Biology:Spironolactone

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Short description: Steroidal antiandrogen and antimineralocorticoid
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
Routes of
administration		By mouth,[4] topical[5]
Drug classAntimineralocorticoid; Steroidal antiandrogen
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein bindingSpironolactone: 88% (to albumin and AGP)[10]
Canrenone: 99.2% (to albumin)[10]
MetabolismLiver, others:
• Deacetylation via CES
• S-Oxygenation via FOM
• S-Methylation via TMT
• Dethioacetylation
• Hydroxylation via CYP3A4
• Lactone hydrolysis via PON3[11][12][13][14][15][16][17]
Elimination half-lifeSpironolactone: 1.4 hrs[11]
7α-TMS: 13.8 hours[11]
6β-OH-7α-TMS: 15.0 hrs[11]
Canrenone: 16.5 hours[11]
ExcretionUrine, bile[12]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC24H32O4S
Molar mass416.58 g·mol−1
3D model (JSmol)
Melting point134 to 135 °C (273 to 275 °F)
  (verify)
Spironolactone 25 mg

Spironolactone, sold under the brand name Aldactone among others, is a medication that is primarily used to treat fluid build-up due to heart failure, liver scarring, or kidney disease.[4] It is also used in the treatment of high blood pressure, low blood potassium that does not improve with supplementation, early puberty in boys, acne and excessive hair growth in women, and as a part of feminizing hormone therapy in trans women.[4][18][19] Spironolactone is taken by mouth.[4]

Common side effects include electrolyte abnormalities, particularly high blood potassium, nausea, vomiting, headache, rashes, and a decreased desire for sex.[4] In those with liver or kidney problems, extra care should be taken.[4] Spironolactone has not been well studied in pregnancy and should not be used to treat 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][20] Spironolactone belongs to a class of medications known as potassium-sparing diuretics.[4]

Spironolactone was discovered in 1957, and was introduced in 1959.[21][22][23] It is on the World Health Organization's List of Essential Medicines.[24][25] It is available as a generic medication.[4] In 2021, it was the 54th most commonly prescribed medication in the United States, with more than 12 million prescriptions.[26][27]

Medical uses

Spironolactone is used primarily to treat heart failure, edematous conditions such as nephrotic syndrome or ascites in people with liver disease, essential hypertension, low blood levels of potassium, secondary hyperaldosteronism (such as occurs with liver cirrhosis), and Conn's syndrome (primary hyperaldosteronism). The most common use of spironolactone is in the treatment of heart failure.[28] On its own, spironolactone is only a weak diuretic because it primarily targets the distal nephron (collecting tubule), where only small amounts of sodium are reabsorbed, but it can be combined with other diuretics to increase efficacy. The classification of spironolactone as a "potassium-sparing diuretic" has been described as obsolete.[29] Spironolactone is also used to treat Bartter's syndrome due to its ability to raise potassium levels.[30]

Spironolactone has antiandrogenic activity. For this reason, it is frequently used to treat a variety of dermatological conditions in which androgens play a role. Some of these uses include acne, seborrhea, hirsutism, and pattern hair loss in women.[31] Spironolactone is the most commonly used medication in the treatment of hirsutism in the United States .[32] High doses of spironolactone, which are needed for considerable antiandrogenic effects, are not recommended for men due to the high risk of feminization and other side effects. Spironolactone can be used to treat symptoms of hyperandrogenism, such as due to polycystic ovary syndrome.[33]

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%.[34]

Spironolactone improves left ventricular diastolic function in patients with heart failure with preserved ejection fraction, however it has no effect on mortality and hospitalization.[35][36]

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.[37]

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.

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.

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.[38] There is no evidence of person-oriented outcome at any dose in this group.[38]

High aldosterone levels

Spironolactone is used in the treatment of hyperaldosteronism (high aldosterone levels or mineralocorticoid excess), for instance primary aldosteronism (Conn's syndrome).[39] Antimineralocorticoids like spironolactone and eplerenone are first-line treatments for hyperaldosteronism.[39] They improve blood pressure and potassium levels, as well as left ventricular hypertrophy, albuminuria, and carotid intima-media thickness, in people with primary aldosteronism.[39] In people with hyperaldosteronism due to unilateral aldosterone-producing adrenocortical adenoma, adrenalectomy should be preferred instead of antimineralocorticoids.[39] Spironolactone should not be used to treat primary aldosteronism in pregnancy due to its antiandrogen-related risk of teratogenicity in male fetuses.[40][41][42][43]

Skin and hair conditions

Androgens like testosterone and DHT play a critical role in the pathogenesis of a number of dermatological conditions including oily skin, acne, seborrhea, hirsutism (excessive facial/body hair growth in women), and male pattern hair loss (androgenic alopecia).[44][45] In demonstration of this, women with complete androgen insensitivity syndrome (CAIS) do not produce sebum or develop acne and have little to no body, pubic, or axillary hair.[46][47] Moreover, men with congenital 5α-reductase type II deficiency, 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.[48][49][50][51][52] 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.[44] In accordance with the preceding, antiandrogens are highly effective in the treatment of the aforementioned androgen-dependent skin and hair conditions.[53][54]

Because of the antiandrogenic activity of spironolactone, it can be quite effective in treating acne in women.[55][56][57] In addition, spironolactone reduces oil that is naturally produced in the skin and can be used to treat oily skin.[56][58][45] Though not the primary intended purpose of the medication, the ability of spironolactone to be helpful with problematic skin and acne conditions was discovered to be one of the beneficial side effects and has been quite successful.[56][58] Oftentimes, for women treating acne, spironolactone is prescribed and paired with a birth control pill.[56][58] Positive results in the pairing of these two medications have been observed, although these results may not be seen for up to three months.[56][58] Spironolactone has been reported to produce a 50 to 100% improvement in acne at sufficiently high doses.[59] Response to treatment generally requires 1 to 3 months in the case of acne and up to 6 months in the case of hirsutism.[59] Ongoing therapy is generally required to avoid relapse of symptoms.[59] Spironolactone is commonly used in the treatment of hirsutism in women, and is considered to be a first-line antiandrogen for this indication.[60] Spironolactone can be used in the treatment of female-pattern hair loss (pattern scalp hair loss in women).[61] There is tentative low quality evidence supporting its use for this indication.[62] Although apparently effective, not all cases of female-pattern hair loss are dependent on androgens.[63]

Antiandrogens like spironolactone are male-specific teratogens which can feminize male fetuses due to their antiandrogenic effects.[53][64][65] For this reason, it is recommended that antiandrogens only be used to treat women who are of reproductive age in conjunction with adequate contraception.[53][64][65] Oral contraceptives, which contain an estrogen and a progestin, are typically used for this purpose.[53] 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.[53][66]

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.[61] As an example, spironolactone has been reported to reduce symptoms of acne in males.[67] An additional example is the usefulness of spironolactone as an antiandrogen in transgender women.[68][69][70]

Topical spironolactone has been found to be effective in the treatment of acne as well.[71] 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.[72][73] 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.[73]

Comparison

Spironolactone, the 5α-reductase inhibitor finasteride, and the nonsteroidal antiandrogen flutamide all appear to have similar effectiveness in the treatment of hirsutism.[60][74][75] However, some clinical research has found that the effectiveness of spironolactone for hirsutism is greater than that of finasteride but is less than that of flutamide.[60] The combination of spironolactone with finasteride is more effective than either alone for hirsutism and the combination of spironolactone with a birth control pill is more effective than a birth control pill alone.[60] One study showed that spironolactone or the steroidal antiandrogen cyproterone acetate both in combination with a birth control pill had equivalent effectiveness for hirsutism.[60] Spironolactone is considered to be a first-line treatment for hirsutism, finasteride and the steroidal antiandrogen cyproterone acetate are considered to be second-line treatments, and flutamide is no longer recommended for hirsutism due to liver toxicity concerns.[60] The nonsteroidal antiandrogen bicalutamide is an alternative option to flutamide with improved safety.[76][77]

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.[56] However, this was based on low- to very-low-quality evidence.[56] Spironolactone may be more effective than birth control pills in the treatment of acne, and the combination of spironolactone with a birth control pill may have greater effectiveness for acne than either alone.[78] In addition, some clinical research has found that flutamide is more effective than spironolactone in the treatment of acne.[56] In one study, flutamide decreased acne scores by 80% within 3 months, whereas spironolactone decreased symptoms by only 40% in the same time period.[79][80][81] However, the use of flutamide for acne is limited by its liver toxicity.[82][83][84][85] Bicalutamide is a potential alternative to flutamide for acne as well.[86][87] Spironolactone can be considered as a first-line treatment for acne in those who have failed other standard treatments such as topical therapies and under certain other circumstances, although this is controversial due to the side effects of spironolactone and its teratogenicity.[78][54]

There is insufficient clinical evidence to compare the effectiveness of spironolactone with other antiandrogens for female-pattern hair loss.[88] The effectiveness of spironolactone in the treatment of both acne and hirsutism appears to be dose-dependent, with higher doses being more effective than lower doses.[78][89][90] However, higher doses also have greater side effects, such as menstrual irregularities.[56]

Transgender hormone therapy

Spironolactone is frequently used off-label as a component of feminizing hormone therapy in transgender women, especially in the United States (where cyproterone acetate is not available), usually in addition to an estrogen.[68][69][70] Effects in transgender women may include decreased male pattern body hair, induction of breast development and of feminization in general, and reduced spontaneous erections.[70]

Forms

Spironolactone is available in the form of tablets (25 mg, 50 mg, 100 mg; brand name Aldactone, others) and suspensions (25 mg/5 mL; brand name CaroSpir) for use by mouth.[91][92][93][94][95] It has also been marketed in the form of 2% and 5% topical cream in Italy for the treatment of acne and hirsutism under the brand name Spiroderm, but this product is no longer available.[5][96] The medication is also available in combination with other medications, such as hydrochlorothiazide (brand name Aldactazide, others).[95][97] Spironolactone has poor water solubility, and for this reason, only oral and topical formulations have been developed; other routes of administration such as intravenous injection are not used.[11] The only antimineralocorticoid that is available as a solution for parenteral use is the related medication potassium canrenoate.[98]

Contraindications

Contraindications of spironolactone include hyperkalemia (high potassium levels), 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.[7][99] 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.[7]

Side effects

One of the most common side effects of spironolactone is frequent urination. Other general side effects include dehydration, hyponatremia (low sodium levels), mild hypotension (low blood pressure),[79] ataxia (muscle incoordination), drowsiness, dizziness,[79] dry skin, and rashes. Because of its antiandrogenic activity, spironolactone can, in men, cause breast tenderness, gynecomastia (breast development), feminization in general, and demasculinization, as well as sexual dysfunction including loss of libido and erectile dysfunction, although these side effects are usually confined to high doses of spironolactone.[100] At very high doses (400 mg/day), spironolactone has also been associated with testicular atrophy and reversibly reduced fertility, including semen abnormalities such as decreased sperm count and motility in men.[101][102] However, such doses of spironolactone are rarely used clinically.[102] In women, spironolactone can cause menstrual irregularities, breast tenderness, and breast enlargement.[31][56][103] Aside from these adverse effects, the side effects of spironolactone in women taking high doses are minimal, and it is well tolerated.[56][79][104]

The most important potential side effect of spironolactone is hyperkalemia (high potassium levels), which, in severe cases, can be life-threatening.[7] Hyperkalemia in these people can present as a normal anion-gap metabolic acidosis.[7] It has been reported that the addition of spironolactone to loop diuretics in patients with heart failure was associated with a higher risk of hyperkalemia and acute kidney injury (AKI).[105] Spironolactone may put people at a heightened risk for gastrointestinal issues like nausea, vomiting, diarrhea, cramping, and gastritis.[7][106] In addition, there has been some evidence suggesting an association between use of the medication and bleeding from the stomach and duodenum,[7] though a causal relationship between the two has not been established.[107][108] Also, spironolactone is immunosuppressive in the treatment of sarcoidosis.[109]

Most of the side effects of spironolactone are dose-dependent.[55] Low-dose spironolactone is generally very well tolerated.[55] Even higher doses of spironolactone, such as 100 mg/day, are well tolerated in most individuals.[55] Dose-dependent side effects of spironolactone include menstrual irregularities, breast tenderness and enlargement, orthostatic hypotension, and hyperkalemia.[55] The side effects of spironolactone are usually mild and rarely result in discontinuation.[55]


High potassium levels

Spironolactone can cause hyperkalemia, or high blood potassium levels.[102] Rarely, this can be fatal.[102] Of people with heart disease prescribed typical dosages of spironolactone, 10 to 15% develop some degree of hyperkalemia, and 6% develop severe hyperkalemia.[102] At a higher dosage, a rate of hyperkalemia of 24% has been observed.[110] An abrupt and major increase in the rate of hospitalization due to hyperkalemia from 0.2% to 11% and in the rate of death due to hyperkalemia from 0.3 per 1,000 to 2.0 per 1,000 between early 1994 and late 2001 has been attributed to a parallel rise in the number of prescriptions written for spironolactone upon the publication of the Randomized Aldactone Evaluation Study (RALES) in July 1999.[102][110][111][28] However, another population-based study in Scotland failed to replicate these findings.[112][113] The risk of hyperkalemia with spironolactone is greatest in the elderly, in people with 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.[102][28][114][115]

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.[56][58][116] 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.[56] 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.[56][58][116] However, other sources have claimed that hyperkalemia can nonetheless also occur in people with more normal renal function and presumably without such risk factors.[28] Occasional testing on a case-by-case basis in those with known risk factors may be justified.[56] 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.[56] Notably, non-use of routine potassium monitoring with spironolactone in young women would reduce costs associated with its use.[56]

Breast changes

Spironolactone frequently causes breast pain and breast enlargement in women.[117][118] This is "probably because of estrogenic effects on target tissue."[102] 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.[119][55] Breast enlargement and tenderness may occur in 26% of women at high doses.[79] Some women regard spironolactone-induced breast enlargement as a positive effect.[56]

Spironolactone also commonly and dose-dependently produces gynecomastia (breast development) as a side effect in men.[101][118][120][121] At low doses, the rate is only 5 to 10%,[121] but at high doses, up to or exceeding 50% of men may develop gynecomastia.[101][118][120] In the RALES, 9.1% of men taking 25 mg/day spironolactone developed gynecomastia, compared to 1.3% of controls.[122] 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.[123][124] The severity of gynecomastia with spironolactone varies considerably, but is usually mild.[101] As with breast enlargement caused by spironolactone in women, gynecomastia due to spironolactone in men is often although inconsistently accompanied by breast tenderness.[101] In the RALES, only 1.7% of men developed breast pain, relative to 0.1% of controls.[122]

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.[122] Gynecomastia induced by spironolactone usually regresses after a few weeks following discontinuation of the medication.[101] However, after a sufficient duration of gynecomastia being present (e.g., one year), hyalinization and fibrosis of the tissue occurs and drug-induced gynecomastia may become irreversible.[125][126]

Menstrual disturbances

Spironolactone at higher doses can cause menstrual irregularities as a side effect in women.[55] These irregularities include metrorrhagia (intermenstrual bleeding), amenorrhea (absence of menstruation), and breakthrough bleeding.[55] They are common during spironolactone therapy, with 10 to 50% of women experiencing them at moderate doses and almost all experiencing them at a high doses.[79][102] For example, about 20% of women experienced menstrual irregularities with 50 to 100 mg/day spironolactone, whereas about 70% experienced menstrual irregularities at 200 mg/day.[55] Most women taking moderate doses of spironolactone develop amenorrhea, and normal menstruation usually returns within two months of discontinuation.[102] Spironolactone produces an irregular and anovulatory pattern of menstrual cycles.[79] It is also associated with metrorrhagia and menorrhagia (heavy menstrual bleeding) in large percentages of women,[117] as well as with polymenorrhea (short menstrual cycles).[127][128] The medication reportedly has no birth control effect.[129]

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.[79][130][131] An alternative proposed cause is inhibition of 17α-hydroxylase and hence sex steroid metabolism by spironolactone and consequent changes in sex hormone levels.[101] Indeed, CYP17A1 genotype is associated with polymenorrhea.[132] Regardless of their mechanism, the menstrual disturbances associated with spironolactone can usually be controlled well by concomitant treatment with a birth control pill, due to the progestin component.[79][133]

Mood changes

Research is mixed on whether antimineralocorticoids like spironolactone have positive or negative effects on mood.[134][135][136] In any case, it is possible that spironolactone might have the capacity to increase the risk of depressive symptoms.[134][135][136] However, a 2017 hybrid systematic review found that the incidence of depression in women treated with spironolactone for acne was less than 1%.[56] 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%.[137]

Lipid changes

Spironolactone has been found to increase LDL ("bad") cholesterol and decrease HDL ("good") cholesterol levels at the relatively high doses used in women with polycystic ovary syndrome (PCOS).[138][139] As such, it may have unfavorable effects on the blood lipid profile in this context.[138][139] Heightened LDL cholesterol levels are a potential risk factor for cardiovascular disease such as atherosclerosis or coronary heart disease.[140] Consequently, it has been said that spironolactone should not be given to women with dyslipidemia (e.g., high cholesterol).[138][139] Unfavorable lipid changes have also been seen with other antiandrogens, like cyproterone acetate[141][142] and bicalutamide.[143][77]

Rare reactions

Aside from hyperkalemia, spironolactone may rarely cause adverse reactions such as anaphylaxis, kidney failure,[144] hepatitis (two reported cases, neither serious),[145] agranulocytosis, DRESS syndrome, Stevens–Johnson syndrome or toxic epidermal necrolysis.[146][147] Five cases of breast cancer in patients who took spironolactone for prolonged periods of time have been reported.[102][121]

Spironolactone bodies

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

Long-term administration of spironolactone gives the histologic characteristic of "spironolactone bodies" in the adrenal cortex. Spironolactone bodies are eosinophilic, round, concentrically laminated cytoplasmic inclusions surrounded by clear halos in preparations stained with hematoxylin and eosin.[148]

Pregnancy and breastfeeding

In the United States, spironolactone is considered pregnancy category C meaning that it is unclear if it is safe for use during pregnancy.[3][4] It is able to cross the placenta.[117] Likewise, it has been found to be present in the breast milk of lactating mothers and, while the effects of spironolactone or its metabolites have not been extensively studied in breastfeeding infants, it is generally recommended that women also not take the medication while nursing.[7] 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.[149]

A study found that spironolactone was not associated with teratogenicity in the offspring of rats.[150][151][152] Because it is an antiandrogen, however, spironolactone could theoretically have the potential to cause feminization of male fetuses at sufficient doses.[150][151] 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).[150][152] Another study found permanent, dose-related reproductive tract abnormalities rat offspring of both sexes at lower doses (50 to 100 mg/kg per day).[152]

In practice however, although experience is limited, spironolactone has never been reported to cause observable feminization or any other congenital defects in humans.[150][151][153][154] Among 31 human newborns exposed to spironolactone in the first trimester, there were no signs of any specific birth defects.[154] A case report described a woman who was prescribed spironolactone during pregnancy with triplets and delivered all three (one boy and two girls) healthy; there was no feminization in the boy.[154] In addition, spironolactone has been used at high doses to treat pregnant women with Bartter's syndrome, and none of the infants (three boys, two girls) showed toxicity, including feminization in the male infants.[149][150] 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).[154] 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.[150][155]

A 2019 systematic review found insufficient evidence that spironolactone causes birth defects in humans.[156] However, there was also insufficient evidence to be certain that it does not.[156]

Overdose

Spironolactone is relatively safe in acute overdose.[7] Symptoms following an acute overdose of spironolactone may include drowsiness, confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, and diarrhea.[7] In rare cases, hyponatremia, hyperkalemia, or hepatic coma may occur in individuals with severe liver disease.[7] However, these adverse reactions are unlikely in the event of an acute overdose.[7] Hyperkalemia can occur following an overdose of spironolactone, and this is especially so in people with decreased kidney function.[7] Spironolactone has been studied at extremely high oral doses of up to 2,400 mg per day in clinical trials.[98][157] Its oral median lethal dose (LD50) is more than 1,000 mg/kg in mice, rats, and rabbits.[7]

There is no specific antidote for overdose of spironolactone.[7] Treatment may consist of induction of vomiting or stomach evacuation by gastric lavage.[7] The treatment of spironolactone overdose is supportive, with the purpose of maintaining hydration, electrolyte balance, and vital functions.[7] Spironolactone should be discontinued in people with impaired kidney function or hyperkalemia.[7]

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.[158] 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.[116] 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.[159]

Spironolactone has been reported to induce the enzymes CYP3A4 and certain UDP-glucuronosyltransferases (UGTs), which can result in interactions with various medications.[13][160][161] However, it has also been reported that metabolites of spironolactone irreversibly inhibit CYP3A4.[162] In any case, spironolactone has been found to reduce the bioavailability of oral estradiol, which could be due to induction of estradiol metabolism via CYP3A4.[163] Spironolactone has also been found to inhibit UGT2B7.[164] Spironolactone can also have numerous other interactions, most commonly with other cardiac and blood pressure medications, for instance digoxin.[7]

Licorice, which has indirect mineralocorticoid activity by inhibiting mineralocorticoid metabolism, has been found to inhibit the antimineralocorticoid effects of spironolactone.[165][166][167] 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.[165][166] On the opposite end of the spectrum, spironolactone is useful in reversing licorice-induced hypokalemia.[168][169] 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.[30][170]

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.[171][172] 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.[173]

Pharmacology

Pharmacodynamics

Main page: Chemistry:Pharmacodynamics of spironolactone
7α-Thiomethylspironolactone, the major active form of spironolactone. It accounts for about 80% of the potassium-sparing effect of spironolactone.[11][174][175]
Canrenone, the second major active form of spironolactone. It accounts for around 10 to 25% of the potassium-sparing effect of spironolactone.[176]

The pharmacodynamics of spironolactone are characterized by high antimineralocorticoid activity, moderate antiandrogenic activity, and weak steroidogenesis inhibition, among other more minor activities.[98][100][123] Spironolactone is a prodrug, so most of its actions are actually mediated by its various active metabolites.[98] The major active forms of spironolactone are 7α-thiomethylspironolactone (7α-TMS) and canrenone (7α-desthioacetyl-δ6-spironolactone).[11][98]

Spironolactone is a potent antimineralocorticoid.[11] That is, it is an antagonist of the mineralocorticoid receptor (MR), the biological target of mineralocorticoids like aldosterone and 11-deoxycorticosterone.[11] By blocking the MR, spironolactone inhibits the effects of mineralocorticoids in the body.[11] The antimineralocorticoid activity of spironolactone is responsible for its therapeutic efficacy in the treatment of edema, high blood pressure, heart failure, hyperaldosteronism, and ascites due to cirrhosis.[177][178] It is also responsible for many of the side effects of spironolactone, such as urinary frequency, dehydration, hyponatremia, low blood pressure, fatigue, dizziness, metabolic acidosis, decreased kidney function, and its risk of hyperkalemia.[179] 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.[53][79]

Spironolactone is a moderate antiandrogen.[100][130][161] That is, it is an antagonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT).[100][130][161] By blocking the AR, spironolactone inhibits the effects of androgens in the body.[100][130][161] The antiandrogenic activity of spironolactone is mainly responsible for its therapeutic efficacy in the treatment of androgen-dependent skin and hair conditions like acne, seborrhea, hirsutism, and pattern hair loss and hyperandrogenism in women, precocious puberty in boys with testotoxicosis, and as a component of feminizing hormone therapy for transgender women.[130][163][180] It is also primarily responsible for some of its side effects, like breast tenderness, gynecomastia, feminization, and demasculinization in men.[101][180] Blockade of androgen signaling in the breast disinhibits the actions of estrogens in this tissue.[181] Although useful as an antiandrogen in women, who have low testosterone levels compared to men,[182][183] spironolactone is described as having relatively weak antiandrogenic activity.[184][180][185][186]

Spironolactone is a weak steroidogenesis inhibitor.[100][123][130][187] That is, it inhibits steroidogenic enzymes, or enzymes involved in the production of steroid hormones.[100][123][130][187] Spironolactone and/or its metabolites have been found in vitro to weakly inhibit a broad array of steroidogenic enzymes including cholesterol side-chain cleavage enzyme, 17α-hydroxylase, 17,20-lyase, 5α-reductase, 3β-hydroxysteroid dehydrogenase, 11β-hydroxylase, 21-hydroxylase, and aldosterone synthase (18-hydroxylase).[130][187][188][189] 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.[56][100][123][130][161] 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.[100][123][190] 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.[100][101] However, its androgen synthesis inhibition is probably clinically insignificant.[59]

Spironolactone has been found in some studies to increase levels of estradiol, an estrogen, although many other studies have found no changes in estradiol levels.[100][123] The mechanism of how spironolactone increases estradiol levels is unclear, but it may involve inhibition of the inactivation of estradiol into estrone and enhancement of the peripheral conversion of testosterone into estradiol.[191][192] It is notable that spironolactone has been found in vitro to act as a weak inhibitor of 17β-hydroxysteroid dehydrogenase 2, an enzyme that is involved in the conversion of estradiol into estrone.[193][194] 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.[191][195][196]

In response to the antimineralocorticoid activity spironolactone, and in an attempt to maintain homeostasis, the body increases aldosterone production in the adrenal cortex.[197][198][199] Some studies have found that levels of cortisol, a glucocorticoid hormone that is also produced in the adrenal cortex, are increased as well.[198][199][200] However, other clinical studies have found no change in cortisol levels with spironolactone,[130][201][90][202] and those that have found increases often have observed only small changes.[203] In accordance, spironolactone has not been associated with conventional glucocorticoid medication effects or side effects.[204][205]

Other activities of spironolactone may include very weak interactions with the estrogen and progesterone receptors and agonism of the pregnane X receptor.[90][206] These activities could contribute to the menstrual irregularities and breast side effects of spironolactone and to its drug interactions, respectively.[207][208][209]

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.[124] Nonetheless, much has been elucidated about the pharmacokinetics of spironolactone over the decades.[210][211][212][11][213][214][215][216]

Absorption

Levels of spironolactone and its major active metabolites after a single oral dose of 100 mg spironolactone in humans.[217]

The bioavailability of spironolactone when taken by mouth is 60 to 90%.[11][12][218] The bioavailability of spironolactone and its metabolites increases significantly (+22–95% increases in levels) when spironolactone is taken with food, although it is uncertain whether this further increases the therapeutic effects of the medication.[219][220][221] The increase in bioavailability is thought to be due to promotion of the gastric dissolution and absorption of spironolactone, as well as due to a decrease of the first-pass metabolism.[219][222][223] 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.[184] Steady-state concentrations of spironolactone are achieved within 8 to 10 days of treatment initiation.[175][224]

Little or no systemic absorption has been observed with topical spironolactone.[225]

Distribution

Spironolactone and its metabolite canrenone are highly plasma protein bound, with percentages of 88.0% and 99.2%, respectively.[11][10] Spironolactone is bound equivalently to albumin and α1-acid glycoprotein, while canrenone is bound only to albumin.[11][10] Spironolactone and its metabolite 7α-thiospironolactone show very low or negligible affinity for sex hormone-binding globulin (SHBG).[226][227] In accordance, a study of high-dosage spironolactone treatment found no change in steroid binding capacity related to SHBG or to corticosteroid-binding globulin (CBG), suggesting that spironolactone does not displace steroid hormones from their carrier proteins.[228] This is in contradiction with widespread statements that spironolactone increases free estradiol levels by displacing estradiol from SHBG.[90][229]

Spironolactone appears to cross the blood–brain barrier.[230][231]

Metabolism

Spironolactone metabolism in humans.[232] Canrenone may be further reduced (into di-, tetra-, and hexahydrogenated metabolites), hydroxylated, and conjugated (e.g., glucuronidated).[232]

Spironolactone is rapidly and extensively metabolized in the liver upon oral administration and has a very short terminal half-life of 1.4 hours.[11][12] The major metabolites of spironolactone are 7α-thiomethylspironolactone (7α-TMS), 6β-hydroxy-7α-thiomethylspironolactone (6β-OH-7α-TMS), and canrenone (7α-desthioacetyl-δ6-spironolactone).[11][12][174] These metabolites have much longer elimination half-lives than spironolactone of 13.8 hours, 15.0 hours, and 16.5 hours, respectively, and are responsible for the therapeutic effects of the medication.[11][12] As such, spironolactone is a prodrug.[233] The 7α-thiomethylated metabolites of spironolactone were not known for many years and it was originally thought that canrenone was the major active metabolite of the medication, but subsequent research identified 7α-TMS as the major metabolite.[11][174][175] Other known but more minor metabolites of spironolactone include 7α-thiospironolactone (7α-TS), which is an important intermediate to the major metabolites of spironolactone,[13] as well as the 7α-methyl ethyl ester of spironolactone and the 6β-hydroxy-7α-methyl ethyl ester of spironolactone.[234]

Spironolactone is hydrolyzed or deacetylated at the thioester of the C7α position into 7α-TS by carboxylesterases.[13][235] Following formation of 7α-TS, it is S-oxygenated by flavin-containing monooxygenases to form an electrophilic sulfenic acid metabolite.[13] This metabolite is involved in the CYP450 inhibition of spironolactone, and also binds covalently to other proteins.[13] 7α-TS is also S-methylated into 7α-TMS, a transformation catalyzed by thiol S-methyltransferase.[13] Unlike the related medication eplerenone, spironolactone is said to not be metabolized by CYP3A4.[236] However, hepatic CYP3A4 is likely responsible for the 6β-hydroxylation of 7α-TMS into 6β-OH-7α-TMS.[14][237] 7α-TMS may also be hydroxylated at the C3α and C3β positions.[15] Spironolactone is dethioacetylated into canrenone.[16] Finally, the C17 γ-lactone ring of spironolactone is hydrolyzed by the paraoxonase PON3.[17][238] It was originally thought to be hydrolyzed by PON1, but this was due to contamination with PON3.[17]

v · d · e Pharmacokinetics of 100 mg/day spironolactone and its metabolites
Compound Cmax (day 1) Cmax (day 15) AUC (day 15) t1/2
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-TMS 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-TMS 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.[239]

Chemistry

Spironolactone, also known as 7α-acetylthiospirolactone, is a steroidal 17α-spirolactone, or more simply a spirolactone.[98] It can most appropriately be conceptualized as a derivative of progesterone,[122][240][224] itself also a potent antimineralocorticoid, in which a hydroxyl group has been substituted at the C17α position (as in 17α-hydroxyprogesterone), the acetyl group at the C17β position has been cyclized with the C17α hydroxyl group to form a spiro 21-carboxylic acid γ-lactone ring, and an acetylthio group has been substituted in at the C7α position.[241][242][243] These structural modifications of progesterone confer increased oral bioavailability and potency,[244] potent antiandrogenic activity, and strongly reduced progestogenic activity.[245] The C7α substitution is likely responsible for or involved in the antiandrogenic activity of spironolactone, as 7α-thioprogesterone (SC-8365), unlike progesterone,[246] is an antiandrogen with similar affinity to the AR as that of spironolactone.[247] 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.[246][248][249]

Names

Spironolactone is also known by the following equivalent chemical names:[241][242][243]

  • 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

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).[98]

Synthesis

Chemical syntheses of spironolactone and its analogues and derivatives have been described and reviewed.[250]

History

The natriuretic effects of progesterone were demonstrated in 1955, and the development of spironolactone as a synthetic antimineralocorticoid analogue of progesterone shortly followed this.[122][240][251][252] Spironolactone was first synthesized in 1957,[21][251][252] was patented between 1958 and 1961,[253][254] and was first marketed, as an antimineralocorticoid, in 1959.[255][256] Gynecomastia was first reported with spironolactone in 1962,[98][257] and the antiandrogenic activity of the medication was first described in 1969.[258] This shortly followed the discovery in 1967 that gynecomastia is an important and major side effect of AR antagonists.[259][260] Spironolactone was first studied in the treatment of hirsutism in women in 1978.[261][165][262][263][264] It has since become the most widely used antiandrogen for dermatological indications in women in the United States.[94][265][266][267] 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.[268][269][270]

Early oral spironolactone tablets showed poor absorption.[271] 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.[271][272]

Society and culture

Generic names

The English, French, and generic name of the medication is spironolactone and this is its INN, USAN, USP, BAN, DCF, and JAN.[96][97][241][273] Its name is spironolactonum in Latin, spironolacton in German, espironolactona in Spanish and Portuguese, and spironolattone in Italian (which is also its DCIT).[96][97][273]

Spironolactone is also known by its developmental code names SC-9420 and NSC-150339.[96][97][241]

Brand names

Spironolactone is marketed under a large number of brand names throughout the world.[96][97] The major brand name of spironolactone is Aldactone.[96][97] 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.[96][97]

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.[97]

Availability

Spironolactone is marketed throughout the world.[96][97]

Research

Prostate conditions

Spironolactone has been studied at a high dosage in the treatment of benign prostatic hyperplasia (BPH; enlarged prostate).[274][275][276] It was found to be better than placebo in terms of symptom relief following three months of treatment.[274][275] However, this was not maintained after six months of treatment, by which point the improvements had largely disappeared.[274][275][276] Moreover, no difference was observed between spironolactone and placebo with regard to volume of residual urine or prostate size.[274][275] Gynecomastia was observed in about 5% of people.[275] On the basis of these results, it has been said that spironolactone has no place in the treatment of BPH.[275]

Spironolactone has been studied and used limitedly in the treatment of prostate cancer.[277][278][30]

Epstein–Barr virus

Spironolactone has been found to block Epstein–Barr virus (EBV) production and that of other human herpesviruses by inhibiting the function of an EBV protein SM, which is essential for infectious virus production.[279] This effect of spironolactone was determined to be independent of its antimineralocorticoid actions.[279] Thus, spironolactone or compounds based on it have the potential to yield novel antiviral medications with a distinct mechanism of action and limited toxicity.[279]

Other conditions

Spironolactone has been studied in the treatment of rosacea in both males and females.[280][281][282][67][283]

Spironolactone has been studied in fibromyalgia in women.[284][285] It has also been studied in bulimia nervosa in women, but was not found to be effective.[286]

References

  1. ↑ The Guide to Off-label Prescription Drugs: New Uses for FDA-approved Prescription Drugs. Simon and Schuster. 2006. pp. 131–. ISBN 978-0-7432-8667-1. https://books.google.com/books?id=fhEFkBxEtH8C&pg=PA131. Retrieved 6 November 2016. 
  2. ↑ Pharmacology. Lippincott Williams & Wilkins. 15 December 2011. pp. 286, 337. ISBN 978-1-4511-1314-3. https://books.google.com/books?id=Y558dgp_PjoC&pg=PA337. Retrieved 6 November 2016. 
  3. ↑ 3.0 3.1 3.2 "Spironolactone Pregnancy and Breastfeeding Warnings". https://www.drugs.com/pregnancy/spironolactone.html. 
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  7. ↑ 7.00 7.01 7.02 7.03 7.04 7.05 7.06 7.07 7.08 7.09 7.10 7.11 7.12 7.13 7.14 7.15 7.16 7.17 7.18 "Aldactone- spironolactone tablet, film coated". 29 November 2018. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0fed2822-3a03-4b64-9857-c682fcd462bc. 
  8. ↑ "Qaialdo EPAR". 25 July 2023. https://www.ema.europa.eu/en/medicines/human/EPAR/qaialdo. 
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  30. ↑ 30.0 30.1 30.2 "Potassium-Retaining Diuretics: Aldosterone Antagonists". Diuretics. Handbook of Experimental Pharmacology. 117. 1995. pp. 335–361. doi:10.1007/978-3-642-79565-7_9. ISBN 978-3-642-79567-1. 
  31. ↑ 31.0 31.1 "Tolerance of spironolactone". The British Journal of Dermatology 118 (5): 687–91. May 1988. doi:10.1111/j.1365-2133.1988.tb02571.x. PMID 2969259. 
  32. ↑ Handbook of Hair in Health and Disease. Springer Science & Business Media. 1 January 2012. pp. 132–. ISBN 978-90-8686-728-8. https://books.google.com/books?id=7N3nEX6eL_MC&pg=PA132. Retrieved 6 October 2016. 
  33. ↑ "Evaluation and therapy of polycystic ovarian syndrome". Endocrinology and Metabolism Clinics of North America 17 (4): 785–813. December 1988. doi:10.1016/S0889-8529(18)30410-9. PMID 3143568. 
  34. ↑ "2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines". Journal of the American College of Cardiology 62 (16): e147-239. October 2013. doi:10.1016/j.jacc.2013.05.019. PMID 23747642. 
  35. ↑ "Effects of spironolactone in heart failure with preserved ejection fraction: A meta-analysis of randomized controlled trials". Medicine 97 (35): e11942. August 2018. doi:10.1097/MD.0000000000011942. PMID 30170387. 
  36. ↑ "Role of spironolactone in the treatment of heart failure with preserved ejection fraction". Annals of Translational Medicine 6 (23): 461. December 2018. doi:10.21037/atm.2018.11.16. PMID 30603649. 
  37. ↑ "Eplerenone is not superior to older and less expensive aldosterone antagonists". The American Journal of Medicine 125 (8): 817–25. August 2012. doi:10.1016/j.amjmed.2011.12.018. PMID 22840667. 
  38. ↑ 38.0 38.1 "Spironolactone for hypertension". The Cochrane Database of Systematic Reviews (8): CD008169. August 2010. doi:10.1002/14651858.CD008169.pub2. PMID 20687095. 
  39. ↑ 39.0 39.1 39.2 39.3 "Mineralocorticoid Receptor Antagonists in Primary Aldosteronism". Curr Pharm Des 24 (46): 5508–5516. 2018. doi:10.2174/1381612825666190311130138. PMID 30854950. 
  40. ↑ "Primary aldosteronism in pregnancy". Rev Endocr Metab Disord 24 (1): 39–48. May 2022. doi:10.1007/s11154-022-09729-6. PMID 35536535. 
  41. ↑ "Primary aldosteronism and pregnancy". Ann Endocrinol (Paris) 77 (2): 148–60. June 2016. doi:10.1016/j.ando.2016.04.009. PMID 27156905. 
  42. ↑ "Progress in primary aldosteronism: mineralocorticoid receptor antagonists and management of primary aldosteronism in pregnancy". Eur J Endocrinol 172 (1): R23–30. January 2015. doi:10.1530/EJE-14-0444. PMID 25163723. 
  43. ↑ "Treatment of primary hyperaldosteronism". Med Clin (Barc) 155 (7): 302–308. October 2020. doi:10.1016/j.medcli.2020.04.029. PMID 32586668. 
  44. ↑ 44.0 44.1 "Androgen action on human skin -- from basic research to clinical significance". Experimental Dermatology 13 (Suppl 4): 5–10. 2004. doi:10.1111/j.1600-0625.2004.00255.x. PMID 15507105. 
  45. ↑ 45.0 45.1 "Oily Skin: A review of Treatment Options". The Journal of Clinical and Aesthetic Dermatology 10 (8): 49–55. August 2017. PMID 28979664. 
  46. ↑ Acne Vulgaris. CRC Press. 21 March 2011. pp. 33–. ISBN 978-1-61631-009-7. https://books.google.com/books?id=CIPOBQAAQBAJ&pg=PA33. 
  47. ↑ Pathogenesis and Treatment of Acne and Rosacea. Springer. 28 July 2014. pp. 121–. ISBN 978-3-540-69375-8. https://books.google.com/books?id=vnQqBAAAQBAJ&pg=PA121. 
  48. ↑ "5alpha-reductase: history and clinical importance". Reviews in Urology 6 (Suppl 9): S11-21. 2004. PMID 16985920. 
  49. ↑ Biology of Women. Cengage Learning. 2002. pp. 160–. ISBN 978-0-7668-1142-3. https://books.google.com/books?id=kqcYyk7zlHYC&pg=PA160. Retrieved 5 July 2017. 
  50. ↑ Penn Clinical Manual of Urology E-Book: Expert Consult - Online. Elsevier Health Sciences. 26 January 2014. pp. 782–. ISBN 978-0-323-24466-4. https://books.google.com/books?id=OQTbAgAAQBAJ&pg=PA782. Retrieved 5 July 2017. 
  51. ↑ Intersex. Berg. 1 August 2007. pp. 123–. ISBN 978-1-84788-339-1. https://books.google.com/books?id=fM6vAwAAQBAJ&pg=PA123. Retrieved 5 July 2017. 
  52. ↑ Hair Growth and Disorders. Springer Science & Business Media. 26 June 2008. pp. 161–162. ISBN 978-3-540-46911-7. https://books.google.com/books?id=pHrX2-huQCoC&pg=PA161. Retrieved 16 July 2017. 
  53. ↑ 53.0 53.1 53.2 53.3 53.4 53.5 "Androgens and therapeutic aspects of antiandrogens in women". Journal of the Society for Gynecologic Investigation 2 (4): 577–92. 1995. doi:10.1177/107155769500200401. PMID 9420861. 
  54. ↑ 54.0 54.1 "Hormonal therapy for acne: why not as first line therapy? facts and controversies". Clinics in Dermatology 28 (1): 17–23. 2010. doi:10.1016/j.clindermatol.2009.03.006. PMID 20082945. 
  55. ↑ 55.0 55.1 55.2 55.3 55.4 55.5 55.6 55.7 55.8 55.9 "Oral Spironolactone in Post-teenage Female Patients with Acne Vulgaris: Practical Considerations for the Clinician Based on Current Data and Clinical Experience". The Journal of Clinical and Aesthetic Dermatology 5 (3): 37–50. March 2012. PMID 22468178. 
  56. ↑ 56.00 56.01 56.02 56.03 56.04 56.05 56.06 56.07 56.08 56.09 56.10 56.11 56.12 56.13 56.14 56.15 56.16 56.17 56.18 56.19 "Oral Spironolactone for Acne Vulgaris in Adult Females: A Hybrid Systematic Review". American Journal of Clinical Dermatology 18 (2): 169–191. April 2017. doi:10.1007/s40257-016-0245-x. PMID 28155090. 
  57. ↑ "Effectiveness of spironolactone for women with acne vulgaris (SAFA) in England and Wales: pragmatic, multicentre, phase 3, double blind, randomised controlled trial". BMJ 381: e074349. May 2023. doi:10.1136/bmj-2022-074349. PMID 37192767. 
  58. ↑ 58.0 58.1 58.2 58.3 58.4 58.5 "Guidelines of care for the management of acne vulgaris". Journal of the American Academy of Dermatology 74 (5): 945–73.e33. May 2016. doi:10.1016/j.jaad.2015.12.037. PMID 26897386. 
  59. ↑ 59.0 59.1 59.2 59.3 "Antiandrogen and hormonal treatment of acne". Dermatologic Clinics 14 (4): 803–11. October 1996. doi:10.1016/S0733-8635(05)70405-8. PMID 9238337. 
  60. ↑ 60.0 60.1 60.2 60.3 60.4 60.5 "Hirsutism: an evidence-based treatment update". American Journal of Clinical Dermatology 15 (3): 247–66. July 2014. doi:10.1007/s40257-014-0078-4. PMID 24889738. 
  61. ↑ 61.0 61.1 "Use of spironolactone in dermatology". Skinmed 8 (6): 328–32; quiz 333. 2010. PMID 21413648. 
  62. ↑ "Hair loss in women". Clinical Obstetrics and Gynecology 58 (1): 185–99. March 2015. doi:10.1097/GRF.0000000000000081. PMID 25517757. 
  63. ↑ "Female pattern hair loss in complete androgen insensitivity syndrome". The British Journal of Dermatology 162 (5): 1135–7. May 2010. doi:10.1111/j.1365-2133.2010.09661.x. PMID 20128792. 
  64. ↑ 64.0 64.1 "An overview of animal toxicology studies with bicalutamide (ICI 176,334)". The Journal of Toxicological Sciences 22 (2): 75–88. May 1997. doi:10.2131/jts.22.2_75. PMID 9198005. 
  65. ↑ 65.0 65.1 Medicinal Chemistry – Fusion of Traditional and Western Medicine. Bentham Science Publishers. 4 April 2013. pp. 306–. ISBN 978-1-60805-149-6. https://books.google.com/books?id=RkDcAwAAQBAJ&pg=PA306. 
  66. ↑ Gynecology: Integrating Conventional, Complementary, and Natural Alternative Therapy. Lippincott Williams & Wilkins. 2002. pp. 86–. ISBN 978-0-7817-2761-7. https://books.google.com/books?id=TYlZsGdwqrQC&pg=PA86. Retrieved 5 July 2017. 
  67. ↑ 67.0 67.1 "Other antiandrogens". Dermatology 196 (1): 153–7. 1998. doi:10.1159/000017850. PMID 9557251. 
  68. ↑ 68.0 68.1 The World Professional Association for Transgender Health (WPATH) (2011). "Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People". http://www.wpath.org/documents/Standards%20of%20Care_FullBook_1g-1.pdf. 
  69. ↑ 69.0 69.1 "Endocrine treatment of transsexual persons: an Endocrine Society clinical practice guideline". The Journal of Clinical Endocrinology and Metabolism 94 (9): 3132–54. September 2009. doi:10.1210/jc.2009-0345. PMID 19509099. 
  70. ↑ 70.0 70.1 70.2 "Spironolactone with physiological female steroids for presurgical therapy of male-to-female transsexualism". Archives of Sexual Behavior 18 (1): 49–57. February 1989. doi:10.1007/bf01579291. PMID 2540730. 
  71. ↑ "Antiandrogens and acne. A topical approach?". Archives of Dermatology 128 (9): 1261–4. September 1992. doi:10.1001/archderm.1992.01680190117017. PMID 1387779. 
  72. ↑ "Facial contact dermatitis due to spironolactone in an anti-acne cream". Contact Dermatitis 29 (5): 277–8. November 1993. doi:10.1111/j.1600-0536.1993.tb03569.x. PMID 8112074. 
  73. ↑ 73.0 73.1 "Therapy of Hirsutism". Diagnosis and Management of Polycystic Ovary Syndrome. 2009. pp. 233–242. doi:10.1007/978-0-387-09718-3_19. ISBN 978-0-387-09717-6. 
  74. ↑ "Interventions for hirsutism (excluding laser and photoepilation therapy alone)". The Cochrane Database of Systematic Reviews 2015 (4): CD010334. April 2015. doi:10.1002/14651858.CD010334.pub2. PMID 25918921. 
  75. ↑ "Treatment Options for Hirsutism: A Systematic Review and Network Meta-Analysis". The Journal of Clinical Endocrinology and Metabolism 103 (4): 1258–1264. April 2018. doi:10.1210/jc.2017-02052. PMID 29522176. 
  76. ↑ "Update on idiopathic hirsutism: diagnosis and treatment". Acta Clinica Belgica 68 (4): 268–74. 2013. doi:10.2143/ACB.3267. PMID 24455796. 
  77. ↑ 77.0 77.1 "Combined Oral Contraception and Bicalutamide in Polycystic Ovary Syndrome and Severe Hirsutism: A Double-Blind Randomized Controlled Trial". The Journal of Clinical Endocrinology and Metabolism 103 (3): 824–838. March 2018. doi:10.1210/jc.2017-01186. PMID 29211888. 
  78. ↑ 78.0 78.1 78.2 "Acne in the adult female patient: a practical approach". International Journal of Dermatology 51 (10): 1162–74. October 2012. doi:10.1111/j.1365-4632.2012.05519.x. PMID 22994662. 
  79. ↑ 79.0 79.1 79.2 79.3 79.4 79.5 79.6 79.7 79.8 79.9 "Current aspects of antiandrogen therapy in women". Current Pharmaceutical Design 5 (9): 707–23. September 1999. doi:10.2174/1381612805666230111201150. PMID 10495361. 
  80. ↑ Advanced Dermatologic Therapy II. W. B. Saunders. 2001. ISBN 978-0-7216-8258-7. https://books.google.com/books?id=vuJsAAAAMAAJ. Retrieved 2 January 2019. 
  81. ↑ Current Management of Polycystic Ovary Syndrome. Cambridge University Press. October 2010. pp. 132–. ISBN 978-1-906985-41-7. https://books.google.com/books?id=0rtUBAAAQBAJ&pg=PA132. Retrieved 2 January 2019. 
  82. ↑ "Flutamide-induced hepatotoxicity: ethical and scientific issues". European Review for Medical and Pharmacological Sciences 21 (1 Suppl): 69–77. March 2017. PMID 28379593. 
  83. ↑ "A Review of hormone-based therapies to treat adult acne vulgaris in women". International Journal of Women's Dermatology 3 (1): 44–52. March 2017. doi:10.1016/j.ijwd.2017.02.018. PMID 28492054. 
  84. ↑ "Hirsutism, Acne, and Hair Loss: Management of Hyperandrogenic Cutaneous Manifestations of Polycystic Ovary Syndrome". Gynecology Obstetrics & Reproductive Medicine 23 (2): 110–119. 2016. doi:10.21613/GORM.2016.613. ISSN 1300-4751. 
  85. ↑ "Hormonal therapies for acne". Clinics in Dermatology 35 (2): 168–172. 2017. doi:10.1016/j.clindermatol.2016.10.009. PMID 28274354. 
  86. ↑ "The use of hormonal agents in the treatment of acne". Seminars in Cutaneous Medicine and Surgery 35 (2): 68–73. June 2016. doi:10.12788/j.sder.2016.027. PMID 27416311. 
  87. ↑ "Androgens in women: Hormone-modulating therapies for skin disease". Journal of the American Academy of Dermatology 80 (6): 1509–1521. June 2019. doi:10.1016/j.jaad.2018.08.061. PMID 30312645. 
  88. ↑ "Interventions for female pattern hair loss". The Cochrane Database of Systematic Reviews 2016 (5): CD007628. May 2016. doi:10.1002/14651858.CD007628.pub4. PMID 27225981. 
  89. ↑ "Spironolactone versus placebo or in combination with steroids for hirsutism and/or acne". The Cochrane Database of Systematic Reviews (2): CD000194. April 2009. doi:10.1002/14651858.CD000194.pub2. PMID 19370553. 
  90. ↑ 90.0 90.1 90.2 90.3 "Antiandrogens: Clinical Aspects". Hair and Hair Diseases. 1990. pp. 827–886. doi:10.1007/978-3-642-74612-3_35. ISBN 978-3-642-74614-7. 
  91. ↑ European Drug Index: European Drug Registrations (Fourth ed.). CRC Press. 19 June 1998. pp. 44–. ISBN 978-3-7692-2114-5. https://books.google.com/books?id=2HBPHmclMWIC&pg=PA44. Retrieved 29 November 2017. 
  92. ↑ Gibaldi's Drug Delivery Systems in Pharmaceutical Care. ASHP. 2007. pp. 312–. ISBN 978-1-58528-136-7. https://books.google.com/books?id=v0rLyVSc8EYC&pg=PA312. Retrieved 1 December 2016. 
  93. ↑ Handbook of Pharmaceutical Manufacturing Formulations, Second Edition: Volume One, Compressed Solid Products. CRC Press. 19 April 2016. pp. 470–. ISBN 978-1-4200-8117-6. https://books.google.com/books?id=XprMBQAAQBAJ&pg=PA470. Retrieved 1 December 2016. 
  94. ↑ 94.0 94.1 Systemic Drug Treatment in Dermatology: A Handbook. CRC Press. 1 June 2002. pp. 32, 35. ISBN 978-1-84076-013-2. https://books.google.com/books?id=F1ZiAgAAQBAJ&pg=PA35. Retrieved 1 December 2016. 
  95. ↑ 95.0 95.1 "Drugs@FDA: FDA Approved Drug Products". United States Food and Drug Administration. http://www.accessdata.fda.gov/scripts/cder/daf/. 
  96. ↑ 96.0 96.1 96.2 96.3 96.4 96.5 96.6 96.7 Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 960–. ISBN 978-3-88763-075-1. https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA960. 
  97. ↑ 97.0 97.1 97.2 97.3 97.4 97.5 97.6 97.7 97.8 "Spironolactone". https://www.drugs.com/international/spironolactone.html. 
  98. ↑ 98.0 98.1 98.2 98.3 98.4 98.5 98.6 98.7 "30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor antagonists: 60 years of research and development". The Journal of Endocrinology 234 (1): T125–T140. July 2017. doi:10.1530/JOE-16-0600. PMID 28634268. 
  99. ↑ Cardio-Renal Clinical Challenges. Springer. 12 November 2014. pp. 167–. ISBN 978-3-319-09162-4. https://books.google.com/books?id=GvZWBQAAQBAJ&pg=PA167. Retrieved 17 August 2018. 
  100. ↑ 100.00 100.01 100.02 100.03 100.04 100.05 100.06 100.07 100.08 100.09 100.10 "Spironolactone and endocrine dysfunction". Annals of Internal Medicine 85 (5): 630–6. November 1976. doi:10.7326/0003-4819-85-5-630. PMID 984618. 
  101. ↑ 101.0 101.1 101.2 101.3 101.4 101.5 101.6 101.7 101.8 Diuretic Agents: Clinical Physiology and Pharmacology. Academic Press. 23 September 1997. pp. 630–632. ISBN 978-0-08-053046-8. https://books.google.com/books?id=VHcsrw6unuAC&pg=PA630. "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." 
  102. ↑ 102.00 102.01 102.02 102.03 102.04 102.05 102.06 102.07 102.08 102.09 102.10 Meyler's Side Effects of Cardiovascular Drugs. Elsevier. 2 March 2009. pp. 253–258. ISBN 978-0-08-093289-7. https://books.google.com/books?id=oeBgU3UwgZkC&pg=PA255. 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." 
  103. ↑ Reproductive Endocrinology and Infertility: Integrating Modern Clinical and Laboratory Practice. Springer Science & Business Media. 23 March 2010. pp. 162–. ISBN 978-1-4419-1436-1. https://books.google.com/books?id=lcBEheiufVcC&pg=PA162. 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." 
  104. ↑ Pediatric Endocrinology: Mechanisms, Manifestations, and Management. Lippincott Williams & Wilkins. 2004. pp. 368–. ISBN 978-0-7817-4059-3. https://books.google.com/books?id=9gvBlktAT6YC&pg=PA368. 
  105. ↑ "Hyperkalemia and Acute Kidney Injury with Spironolactone Use Among Patients with Heart Failure". Mayo Clinic Proceedings 95 (11): 2408–2419. November 2020. doi:10.1016/j.mayocp.2020.03.035. PMID 33153631. 
  106. ↑ "Spironolactone". MedlinePlus. U.S. National Library of Medicine. 2019. https://medlineplus.gov/druginfo/meds/a682627.html. 
  107. ↑ "Spironolactone and risk of upper gastrointestinal events: population based case-control study". BMJ 333 (7563): 330. August 2006. doi:10.1136/bmj.38883.479549.2F. PMID 16840442. 
  108. ↑ "Spironolactone use and the risk of upper gastrointestinal bleeding: a population-based case-control study". Br J Clin Pharmacol 66 (2): 294–9. August 2008. doi:10.1111/j.1365-2125.2008.03205.x. PMID 18507655. 
  109. ↑ "[Aldactone in the treatment of sarcoidosis of the lungs (author's transl)]". Zeitschrift für Erkrankungen der Atmungsorgane 149 (1): 156–9. July 1977. PMID 607621. 
  110. ↑ 110.0 110.1 "Safety profile of mineralocorticoid receptor antagonists: Spironolactone and eplerenone". International Journal of Cardiology 200: 25–9. December 2015. doi:10.1016/j.ijcard.2015.05.127. PMID 26404748. 
  111. ↑ "Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study". The New England Journal of Medicine 351 (6): 543–51. August 2004. doi:10.1056/NEJMoa040135. PMID 15295047. 
  112. ↑ "Mineralocorticoid receptor antagonists for heart failure with reduced ejection fraction: integrating evidence into clinical practice". European Heart Journal 33 (22): 2782–95. November 2012. doi:10.1093/eurheartj/ehs257. PMID 22942339. 
  113. ↑ "Spironolactone use and renal toxicity: population based longitudinal analysis". BMJ 340: c1768. May 2010. doi:10.1136/bmj.c1768. PMID 20483947. 
  114. ↑ "Trimethoprim-sulfamethoxazole induced hyperkalaemia in elderly patients receiving spironolactone: nested case-control study". BMJ 343: d5228. September 2011. doi:10.1136/bmj.d5228. PMID 21911446. 
  115. ↑ "Trimethoprim-sulfamethoxazole and risk of sudden death among patients taking spironolactone". CMAJ 187 (4): E138–E143. March 2015. doi:10.1503/cmaj.140816. PMID 25646289. 
  116. ↑ 116.0 116.1 116.2 "Low Usefulness of Potassium Monitoring Among Healthy Young Women Taking Spironolactone for Acne". JAMA Dermatology 151 (9): 941–4. September 2015. doi:10.1001/jamadermatol.2015.34. PMID 25796182. 
  117. ↑ 117.0 117.1 117.2 Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. 2001. pp. 708, 777, 1087, 1196. ISBN 978-0-7817-1750-2. https://books.google.com/books?id=FVfzRvaucq8C&pg=PA1196. 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" 
  118. ↑ 118.0 118.1 118.2 Interventional Therapies for Secondary and Essential Hypertension. Springer. 15 August 2016. p. 44. ISBN 978-3-319-34141-5. https://books.google.com/books?id=MFfYDAAAQBAJ&pg=PA44. 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]." 
  119. ↑ "Managing hirsutism in gynaecological practice". British Journal of Obstetrics and Gynaecology 105 (7): 687–96. July 1998. doi:10.1111/j.1471-0528.1998.tb10197.x. PMID 9692407. "Breast tenderness is not uncommon and is recorded in up to 40% of women taking higher doses63.". 
  120. ↑ 120.0 120.1 Side Effects of Drugs Annual: A worldwide yearly survey of new data in adverse drug reactions. Elsevier Science. 1 December 2014. p. 293. ISBN 978-0-444-63391-0. https://books.google.com/books?id=NfqxAwAAQBAJ&pg=PA293. "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]." 
  121. ↑ 121.0 121.1 121.2 Clinical Pharmacology and Therapeutics of Hypertension. Elsevier. 2008. p. 125. ISBN 978-0-444-51757-9. https://books.google.com/books?id=9nqP9iz7NNAC&pg=PA125. 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" 
  122. ↑ 122.0 122.1 122.2 122.3 122.4 "The 45-year story of the development of an anti-aldosterone more specific than spironolactone". Molecular and Cellular Endocrinology 217 (1–2): 45–52. March 2004. doi:10.1016/j.mce.2003.10.008. PMID 15134800. "[Spironolactone] was synthesized after the demonstration of the natriuretic effect of progesterone (Landau et al., 1955).". 
  123. ↑ 123.0 123.1 123.2 123.3 123.4 123.5 123.6 "Drug-induced gynecomastia". Pharmacotherapy 13 (1): 37–45. 1993. doi:10.1002/j.1875-9114.1993.tb02688.x. PMID 8094898. 
  124. ↑ 124.0 124.1 Therapy in Nephrology and Hypertension E-Book: A Companion to Brenner & Rector's The Kidney. Elsevier Health Sciences. 22 August 2008. pp. 607–. ISBN 978-1-4377-1124-0. https://books.google.com/books?id=XcnpBdq84MEC&pg=PA607. Retrieved 17 August 2018. 
  125. ↑ "Drug-induced gynecomastia". Expert Opinion on Drug Safety 7 (6): 691–702. November 2008. doi:10.1517/14740330802442382. PMID 18983216. 
  126. ↑ "Gynecomastia: pathomechanisms and treatment strategies". Hormone Research 48 (3): 95–102. 1997. doi:10.1159/000185497. PMID 11546925. 
  127. ↑ "Spironolactone for hirsutism in polycystic ovary syndrome". The Annals of Pharmacotherapy 39 (9): 1517–21. September 2005. doi:10.1345/aph.1G025. PMID 16076921. 
  128. ↑ "Spironolactone as a single agent for long-term therapy of hirsute patients". Clinical Endocrinology 52 (5): 587–94. May 2000. doi:10.1046/j.1365-2265.2000.00982.x. PMID 10792338. 
  129. ↑ "Treatment of hyperandrogenism in women". Gynecological Endocrinology 10 (sup3): 1–44. 2009. doi:10.3109/09513599609045658. ISSN 0951-3590. 
  130. ↑ 130.0 130.1 130.2 130.3 130.4 130.5 130.6 130.7 130.8 130.9 "Hirsutism and the effectiveness of spironolactone in its management". Journal of Endocrinological Investigation 16 (11): 925–32. December 1993. doi:10.1007/BF03348960. PMID 8144871. 
  131. ↑ "Absence of progestational activity of oral spironolactone". Fertility and Sterility 52 (1): 155–8. July 1989. doi:10.1016/s0015-0282(16)60807-5. PMID 2744183. 
  132. ↑ "The Menstrual Cycle and Risk of Breast Cancer: A Review". Frontiers in Oncology 10: 21. 2020. doi:10.3389/fonc.2020.00021. PMID 32038990. 
  133. ↑ Hidradenitis Suppurativa. Springer Science & Business Media. 24 November 2006. pp. 125–. ISBN 978-3-540-33101-8. https://books.google.com/books?id=hpKFsXwcKlgC&pg=PA125. Retrieved 15 August 2018. 
  134. ↑ 134.0 134.1 "The brain mineralocorticoid receptor and stress resilience". Psychoneuroendocrinology 52: 92–110. February 2015. doi:10.1016/j.psyneuen.2014.10.022. PMID 25459896. 
  135. ↑ 135.0 135.1 Schultebraucks K (2016). The Role of the Mineralocorticoid Receptor for Cognitive Function, Mood and Social Cognition (PDF) (Dissertation). 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.
  136. ↑ 136.0 136.1 "The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists to treat depression and anxiety". Journal of Psychiatric Research 33 (3): 181–214. 1999. doi:10.1016/S0022-3956(98)90056-5. PMID 10367986. 
  137. ↑ "Hormonal Therapy of Gender Dysphoria: The Male-to-Female Transsexual". Current Concepts in Transgender Identity. Taylor & Francis. 1998. pp. 277–296. doi:10.4324/9780203775134. ISBN 978-1-134-82110-5. https://books.google.com/books?id=zJBvR-Zy7LgC&pg=PA286. Retrieved 2 January 2019. 
  138. ↑ 138.0 138.1 138.2 "The cardiometabolic effect of current management of polycystic ovary syndrome: strategies of prevention and treatment". Gynecol Endocrinol 34 (2): 87–91. February 2018. doi:10.1080/09513590.2017.1381681. PMID 28944709. 
  139. ↑ 139.0 139.1 139.2 "Short term effects of spironolactone on blood lipid profile: a 3-month study on a cohort of young women with hirsutism". Br J Clin Pharmacol 68 (4): 634–7. October 2009. doi:10.1111/j.1365-2125.2009.03483.x. PMID 19843067. 
  140. ↑ "2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines". Circulation 139 (25): e1082–e1143. June 2019. doi:10.1161/CIR.0000000000000625. PMID 30586774. 
  141. ↑ "Standards of Care for the Health of Transgender and Gender Diverse People, Version 8". International Journal of Transgender Health 23 (Suppl 1): S1–S259. 19 August 2022. doi:10.1080/26895269.2022.2100644. ISSN 2689-5269. PMID 36238954. 
  142. ↑ "Sex, plasma lipoproteins, and atherosclerosis: prevailing assumptions and outstanding questions". American Heart Journal 114 (6): 1467–1503. December 1987. doi:10.1016/0002-8703(87)90552-7. PMID 3318361. 
  143. ↑ "Pharmacological Approaches to Controlling Cardiometabolic Risk in Women with PCOS". Int J Mol Sci 21 (24): 9554. December 2020. doi:10.3390/ijms21249554. PMID 33334002. 
  144. ↑ "Safety of spironolactone use in ambulatory heart failure patients". Clinical Cardiology 31 (11): 509–13. November 2008. doi:10.1002/clc.20284. PMID 19006114. 
  145. ↑ "Spironolactone-induced hepatitis". The Australasian Journal of Dermatology 42 (3): 180–2. August 2001. doi:10.1046/j.1440-0960.2001.00510.x. PMID 11488711. 
  146. ↑ "Aldactazide (spironolactone/hydrochlorothiazide) Tablets". https://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm258786.htm. 
  147. ↑ online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7699#f_adverse-reactions
  148. ↑ "Spironolactone bodies in aldosteronomas and in the attached adrenals. Enzyme histochemical study of 19 cases of primary aldosteronism and a case of aldosteronism due to bilateral diffuse hyperplasia of the zona glomerulosa". The American Journal of Pathology 103 (3): 404–10. June 1981. PMID 7195152. 
  149. ↑ 149.0 149.1 Neonatal Formulary: Drug Use in Pregnancy and the First Year of Life. John Wiley & Sons. 10 November 2014. pp. 486–. ISBN 978-1-118-81959-3. https://books.google.com/books?id=VOLhBQAAQBAJ&pg=PA486. 
  150. ↑ 150.0 150.1 150.2 150.3 150.4 150.5 Drugs and Pregnancy: A Handbook. CRC Press. 29 September 2006. pp. 63–. ISBN 978-0-340-80917-4. https://books.google.com/books?id=lnySHcBjXsEC&pg=PA63. 
  151. ↑ 151.0 151.1 151.2 Prescribing in Pregnancy. John Wiley & Sons. 30 April 2008. pp. 83–. ISBN 978-0-470-69555-5. https://books.google.com/books?id=2zHGHec53oMC&pg=PA83. 
  152. ↑ 152.0 152.1 152.2 Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk. Lippincott Williams & Wilkins. 2011. pp. 1349–. ISBN 978-1-60831-708-0. https://books.google.com/books?id=OIgTE4aynrMC&pg=PA1349. 
  153. ↑ Cardiac Problems in Pregnancy: Diagnosis and Management of Maternal and Fetal Heart Disease. John Wiley & Sons. 23 June 1998. pp. 353–. ISBN 978-0-471-16358-9. https://books.google.com/books?id=z6E-Hgeu1nYC&pg=PA353. 
  154. ↑ 154.0 154.1 154.2 154.3 Drugs During Pregnancy and Lactation: Handbook of Prescription Drugs and Comparative Risk Assessment. Gulf Professional Publishing. 2001. pp. 115, 143. ISBN 978-0-444-50763-1. https://books.google.com/books?id=CE569saGK70C&pg=PA115. 
  155. ↑ Australian Drug Guide. Black Inc.. 2006. pp. 671–. ISBN 978-1-86395-174-6. https://books.google.com/books?id=7O9kiqN2q2YC&pg=PA671. 
  156. ↑ 156.0 156.1 "Lack of evidence for feminization of males exposed to spironolactone in utero: A systematic review". Journal of the American Academy of Dermatology 80 (4): 1147–1148. April 2019. doi:10.1016/j.jaad.2018.10.023. PMID 30352280. 
  157. ↑ "The evolution of aldosterone antagonists". Molecular and Cellular Endocrinology 217 (1–2): 27–31. March 2004. doi:10.1016/j.mce.2003.10.005. PMID 15134797. 
  158. ↑ "Advisory Statement". Klinge Chemicals / LoSalt. http://www.losalt.com/docs/lo_salt_web_advice.pdf. 
  159. ↑ "Life-threatening hyperkalemia: a potentially lethal drug combination". Connecticut Medicine 77 (8): 491–3. September 2013. PMID 24156179. 
  160. ↑ Opioids in Cancer Pain. OUP Oxford. 28 May 2009. pp. 222–. ISBN 978-0-19-923664-0. https://books.google.com/books?id=aEzg6i2nPMQC&pg=PA222. Retrieved 6 October 2016. 
  161. ↑ 161.0 161.1 161.2 161.3 161.4 "Spironolactone in dermatologic therapy". Journal of the American Academy of Dermatology 24 (2 Pt 1): 236–43. February 1991. doi:10.1016/0190-9622(91)70034-Y. PMID 1826112. 
  162. ↑ Comprehensive Dermatologic Drug Therapy. Elsevier Health Sciences. 8 March 2007. pp. 2677–. ISBN 978-1-4377-2070-9. https://books.google.com/books?id=AaJwq_X6U6MC&pg=PT2677. Retrieved 7 May 2017. 
  163. ↑ 163.0 163.1 "Hormonal Treatment of Transgender Women with Oral Estradiol". Transgender Health 3 (1): 74–81. 2018. doi:10.1089/trgh.2017.0035. PMID 29756046. 
  164. ↑ "Extrahepatic Drug-Metabolizing Enzymes and Their Significance". Encyclopedia of Drug Metabolism and Interactions. 2012. pp. 1–99. doi:10.1002/9780470921920.edm028. ISBN 978-0-470-92192-0. 
  165. ↑ 165.0 165.1 165.2 "Spironolactone in the treatment of polycystic ovary syndrome". Expert Opinion on Pharmacotherapy 17 (13): 1713–5. September 2016. doi:10.1080/14656566.2016.1215430. PMID 27450358. 
  166. ↑ 166.0 166.1 "Treatment of polycystic ovary syndrome with spironolactone plus licorice". European Journal of Obstetrics, Gynecology, and Reproductive Biology 131 (1): 61–67. March 2007. doi:10.1016/j.ejogrb.2006.10.013. PMID 17113210. 
  167. ↑ "Inhibition of the "mineralocorticoid" activity of licorice by spironolactone". The Journal of Clinical Endocrinology and Metabolism 22 (11): 1156–9. November 1962. doi:10.1210/jcem-22-11-1156. PMID 13991036. 
  168. ↑ "Licorice abuse: time to send a warning message". Therapeutic Advances in Endocrinology and Metabolism 3 (4): 125–38. August 2012. doi:10.1177/2042018812454322. PMID 23185686. 
  169. ↑ "An unusual cause of hypokalemic paralysis: chronic licorice ingestion". The American Journal of the Medical Sciences 325 (3): 153–6. March 2003. doi:10.1097/00000441-200303000-00008. PMID 12640291. 
  170. ↑ "Mineralocorticoid receptor antagonists". Current Hypertension Reports 9 (1): 45–52. March 2007. doi:10.1007/s11906-007-0009-3. PMID 17362671. 
  171. ↑ Holsboer, F. The Rationale for Corticotropin-Releasing Hormone Receptor (CRH-R) Antagonists to Treat Depression and Anxiety. J. Psychiatr. Res. 33, 181–214 (1999).
  172. ↑ "Modulation of the mineralocorticoid receptor as add-on treatment in depression: a randomized, double-blind, placebo-controlled proof-of-concept study". Journal of Psychiatric Research 44 (6): 339–46. April 2010. doi:10.1016/j.jpsychires.2009.10.006. PMID 19909979. 
  173. ↑ "Antidepressant-like effects of mineralocorticoid but not glucocorticoid antagonists in the lateral septum: interactions with the serotonergic system". Behavioural Brain Research 223 (1): 88–98. September 2011. doi:10.1016/j.bbr.2011.04.008. PMID 21515309. 
  174. ↑ 174.0 174.1 174.2 "A safe and practical method for the preparation of 7α-thioether and thioester derivatives of spironolactone". Steroids 78 (1): 102–7. January 2013. doi:10.1016/j.steroids.2012.09.005. PMID 23063964. 
  175. ↑ 175.0 175.1 175.2 International Agency for Research on Cancer; World Health Organization (2001). Some Thyrotropic Agents. World Health Organization. pp. 325–. ISBN 978-92-832-1279-9. https://books.google.com/books?id=l965aqw_LSkC&pg=PA325. Retrieved 6 October 2016. 
  176. ↑ Ascites and Renal Dysfunction in Liver Disease: Pathogenesis, Diagnosis, and Treatment. John Wiley & Sons. 15 April 2008. pp. 229, 231. ISBN 978-1-4051-4370-7. https://books.google.com/books?id=Z3PARx4oYDgC&pg=PA231. 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)." 
  177. ↑ Heart Failure: Pharmacologic Management. John Wiley & Sons. 15 April 2008. pp. 89–103. ISBN 978-1-4051-7253-0. https://books.google.com/books?id=6IfumyQQ35wC&pg=PA89. Retrieved 13 August 2018. 
  178. ↑ Pharmacology (6th ed.). Wolter Kluwer Health. 15 June 2015. pp. 248–249. GGKEY:N57K51AQ0UA. https://books.google.com/books?id=AK1fDwAAQBAJ&pg=PA248. [yes|permanent dead link|dead link}}]
  179. ↑ "Diuretics in the treatment of hypertension. Part 2: loop diuretics and potassium-sparing agents". Expert Opinion on Pharmacotherapy 15 (5): 605–21. April 2014. doi:10.1517/14656566.2014.879117. PMID 24456327. 
  180. ↑ 180.0 180.1 180.2 "The spironolactone renaissance". Expert Opinion on Investigational Drugs 10 (5): 943–54. May 2001. doi:10.1517/13543784.10.5.943. PMID 11322868. 
  181. ↑ Yen and Jaffe's Reproductive Endocrinology. Elsevier Health Sciences. 13 September 2013. pp. 237–. ISBN 978-1-4557-2758-2. https://books.google.com/books?id=KZ95AAAAQBAJ&pg=PA237. Retrieved 13 August 2018. 
  182. ↑ "Treatment of hirsutism with spironolactone". Clinics in Endocrinology and Metabolism 15 (2): 363–71. May 1986. doi:10.1016/S0300-595X(86)80030-5. PMID 2941190. 
  183. ↑ Essentials of Strength Training and Conditioning 4th Edition. Human Kinetics. 23 September 2015. pp. 76–. ISBN 978-1-4925-0162-6. https://books.google.com/books?id=bfuXCgAAQBAJ&pg=PA76. Retrieved 14 August 2018. 
  184. ↑ 184.0 184.1 Comprehensive Dermatologic Drug Therapy E-Book. Elsevier Health Sciences. 18 October 2012. pp. 364–. ISBN 978-1-4557-3801-4. https://books.google.com/books?id=Tqpsm5WKKlcC&pg=PA364. 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" 
  185. ↑ Chronic Hyperandrogenic Anovulation. CRC Press. 15 December 1990. pp. 152–. ISBN 978-1-85070-322-8. https://books.google.com/books?id=q6zqFrCLUoIC&pg=PA152. Retrieved 6 October 2016. 
  186. ↑ "Antiandrogen therapy in dermatology". International Journal of Dermatology 35 (11): 770–8. November 1996. doi:10.1111/j.1365-4362.1996.tb02970.x. PMID 8915726. 
  187. ↑ 187.0 187.1 187.2 "Chemical suppression of steroidogenesis". Environmental Health Perspectives 38: 119–27. April 1981. doi:10.1289/ehp.8138119. PMID 6786868. 
  188. ↑ "Polycystic ovary syndrome: chemical pharmacotherapy". Expert Opinion on Pharmacotherapy 16 (9): 1369–93. June 2015. doi:10.1517/14656566.2015.1047344. PMID 26001184. 
  189. ↑ "Contrasting effects of eplerenone and spironolactone on adrenal cell steroidogenesis". Hormone and Metabolic Research 41 (1): 35–9. January 2009. doi:10.1055/s-0028-1087188. PMID 18819053. 
  190. ↑ Brody's Human Pharmacology - E-Book. Elsevier Health Sciences. 1 April 2009. pp. 472–. ISBN 978-0-323-07575-6. https://books.google.com/books?id=kfsrz_-OrMQC&pg=PA472. 
  191. ↑ 191.0 191.1 "On the inhibitory action of 29 drugs having side effect gynecomastia on estrogen production". The Journal of Steroid Biochemistry and Molecular Biology 82 (2–3): 209–16. October 2002. doi:10.1016/S0960-0760(02)00154-1. PMID 12477487. 
  192. ↑ "Pathophysiology of spironolactone-induced gynecomastia". Annals of Internal Medicine 87 (4): 398–403. October 1977. doi:10.7326/0003-4819-87-4-398. PMID 907238. 
  193. ↑ "Inhibitors of 17 beta-hydroxysteroid dehydrogenases". Current Medicinal Chemistry 10 (6): 453–77. March 2003. doi:10.2174/0929867033368222. PMID 12570693. 
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  195. ↑ "Spironolactone use and the risk of breast and gynecologic cancers". Cancer Epidemiology 37 (6): 870–5. December 2013. doi:10.1016/j.canep.2013.10.004. PMID 24189467. 
  196. ↑ "Type 2 17-β hydroxysteroid dehydrogenase as a novel target for the treatment of osteoporosis". Future Medicinal Chemistry 7 (11): 1431–56. 2015. doi:10.4155/fmc.15.74. PMID 26230882. 
  197. ↑ Pharmacologic Approaches to Heart Failure, An Issue of Heart Failure Clinics, E-Book. Elsevier Health Sciences. 28 October 2014. pp. 562–. ISBN 978-0-323-32612-4. https://books.google.com/books?id=KNWlBAAAQBAJ&pg=PA562. Retrieved 13 August 2018. 
  198. ↑ 198.0 198.1 "Role of mineralocorticoid receptors on the hypothalamus-pituitary-adrenal axis in humans". Endocrine 43 (1): 51–8. February 2013. doi:10.1007/s12020-012-9750-8. PMID 22836869. 
  199. ↑ 199.0 199.1 "Blockade of the mineralocorticoid receptor in healthy men: effects on experimentally induced panic symptoms, stress hormones, and cognition". Neuropsychopharmacology 32 (1): 232–8. January 2007. doi:10.1038/sj.npp.1301217. PMID 17035932. 
  200. ↑ "Mineralocorticoid receptor function in depressed patients and healthy individuals". Progress in Neuro-Psychopharmacology & Biological Psychiatry 71: 183–8. November 2016. doi:10.1016/j.pnpbp.2016.08.003. PMID 27519144. 
  201. ↑ Clinical Reproductive Medicine and Surgery. Elsevier Health Sciences. 1 January 2007. pp. 271–. ISBN 978-0-323-03309-1. https://books.google.com/books?id=fOPtaEIKvcIC&pg=PA271. Retrieved 13 August 2018. 
  202. ↑ "Non-interaction of spironolactone medication and cortisol metabolism in man". Klinische Wochenschrift 56 (3): 135–8. February 1978. doi:10.1007/BF01478568. PMID 628197. 
  203. ↑ "Effect of eplerenone versus spironolactone on cortisol and hemoglobin A1(c) levels in patients with chronic heart failure". American Heart Journal 160 (5): 915–21. November 2010. doi:10.1016/j.ahj.2010.04.024. PMID 21095280. 
  204. ↑ Hepatology: Textbook and Atlas. Springer Science & Business Media. 11 March 2009. pp. 312–. ISBN 978-3-540-76839-5. https://books.google.com/books?id=oL6d9KuVqLQC&pg=PA312. Retrieved 13 August 2018. 
  205. ↑ Williams Textbook of Endocrinology E-Book. Elsevier Health Sciences. 12 May 2011. pp. 571–. ISBN 978-1-4377-3600-7. https://books.google.com/books?id=nbg1QOAObicC&pg=PA571. 
  206. ↑ "The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism". Endocrine Reviews 23 (5): 687–702. October 2002. doi:10.1210/er.2001-0038. PMID 12372848. 
  207. ↑ "Spironolactone and intermenstrual bleeding in polycystic ovary syndrome with normal BMI". Journal of Endocrinological Investigation 39 (9): 1015–21. September 2016. doi:10.1007/s40618-016-0466-0. PMID 27072668. 
  208. ↑ "Mineralocorticoid receptor antagonists: the evolution of utility and pharmacology". Kidney International 57 (4): 1408–11. April 2000. doi:10.1046/j.1523-1755.2000.00983.x. PMID 10760075. 
  209. ↑ "The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions". The Journal of Clinical Investigation 102 (5): 1016–23. September 1998. doi:10.1172/JCI3703. PMID 9727070. 
  210. ↑ "Spironolactone: disposition, metabolism, pharmacodynamics, and bioavailability". Drug Metabolism Reviews 8 (1): 151–88. 1978. doi:10.3109/03602537808993782. PMID 363379. 
  211. ↑ "Aspects on pharmacokinetics of some diuretics". Acta Pharmacologica et Toxicologica 54 (Suppl 1): 17–29. 1984. doi:10.1111/j.1600-0773.1984.tb03626.x. PMID 6369882. 
  212. ↑ "The metabolism and biopharmaceutics of spironolactone in man". Reviews on Drug Metabolism and Drug Interactions 5 (4): 273–302. 1987. doi:10.1515/DMDI.1987.5.4.273. PMID 3333882. 
  213. ↑ "Update in diuretic therapy: clinical pharmacology". Seminars in Nephrology 31 (6): 483–94. November 2011. doi:10.1016/j.semnephrol.2011.09.003. PMID 22099505. 
  214. ↑ "Molecular pharmacology of the mineralocorticoid receptor: prospects for novel therapeutics". Molecular and Cellular Endocrinology 350 (2): 310–7. March 2012. doi:10.1016/j.mce.2011.06.025. PMID 21771637. 
  215. ↑ "Mineralocorticoid receptor antagonists-pharmacodynamics and pharmacokinetic differences". Current Opinion in Pharmacology 27: 78–85. April 2016. doi:10.1016/j.coph.2016.02.005. PMID 26939027. 
  216. ↑ "Steroidal and Novel Non-steroidal Mineralocorticoid Receptor Antagonists in Heart Failure and Cardiorenal Diseases: Comparison at Bench and Bedside". Heart Failure. Handbook of Experimental Pharmacology. 243. 2017. pp. 271–305. doi:10.1007/164_2016_76. ISBN 978-3-319-59658-7. 
  217. ↑ "Simultaneous determination of spironolactone and its metabolites in human plasma". Journal of Pharmaceutical and Biomedical Analysis 14 (8–10): 1359–65. June 1996. doi:10.1016/S0731-7085(96)01767-0. PMID 8818057. 
  218. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named CaroneOxberry2017
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  220. ↑ "Influence of food on the bioavailability of spironolactone". Clinical Pharmacology and Therapeutics 40 (5): 531–6. November 1986. doi:10.1038/clpt.1986.219. PMID 3769384. 
  221. ↑ "Enhancement by food of canrenone bioavailability from spironolactone". Clinical Pharmacology and Therapeutics 22 (1): 100–3. July 1977. doi:10.1002/cpt1977221100. PMID 872489. 
  222. ↑ "Biological actions and metabolism of currently used pharmacological agents for the treatment of congestive heart failure". Current Drug Metabolism 10 (3): 206–19. March 2009. doi:10.2174/138920009787846314. PMID 19442083. 
  223. ↑ "Spironolactone". Analytical Profiles of Drug Substances and Excipients 29: 261–320. 2002. doi:10.1016/S1075-6280(02)29009-6. ISBN 978-0-12-260829-2. ISSN 1075-6280. 
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  226. ↑ "Interaction of digitalis and spironolactone with human sex steroid receptors". The Journal of Clinical Endocrinology and Metabolism 46 (2): 338–44. February 1978. doi:10.1210/jcem-46-2-338. PMID 86546. 
  227. ↑ "Transport of steroid hormones: interaction of 70 drugs with testosterone-binding globulin and corticosteroid-binding globulin in human plasma". The Journal of Clinical Endocrinology and Metabolism 53 (1): 69–75. July 1981. doi:10.1210/jcem-53-1-69. PMID 7195405. 
  228. ↑ "[Binding capacity of sex hormone binding globulin and corticosteroid binding globulin in serum of male patients with liver cirrhosis (author's transl)]" (in de). Journal of Clinical Chemistry and Clinical Biochemistry. Zeitschrift für klinische Chemie und klinische Biochemie 18 (2): 137–43. February 1980. PMID 7189544. 
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  230. ↑ "Genetic, molecular and clinical determinants for the involvement of aldosterone and its receptors in major depression". Nephron Physiology 128 (1–2): 17–25. 2014. doi:10.1159/000368265. PMID 25376974. 
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  236. ↑ Pharmacology for Nurses. Jones & Bartlett Publishers. 1 November 2014. pp. 169–. ISBN 978-1-4496-8940-7. https://books.google.com/books?id=7P-9BQAAQBAJ&pg=PA169. Retrieved 6 October 2016. 
  237. ↑ Cytochrome P450: Structure, Mechanism, and Biochemistry. Springer. 13 March 2015. pp. 867–. ISBN 978-3-319-12108-6. https://books.google.com/books?id=abZnBwAAQBAJ&pg=PA867. 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." 
  238. ↑ Advances in Clinical Chemistry. Academic Press. 31 December 2012. pp. 69–. ISBN 978-0-12-405852-1. https://books.google.com/books?id=sC8h4KM0nmYC&pg=PA69. 
  239. ↑ Analytical Profiles of Drug Substances and Excipients. Academic Press. 26 November 2002. p. 309. ISBN 978-0-12-260829-2. https://books.google.com/books?id=RMN5zMW64ZEC&pg=PA309. Retrieved 27 May 2012. 
  240. ↑ 240.0 240.1 Endocrinology - E-Book: Adult and Pediatric. Elsevier Health Sciences. 18 May 2010. pp. 2401–. ISBN 978-1-4557-1126-0. https://books.google.com/books?id=W4dZ-URK8ZoC&pg=PA2401. "[Spironolactone] is a potent antimineralocorticoid which was developed as a progestational analog [...]" 
  241. ↑ 241.0 241.1 241.2 241.3 The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. 14 November 2014. p. 1111. ISBN 978-1-4757-2085-3. https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA1111. 
  242. ↑ 242.0 242.1 "Spironolactone". https://pubchem.ncbi.nlm.nih.gov/compound/5833. 
  243. ↑ 243.0 243.1 "Spironolactone | C24H32O4S". ChemSpider. Royal Society of Chemistry. http://www.chemspider.com/Chemical-Structure.5628.html?rid=b578a389-d64b-4ec2-ae20-309e5f3abd11. 
  244. ↑ "Micronized progesterone: vaginal and oral uses". Clinical Obstetrics and Gynecology 38 (4): 902–14. December 1995. doi:10.1097/00003081-199538040-00024. PMID 8616985. 
  245. ↑ "Molecular mechanisms of mineralocorticoid receptor antagonism by eplerenone". Mini Reviews in Medicinal Chemistry 5 (8): 709–18. August 2005. doi:10.2174/1389557054553811. PMID 16101407. 
  246. ↑ 246.0 246.1 "Pharmacology of estrogens and progestogens: influence of different routes of administration". Climacteric 8 (Suppl 1): 3–63. August 2005. doi:10.1080/13697130500148875. PMID 16112947. 
  247. ↑ "SC 25152: A potent mineralocorticoid antagonist with reduced affinity for the 5 alpha-dihydrotestosterone receptor of human and rat prostate". The Journal of Clinical Endocrinology and Metabolism 47 (1): 171–5. July 1978. doi:10.1210/jcem-47-1-171. PMID 263288. 
  248. ↑ "Progestational activity of certain steroid-17-spirolactones". Proceedings of the Society for Experimental Biology and Medicine 99 (2): 451–2. November 1958. doi:10.3181/00379727-99-24380. PMID 13601900. 
  249. ↑ The British Encyclopaedia of Medical Practice: Medical progress. Butterworth & Company. 1961. p. 302. https://books.google.com/books?id=wvIfAQAAMAAJ. 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." 
  250. ↑ "Synthetic approaches towards the multi target drug spironolactone and its potent analogues/derivatives". Steroids 118: 76–92. February 2017. doi:10.1016/j.steroids.2016.12.010. PMID 28041953. 
  251. ↑ 251.0 251.1 "Action of new steroids in blocking effects of aldosterone and desoxycorticosterone on salt". Science 126 (3281): 1015–6. November 1957. doi:10.1126/science.126.3281.1015. PMID 13486053. Bibcode: 1957Sci...126.1015K. 
  252. ↑ 252.0 252.1 "Sodium diuresis induced by steroidal antagonists of aldosterone". Science 126 (3281): 1016–8. November 1957. doi:10.1126/science.126.3281.1016. PMID 13486054. Bibcode: 1957Sci...126.1016L. 
  253. ↑ Pharmaceutical Substances, 5th Edition, 2009: Syntheses, Patents and Applications of the most relevant APIs. Thieme. 14 May 2014. pp. 1279–1280. ISBN 978-3-13-179275-4. https://books.google.com/books?id=4lCGAwAAQBAJ&pg=PA1279. Retrieved 27 December 2016. 
  254. ↑ Pharmaceutical Innovation: Revolutionizing Human Health. Chemical Heritage Foundation. 1999. pp. 198–. ISBN 978-0-941901-21-5. https://books.google.com/books?id=IH4lPs6S1bMC&pg=PA198. Retrieved 27 December 2016. "Spironolactone was patented in 1961 and has been used since then to treat heart failure, liver cirrhosis, and nephrotic syndrome." 
  255. ↑ Aging and Heart Failure: Mechanisms and Management. Springer Science & Business Media. 19 February 2014. pp. 175–. ISBN 978-1-4939-0268-2. https://books.google.com/books?id=0e23BAAAQBAJ&pg=PA175. Retrieved 27 December 2016. 
  256. ↑ The Practice of Medicinal Chemistry. Academic Press. 2 May 2011. pp. 34–. ISBN 978-0-08-056877-5. https://books.google.com/books?id=Qmt1_DQkCpEC&pg=PA34. 
  257. ↑ "Spironolactone and gynaecomastia". The Lancet 280 (7261): 886. 1962. doi:10.1016/S0140-6736(62)90668-2. ISSN 0140-6736. 
  258. ↑ "Anti-androgenic activity of spironolactone". Steroids 14 (4): 449–50. October 1969. doi:10.1016/s0039-128x(69)80007-3. PMID 5344274. 
  259. ↑ "Antiandrogens and the skin". International Journal of Dermatology 17 (3): 167–79. April 1978. doi:10.1111/j.1365-4362.1978.tb06057.x. PMID 148431. 
  260. ↑ "Endocrinology: Relationship Between the Plasma Levels of Luteinizing Hormone and Progesterone During the Normal Menstrual Cycle". Obstetrical & Gynecological Survey 23 (3): 271–277. 1968. 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.". 
  261. ↑ "Androgen antagonists in androgen target tissues". Pharmacology & Therapeutics 24 (3): 367–400. 1984. doi:10.1016/0163-7258(84)90010-X. PMID 6205409. 
  262. ↑ "Spironolactone therapy for hirsutism in a hyperandrogenic woman". Annals of Internal Medicine 89 (5 Pt 1): 643–4. November 1978. doi:10.7326/0003-4819-89-5-643. PMID 717935. 
  263. ↑ "New therapeutic approach to the hirsute patient". Fertility and Sterility 32 (3): 276–9. September 1979. doi:10.1016/s0015-0282(16)44232-9. PMID 488407. 
  264. ↑ "A novel use of spironolactone: treatment of hirsutism". The Journal of Clinical Endocrinology and Metabolism 51 (3): 429–32. September 1980. doi:10.1210/jcem-51-3-429. PMID 7410528. 
  265. ↑ Glass' Office Gynecology. Lippincott Williams & Wilkins. 2014. pp. 47–. ISBN 978-1-60831-820-9. https://books.google.com/books?id=w2AGBAAAQBAJ&pg=PA47. 
  266. ↑ The Polycystic Ovary Syndrome. Orient Blackswan. 2004. pp. 78–. ISBN 978-81-250-2633-4. https://books.google.com/books?id=Jxd03OBIn9wC&pg=PA78. Retrieved 4 July 2017. 
  267. ↑ Practical Pediatric and Adolescent Gynecology. John Wiley & Sons. 29 March 2013. pp. 371–. ISBN 978-1-118-53857-9. https://books.google.com/books?id=vAA5Z5aqlUQC&pg=PT371. Retrieved 4 July 2017. 
  268. ↑ "Physical Aspects of Transgender Endocrine Therapy". International Journal of Transgenderism 9 (3–4): 111–134. 2006. doi:10.1300/J485v09n03_06. ISSN 1553-2739. 
  269. ↑ "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. 
  270. ↑ "Endocrine Treatment of Transsexual Male-to-Female Persons". Management of Gender Dysphoria. 2015. pp. 83–91. doi:10.1007/978-88-470-5696-1_10. ISBN 978-88-470-5695-4. 
  271. ↑ 271.0 271.1 Steroidal Activity in Experimental Animals and Man. Elsevier Science. 5 December 2016. pp. 392–. ISBN 978-1-4832-7299-3. https://books.google.com/books?id=BbLfBAAAQBAJ&pg=PA392. 
  272. ↑ Aldosterone: International Series of Monographs in Pure and Applied Biology. Elsevier Science. 11 January 2017. pp. 379. ISBN 978-1-4831-5997-3. https://books.google.com/books?id=ya3YBAAAQBAJ&pg=PA380. Retrieved 31 December 2020. 
  273. ↑ 273.0 273.1 Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. 31 October 1999. pp. 261–. ISBN 978-0-7514-0499-9. https://books.google.com/books?id=mqaOMOtk61IC&pg=PA261. Retrieved 1 December 2016. 
  274. ↑ 274.0 274.1 274.2 274.3 Benign Prostatic Hypertrophy. Springer Science & Business Media. 6 December 2012. pp. 266–. ISBN 978-1-4612-5476-8. https://books.google.com/books?id=Z5K-BwAAQBAJ&pg=PA266. Retrieved 30 July 2017. 
  275. ↑ 275.0 275.1 275.2 275.3 275.4 275.5 "Endocrine treatment of benign prostatic hypertrophy: current concepts". Urology 37 (1): 1–16. January 1991. doi:10.1016/0090-4295(91)80069-j. PMID 1702565. 
  276. ↑ 276.0 276.1 "A double-blind, controlled, clinical trial of spironolactone for benign prostatic hypertrophy". The British Journal of Surgery 58 (7): 485–9. July 1971. doi:10.1002/bjs.1800580703. PMID 4104441. 
  277. ↑ "Hormonal Therapy of Prostatic Cancer". Cancer 45 (Suppl 7): 1929–1936. April 1980. doi:10.1002/cncr.1980.45.s7.1929. PMID 29603164. 
  278. ↑ "New methods of endocrine management of prostatic cancer". The Journal of Urology 137 (1): 1–10. January 1987. doi:10.1016/S0022-5347(17)43855-9. PMID 3540320. 
  279. ↑ 279.0 279.1 279.2 "Spironolactone blocks Epstein-Barr virus production by inhibiting EBV SM protein function". Proceedings of the National Academy of Sciences of the United States of America 113 (13): 3609–14. March 2016. doi:10.1073/pnas.1523686113. PMID 26976570. Bibcode: 2016PNAS..113.3609V. 
  280. ↑ "Rosacea: II. Therapy". Journal of the American Academy of Dermatology 51 (4): 499–512; quiz 513–4. October 2004. doi:10.1016/j.jaad.2004.03.033. PMID 15389184. 
  281. ↑ "Rosacea and its comorbidities". Journal of Translational Medicine and Research 21 (1): 17. 2016. doi:10.21614/jtmr-21-1-68. ISSN 2393-4999. 
  282. ↑ "Nonclassical Treatments". Pathogenesis and Treatment of Acne and Rosacea. 2014. pp. 713–717. doi:10.1007/978-3-540-69375-8_95. ISBN 978-3-540-69374-1. 
  283. ↑ "Spironolactone may reduce the risk of incident rosacea". The Journal of Investigative Dermatology 133 (10): 2480–2483. October 2013. doi:10.1038/jid.2013.186. PMID 23594595. 
  284. ↑ "Long-term efficacy of spironolactone on pain, mood, and quality of life in women with fibromyalgia: An observational case series". Scandinavian Journal of Pain 5 (2): 63–71. April 2014. doi:10.1016/j.sjpain.2013.12.003. PMID 29913681. 
  285. ↑ "From patient observation to potential new therapies-Is old spironolactone a new analgesic?". Scandinavian Journal of Pain 5 (2): 61–62. April 2014. doi:10.1016/j.sjpain.2014.02.006. PMID 29913669. 
  286. ↑ "Current pharmacotherapy options for bulimia nervosa and binge eating disorder". Expert Opinion on Pharmacotherapy 13 (14): 2015–26. October 2012. doi:10.1517/14656566.2012.721781. PMID 22946772. 



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