Why Does Spironolactone Cause Breast Development?

🥼 Practice and Clinical
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Introduction

It is well known that spironolactone is a diuretic drug belonging to the class of aldosterone antagonists.

However, during rounds today, the teaching instructor mentioned that excessive use of spironolactone can cause breast development. Why is that?

Main Text

  1. Separation of Spironolactone’s Core Effects and Side Effects

Main Pharmacological Mechanism
As an aldosterone antagonist, spironolactone blocks aldosterone receptors on renal tubules, reducing sodium reabsorption and potassium excretion. It is used to treat hypertension, heart failure, and edema.

Independent Mechanism of Side Effects
Gynecomastia is a sex hormone-related side effect and is associated with spironolactone’s interference with androgen/estrogen balance rather than the aldosterone pathway.

  1. How Does Spironolactone Interfere with Sex Hormone Balance?

(1) Direct Anti-Androgen Effects

Androgen Receptor Antagonism
Spironolactone and its metabolites (such as canrenone) competitively bind to androgen receptors, blocking the effects of testosterone and dihydrotestosterone (DHT), leading to weakened androgen signaling.
Example: Similar to the action of finasteride but with a different mechanism.

(2) Increased Estrogen Levels

Inhibition of Testosterone Synthesis
Spironolactone may inhibit cytochrome P450 enzymes (such as CYP17A1), reducing testosterone synthesis.
Promotion of Testosterone Conversion to Estrogen
With androgen reduction, the proportion of testosterone converted to estrogen (estradiol) by aromatase in peripheral tissues (such as fat) relatively increases.

(3) Changes in Sex Hormone Binding Globulin (SHBG)
Spironolactone may increase SHBG levels, binding more free testosterone, further lowering the biologically active free androgen concentration.

References

Further Reading

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Our group’s bed 5 【Dong Peizhan, male, 65 years old, diabetic nephropathy】 was found to have breast development after admission. Before admission, he was taking finerenone to delay renal failure. After an ultrasound reported mammary gland hyperplasia, finerenone was discontinued.
☆ Spironolactone is a first-generation aldosterone receptor antagonist (MRA), finerenone is the third generation, and the second generation eplerenone is not available domestically.
△ Clinical trials indicate that finerenone has higher selectivity for aldosterone receptors, with a lower risk of hyperkalemia and adverse sexual hormone-related events. (Personal thought: suspect it may not necessarily be caused by finerenone, possibly due to previous use of drugs with aldosterone-like mechanisms)

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