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Lexicon
Lexicon

Spironolactone (Aldactone)

Potassium-sparing diuretic and anti-androgen in one - which is exactly why it is tricky for men.

3 min read 6 sources

To the sources
Large steroid molecule model of glossy blue, white and one yellow sphere floats above a white podium in a bright lab, symbolic image for spironolactone
Compound approved · since 1960

Summary

At a glance

Sources checked on 26 Oct 2026

Risk of death in RALES
-30 %

1,663 people with severe heart failure, 35 instead of 46% died, stopped early1

Home blood pressure versus placebo
-8.7 mmHg

PATHWAY-2, resistant hypertension, also better than bisoprolol and doxazosin2

Men with breast swelling or pain
10 %

RALES, on placebo 1%1

Potassium too high in TOPCAT
18.7 %

on placebo 9.1%, so twice as often3

Acne better after 24 weeks
82 %

SAFA, women, on placebo 63%4

  • Spironolactone blocks the mineralocorticoid receptor, where the hormone aldosterone acts. The kidney therefore retains less sodium and excretes less potassium.62
  • In addition it binds to the androgen receptor according to measurement data in ChEMBL. In RALES 10 percent of men had breast swelling or breast pain, on placebo 1 percent.61
  • In severe heart failure it lowered the risk of death by 30 percent in RALES. In heart failure with preserved pumping function (TOPCAT) it missed the primary goal.13
  • In resistant hypertension it was the most effective fourth agent (PATHWAY-2), in acne in women it improved the skin against placebo (SAFA).24
  • Potassium is the hard limit: in TOPCAT it was too high twice as often as on placebo. According to ChEMBL spironolactone has been approved since 1960. Everything here is the state of research, not a recommendation.36
Profile

Updated July 2026

Class
Aldosterone antagonist

potassium-sparing diuretic

Second action
Also blocks the androgen receptor
Use
Oral

once daily

Onset
Slow

full effect after 2 to 4 weeks

Hard limit
Potassium

especially with an ACE inhibitor or sartan

Contents 12 sections
  1. At a glance
  2. What is spironolactone?
  3. How it works
  4. Use and dosing
  5. What the research shows
  6. Research status
  7. Side effects
  8. Storage
  9. Related compounds
  10. FAQ
  11. Glossary
  12. Sources

What is spironolactone?

Spironolactone has two faces and you need to know both. First it is an aldosterone antagonist: it blocks the mineralocorticoid receptor in the kidney, so less sodium is retained and less potassium is excreted. Hence the name potassium-sparing diuretic.

Second it is an anti-androgen, because it additionally blocks the androgen receptor and inhibits testosterone synthesis. That is not a side effect in the sense of an accident, it is a genuine second pharmacological action of the same substance. For men that is the decisive point.

This information is for research and educational purposes only. No medical advice.

Comparison

Diuretics and blood pressure in the lexicon

Related compounds in the TPD lexicon with their target, as described there. Tap a card to open its entry.

Potassium-sparing, aldosterone antagonist Spironolactone (Aldactone) MRAR
Loop diuretic Furosemide (Lasix) NKCC2 Loop diuretic Torsemide (Torem, Demadex) NKCC2 Beta blocker Bisoprolol (Concor) β1

Simplified: loop diuretics remove water fast and flush out potassium, spironolactone acts slowly and retains potassium. 6

How it works

Aldosterone acts in the collecting duct of the kidney through a receptor in the cell nucleus that first has to drive production of transport proteins. That is exactly why spironolactone works slowly: the full effect takes two to four weeks. As rapid water loss before an event it is the wrong tool, furosemide is built for that.

For blood pressure, on the other hand, it is the strongest fourth agent there is. The reason: a large share of resistant hypertension has an excessive aldosterone level behind it. No other agent attacks that directly.

The anti-androgen effect is small at low dose and rises clearly with dose. It can be noticeable even at 25mg, though: in RALES 10 percent of men had breast enlargement or breast pain, versus 1 percent on placebo.

Where it acts

Where spironolactone acts

Tap a point or a card. Colour = receptor, grey = observed in studies.

  1. Kidney

    Blocks aldosterone, potassium was too high twice as often in TOPCAT3

    MR
  2. Heart

    30 percent fewer deaths in severe heart failure (RALES)1

    Observed in trials
  3. Blood pressure

    Home blood pressure 8.7 mmHg lower than on placebo (PATHWAY-2)2

    Observed in trials
  4. Skin

    Acne improved in women (SAFA)4

    AR
  5. Hormone effect in men

    Breast swelling or pain in 10 instead of 1 percent of men (RALES)1

    AR

Targets in the ChEMBL database6

Compound CHEMBL1393: two recorded mechanisms, type of action on each card.

Mineralocorticoid receptor
Gene
NR3C2
UniProt
P08235
ChEMBL
CHEMBL1994
Action
Antagonist, direct binding
Androgen receptor
Gene
AR
UniProt
P10275
ChEMBL
CHEMBL1871
Action
Antagonist according to lab measurements in ChEMBL
Translucent cells of a glass kidney tubule, blue molecules sit in pockets in two cells, small crystals trickle out below
In the kidney spironolactone blocks the receptor for aldosterone. Symbolic image.

Use and dosing

Dosing

Dosing, titration and syringe

Loading the dosing information …

  • Getting started and stepping up, drawn as a staircase
  • Units on the U-100 syringe for every step
  • How long one vial lasts
White folding box with the TPD logo next to a blister of ten round white tablets, two loose tablets in front on a bright lab bench
Tablets in a blister. Symbolic image.

What the research shows

RALES (NEJM 1999) is the classic. Over 1,600 patients with severe heart failure received an additional 25mg spironolactone or placebo. The trial was stopped early: 30 percent lower mortality. The dose was deliberately low, this was not about diuresis but about receptor blockade.

PATHWAY-2 (Lancet 2015) answered the question of which fourth agent works best in resistant hypertension. Spironolactone clearly beat both bisoprolol and doxazosin. That is why it is standard at this position today.

TOPCAT (NEJM 2014) belongs here for honesty: in heart failure with preserved ejection fraction, spironolactone missed its primary endpoint. Later analysis found strong regional differences, with a clear effect in North and South America and none in Eastern Europe, which raised doubts about trial conduct there. The benefit in preserved ejection fraction is still not considered proven.

SAFA (BMJ 2023) documented the dermatological use: in women with acne, spironolactone significantly improved skin findings versus placebo.

Study results

What the trials measured

Interactive: switch tabs, tap points, show or hide arms. Arms are named relative to each other, no dosing advice.

Died within a mean of 24 months1

1,663 people with severe heart failure, on top of standard therapy

Deaths1 386 versus 284
Placebo 46%
Spironolactone 35%

Relative risk 0.70. In addition 35 percent fewer hospital stays for heart failure. The trial was stopped early because the benefit was clear at an interim analysis.

Systolic home blood pressure compared2

Difference on spironolactone versus each comparison, resistant hypertension

versus placebo2
Spironolactone -8.70 mmHg
versus bisoprolol2
Spironolactone -4.48 mmHg
versus doxazosin2
Spironolactone -4.03 mmHg

Each person received all four treatments one after the other for 12 weeks each (crossover), on top of three blood pressure drugs. In 6 of 285 potassium rose above 6.0 mmol/l once.

TOPCAT after a mean of 3.3 years3

3,445 people with heart failure and preserved pumping function

Primary goal: cardiac death, cardiac arrest or hospital3 not significant
Placebo 20.4%
Spironolactone 18.6%
Hospital for heart failure3 part of the primary goal
Placebo 14.2%
Spironolactone 12.0%

Hazard ratio 0.89, the primary goal was missed. Only hospital stays for heart failure fell significantly, total deaths did not.

Acne in women4

Share in percent, 410 women, dose doubled after 6 weeks

Better according to participant, week 244
Placebo 63%
Spironolactone 82%
Better according to participant, week 124 not significant
Placebo 68%
Spironolactone 72%
Success according to investigator, week 124
Placebo 6%
Spironolactone 19%

The difference was larger at week 24 than at week 12. In the end the highest study dose (100 mg) was given.

Glass heart and a milky white kidney, surrounded by bright bands of light on a white surface
The large trials measured deaths and hospital stays, not just lab values. Symbolic image.

Research status

Where the research stands

Spironolactone has been approved since 1960, on ClinicalTrials.gov 330 trials list it among their interventions. Shown are large phase 3 trials, including TOPCAT from this entry. RALES is not listed there, PATHWAY-2 has an unknown status, SAFA is in the British ISRCTN registry. As of 26 Oct 2026. 5

  1. Preclinical Principle: block the mineralocorticoid receptor
  2. Phase 1 no registered trial
  3. Phase 2 no registered trial
  4. Phase 3 5 trials, 4 completed
  5. Approval since 1960
9,586 participants in phase 3 Planned figures for running trials Approved: ChEMBL lists spironolactone with phase 4 as the highest phase and first approval in 1960.6
Show all 5 phase 3 trials on a timelineHide timeline 4 completed 1 running 1 with results
Phase 3

Bar: start to primary endpoint (planned for running trials). Green = completed, blue = progress until 26 Oct 2026.

Side effects

  • Raised potassium: the most dangerous side effect, because it can hit the heart without warning signs. Combined with ACE inhibitors or sartans it must be tracked with bloodwork.
  • Gynecomastia in men: dose-dependent, but not rare even at 25mg: in RALES 10 percent of men on spironolactone reported breast enlargement or breast pain, versus 1 percent on placebo. It happens more often at higher doses. Usually recedes after stopping, but not always completely.
  • Loss of libido and erectile problems: same cause, same dose dependence.
  • Cycle irregularities in women: common at the dermatological dose.
  • Kidney values: need checking with longer use.

Tolerability

Frequency in three trials

Out of 100 participants per group, how many had the event. Each row comes from a different trial with different people.

1 of 100 Placebo
10 of 100 Spironolactone
Event PlaceboSpironolactone
Breast swelling or pain (men, RALES)1 1%10%
Potassium too high (TOPCAT)3 9%19%
Headache (SAFA)4 12%20%

In RALES serious hyperkalaemia was rare in both groups, in PATHWAY-2 potassium rose above 6.0 mmol/l once in 6 of 285. In TOPCAT creatinine also rose. In SAFA there were no serious side effects.1342

Storage

Store dry, at room temperature and protected from light. Keep out of reach of children.

Three white tablet bottles on a bright shelf next to a folded light blue towel
Dry, at room temperature and away from light. Symbolic image.

Related

Related compounds

A different path: all in the TPD lexicon.

Spironolactone (Aldactone)
Furosemide (Lasix) Fast water removal, flushes out potassium Torsemide (Torem, Demadex) Loop diuretic, longer acting Bisoprolol (Concor) Comparison in PATHWAY-2 Ramipril (Altace) ACE inhibitor, also raises potassium Losartan (Cozaar) Sartan, also raises potassium Finasteride Different path against androgen action: 5α-reductase inhibitor

FAQ

Common questions about Spironolactone (Aldactone)

Short answers, each backed by the sources below.

How does spironolactone work?

It blocks the mineralocorticoid receptor, where aldosterone acts. The kidney retains less sodium and keeps more potassium. According to ChEMBL it also binds to the androgen receptor, hence the anti-androgen effect. According to ChEMBL it has been approved since 1960.62

What did RALES show?

1,663 people with severe heart failure received spironolactone or placebo on top of standard therapy. After a mean of 24 months 35 instead of 46 percent had died, the risk of death fell by 30 percent. The trial was therefore stopped early.1

Why is it the fourth agent in hypertension?

In PATHWAY-2 people whose blood pressure stayed too high despite three drugs received spironolactone, bisoprolol, doxazosin and placebo one after the other. Spironolactone lowered home blood pressure the most, by 8.7 mmHg more than placebo and about 4 to 4.5 mmHg more than the other two.2

And in heart failure with preserved pumping function?

There it missed the primary goal in TOPCAT: 18.6 versus 20.4 percent cardiac death, cardiac arrest or hospital stay. Only hospital stays for heart failure fell. Potassium that was too high occurred twice as often as on placebo.3

What does spironolactone have to do with acne?

Through the anti-androgen effect. In SAFA 410 women with acne received spironolactone or placebo. After 24 weeks 82 instead of 63 percent reported improvement. Headache was more common (20 versus 12 percent), there were no serious side effects.4

Why is it tricky for men?

Because it also blocks the androgen receptor. In RALES 10 percent of men on spironolactone had breast swelling or breast pain, on placebo 1 percent. Anyone relying on testosterone at the same time works against its effect.16

Why is potassium the hard limit?

Spironolactone keeps potassium in the body. In TOPCAT potassium was too high in 18.7 percent, on placebo in 9.1 percent. In PATHWAY-2 it rose above 6.0 mmol/l once in 6 of 285. ACE inhibitors and sartans raise potassium too, this combination needs bloodwork.32

Glossary

Terms explained briefly

Dotted words in the text open these explanations directly.

Aldosterone
Adrenal hormone that makes the kidney retain sodium and excrete potassium.
Androgen receptor
Receptor that testosterone and DHT bind to. Blocking it weakens the male hormone effect.
Anti-androgen
A substance that slows the effect of male hormones.
Crossover
Trial design in which each person receives all treatments in turn and is compared with themselves.
Diuretic
Water tablet. Potassium-sparing means it does not flush out potassium but retains it.
Ejection fraction
Share of blood the left ventricle ejects per beat. Preserved means from about 45 percent.
Gynecomastia
Growth of breast gland tissue in men.
Heart failure
The heart no longer pumps enough blood for the body's needs.
Hyperkalaemia
Too much potassium in the blood. It can disturb heart rhythm without warning signs.
Mineralocorticoid receptor
Receptor in the cell nucleus where aldosterone acts, mainly in the kidney.
Placebo
Dummy preparation without active substance. Comparing against it shows what is due to the substance itself.
Resistant hypertension
High blood pressure that stays too high despite three blood pressure drugs at full dose.

Evidence

Sources

Show all 6 sourcesHide sources 4 Studies1 Trial registry1 Database checked 26 Oct 2026

Studies

  1. RALES: spironolactone in severe heart failure

    Pitt et al., New England Journal of Medicine, 1999

    DOI 10.1056/NEJM199909023411001 PMID 10471456
    Checked 26 Oct 2026 via doi.org, Crossref, PubMed
  2. PATHWAY-2: fourth agent in resistant hypertension

    Williams et al., The Lancet, 2015

    DOI 10.1016/S0140-6736(15)00257-3 PMID 26414968 NCT02369081
    Checked 26 Oct 2026 via doi.org, Crossref, PubMed
  3. TOPCAT: heart failure with preserved ejection fraction

    Pitt et al., New England Journal of Medicine, 2014

    DOI 10.1056/NEJMoa1313731 PMID 24716680 NCT00094302
    Checked 26 Oct 2026 via doi.org, Crossref, PubMed
  4. SAFA: spironolactone for acne in women

    Santer et al., BMJ, 2023

    DOI 10.1136/bmj-2022-074349 PMID 37192767
    Checked 26 Oct 2026 via doi.org, Crossref, PubMed

Trial registry

  1. Trials on spironolactone on ClinicalTrials.gov

    ClinicalTrials.gov, U.S. National Library of Medicine

    Checked 26 Oct 2026 via ClinicalTrials.gov API v2

Database

  1. Mechanism, measurements and approval in ChEMBL

    ChEMBL, EMBL-EBI (CHEMBL1393)

    Checked 26 Oct 2026 via ChEMBL