Spironolactone

Source: Wikipedia, the free encyclopedia.
Not to be confused with Spirolactone.

Spironolactone
Skeletal formula of spironolactone
Ball-and-stick model of the spironolactone molecule
Clinical data
Pronunciation/ˌspaɪroʊnoʊˈlæktoʊn/ SPY-roh-noh-LAK-tone,[1] /ˌspɪəroʊnoʊˈlæktoʊn/ SPEER-oh-noh-LAK-tone[2]
Trade namesAldactone, others
Other namesSC-9420; NSC-150339; 7α-Acetylthiospirolactone; 7α-Acetylthio-17α-hydroxy-3-oxopregn-4-ene-21-carboxylic acid γ-lactone
AHFS/Drugs.comMonograph
MedlinePlusa682627
License data
Pregnancy
category
Antimineralocorticoid; Steroidal antiandrogen
ATC code
Legal status
Legal status
6β-OH-7α-TMSTooltip 6β-hydroxy-7α-thiomethylspironolactone: 15.0 hrs[11]
Canrenone: 16.5 hours[11]
ExcretionUrine, bile[12]
Identifiers
  • S-[(7R,8R,9S,10R,13S,14S,17R)-10,13-Dimethyl-3,5'-dioxospiro[2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthrene-17,2'-oxolane]-7-yl] ethanethioate
JSmol)
Melting point134 to 135 °C (273 to 275 °F)
  • O=C5O[C@@]4([C@@]3([C@H]([C@@H]2[C@H](SC(=O)C)C/C1=C/C(=O)CC[C@]1(C)[C@H]2CC3)CC4)C)CC5
  • InChI=1S/C24H32O4S/c1-14(25)29-19-13-15-12-16(26)4-8-22(15,2)17-5-9-23(3)18(21(17)19)6-10-24(23)11-7-20(27)28-24/h12,17-19,21H,4-11,13H2,1-3H3/t17-,18-,19+,21+,22-,23-,24+/m0/s1 checkY
  • Key:LXMSZDCAJNLERA-ZHYRCANASA-N checkY
  (verify)
Spironolactone 25 mg

Spironolactone, sold under the brand name Aldactone among others, is a

anti-androgenic, used to treat early puberty in boys, acne and excessive hair growth in women, and as a part of feminizing hormone therapy in trans women.[4][22][23] Spironolactone is taken by mouth.[4]

Common

high blood pressure of pregnancy.[3] It is a steroid that blocks the effects of the hormones aldosterone and testosterone and has some estrogen-like effects.[4][24] Spironolactone belongs to a class of medications known as potassium-sparing diuretics.[4]

Spironolactone was discovered in 1957, and was introduced in 1959.

generic medication.[4] In 2021, it was the 54th most commonly prescribed medication in the United States, with more than 12 million prescriptions.[30][31]

Medical uses

Spironolactone is used primarily to treat

Bartter's syndrome due to its ability to raise potassium levels.[34]

Spironolactone has antiandrogenic activity. For this reason, it is frequently used to treat a variety of

symptoms of hyperandrogenism, such as due to polycystic ovary syndrome.[37]

Heart failure

While

loop diuretics remain first-line for most people with heart failure, spironolactone has shown to reduce both morbidity and mortality in numerous studies and remains an important agent for treating fluid retention, edema, and symptoms of heart failure. Current recommendations from the American Heart Association are to use spironolactone in patients with NYHA Class II-IV heart failure who have a left ventricular ejection fraction of less than 35%.[38]

Spironolactone improves left ventricular diastolic function in patients with heart failure with preserved ejection fraction, however it has no effect on mortality and hospitalization.[39][40]

Due to its antiandrogenic properties, spironolactone can cause effects associated with low androgen levels and hypogonadism in males. For this reason, men are typically not prescribed spironolactone for any longer than a short period of time, e.g., for an acute exacerbation of heart failure. A newer medication, eplerenone, has been approved by the U.S. Food and Drug Administration for the treatment of heart failure, and lacks the antiandrogenic effects of spironolactone. As such, it is far more suitable for men for whom long-term medication is being chosen. However, eplerenone may not be as effective as spironolactone or the related medication canrenone in reducing mortality from heart failure.[41]

The clinical benefits of spironolactone as a diuretic are typically not seen until 2–3 days after dosing begins. Likewise, the maximal antihypertensive effect may not be seen for 2–3 weeks.[medical citation needed]

Unlike with some other diuretics, potassium supplementation should not be administered while taking spironolactone, as this may cause dangerous elevations in serum potassium levels resulting in hyperkalemia and potentially deadly abnormal heart rhythms.[medical citation needed]

High blood pressure

About 1 in 100 people with hypertension have elevated levels of aldosterone; in these people, the antihypertensive effect of spironolactone may exceed that of complex combined regimens of other antihypertensives since it targets the primary cause of the elevated blood pressure. However, a

Cochrane review found adverse effects at high doses and little effect on blood pressure at low doses in the majority of people with high blood pressure.[42] There is no evidence of person-oriented outcome at any dose in this group.[42]

High aldosterone levels

Spironolactone is used in the treatment of

teratogenicity in male fetuses.[44][45][46][47]

Skin and hair conditions

Androgens like testosterone and DHT play a critical role in the

5α-reductase being an enzyme that greatly potentiates the androgenic effects of testosterone in the skin, have little to no acne, scanty facial hair, reduced body hair, and reportedly no incidence of male-pattern hair loss.[52][53][54][55][56] Conversely, hyperandrogenism in women, for instance due to polycystic ovary syndrome (PCOS) or congenital adrenal hyperplasia (CAH), is commonly associated with acne and hirsutism as well as virilization (masculinization) in general.[48] In accordance with the preceding, antiandrogens are highly effective in the treatment of the aforementioned androgen-dependent skin and hair conditions.[57][58]

Because of the antiandrogenic activity of spironolactone, it can be quite effective in treating acne in women.

female-pattern hair loss (pattern scalp hair loss in women).[65] There is tentative low quality evidence supporting its use for this indication.[66] Although apparently effective, not all cases of female-pattern hair loss are dependent on androgens.[67]

Antiandrogens like spironolactone are male-specific

progestin, are typically used for this purpose.[57] Moreover, oral contraceptives themselves are functional antiandrogens and are independently effective in the treatment of androgen-dependent skin and hair conditions, and hence can significantly augment the effectiveness of antiandrogens in the treatment of such conditions.[57][70]

Spironolactone is not generally used in men for the treatment of androgen-dependent dermatological conditions because of its feminizing side effects, but it is effective for such indications in men similarly.[65] As an example, spironolactone has been reported to reduce symptoms of acne in males.[71] An additional example is the usefulness of spironolactone as an antiandrogen in transgender women.[72][73][74]

Topical spironolactone has been found to be effective in the treatment of acne as well.[75] As a result, topical pharmaceutical formulations containing 2% or 5% spironolactone cream became available in Italy for the treatment of acne and hirsutism in the early 1990s.[76][77] The products were discontinued in 2006 when the creams were added to the list of doping substances with a decree of the Ministry of Health that year.[77]

Comparison

Spironolactone, the

safety.[80][81]

The combination of spironolactone with a birth control pill in the treatment of acne appears to have similar effectiveness to a birth control pill alone and the combination of a birth control pill with cyproterone acetate, flutamide, or finasteride.

teratogenicity.[82][58]

There is insufficient clinical evidence to compare the effectiveness of spironolactone with other antiandrogens for female-pattern hair loss.

menstrual irregularities.[60]

Transgender hormone therapy

Spironolactone is frequently used

spontaneous erections.[74]

Forms

Spironolactone is available in the form of

parenteral use is the related medication potassium canrenoate.[102]

Contraindications

severe and end-stage kidney disease (due to high hyperkalemia risk, except possibly in those on dialysis), Addison's disease (adrenal insufficiency and low aldosterone levels), and concomitant use of eplerenone.[8][103] It should also be used with caution in people with certain neurological disorders
, as well as those who experience or have experienced anuria (lack of urine production), acute kidney injury, or significant impairment of kidney excretory function with risk of hyperkalemia.[8]

Side effects

One of the most common side effects of spironolactone is

breast tenderness, and breast enlargement.[35][60][107] Aside from these adverse effects, the side effects of spironolactone in women taking high doses are minimal, and it is well tolerated.[60][83][108]

The most important potential side effect of spironolactone is

bleeding from the stomach and duodenum,[8] though a causal relationship between the two has not been established.[111][112] Also, spironolactone is immunosuppressive in the treatment of sarcoidosis.[113]

Most of the side effects of spironolactone are dose-dependent.[59] Low-dose spironolactone is generally very well tolerated.[59] Even higher doses of spironolactone, such as 100 mg/day, are well tolerated in most individuals.[59] Dose-dependent side effects of spironolactone include menstrual irregularities, breast tenderness and enlargement, orthostatic hypotension, and hyperkalemia.[59] The side effects of spironolactone are usually mild and rarely result in discontinuation.[59]

Side effects of spironolactone in clinical studies for acne in women
Side effect
RCTsTooltip Randomized controlled trials (n (ITT
Tooltip Intention-to-treat analysis) = 326)		 Case series (n (ITTTooltip Intention-to-treat analysis) = 663)
Number % Number %
Menstrual irregularities
 38 13.4 (of 283) 216 33.4 (of 646)
Breast tenderness
 8 2.5 30 4.5
Breast enlargement 7 2.1 13 2.0
Dizziness/vertigo/lightheadedness 11 3.4 ≥19a ≥2.9
Headache 5 1.5 ≥10a ≥1.5
Nausea and/or vomiting 6 1.8 24 3.6
Weight gainb 5 1.5 1 0.2
Abdominal pain 0 0 ≥11a ≥1.7
Polyuria 2 0.6 8 1.2
Fatigue/lethargy 1 0.3 ≥12a ≥1.8
Footnotes: a = Precise values unavailable due to inadequate reporting. b = Not monitored in most studies. Description:
quality of evidence
was low to very low. Sources: See template.

High potassium levels

Spironolactone can cause hyperkalemia, or high blood potassium levels.

renal impairment (e.g., due to chronic kidney disease or diabetic nephropathy), in people taking certain other medications (including ACE inhibitors, angiotensin II receptor blockers, nonsteroidal anti-inflammatory drugs, the antibiotic trimethoprim, and potassium supplements), and at higher dosages of spironolactone.[106][32][118][119]

Although spironolactone poses an important risk of hyperkalemia in the elderly, in those with kidney or cardiovascular disease, and/or in those taking medications or supplements which increase circulating potassium levels, a large retrospective study found that the rate of hyperkalemia in young women without such characteristics who had been treated with high doses of spironolactone for dermatological conditions did not differ from that of controls.[60][62][120] This was the conclusion of a 2017 hybrid systematic review of studies of spironolactone for acne in women as well, which found that hyperkalemia was rare and was invariably mild and clinically insignificant.[60] These findings suggest that hyperkalemia may not be a significant risk in such individuals, and that routine monitoring of circulating potassium levels may be unnecessary in this population.[60][62][120] However, other sources have claimed that hyperkalemia can nonetheless also occur in people with more normal renal function and presumably without such risk factors.[32] Occasional testing on a case-by-case basis in those with known risk factors may be justified.[60] Side effects of spironolactone which may be indicative of hyperkalemia and if persistent could justify serum potassium testing include nausea, fatigue, and particularly muscle weakness.[60] Notably, non-use of routine potassium monitoring with spironolactone in young women would reduce costs associated with its use.[60]

Among young gender-diverse individuals taking spironolactone, hyperkalemia is rare and (if present) transient and asymptomatic. Larger doses do not appear to increase risks in this population.[121] A broader retrospective study found that the rate of hyperkalemia in gender-diverse individuals is correlated with age, with those above 45 years old being more at risk. The finding suggests that patients below or at 45 years old without other conditions that affect potassium handling can be spared from routine monitoring.[122]

Breast changes

Spironolactone frequently causes

breast pain and breast enlargement in women.[123][124] This is "probably because of estrogenic effects on target tissue."[106] At low doses, breast tenderness has been reported in only 5% of women, but at high doses, it has been reported in up to 40% of women.[125][59] Breast enlargement and tenderness may occur in 26% of women at high doses.[83] Some women regard spironolactone-induced breast enlargement as a positive effect.[60]

Spironolactone also commonly and dose-dependently produces gynecomastia (breast development) as a side effect in men.[105][124][126][127] At low doses, the rate is only 5 to 10%,[127] but at high doses, up to or exceeding 50% of men may develop gynecomastia.[105][124][126] In the RALES, 9.1% of men taking 25 mg/day spironolactone developed gynecomastia, compared to 1.3% of controls.[128] Conversely, in studies of healthy men given high-dose spironolactone, gynecomastia occurred in 3 of 10 (30%) at 100 mg/day, in 5 of 8 (62.5%) at 200 mg/day, and in 6 of 9 (66.7%) at 400 mg/day, relative to none of 12 controls.[129][130] The severity of gynecomastia with spironolactone varies considerably, but is usually mild.[105] As with breast enlargement caused by spironolactone in women, gynecomastia due to spironolactone in men is often although inconsistently accompanied by breast tenderness.[105] In the RALES, only 1.7% of men developed breast pain, relative to 0.1% of controls.[128]

The time to onset of spironolactone-induced gynecomastia has been found to be 27 ± 20 months at low doses and 9 ± 12 months at high doses.

hyalinization and fibrosis of the tissue occurs and drug-induced gynecomastia may become irreversible.[131][132]

Menstrual disturbances

Spironolactone at higher doses can cause

birth control effect.[135]

It has been suggested that the weak progestogenic activity of spironolactone is responsible for these effects, although this has not been established and spironolactone has been shown to possess insignificant progestogenic and antiprogestogenic activity even at high dosages in women.

progestin component.[83][139]

Mood changes

Research is mixed on whether antimineralocorticoids like spironolactone have positive or negative effects on mood.[140][141][142] In any case, it is possible that spironolactone might have the capacity to increase the risk of depressive symptoms.[140][141][142] However, a 2017 hybrid systematic review found that the incidence of depression in women treated with spironolactone for acne was less than 1%.[60] Likewise, a 10-year observational study found that the incidence of depression in 196 transgender women taking high-dose spironolactone in combination with an estrogen was less than 1%.[143]

Lipid changes

Spironolactone has been found to increase

coronary heart disease.[146] Consequently, it has been said that spironolactone should not be given to women with dyslipidemia (e.g., high cholesterol).[144][145] Unfavorable lipid changes have also been seen with other antiandrogens, like cyproterone acetate[147][148] and bicalutamide.[149][81]

Rare reactions

Aside from hyperkalemia, spironolactone may rarely cause adverse reactions such as

DRESS syndrome, Stevens–Johnson syndrome or toxic epidermal necrolysis.[152][153] Five cases of breast cancer in patients who took spironolactone for prolonged periods of time have been reported.[106][127]

Spironolactone bodies

Micrograph (H&E stain) of an adrenal gland showing spironolactone bodies.

Long-term administration of spironolactone gives the

hematoxylin and eosin.[154]

Pregnancy and breastfeeding

In the United States, spironolactone is considered

nursing.[8] However, only very small amounts of spironolactone and its metabolite canrenone enter breast milk, and the amount received by an infant during breastfeeding (<0.5% of the mother's dose) is considered to be insignificant.[155]

A study found that spironolactone was not associated with

teratogenicity in the offspring of rats.[156][157][158] Because it is an antiandrogen, however, spironolactone could theoretically have the potential to cause feminization of male fetuses at sufficient doses.[156][157] In accordance, a subsequent study found that partial feminization of the genitalia occurred in the male offspring of rats that received doses of spironolactone that were five times higher than those normally used in humans (200 mg/kg per day).[156][158] Another study found permanent, dose-related reproductive tract abnormalities rat offspring of both sexes at lower doses (50 to 100 mg/kg per day).[158]

In practice however, although experience is limited, spironolactone has never been reported to cause observable feminization or any other congenital defects in humans.

Bartter's syndrome, and none of the infants (three boys, two girls) showed toxicity, including feminization in the male infants.[155][156] There are similar findings, albeit also limited, for another antiandrogen, cyproterone acetate (prominent genital defects in male rats, but no human abnormalities (including feminization of male fetuses) at both a low dose of 2 mg/day or high doses of 50 to 100 mg/day).[160] In any case, spironolactone is nonetheless not recommended during pregnancy due to theoretical concerns relating to feminization of males and also to potential alteration of fetal potassium levels.[156][161]

A 2019 systematic review found insufficient evidence that spironolactone causes birth defects in humans.[162] However, there was also insufficient evidence to be certain that it does not.[162]

Overdose

Spironolactone is relatively safe in acute

adverse reactions are unlikely in the event of an acute overdose.[8] Hyperkalemia can occur following an overdose of spironolactone, and this is especially so in people with decreased kidney function.[8] Spironolactone has been studied at extremely high oral doses of up to 2,400 mg per day in clinical trials.[102][163] Its oral median lethal dose (LD50) is more than 1,000 mg/kg in mice, rats, and rabbits.[8]

There is no specific

vital functions.[8] Spironolactone should be discontinued in people with impaired kidney function or hyperkalemia.[8]

Interactions

Spironolactone often increases serum potassium levels and can cause hyperkalemia, a very serious condition. Therefore, it is recommended that people using this medication avoid potassium supplements and salt substitutes containing potassium.[164] Physicians must be careful to monitor potassium levels in both males and females who are taking spironolactone as a diuretic, especially during the first twelve months of use and whenever the dosage is increased. Doctors may also recommend that some patients may be advised to limit dietary consumption of potassium-rich foods. However, recent data suggests that both potassium monitoring and dietary restriction of potassium intake is unnecessary in healthy young women taking spironolactone for acne[120] and in healthy young gender-diverse individuals taking spironolactone for hormone therapy.[122] Spironolactone together with trimethoprim/sulfamethoxazole increases the likelihood of hyperkalemia, especially in the elderly. The trimethoprim portion acts to prevent potassium excretion in the distal tubule of the nephron.[165]

Spironolactone has been reported to induce the

cardiac and blood pressure medications, for instance digoxin.[8]

Licorice, which has indirect mineralocorticoid activity by inhibiting mineralocorticoid metabolism, has been found to inhibit the antimineralocorticoid effects of spironolactone.[171][172][173] Moreover, the addition of licorice to spironolactone has been found to reduce the antimineralocorticoid side effects of spironolactone in women treated with it for hyperandrogenism, and licorice hence may be used to reduce these side effects in women treated with spironolactone as an antiandrogen who are bothered by them.[171][172] On the opposite end of the spectrum, spironolactone is useful in reversing licorice-induced hypokalemia.[174][175] Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have been found to attenuate the diuresis and natriuresis induced by spironolactone, but, not to affect its antihypertensive effect.[34][176]

Some research has suggested that spironolactone might be able to interfere with the effectiveness of antidepressant treatment. As the medication acts as an antimineralocorticoid, it is thought that it might be able to reduce the effectiveness of certain antidepressants by interfering with normalization of the hypothalamic–pituitary–adrenal axis and by increasing levels of glucocorticoids such as cortisol.[177][178] However, other research contradicts this hypothesis and has suggested that spironolactone might actually produce antidepressant effects, for instance studies showing antidepressant-like effects of spironolactone in animals.[179]

Pharmacology

Pharmacodynamics

Main article: Pharmacodynamics of spironolactone
7α-Thiomethylspironolactone, the major active form of spironolactone. It accounts for about 80% of the potassium-sparing effect of spironolactone.[11][180][181]
Canrenone, the second major active form of spironolactone. It accounts for around 10 to 25% of the potassium-sparing effect of spironolactone.[182]

The

7α-thiomethylspironolactone (7α-TMS) and canrenone (7α-desthioacetyl-δ6-spironolactone).[11][102]

Spironolactone is a

kidney function, and its risk of hyperkalemia.[185] Due to the antimineralocorticoid activity of spironolactone, levels of aldosterone are significantly increased by the medication, probably reflecting an attempt of the body to maintain homeostasis.[57][83]

Spironolactone is a moderate antiandrogen.

demasculinization in men.[105][186] Blockade of androgen signaling in the breast disinhibits the actions of estrogens in this tissue.[187] Although useful as an antiandrogen in women, who have low testosterone levels compared to men,[188][189] spironolactone is described as having relatively weak antiandrogenic activity.[190][186][191][192]

Spironolactone is a weak steroidogenesis inhibitor.

21-hydroxylase, and aldosterone synthase (18-hydroxylase).[136][193][194][195] However, although very high doses of spironolactone can considerably decrease steroid hormone levels in animals, spironolactone has shown mixed and inconsistent effects on steroid hormone levels in clinical studies, even at high clinical doses.[60][104][129][136][167] In any case, the levels of most steroid hormones, including testosterone and cortisol, are usually unchanged by spironolactone in humans, which may in part be related to compensatory upregulation of their synthesis.[104][129][196] The weak steroidogenesis inhibition of spironolactone might contribute to its antiandrogenic efficacy to some degree and may explain its side effect of menstrual irregularities in women.[104][105] However, its androgen synthesis inhibition is probably clinically insignificant.[63]

Spironolactone has been found in some studies to increase levels of

17β-hydroxysteroid dehydrogenase 2, an enzyme that is involved in the conversion of estradiol into estrone.[199][200] Increased levels of estradiol with spironolactone may be involved in its preservation of bone density and in its side effects such as breast tenderness, breast enlargement, and gynecomastia in women and men.[197][201][202]

In response to the antimineralocorticoid activity spironolactone, and in an attempt to maintain homeostasis, the body increases aldosterone production in the adrenal cortex.[203][204][205] Some studies have found that levels of cortisol, a glucocorticoid hormone that is also produced in the adrenal cortex, are increased as well.[204][205][206] However, other clinical studies have found no change in cortisol levels with spironolactone,[136][207][94][208] and those that have found increases often have observed only small changes.[209] In accordance, spironolactone has not been associated with conventional glucocorticoid medication effects or side effects.[210][211]

Other activities of spironolactone may include very weak interactions with the

menstrual irregularities and breast side effects of spironolactone and to its drug interactions, respectively.[213][214][215]

Pharmacokinetics

The pharmacokinetics of spironolactone have not been studied well, which is in part because it is an old medication that was developed in the 1950s.[130] Nonetheless, much has been elucidated about the pharmacokinetics of spironolactone over the decades.[216][217][218][11][219][220][221][222]

Absorption

Levels of spironolactone and its major active metabolites after a single oral dose of 100 mg spironolactone in humans.[223]

The

first-pass metabolism.[224][227][228] The relationship between a single dose of spironolactone and plasma levels of canrenone, a major active metabolite of spironolactone, has been found to be linear across a dose range of 25 to 200 mg spironolactone.[190] Steady-state concentrations of spironolactone are achieved within 8 to 10 days of treatment initiation.[181][229]

Little or no systemic

absorption has been observed with topical spironolactone.[230]

Distribution

Spironolactone and its metabolite canrenone are highly

carrier proteins.[233] This is in contradiction with widespread statements that spironolactone increases free estradiol levels by displacing estradiol from SHBG.[94][234]

Spironolactone appears to cross the blood–brain barrier.[235][236]

Metabolism

conjugated (e.g., glucuronidated).[237]

Spironolactone is rapidly and extensively

7α-thiospironolactone (7α-TS), which is an important intermediate to the major metabolites of spironolactone,[17] as well as the 7α-methyl ethyl ester of spironolactone and the 6β-hydroxy-7α-methyl ethyl ester of spironolactone.[15]

Spironolactone is

dethioacetylated into canrenone.[20] Finally, the C17 γ-lactone ring of spironolactone is hydrolyzed by the paraoxonase PON3.[21][242] It was originally thought to be hydrolyzed by PON1, but this was due to contamination with PON3.[21]

Pharmacokinetics of 100 mg/day spironolactone and its metabolites
Compound
Cmax
Tooltip Peak concentrations (day 1)
Cmax
Tooltip Peak concentrations (day 15)
AUC
Tooltip Area-under-the-curve concentrations (day 15)
t1/2
Tooltip Elimination half-life
Spironolactone 72 ng/mL (173 nmol/L) 80 ng/mL (192 nmol/L) 231 ng•hour/mL (555 nmol•hour/L) 1.4 hours
Canrenone 155 ng/mL (455 nmol/L) 181 ng/mL (532 nmol/L) 2,173 ng•hour/mL (6,382 nmol•hour/L) 16.5 hours
7α-TMSTooltip 7α-Thiomethylspironolactone 359 ng/mL (924 nmol/L) 391 ng/mL (1,006 nmol/L) 2,804 ng•hour/mL (7,216 nmol•hour/L) 13.8 hours
6β-OH-7α-TMSTooltip 6β-Hydroxy-7α-thiomethylspironolactone 101 ng/mL (250 nmol/L) 125 ng/mL (309 nmol/L) 1,727 ng•hour/mL (4,269 nmol•hour/L) 15.0 hours
Sources: See template.

Elimination

The majority of spironolactone is eliminated by the kidneys, while minimal amounts are handled by biliary excretion.[243]

Chemistry

See also: Spirolactone and List of steroidal antiandrogens § Spirolactone derivatives

Spironolactone, also known as 7α-acetylthiospirolactone, is a

7α-thioprogesterone (SC-8365), unlike progesterone,[250] is an antiandrogen with similar affinity to the AR as that of spironolactone.[251] In addition, the C7α substitution appears to be responsible for the loss of progestogenic activity and good oral bioavailability of spironolactone, as SC-5233, the analogue of spironolactone without a C7α substitution, has potent progestogenic activity but very poor oral bioavailability similarly to progesterone.[250][252][253]

Names

Spironolactone is also known by the following equivalent chemical names:[245][246][247]

  • 7α-Acetylthio-17α-hydroxy-3-oxopregn-4-ene-21-carboxylic acid γ-lactone
  • 7α-Acetylthio-3-oxo-17α-pregn-4-ene-21,17β-carbolactone
  • 3-(3-Oxo-7α-acetylthio-17β-hydroxyandrost-4-en-17α-yl)propionic acid lactone
  • 7α-Acetylthio-17α-(2-carboxyethyl)androst-4-en-17β-ol-3-one γ-lactone
  • 7α-Acetylthio-17α-(2-carboxyethyl)testosterone γ-lactone

Analogues

Chemical structures of spirolactones
The image above contains clickable links
Chemical structures of progesterone and spirolactones (steroid-17α-spirolactones).

Spironolactone is closely related structurally to other clinically used spirolactones such as canrenone, potassium canrenoate, drospirenone, and eplerenone, as well as to the never-marketed spirolactones SC-5233 (6,7-dihydrocanrenone; 7α-desthioacetylspironolactone), SC-8109 (19-nor-6,7-dihydrocanrenone), spiroxasone, prorenone (SC-23133), mexrenone (SC-25152, ZK-32055), dicirenone (SC-26304), spirorenone (ZK-35973), and mespirenone (ZK-94679).[102]

Synthesis

derivatives have been described and reviewed.[254]

History

The

synthetic antimineralocorticoid analogue of progesterone shortly followed this.[128][244][255][256] Spironolactone was first synthesized in 1957,[25][255][256] was patented between 1958 and 1961,[257][258] and was first marketed, as an antimineralocorticoid, in 1959.[259][260] Gynecomastia was first reported with spironolactone in 1962,[102][261] and the antiandrogenic activity of the medication was first described in 1969.[262] This shortly followed the discovery in 1967 that gynecomastia is an important and major side effect of AR antagonists.[263][264] Spironolactone was first studied in the treatment of hirsutism in women in 1978.[265][171][266][267][268] It has since become the most widely used antiandrogen for dermatological indications in women in the United States.[98][269][270][271] Spironolactone was first studied as an antiandrogen in transgender women in 1986, and has since become widely adopted for this purpose as well, particularly in the United States where cyproterone acetate is not available.[272][273][274]

Early oral spironolactone tablets showed poor absorption.[275] The formulation was eventually changed to a micronized formulation with particle sizes of less than 50 μg, which resulted in approximately 4-fold increased potency.[275][276]

Society and culture

Generic names

The English,

Latin, spironolacton in German, espironolactona in Spanish and Portuguese, and spironolattone in Italian (which is also its DCITTooltip Denominazione Comune Italiana).[100][101][277]

Spironolactone is also known by its developmental code names SC-9420 and NSC-150339.[100][101][245]

Brand names

Spironolactone is marketed under a large number of brand names throughout the world.[100][101] The major brand name of spironolactone is Aldactone.[100][101] Other important brand names include Aldactone-A, Berlactone, CaroSpir, Espironolactona, Espironolactona Genfar, Novo-Spiroton, Prilactone (veterinary), Spiractin, Spiridon, Spirix, Spiroctan, Spiroderm (discontinued),[5] Spirogamma, Spirohexal, Spirolon, Spirolone, Spiron, Spironolactone Actavis, Spironolactone Orion, Spironolactone Teva, Spirotone, Tempora (veterinary), Uractone, Uractonum, Verospiron, and Vivitar.[100][101]

Spironolactone is also formulated in combination with a variety of other medications, including with hydrochlorothiazide as Aldactazide, with hydroflumethiazide as Aldactide, Lasilacton, Lasilactone, and Spiromide, with altizide as Aldactacine and Aldactazine, with furosemide as Fruselac, with benazepril as Cardalis (veterinary), with metolazone as Metolactone, with bendroflumethiazide as Sali-Aldopur, and with torasemide as Dytor Plus, Torlactone, and Zator Plus.[101]

Availability

Spironolactone is marketed throughout the world.[100][101]

Research

Prostate conditions

Spironolactone has been studied at a high dosage in the treatment of benign prostatic hyperplasia (BPH; enlarged prostate).[278][279][280] It was found to be better than placebo in terms of symptom relief following three months of treatment.[278][279] However, this was not maintained after six months of treatment, by which point the improvements had largely disappeared.[278][279][280] Moreover, no difference was observed between spironolactone and placebo with regard to volume of residual urine or prostate size.[278][279] Gynecomastia was observed in about 5% of people.[279] On the basis of these results, it has been said that spironolactone has no place in the treatment of BPH.[279]

Spironolactone has been studied and used limitedly in the treatment of prostate cancer.[281][282][34]

Epstein–Barr virus

Spironolactone has been found to block

antiviral medications with a distinct mechanism of action and limited toxicity.[283]

Other conditions

Spironolactone has been studied in the treatment of rosacea in both males and females.[284][285][286][71][287]

Spironolactone has been studied in fibromyalgia in women.[288][289] It has also been studied in bulimia nervosa in women, but was not found to be effective.[290]

References

  1. ISBN 978-0-7432-8667-1. Archived
    from the original on 7 October 2022. Retrieved 6 November 2016.
  2. ISBN 978-1-4511-1314-3. Archived
    from the original on 7 October 2022. Retrieved 6 November 2016.
  3. ^ a b c "Spironolactone Pregnancy and Breastfeeding Warnings". Archived from the original on 2 December 2015. Retrieved 29 November 2015.
  4. ^ a b c d e f g h i j "Spironolactone". The American Society of Health-System Pharmacists. Archived from the original on 16 November 2015. Retrieved 24 October 2015.
  5. ^
    ISBN 978-0-387-09718-3. Archived
    from the original on 7 October 2022. Retrieved 6 November 2016.
  6. FDA
    . Retrieved 22 October 2023.
  7. ^ "Aldactone 25 mg Film-Coated TabletsSummary of Product Characteristics (SmPC)". (emc). 3 February 2022. Archived from the original on 6 October 2022. Retrieved 2 August 2023.
  8. ^ a b c d e f g h i j k l m n o p q r s "Aldactone- spironolactone tablet, film coated". DailyMed. 29 November 2018. Archived from the original on 10 September 2015. Retrieved 1 January 2020.
  9. ^ "Qaialdo EPAR". European Medicines Agency (EMA). 25 July 2023. Archived from the original on 27 July 2023. Retrieved 2 August 2023.
  10. ^ "Qaialdo". Union Register of medicinal products. 31 May 2023. Archived from the original on 6 June 2023. Retrieved 6 June 2023.
  11. ^
    S2CID 21437788
    .
  12. ^
    PMID 18729003
    .
  13. ^
    PMID 28024992
    .
  14. ^
    S2CID 13227538
    .
  15. ^
    ISBN 978-0-8493-4724-5
    .
  16. ISBN 978-0-19-957772-9. Archived
    from the original on 27 March 2017.
  17. ^ a b c d e f g Parkinson A (2001). Biotransformation of Xenobiotics. McGraw-Hill. pp. 137–138, 169, 171, 180, 195, 208. Archived from the original on 7 October 2022. Retrieved 12 August 2018.
  18. ^
    ISBN 978-0-07-159351-9. Archived
    from the original on 7 October 2022. Retrieved 12 August 2018. Some P450 enzymes (such as the rate enzyme CYP2A1) preferentially catalyze the 6α-hydroxylation reaction, whereas other P450 enzymes (such as the CYP3A enzymes in all mammalian species) preferentially catalyze the 6β-hydroxylation reaction (which is a major route of hepatic steroid biotransformation).
  19. ^
    PMID 7895608
    .
  20. ^
    ISBN 978-1-4377-1078-6. Archived
    from the original on 7 October 2022. Retrieved 12 August 2018.
  21. ^
    S2CID 15825605
    .
  22. PMID 27141564
    .
  23. ISBN 978-0-19-021480-7
    .
  24. ISBN 978-93-5090-723-8. Archived
    from the original on 7 October 2022. Retrieved 5 July 2017.
  25. ^
    ISBN 978-3-527-62330-3. Archived
    from the original on 21 June 2013. Retrieved 28 May 2012.
  26. ISBN 978-0-12-374194-3. Archived
    from the original on 21 June 2013. Retrieved 27 May 2012.
  27. ISBN 978-0-8155-1144-1. Archived
    from the original on 20 June 2013. Retrieved 27 May 2012.
  28. hdl:10665/325771
    . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  29. hdl:10665/345533
    . WHO/MHP/HPS/EML/2021.02.
  30. ^ "The Top 300 of 2021". ClinCalc. Archived from the original on 15 January 2024. Retrieved 14 January 2024.
  31. ^ "Spironolactone - Drug Usage Statistics". ClinCalc. Retrieved 14 January 2024.
  32. ^
    ISBN 978-0-323-51199-5. Archived
    from the original on 7 October 2022. Retrieved 17 August 2018.
  33. PMID 10760075
    . When spironolactone was developed nearly 30 years ago, the scientific study of aldosterone was limited to effects on epithelial ion transport, and even this knowledge was in its infancy. As a result, spironolactone was classified as a potassium-sparing diuretic. Given that the compelling evidence of the role of aldosterone in the pathophysiology of cardiovascular disease extends beyond ion transport, this classification is presently obsolete.
  34. ^
    ISSN 0171-2004
    .
  35. ^
    S2CID 208286107
    .
  36. ISBN 978-90-8686-728-8. Archived
    from the original on 7 October 2022. Retrieved 6 October 2016.
  37. PMID 3143568
    .
  38. PMID 23747642
    .
  39. PMID 30170387
    .
  40. PMID 30603649
    .
  41. PMID 22840667
    .
  42. ^
    PMID 20687095
    .
  43. ^
    S2CID 73727928
    .
  44. S2CID 248574316
    .
  45. PMID 27156905
    .
  46. S2CID 43338556
    .
  47. S2CID 225657804
    .
  48. ^
    S2CID 34863608
    .
  49. ^
    PMID 28979664
    .
  50. ISBN 978-1-61631-009-7. Archived
    from the original on 9 December 2016.
  51. ISBN 978-3-540-69375-8. Archived
    from the original on 10 December 2016.
  52. PMID 16985920
    .
  53. ISBN 978-0-7668-1142-3. Archived
    from the original on 7 October 2022. Retrieved 5 July 2017.
  54. ISBN 978-0-323-24466-4. Archived
    from the original on 7 October 2022. Retrieved 5 July 2017.
  55. ISBN 978-1-84788-339-1. Archived
    from the original on 7 October 2022. Retrieved 5 July 2017.
  56. ISBN 978-3-540-46911-7. Archived
    from the original on 7 October 2022. Retrieved 16 July 2017.
  57. ^
    S2CID 32242838
    .
  58. ^
    PMID 20082945
    .
  59. ^
    PMID 22468178
    .
  60. ^
    PMID 28155090
    .
  61. S2CID 258717921
    .
  62. ^
    PMID 26897386
    .
  63. ^
    PMID 9238337
    .
  64. ^
    S2CID 45234892
    .
  65. ^
    PMID 21413648
    .
  66. S2CID 20364810
    .
  67. S2CID 205259907
    .
  68. ^
    PMID 9198005
    .
  69. ^
    ISBN 978-1-60805-149-6. Archived
    from the original on 29 May 2016.
  70. ISBN 978-0-7817-2761-7. Archived
    from the original on 6 October 2022. Retrieved 5 July 2017.
  71. ^
    S2CID 22119267
    .
  72. ^ a b The World Professional Association for Transgender Health (WPATH) (2011). "Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People" (PDF). Archived from the original (PDF) on 23 May 2012. Retrieved 27 May 2012.
  73. ^
    PMID 19509099
    .
  74. ^
    S2CID 22802329
    .
  75. PMID 1387779
    .
  76. S2CID 19134415
    .
  77. ^
    ISBN 978-0-387-09717-6
    .
  78. PMID 25918921
    .
  79. S2CID 3783739
    .
  80. S2CID 39120534
    .
  81. ^
    S2CID 3784055
    .
  82. ^
    S2CID 5777817
    .
  83. ^
    PMID 10495361
    .
  84. ISBN 978-0-7216-8258-7. Archived
    from the original on 6 October 2022. Retrieved 2 January 2019.
  85. ISBN 978-1-906985-41-7. Archived
    from the original on 6 October 2022. Retrieved 2 January 2019.
  86. PMID 28379593
    .
  87. PMID 28492054
    .
  88. ISSN 1300-4751
    .
  89. PMID 28274354
    .
  90. PMID 27416311
    .
  91. S2CID 52973096
    .
  92. PMID 27225981
    .
  93. PMID 19370553
    .
  94. ^
    ISBN 978-3-642-74614-7
    .
  95. ISBN 978-3-7692-2114-5. Archived
    from the original on 7 October 2022. Retrieved 29 November 2017.
  96. ISBN 978-1-58528-136-7. Archived
    from the original on 7 October 2022. Retrieved 1 December 2016.
  97. ISBN 978-1-4200-8117-6. Archived
    from the original on 7 October 2022. Retrieved 1 December 2016.
  98. ^
    ISBN 978-1-84076-013-2. Archived
    from the original on 7 October 2022. Retrieved 1 December 2016.
  99. ^ a b "Drugs@FDA: FDA Approved Drug Products". United States Food and Drug Administration. Archived from the original on 16 November 2016. Retrieved 14 August 2018.
  100. ^
    ISBN 978-3-88763-075-1
    .
  101. ^ a b c d e f g h i "Spironolactone". Archived from the original on 2 December 2016. Retrieved 1 December 2016.
  102. ^
    PMID 28634268
    .
  103. ISBN 978-3-319-09162-4. Archived
    from the original on 7 October 2022. Retrieved 17 August 2018.
  104. ^
    PMID 984618
    .
  105. ^
    ISBN 978-0-08-053046-8. Archived
    from the original on 4 July 2014. The incidence of spironolactone in men is dose related. It is estimated that 50% of men treated with ≥150 mg/day of spironolactone will develop gynecomastia. The degree of gynecomastia varies considerably from patient to patient but in most instances causes mild symptoms. Associated breast tenderness is common but an inconsistent feature.
  106. ^
    ISBN 978-0-08-093289-7. Archived
    from the original on 7 October 2022. Retrieved 16 October 2016. Spironolactone causes breast tenderness and enlargement, mastodynia, infertility, cholasma, altered vaginal lubrica- tion, and reduced libido in women, probably because of estrogenic effects on target tissue.
  107. ISBN 978-1-4419-1436-1. Archived
    from the original on 7 October 2022. Retrieved 6 October 2016. A modest improvement in hirsutism can be anticipated in 70-80% of women using even the minimum of 100 mg of spironolactone per day for 6 months [157]. [...] The most common dosage is 100-200 mg per day in a divided dosage. Women treated with 200 mg/day show a greater reduction in hair shaft diameter than women receiving 100 mg/day [159]. [...] Menstrual irregularity (usually metrorrhagia), is the most common side effect of spironolactone and occurs in over 50% of patients with a dosage of 200 mg/day [159]. [...] Patients must be counseled to use contraception while taking spironolactone because it theoretically can feminize a male fetus.
  108. ISBN 978-0-7817-4059-3
    .
  109. PMID 33153631
    .
  110. ^ "Spironolactone". MedlinePlus. U.S. National Library of Medicine. 2019. Archived from the original on 5 July 2016. Retrieved 31 October 2019.
  111. PMID 16840442
    .
  112. PMID 18507655
    .
  113. PMID 607621
    .
  114. ^
    PMID 26404748
    .
  115. PMID 15295047
    .
  116. PMID 22942339
    .
  117. S2CID 14815504
    .
  118. PMID 21911446
    .
  119. PMID 25646289
    .
  120. ^
    PMID 25796182
    .
  121. PMID 31065620
    .
  122. ^
    PMID 36267595
    .
  123. ^
    ISBN 978-0-7817-1750-2. Archived
    from the original on 6 October 2022. Retrieved 6 May 2018. Spironolactone has been used successfully in dosages of 100 to 200 mg daily for the treatment of idiopathic hirsutism and hirsutism associated with polycystic ovarian disease (see Chaps. 96 and 101).184 [...] Spironolactone also is both an antiandrogen and a progestagen, and this explains many of its distressing side effects; decreased libido, mastodynia, and gynecomastia may occur in 50% or more of men, and menometrorrhagia and breast pain may occur in an equally large number of women taking the drug.27
  124. ^
    ISBN 978-3-319-34141-5. Archived
    from the original on 7 October 2022. Retrieved 16 October 2016. Gynecomastia is dose related and reaches almost 50% with high spironolactone doses (>150 mg daily), while it is much less common (5–10%) with low doses (25–50 mg spironolactone daily) [135].
  125. S2CID 34751086
    . Breast tenderness is not uncommon and is recorded in up to 40% of women taking higher doses63.
  126. ^
    ISBN 978-0-444-63391-0
    . It is well known that gynecomastia is a side effect of spironolactone in men and occurs in a dose-dependent manner in ~7% of cases with doses of <50 mg per day, and up to 50% of cases with doses of >150 mg per day [40,41].
  127. ^
    ISBN 978-0-444-51757-9. Archived
    from the original on 7 October 2022. Retrieved 6 October 2016. Spironolactone lacks specificty for mineralocorticoid receptors and binds to both progesterone and dihydrotestosterone receptors. This can lead to various endocrine side effects that can limit the use of spironolactone. In females spironolactone can induce menstrual disturbances, breast enlargement and breast tenderness.78 In men spironolactone can induce gynecomastia and impotence. In RALES gynaecomastia or breast pain was reported by 10% of the men in the spironolactone group and 1% of the men in the placebo group (p<0.001), causing more patients in the spironolactone group than in the placebo group to discontinue treatment, despite a mean spironolactone dose of 26 mg.18
  128. ^
    S2CID 19701784
    . [Spironolactone] was synthesized after the demonstration of the natriuretic effect of progesterone (Landau et al., 1955).
  129. ^
    S2CID 30322620
    .
  130. ^
    ISBN 978-1-4377-1124-0. Archived
    from the original on 7 October 2022. Retrieved 17 August 2018.
  131. S2CID 72716346
    .
  132. PMID 11546925
    .
  133. S2CID 45708497
    .
  134. S2CID 40606594
    .
  135. ISSN 0951-3590
    .
  136. ^
    S2CID 42231952
    .
  137. PMID 2744183
    .
  138. PMID 32038990
    .
  139. ISBN 978-3-540-33101-8. Archived
    from the original on 7 October 2022. Retrieved 15 August 2018.
  140. ^
    S2CID 14297156
    .
  141. ^
    doi:10.17169/refubium-6940. Archived
    from the original on 28 December 2018. Retrieved 27 December 2018. [...] Taken together, there is evidence that the MR influences mood in healthy participants and patients with psychiatric disorders. However, due to the heterogeneous findings, it still remains unclear whether MR stimulation (e.g. fludrocortisone) or rather MR blockage (e.g. spironolactone) leads to better mood.
  142. ^
    PMID 10367986
    .
  143. ISBN 978-1-134-82110-5. Archived
    from the original on 7 October 2022. Retrieved 2 January 2019.
  144. ^
    S2CID 205631980
    .
  145. ^
    PMID 19843067
    .
  146. PMID 30586774
    .
  147. PMID 36238954
    .
  148. PMID 3318361
    .
  149. PMID 33334002
    .
  150. PMID 19006114
    .
  151. S2CID 12160891
    .
  152. ^ "Aldactazide (spironolactone/hydrochlorothiazide) Tablets". Food and Drug Administration. Archived from the original on 10 March 2015. Retrieved 3 March 2014.
  153. ^ online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7699#f_adverse-reactions
  154. PMID 7195152
    .
  155. ^
    ISBN 978-1-118-81959-3. Archived
    from the original on 8 September 2017.
  156. ^
    ISBN 978-0-340-80917-4. Archived
    from the original on 8 September 2017.
  157. ^
    ISBN 978-0-470-69555-5. Archived
    from the original on 8 September 2017.
  158. ^
    ISBN 978-1-60831-708-0. Archived
    from the original on 8 September 2017.
  159. ISBN 978-0-471-16358-9. Archived
    from the original on 8 September 2017.
  160. ^
    ISBN 978-0-444-50763-1. Archived
    from the original on 8 September 2017.
  161. ISBN 978-1-86395-174-6. Archived
    from the original on 8 September 2017.
  162. ^
    S2CID 53022388
    .
  163. S2CID 8499861
    .
  164. ^ "Advisory Statement" (PDF). Klinge Chemicals / LoSalt. Archived from the original (PDF) on 15 November 2006. Retrieved 15 March 2007.
  165. PMID 24156179
    .
  166. ISBN 978-0-19-923664-0. Archived
    from the original on 7 October 2022. Retrieved 6 October 2016.
  167. ^
    PMID 1826112
    .
  168. ISBN 978-1-4377-2070-9. Archived
    from the original on 7 October 2022. Retrieved 7 May 2017.
  169. ^
    PMID 29756046
    .
  170. ISBN 978-0-470-92192-0
    .
  171. ^
    S2CID 19345088
    .
  172. ^
    PMID 17113210
    .
  173. PMID 13991036
    .
  174. PMID 23185686
    .
  175. PMID 12640291
    .
  176. S2CID 2090391
    .
  177. ^ Holsboer, F. The Rationale for Corticotropin-Releasing Hormone Receptor (CRH-R) Antagonists to Treat Depression and Anxiety. J. Psychiatr. Res. 33, 181–214 (1999).
  178. PMID 19909979
    .
  179. S2CID 26986501
    .
  180. ^
    S2CID 8992318
    .
  181. ^
    ISBN 978-92-832-1279-9. Archived
    from the original on 7 October 2022. Retrieved 6 October 2016.
  182. ISBN 978-1-4051-4370-7. Archived
    from the original on 7 October 2022. Retrieved 6 May 2018. The most rational treatment of cirrhotic patients with ascites appears to be the administration of an aldosterone antagonist. A stepwise equential therapy with increasing oral doses of an aldosterone antagonist (up to 400 mg/day) may be effective in mobilizing ascites in 60-80% of non-azotemic cirrhotic patients with ascites who do not respond to bed rest and dietary sodium restriction (11,12,74). The effective dosage of aldosterone antagonists depends on plasma aldosterone levels (75). Patients with moderately increased plasma levels require low doses of those drugs (100-150 mg/day), whereas patients with marked hyperaldosteronism may require as much as 200-400 mg/day. A further increase of the dosage up to 500-600 mg/day is of limited usefulness (11,12).
  183. ISBN 978-1-4051-7253-0. Archived
    from the original on 7 October 2022. Retrieved 13 August 2018.
  184. ^ Walar K (15 June 2015). Pharmacology (6th ed.). Wolter Kluwer Health. pp. 248–249. GGKEY:N57K51AQ0UA.[permanent dead link]
  185. S2CID 2338377
    .
  186. ^
    S2CID 39820875
    .
  187. ISBN 978-1-4557-2758-2. Archived
    from the original on 7 October 2022. Retrieved 13 August 2018.
  188. PMID 2941190
    .
  189. ISBN 978-1-4925-0162-6. Archived
    from the original on 7 October 2022. Retrieved 14 August 2018.
  190. ^
    ISBN 978-1-4557-3801-4. Archived
    from the original on 7 October 2022. Retrieved 6 May 2018. Spironolactone is an aldosterone antagonist and a relatively weak antiandrogen that blocks the AR and inhibits androgen biosynthesis. Spironolactone does not inhibit 5α-reductase. [...] The progestational activity of spironolactone is variable. The drug influences the ratio of luteinizing hormone (LH) to follicle-stimulating hormone (FSH) by reducing the response of LH to GnRH. [...] In a dose range of 25-200 mg a linear relationship between a single dose of spironolactone and plasma levels of canrenone occurs within 96 hours. [...] Common doses [of spironolactone for dermatological indications] range between 50 and 200 mg daily, with 100 mg daily typically being better tolerated than higher dosages.20
  191. ISBN 978-1-85070-322-8. Archived
    from the original on 7 October 2022. Retrieved 6 October 2016.
  192. S2CID 39334280
    .
  193. ^
    PMID 6786868
    .
  194. S2CID 43770017
    .
  195. PMID 18819053
    .
  196. ISBN 978-0-323-07575-6
    .
  197. ^
    S2CID 9972497
    .
  198. PMID 907238
    .
  199. PMID 12570693
    .
  200. PMID 19601747
    .
  201. PMID 24189467
    .
  202. PMID 26230882
    .
  203. ISBN 978-0-323-32612-4. Archived
    from the original on 7 October 2022. Retrieved 13 August 2018.
  204. ^
    S2CID 34916537
    .
  205. ^
    S2CID 10624783
    .
  206. S2CID 4775178
    .
  207. ISBN 978-0-323-03309-1. Archived
    from the original on 7 October 2022. Retrieved 13 August 2018.
  208. S2CID 30885047
    .
  209. PMID 21095280
    .
  210. ISBN 978-3-540-76839-5. Archived
    from the original on 7 October 2022. Retrieved 13 August 2018.
  211. ISBN 978-1-4377-3600-7
    .
  212. PMID 12372848
    .
  213. S2CID 34201900
    .
  214. PMID 10760075
    .
  215. PMID 9727070
    .
  216. PMID 363379
    .
  217. PMID 6369882
    .
  218. S2CID 29482256
    .
  219. PMID 22099505
    .
  220. S2CID 36894459
    .
  221. PMID 26939027
    .
  222. PMID 27830348
    .
  223. PMID 8818057
    .
  224. ^
    PMID 26213109
    .
  225. S2CID 32313529
    .
  226. S2CID 12827850
    .
  227. PMID 19442083
    .
  228. ISSN 1075-6280
    .
  229. ^
    ISBN 978-0-12-817783-9. Archived
    from the original on 7 October 2022. Retrieved 20 September 2019. In addition to spironolactone, which is a derivative of progesterone [...]
  230. S2CID 30535049
    .
  231. PMID 86546
    .
  232. PMID 7195405
    .
  233. PMID 7189544
    .
  234. ISBN 978-1-4377-1121-9. Archived
    from the original on 7 October 2022. Retrieved 14 September 2017.
  235. S2CID 19905165
    .
  236. S2CID 23273751
    .
  237. ^
    PMID 1629288
    .
  238. ISBN 978-0-19-262922-7. Archived
    from the original on 7 October 2022. Retrieved 6 October 2016.
  239. ISBN 978-3-527-64632-6. Archived
    from the original on 7 October 2022. Retrieved 12 August 2018.
  240. ISBN 978-1-4496-8940-7. Archived
    from the original on 7 October 2022. Retrieved 6 October 2016.
  241. ISBN 978-3-319-12108-6. Archived
    from the original on 7 October 2022. Retrieved 12 August 2018. CYP3A4 catalyzes 6β-hydroxylation of progesterone, cortisol, and testosterone; this reaction accounts for a considerable amount of hormone inactivation, particularly when it is orally administered.
  242. ISBN 978-0-12-405852-1
    .
  243. ISBN 978-0-12-260829-2. Archived
    from the original on 21 June 2013. Retrieved 27 May 2012.
  244. ^
    ISBN 978-1-4557-1126-0
    . [Spironolactone] is a potent antimineralocorticoid which was developed as a progestational analog [...]
  245. ^
    ISBN 978-1-4757-2085-3. Archived
    from the original on 15 February 2017.
  246. ^ a b "Spironolactone". Archived from the original on 30 June 2016. Retrieved 4 July 2017.
  247. ^ a b "Spironolactone | C24H32O4S". ChemSpider. Royal Society of Chemistry. Archived from the original on 9 September 2017. Retrieved 4 July 2017.
  248. PMID 8616985
    .
  249. PMID 16101407
    .
  250. ^
    S2CID 24616324
    .
  251. PMID 263288
    .
  252. S2CID 20150966
    .
  253. ^ The British Encyclopaedia of Medical Practice: Medical progress. Butterworth & Company. 1961. p. 302. Archived from the original on 7 October 2022. Retrieved 2 February 2018. Cena and Kagawa first synthesized 3-(3-oxo-17β-hydroxy-4-androsten-17α-yl)-propionic acid-gamma-lactone and later prepared its 19-nor analogue. These compounds were designated SC-5233 and SC-8109, respectively. Both have anti-aldosterone activity and most of the early work on aldosterone antagonism was done with their aid. SC-5233 is not appreciably absorbed when given by mouth and the parenteral dose is large.
  254. S2CID 7003499
    .
  255. ^
    PMID 13486053
    .
  256. ^
    PMID 13486054
    .
  257. ISBN 978-3-13-179275-4. Archived
    from the original on 7 October 2022. Retrieved 27 December 2016.
  258. ISBN 978-0-941901-21-5. Archived
    from the original on 7 October 2022. Retrieved 27 December 2016. Spironolactone was patented in 1961 and has been used since then to treat heart failure, liver cirrhosis, and nephrotic syndrome.
  259. ISBN 978-1-4939-0268-2. Archived
    from the original on 7 October 2022. Retrieved 27 December 2016.
  260. ISBN 978-0-08-056877-5. Archived
    from the original on 21 June 2013.
  261. ISSN 0140-6736
    .
  262. PMID 5344274
    .
  263. S2CID 43649686
    .
  264. doi:10.1097/00006254-196803000-00006
    . 17a-methyl-B-nortestosterone (Benorterone) (SKF-7690) has satisfactorily undergone extensive pharmacologic and toxicologic studies in animals, plus preliminary clinical studies in humans with somewhat encouraging results. It was therefore subjected to further clinical trials, especially in relation to the treatment of acne vulgaris. This communication reports the promptly reversible development of gynecomastia in 12 of 13 postpuberal males who participated in such a clinical study. It is believed that this complication has not been reported previously with a nonestrogenic antiandrogenic agent.
  265. PMID 6205409
    .
  266. PMID 717935
    .
  267. PMID 488407
    .
  268. PMID 7410528
    .
  269. ISBN 978-1-60831-820-9
    .
  270. ISBN 978-81-250-2633-4. Archived
    from the original on 7 October 2022. Retrieved 4 July 2017.
  271. ISBN 978-1-118-53857-9. Archived
    from the original on 7 October 2022. Retrieved 4 July 2017.
  272. S2CID 146232471
    .
  273. ^ Prior JC, Vigna YM, Watson D, Diewold P, Robinow O. "Spironolactone in the presurgical therapy of male to female transsexuals: Philosophy and experience of the Vancouver Gender Dysphoria Clinic". Journal of Sex Information & Education Council of Canada (1): 1–7.
  274. ISBN 978-88-470-5695-4
    .
  275. ^
    ISBN 978-1-4832-7299-3
    .
  276. ISBN 978-1-4831-5997-3. Archived
    from the original on 10 October 2022. Retrieved 31 December 2020.
  277. ^
    ISBN 978-0-7514-0499-9. Archived
    from the original on 7 October 2022. Retrieved 1 December 2016.
  278. ^
    ISBN 978-1-4612-5476-8. Archived
    from the original on 7 October 2022. Retrieved 30 July 2017.
  279. ^
    PMID 1702565
    .
  280. ^
    S2CID 27601630
    .
  281. S2CID 4492779
    .
  282. PMID 3540320
    .
  283. ^
    PMID 26976570
    .
  284. PMID 15389184
    .
  285. ISSN 2393-4999
    .
  286. ISBN 978-3-540-69374-1
    .
  287. PMID 23594595
    .
  288. S2CID 49305801
    .
  289. S2CID 49298333
    .
  290. S2CID 1747393
    .