Why “Weak” Estrogens Can Be Stronger Than Estradiol – The Potency Myth Exposed

• If different estrogens act like distinct “keys” fitting the same estrogen receptor “lock,” but with varying ability to recruit helper proteins and trigger downstream signals, how should this influence decisions about which form of estrogen (e.g., bioidentical estradiol vs. other compounds) is best for individual HRT goals like symptom relief or long-term health?
• Why is it misleading to label estradiol as the universally “strongest” estrogen for HRT based solely on its high receptor affinity, and what additional testing or considerations (beyond potency metrics) should clinicians and patients weigh to optimize vasomotor, physiologic, metabolic, and immunologic outcomes?

Effects is measured by the Vasomotor, Metabolic, Physiologic, and Immunologic effects the Estrogen(s) cause.

Estrogen(s) of low “Potency” can have stronger “Effects” than those with “High Potency”.

Potency is basically affinity × efficacy combined. So the meme that Estradiol being the “strongest” has nothing to do with the vasomotor, physiologic, immunologic and metabolic effects of the hormone. The “strength” is about estradiol ability to attach to hormone receptors.
¹Watson CS, Jeng YJ, & Kochukov MY (2008). Nongenomic actions of estradiol compared with estrone and estriol in pituitary tumor cell signaling and proliferation. FASEB J, 22(9), 3328–3336.^,2Fuentes N, Silveyra P. Estrogen receptor signaling mechanisms. Adv Protein Chem Struct Biol. 2019;116:135-170.

Some hormones don’t stick very tightly (low potency), but they can still cause a strong estrogen effect in certain cells.³Jeyakumar M, Carlson KE, Gunther JR, Katzenellenbogen JA. Exploration of dimensions of estrogen potency: parsing ligand binding and coactivator binding affinities. J Biol Chem. 2011 Apr 15;286(15):12971-82. Why? Those cells might have extra helper proteins (called co-activators) that really like to team up with the receptor when that substance is attached. The helpers make the effect bigger.

A substance’s real power as a hormone also depends on other things:⁴Jeyakumar M, Carlson KE, Gunther JR, Katzenellenbogen JA. Exploration of dimensions of estrogen potency: parsing ligand binding and coactivator binding affinities. J Biol Chem. 2011 Apr 15;286(15):12971-82.^,5Ruggiero RJ, Likis FE. Estrogen: physiology, pharmacology, and formulations for replacement therapy. Journal of Midwifery & Women’s Health. 2002 May-Jun;47(3):130-138.

• Outside factors (like how the body absorbs it, moves it around, breaks it down, or gets rid of it). These are hard to guess without testing in living things.
• Inside factors (like sticking to the receptor and getting those helper proteins to join). These happen right inside cells and are easier to study in labs.

So, while sticking to the receptor is the starting point for estrogen-like action, the final strength comes from what happens after sticking—like how well it turns on the cell’s signals and brings in helpers.⁶Chen P, Li B, Ou-Yang L. Role of estrogen receptors in health and disease. Front Endocrinol (Lausanne). 2022 Aug 18;13:839005.^,7Marvin J. Meyers, Jun Sun, Kathryn E. Carlson, Gwendolyn A. Marriner, Benita S. Katzenellenbogen, and John A. Katzenellenbogen. Estrogen Receptor-β Potency-Selective Ligands:  Structure−Activity Relationship Studies of Diarylpropionitriles and Their Acetylene and Polar Analogues. Journal of Medicinal Chemistry 2001 44 (24), 4230-4251^,8Stanley G. Korenman, Comparative binding affinity of estrogens and its relation to estrogenic potency, Steroids, Volume 13, Issue 2, 1969, Pages 163-177

In short:

Potency = affinity × efficacy

How strong an estrogen effect is also depends on which kind of key fits into the estrogen lock (called the estrogen receptor). Different helper proteins (co-activators) can change how easily the lock accepts certain keys.

Think of the estrogens in your body like four different keys. Your cells have special locks on them—these locks are the estrogen receptors.

• When a key fits really well and turns the lock, different things happen in the body. These can affect blood vessels (like hot flashes), body functions, how you use energy (metabolism, fat deposits), and even your immune system.
• Depending on which key fits, the cell starts doing lots of “estrogen-like” jobs. Examples are: growing milk glands in breasts, making the uterus lining get thicker, or causing a period.

When people say something has low or weak estrogen power, it still acts a little like estrogen. It can help the body get ready for pregnancy, support pregnancy, and help with being a mom—but the effects are just as strong as the main keys.

References

• 1
  Watson CS, Jeng YJ, & Kochukov MY (2008). Nongenomic actions of estradiol compared with estrone and estriol in pituitary tumor cell signaling and proliferation. FASEB J, 22(9), 3328–3336.
• 2
  Fuentes N, Silveyra P. Estrogen receptor signaling mechanisms. Adv Protein Chem Struct Biol. 2019;116:135-170.
• 3
  Jeyakumar M, Carlson KE, Gunther JR, Katzenellenbogen JA. Exploration of dimensions of estrogen potency: parsing ligand binding and coactivator binding affinities. J Biol Chem. 2011 Apr 15;286(15):12971-82.
• 4
  Jeyakumar M, Carlson KE, Gunther JR, Katzenellenbogen JA. Exploration of dimensions of estrogen potency: parsing ligand binding and coactivator binding affinities. J Biol Chem. 2011 Apr 15;286(15):12971-82.
• 5
  Ruggiero RJ, Likis FE. Estrogen: physiology, pharmacology, and formulations for replacement therapy. Journal of Midwifery & Women’s Health. 2002 May-Jun;47(3):130-138.
• 6
  Chen P, Li B, Ou-Yang L. Role of estrogen receptors in health and disease. Front Endocrinol (Lausanne). 2022 Aug 18;13:839005.
• 7
  Marvin J. Meyers, Jun Sun, Kathryn E. Carlson, Gwendolyn A. Marriner, Benita S. Katzenellenbogen, and John A. Katzenellenbogen. Estrogen Receptor-β Potency-Selective Ligands:  Structure−Activity Relationship Studies of Diarylpropionitriles and Their Acetylene and Polar Analogues. Journal of Medicinal Chemistry 2001 44 (24), 4230-4251
• 8
  Stanley G. Korenman, Comparative binding affinity of estrogens and its relation to estrogenic potency, Steroids, Volume 13, Issue 2, 1969, Pages 163-177