Correspondence: Hormone Therapy for Postmenopausal Women

Correspondence: Hormone Therapy for Postmenopausal Women


In an assessment of therapies to treat the symptoms of menopause,
Pinkerton (Jan. 30 issue)1 dismisses compounded therapies (except
for those used in patients with allergies or when there is a medical
need for unusual dosing regimens), and she notes safety concerns.
This blanket generalization overlooks the substantial Food and
Drug Administration (FDA) oversight established by the 2013 Drug
Quality and Security Act (DQSA).
Contrary to Pinkerton’s assertion of “minimal government
regulation and monitoring,” the drug outsourcing facilities
supervised under the DQSA must register with the FDA, be subject
to regular unannounced inspections, comply with Current Good
Manufacturing Practices, and use FDA regulated ingredients.
Patients have depended on compounders and outsourcing facilities
for decades to provide the customized formulations that work
well for them, along with counseling on use of the compounded
medication. I am extremely concerned about the potential
consequences for women who use these therapies of disregarding
this sector in its entirety owing to unfounded safety concerns.
New York, NY

No potential conflict of interest relevant to this letter was reported.

1. Pinkerton JV. Hormone therapy for postmenopausal women. N Engl J Med
2020; 382: 446-55.


In her article on hormone therapy, Pinkerton focused on data from
the Women’s Health Initiative and did not mention the Danish
Osteoporosis Prevention Study, which randomly assigned 1006
recently postmenopausal or perimenopausal women to estradiol or
no estradiol for 11 years and followed them for 16 years. Women
who received estradiol had significantly lower mortality (among
15 women vs. 26 women) and a significantly lower incidence of
myocardial infarction (5 vs. 11) than women who did not receive
estradiol, without an increase in the incidence of cancer (36 and
39, respectively), venous thromboembolism (2 and 1), or stroke (11
and 14).1

The article by Pinkerton also did not address sexual dysfunction2
or menopause-related cognitive impairment,3 which has
been reported to be present in 60% of perimenopausal and
postmenopausal women.2-4 Subjective reports of symptoms are
confirmed by objective evidence of decreases in measures of
verbal memory, episodic memory, list learning, verbal fluency, or
executive functioning.2-4 Lack of awareness among physicians of
this association between memory loss and menopause may have
disastrous consequences for menopausal women, including the
misdiagnosis of dementia in women with these symptoms.3

New York, NY

New York, NY

New Brunswick, NJ

No potential conflict of interest relevant to this letter was reported.

1. Schierbeck LL, Rejnmark L, Tofteng CL, et al. Effect of hormone replacement
therapy on cardiovascular events in recently postmenopausal women:
randomised trial. BMJ 2012; 345: e6409.
2. Davis SR, Lambrinoudaki I, Lumsden M, et al. Menopause. Nat Rev Dis Primers
2015; 1: 15004.
3. Devi G. Menopause-related cognitive impairment. Obstet Gynecol 2018; 132:
4. Greendale GA, Derby CA, Maki PM. Perimenopause and cognition. Obstet
Gynecol Clin North Am 2011; 38: 519-35..


Schwartz notes concerns about the recommendation to avoid the
use of compounded therapies except in special circumstances.
The 2013 DQSA provides national licensure standards and FDA
inspections for outsourcing wholesale distributors and third-party
logistics providers who ship across state lines.1 Compounding
pharmacies that are not outsourcing providers are monitored
by states, with wide variability in oversight.1 The Pharmacy
Compounding Accreditation Board assesses voluntary compliance
with sterile and nonsterile pharmacy compounding processes. Major
medical societies, including the American Medical Association, the
American College of Obstetricians and Gynecologists, and the North
American Menopause Society, recommend against compounded
hormone therapies owing to safety concerns regarding overdosing
or underdosing, impurities, the lack of sterility, insufficient scientific
efficacy and safety data, and the lack of labels providing information
on dosing, ingredients, and risks.

FDA-approved bioidentical therapies include systemic and vaginal
estrogen and progesterone and vaginal dehydroepiandrosterone.
Medical indications for compounded hormone therapies should
be documented.1,2 For example, oral progesterone should not
be used in patients with peanut allergy, preservative-free vaginal
estrogen may be warranted, pellets with supraphysiologic levels
of testosterone for sexual disorders are not recommended, and
special dosing or formulations may be required. Federal and state
oversight is needed for increased transparency about compounded
product ingredients, financial conflicts of interest, and monitoring
of adverse events.

With respect to the comments by Devi and colleagues: since the
Danish Osteoporosis Prevention Study was open-label, did not
involve a placebo, and was much smaller than the Women’s Health
initiative, the data are less robust. Devi et al. also call attention to
the effects of menopause on sexual function and memory. Systemic
and vaginal estrogen improve lubrication and blood flow and
decrease the symptoms of genitourinary syndrome of menopause
and painful sex, without effects on sexual interest, arousal, or orgasm
beyond reduced vasomotor symptoms.2 For women with low libido,
transdermal estrogen is recommended because it has less effect on
testosterone bioavailability than oral hormone therapy.
Memory problems during menopause (e.g., forgetfulness, losing
keys, and difficulty concentrating or retrieving names) are usually
not associated with clinically significant impairment. Treatment of
depression, anxiety, and sleep disturbances, increased concentration
to focus attention, and increased exercise may decrease memory
problems.3 Neuropsychological testing is recommended if cognitive
symptoms interfere with daily life.3 Estrogen has been associated
with improved cognition after early surgical menopause,3 has
neutral effects if used early in postmenopausal women,4,5 and may
worsen memory if initiated in patients older than 65 years of age.2
Hormone therapy is not recommended to prevent or treat cognitive
dysfunction or decline.


Since publication of her article, the author reports no further potential conflict of

1. 1. Pinkerton JV, Pickar JH. Update on medical and regulatory issues pertaining to
compounded and FDA-approved drugs, including hormone therapy. Menopause
2016; 23: 215-23.
2. The NAMS 2017 Hormone Therapy Position Statement Advisory Panel. The
2017 hormone therapy position statement of the North American Menopause
Society. Menopause 2017; 24: 728-53.
3. Greendale GA, Karlamangla AS, Maki PM. The menopause transition and
cognition. JAMA 2020; 323: 1495-6.
4. Gleason CE, Dowling NM, Wharton W, et al. Effects of hormone therapy on
cognition and mood in recently postmenopausal women: findings from the
randomized, controlled KEEPS-Cognitive and Affective Study. PLoS Med
2015;12(6): e1001833.
5. Henderson VW, St John JA, Hodis HN, et al. Cognitive effects of estradiol after
menopause: a randomized

Disclaimer: These statements have not been evaluated by the Food and Drug Administration. These products are not intended to diagnose, treat, cure, or prevent any disease.