To the Editor: In the August issue, Dr. Butts1 presents the dangers of premature ovarian insufficiency (POI) and correctly states that they are caused by the longer duration of hypoestrogenism in POI. The author also points out the differences between POI and natural menopause; however, hypoestrogenism is a simple hormone deficiency and its effects are the same in all cases, as are the benefits of hormone replacement with the correct human molecules, delivered by the best routes.
The author mentions that the findings of the Women’s Health Initiative (WHI) do not apply in POI due to the older age of the women included in the study. In fact, the WHI findings do not apply to any menopausal hormone therapy except what was studied: oral conjugated equine estrogens and medroxyprogesterone acetate. In particular, the WHI study findings do not apply to properly delivered human hormones—transdermal estradiol2 and oral micronized progesterone.3
The author bemoans the undertreatment of POI but then promotes that undertreatment by citing the contraindications to menopausal hormone therapy listed in a paragraph of the 2022 North American Menopause Society (NAMS) position statement.4 However, outside that paragraph, NAMS states that history of breast cancer is not an absolute contraindication, and that the cardiovascular risks seen with conjugated equine estrogens and medroxyprogesterone acetate in the WHI study “may not” apply to transdermal estradiol and oral micronized progesterone.
Also, women must be informed that estradiol does not cause breast cancer; inherited and acquired genetic mutations do.5 Estradiol has only a permissive role by stimulating the proliferation of both normal and cancerous breast cells. Women should also be reassured that their health and well-being require only the same low free estradiol levels that men have, not high levels that they had at times during their menstrual cycles.
It seems that the WHI findings continue to be inappropriately applied to all menopausal hormone therapy because the WHI was a randomized controlled trial, but randomized controlled trials are not the only type of evidence. We must look at all the evidence and at the cogent arguments for using only bioidentical human hormones. Estrogen replacement should consist of transdermal human estradiol and human progesterone. Any discussion of menopausal hormone therapy should emphasize the efficacy and safety of this best-quality hormone treatment.
When they have all the facts, both clinicians and patients will lose their irrational fear of ovarian hormone replacement therapy.
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REFERENCES
- 1↵Butts SF. The overlooked and undertreated perils of premature ovarian insufficiency. Cleve Clin J Med 2025; 92(8):475–482. doi:10.3949/ccjm.92gr.25056
- 2↵ACOG committee opinion no. 556: postmenopausal estrogen therapy: route of administration and risk of venous thromboembolism. Obstet Gynecol 2013; 121(4):887–890. doi:10.1097/01.AOG.0000428645.90795.d9
- 3↵Shufelt CL, Manson JE. Menopausal hormone therapy and cardiovascular disease: the role of formulation, dose, and route of delivery. J Clin Endocrinol Metab 2021; 106(5):1245–1254. doi:10.1210/clinem/dgab042
- 4↵The North American Menopause Society Advisory Panel. The 2022 hormone therapy position statement of The North American Menopause Society. Menopause 2022; 29(7):767–794. doi:10.1097/GME.0000000000002028
- 5↵Rizzolo P, Silvestri V, Falchetti M, Ottini L. Inherited and acquired alterations in development of breast cancer. Appl Clin Genet 2011; 4:145–158. doi:10.2147/TACG.S13226
