pharmacologic Treatments for Females With Menopausal Vasomotor Symptoms: A Clinical Guideline From the American College of Physicians.1 This is apparently a first for them, so it’s good to see the ACP taking interest in menopause. Many clinicians will see the guidelines as they are published in the Annals of Internal Medicine, so the audience should be wide. This kind of visibility can, over time, improve comfort with prescribing. It may also help with education, as the article could become the focus of a residency journal club or even be part of the reading needed to maintain certification.
FYI, the guideline is meant to aid with drug selection, not with dosing, or individualized prescribing. It’s really about ranking the medications regarding effectiveness and safety.
While guidelines don’t compel anyone, they can influence insurers, pharmacy benefit managers, or governments to cover therapies and may also affect the price. This guideline has a list of three tiers, so if an expensive drug is the third tier, this provides ammunition for an insurer/government to charge a lot more for this therapy, not cover the medication at all, or make it part of step therapy, where other tiers must be tried first.
One point, these guidelines do not apply to all women, and some groups were explicitly excluded:
The population is adult females with menopausal VMS. This guideline does not address females with current breast cancer and/or those receiving hormonal treatment for breast cancer, females with premature ovarian failure (menopause before age 40 years), or transgender people already taking hormones for transitioning gender.
The guidelines excluded compounded medications, and right so as they are inferior. They reference the National Academies for Sciences, Engineering, and Medicine, which has thoroughly reviewed these products, and so their decision to not consider these medications is valid.
Overall the recommendations for estrogen, with or without progestogens, as first-line or tier one are sound. However, I have some issues, and I feel they are worth discussing.
Before we begin, some of my detractors accuse me of blind allegiance to guidelines, but perhaps they are unaware that I deeply interrogate what’s written and the evidence behind the guidelines, as well as compare them with other guidelines. And when guidelines fall short, I will absolutely point that out, as I am doing in this post.
Guidelines don’t require lock step adherence, but overall they are generally evidence based. When people deviate from the guidelines, that should be based on evidence (as I will present here), and not because the guidelines conflict with the latest money making trend.
I’ve done a pretty deep dive, because I fell down some rabbit holes based on what was excluded. So, here’s a summary for those who just want the TL;DR (too long; didn’t read):
The American College of Physicians set out to rank menopause drugs by effectiveness and safety. They created a three-tiered ranking, appropriately putting estrogen products in the first tier. But the ranking, and what they decided to exclude, gets weird: tibolone was shown the door for unexplained “safety concerns,” Premarin/bazedoxifene was left out over supposedly insufficient harms data, and newer drugs for hot flashes seem to have been shuffled down the list because of their price tags. The lack of transparency makes some of these decisions difficult to interpret, and women who can’t take estrogen risk being treated less like patients who need relief and more like a line item on a spreadsheet. Turns out the hot flashes aren’t the only thing getting managed.
And for those who think I’m being harsh, guidelines can have far-reaching effects, so evaluating their rigor is essential. Peer review doesn’t end with publication; I’d argue that’s where it starts.
Read on for the rabbit holes.
Issue 1: Tibolone
The guideline excluded tibolone for what the authors write are “safety reasons,” but they provide no analysis showing why its safety profile would preclude its use for hot flashes and night sweats. It is true there is a safety signal from a clinical trial data showing an increased stroke risk in women ages 60-85 years (LIFT trial) who were prescribed tibolone for osteoporosis prevention, but those findings may not apply in the same way to women seeking treatment for vasomotor symptoms, who are likely closer to age 50 (either a little younger or older). Also, I am only guessing the LIFT trial was an issue; as there is no analysis, it isn’t possible to know what data led to the safety concerns.
Other guidelines have balanced the effectiveness of tibolone versus safety, and found that it has a place in treatment for hot flashes and night sweats. The Endocrine Society, the Society of Obstetricians and Gynecologists of Canada, the Australasian Menopause Society, and the British Menopause Society all consider tibolone to be a treatment option.3-6 The latest International Menopause Society guidelines recognizes tibolone as a treatment option for menopausal symptoms in women under 60 or within 10 years of menopause at low baseline risk, and they say this is supported by Level A evidence (screenshot from the guideline)7:
I think it’s important to point out that the most recent Cochrane analysis found the evidence more moderate than the IMS, concluding:8
Moderate‐quality evidence suggests that tibolone is more effective than placebo but less effective than HT in reducing menopausal vasomotor symptoms, and that tibolone is associated with a higher rate of unscheduled bleeding than placebo but with a lower rate than HT.
Compared with placebo, tibolone increases recurrent breast cancer rates in women with a history of breast cancer, and may increase stroke rates in women over 60 years of age. No evidence indicates that tibolone increases the risk of other long‐term adverse events, or that it differs from HT with respect to long‐term safety.
Much of the evidence was of low or very low quality. Limitations included high risk of bias and imprecision. Most studies were financed by drug manufacturers or failed to disclose their funding source.
Much of the evidence was of low or very low quality. Limitations included high risk of bias and most studies were financed by drug manufacturers or failed to disclose their funding source.
I’m not arguing that tibolone is superior to menopause hormone therapy, because it isn’t, but a blanket statement about it being excluded for “safety concerns” without showing the evidence behind the decision is difficult to justify, especially given the number of other societies that endorse its use and the conclusions of the Cochrane Review.
It would have been completely acceptable to exclude tibolone because it is not approved in the United States, but once safety is listed as the reason, that decision requires and explanation supported by evidence. The same standards should be applied to all the medications. It’s a bit of a juxtaposition to read about how all the evidence was weighed for all the other medications, and then for tibolone, it feels like the equivalent of “Nah, unsafe, next.” The other issue is that someone from another country who may read or reference these guidelines may think it means tibolone is unsafe, when in reality, this guideline did not evaluate the medication and provides no reference for the safety concerns.
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Issue 2: Excluding Premarin/Bazedoxifene
The document states:
Likewise, the ACP CGC did not develop recommendations for estrogen in combination with bazedoxifene or progestogen monotherapy because of insufficient or no available evidence for harms of these treatments.
The guidelines use GRADE (Grading of Recommendations Assessment, Development and Evaluation), the internationally standard system guideline panels use to rate how certain the evidence is (high, moderate, low, or very low) and the strength of the resulting recommendation is (strong or conditional/weak). Under GRADE, recommendations reflect the balance of benefits against harms. If the panel thinks the evidence of harms is too weak to characterize that balance, then it is completely valid to exclude a medication instead of issuing a weak recommendation. But, in that case, the panel should explain why it reached that conclusion.
Duavee (CEE/BZA) is FDA-approved for the treatment of moderate to severe vasomotor symptoms, and its trials assessed benefit for these symptoms as well as endometrial safety. Yet the ACP supplement leaves the evidence table blank for this drug for major adverse events, endometrial hyperplasia, and endometrial cancer. FDA approval does not mean that all long-term risks are known, but enough safety information and trial data exist that the value of that evidence can be assessed. If the ACP considered the evidence sufficient to assess efficacy but insufficient to assess harms, it should explain that distinction and identify the evidence it reviewed, especially as endometrial hyperplasia was a primary endpoint in two of the trials submitted to the FDA (SMART-1 and SMART-1). What specifically about these trials were wanting, safety-wise?
I think it is fair to point out that the “harms” base was pretty thin for almost everything they reviewed as most studies are relatively shorter term (this is a major problem in the field). If lack of data on harms for CEE/BZA were truly disqualifying, then I could probably make a case for neurokinin receptor antagonists, SSRIs, and gabapentin to be excluded for the same reason.
The guideline also lumps progestins and progesterone together for endometrial safety, but a 2023 systematic review included 84 randomized trials and found that FDA endometrial-safety criteria were met for only some progestogen formulations. Table 1a in the supplement provides no safety estimates for endometrial hyperplasia or endometrial cancer for either CEE/BZA or progestogens, yet the ACP excludes CEE/BZA from its recommendations because of insufficient evidence on harms while recommending estrogen with a progestogen. The panel should have explained why uncertainty about endometrial safety was disqualifying for one regimen but not the other. The same evidentiary standard should apply to all regimens, otherwise singling out Premarin/Bazedoxifene for safety is an inconsistency that is hard to swallow.
The 2026 VA/DOD guideline has weak recommendation for CE/BZA, with a very low certainty of evidence because the available studies differed in ways that made their results difficult to combine, not because the safety data were entirely absent. This doesn’t mean the VA/DOD guideline is better or worse than the ACP guideline, but it shows that another panel considered the evidence sufficient to make a recommendation. The ACP should explain why it reached a different conclusion.
Excluding Premarin/Bazedoxifene is clinically an issue because it may be the better option for women who have bleeding issues with progestogens or intolerable progestin related side effects.
Issue 3: Inappropriately listing Neurokinin Receptor Antagonists as a Third Tier Option
Here are the recommendations from the ACP document:
First-line (strong recommendation): estrogen + progestogen (uterus) or estrogen monotherapy (no uterus): these were supported by high-certainty evidence.
Second-line (conditional): SNRIs, desvenlafaxine or venlafaxine: these received moderate-certainty evidence.
Third-line (conditional): SSRIs escitalopram/paroxetine (low-certainty); gabapentin (low-certainty); or NKRAs elinzanetant/fezolinetant (moderate-certainty).
Estrogen with or without a progestogen is the most effective treatment for vasomotor symptoms, with high-certainty randomized controlled trials.9 Listing them as first-line therapy is appropriate.
The neurokinin receptor antagonists (NKRAs) are relegated to third-line despite having the same certainty-of-evidence grade as the second-line agents and a higher grade than the other third-line drugs. In the paper, the guideline essentially admits this is because of their cost:
Although moderate-certainty evidence indicates that benefits are greater than harms for NKRAs, compared with placebo, the ACP CGC considered them third-line treatment due to the NKRA fezolinetant being a low-value treatment (moderate-certainty evidence) and elinzanetant having a higher WAC than fezolinetant.
WAC = wholesale acquisition cost
The NKRAs do not qualify for tier one because although they reduce the frequency of hot flashes, the data for reducing severity is less and the evidence supporting them is moderate certainty, compared with high-certainty evidence for estrogen with or without a progestogen. But that does not explain why they are placed in tier three rather than tier two.
There are several problems with demoting NKRAs to the third tier.
The ACP says that estrogens with/without progestogens are “high economic value,” and the NKRA fezolinetant is “low value.” The recommendations considered “financial burden, and access to and availability of treatments,” but the guideline is not sufficiently transparent about how these considerations translated into the treatment hierarchy. I should easily be able to tell if a drug is in tier 3 because of cost or because of effectiveness. The summary recommendations, which are what many readers will see, do not make that distinction clear. Clinicians may therefore interpret third-line placement as evidence that NKRAs are less effective, when the guideline itself rates their evidence as moderate certainty, the same as for second-line SNRIs.
Demoting a drug to a third tier based on cost becomes a self-fulfilling prophecy, as many insurers and pharmacy benefit managers look at these tiers to design coverage or as excuses to exclude the more expensive drugs. This is why you hear statements, such as, “Oh it’s third line, we don’t cover that” Or, “Third line drugs require that you fail two prior therapies.” But for a woman with a history of breast cancer or with another reason not to take estrogen–women this guideline supposedly includes–may then be forced to try a drug that is not as effective, like gabapentin, before getting to try a NKRA. What does second tier even mean to someone who is categorically excluded from the entire first tier?
NKRAs should be in the second tier, and there should be a comment indicating that when estrogen and/or progestogens are contraindicated that tier two effectively becomes tier one.
What Does All This Mean
It’s correct to list estrogen with or without a progestogen as first line therapy, and discussing menopause and treatment in this way will be good for women. But guidelines carry a TON of weight, and they need to be precise, and I feel there are some problems here that will affect some women. Some may call me pedantic, but the process matters, it can’t be applied in one way to one drug and then differently to a second drug. Also, over my career I have cared for a lot of women who can’t take hormones or who have had issues with them, so I may be more attuned to the needs of both the exceptions as well as the majority, and not just the majority who can take hormones.
In the United States, the tibolone exclusion doesn’t likely mean much, but it might needlessly scare some women and their clinicians in other countries.
Guideline guide practice, so not including Premarin/Bazedoxifene because of supposedly insufficient data about harms could be interpreted as the medication being “unsafe,” and downgrading NKRAs to the third tier due to price could be misinterpreted as being less effective. his may affect prescribing and deny many women excellent options.
Equally as important, and possibly more so, guidelines like these become the template for how drugs are covered by insurers. The new ACP guideline functionally codifies the price barrier that already exists for Premarin/Bazedoxifene and NKRAs. These are the most expensive options, and they are likely to stay that way when they are, in my opinion, excluded or downgraded inappropriately in guidelines.
This means that some women who can’t take standard MHT become a cost to be managed rather than patients to be treated and a treatment hierarchy designed around the average patient can disadvantage the women with the fewest options. And I’m fighting for all women.
References
Qaseem A, Mackey K, Yost J, Shekelle PG, Shamliyan TA, Cross JT Jr; Clinical Guidelines Committee of the American College of Physicians. Pharmacologic Treatments for Females With Menopausal Vasomotor Symptoms: A Clinical Guideline From the American College of Physicians. Ann Intern Med. 2026 Oct 6. doi: 10.7326/ANNALS-26-01205.
Cummings SR, Ettinger B, Delmas PD, et al. The Effects of Tibolone in Older Postmenopausal Women. New Eng J Med 2008.
Stuenkel CA, Davis SR, Gompel A, et al. Treatment of Symptoms of the Menopause: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015;100(11):3975–4011. doi: 10.1210/jc.2015-223
AMS Tibolone fact sheet https://hub.menopause.org.au/Play?pId=cd672260-9748-43f2-81a6-905057c0c2ea
Blake J, Wolfman W, Fortier M, et al. Guideline No. 422a: Menopause: Vasomotor Symptoms, Prescription Therapeutic Agents, Complementary and Alternative Medicine, Nutrition, and Lifestyle. J Obstet Gynaecol Can. 2021;43(10):1188–1204.e1.
BMS Prescribing Fact sheet https://thebms.org.uk/wp-content/uploads/2026/08/03-NEW-BMS-TfC-Practical-Prescribing-AUGUST2026-A.pdf
Panay N, Fenton A, Hamoda H, et al.; IMS Recommendations Writing Group. International Menopause Society (IMS) recommendations and key messages on women’s midlife health and menopause. Climacteric. 2025;28(6):634–656.
Formoso G, Perrone E, Maltoni S, Balduzzi S, Wilkinson J, Basevi V, et al. Short-term and long-term effects of tibolone in postmenopausal women. Cochrane Database Syst Rev. 2016;10(10):CD008536.
Maclennan AH, Broadbent JL, Lester S, Moore V. Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes. Cochrane Database Syst Rev. 2004 Oct 18;2004(4):CD002978. doi: 10.1002/14651858.CD002978.pub2