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 transgender hormone therapy in transfeminine people.[4][17][18] 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][19] Spironolactone belongs to a class of medications known as potassium-sparing diuretics.[4]
Spironolactone was discovered in 1957, and was introduced in 1959.[20][21][22] It is on the World Health Organization's List of Essential Medicines.[23][24] It is available as a generic medication.[4] In 2020, it was the 51st most commonly prescribed medication in the United States, with more than 13 million prescriptions.[25][26]
Medical uses[edit]
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.[27] 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.[28] Spironolactone is also used to treat Bartter's syndrome due to its ability to raise potassium levels.[29]
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.[30] Spironolactone is the most commonly used medication in the treatment of hirsutism in the United States.[31] 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, in women, dose of 50-100mg in 1 or 2 doses.[32]
Heart failure[edit]
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%.[33]
In a randomized evaluation which studied people with severe congestive heart failure, people treated with spironolactone were found to have a relative risk of death of 0.70 or an overall 30% relative risk reduction compared to the placebo group, indicating a significant death and morbidity benefit of the medication. People in the study's intervention arm also had fewer symptoms of heart failure and were hospitalized less frequently.[34] Likewise, it has shown benefit for and is recommended in patients who recently had a heart attack and have an ejection fraction less than 40%, who develop symptoms consistent with heart failure, or have a history of diabetes mellitus. Spironolactone should be considered a good add-on agent, particularly in those patients "not" yet optimized on ACE inhibitors and beta-blockers.[33] Of note, a recent randomized, double-blinded study of spironolactone in patients with symptomatic heart failure with "preserved" ejection fraction (i.e. >45%) found no reduction in death from cardiovascular events, aborted cardiac arrest, or hospitalizations when spironolactone was compared to placebo.[35]
It is recommended that alternatives to spironolactone be considered if serum creatinine is greater than 2.5 mg/dL (221 μmol/L) in males or greater than 2 mg/dL (176.8 μmol/L) in females, if glomerular filtration rate is below 30 mL/min or with a serum potassium of greater than 5.0 mEq/L given the potential for adverse events detailed elsewhere in this article. Doses should be adjusted according to the degree of kidney function as well.[33]
According to a systematic review, in heart failure with preserved ejection fraction, treatment with spironolactone did not improve patient outcomes. This is based on the TOPCAT Trial examining this issue, which found that of those treated with placebo had a 20.4% incidence of negative outcome vs 18.6% incidence of negative outcome with spironolactone. However, because the p-value of the study was 0.14, and the unadjusted hazard ratio was 0.89 with a 95% confidence interval of 0.77 to 1.04, it is determined the finding had no statistical significance. Hence the finding that patient outcomes are not improved with use of spironolactone.[36] When blood samples from 366 participants in the TOPCAT study were analyzed for presence of canrenone (an active metabolite of spironolactone), 30% of blood samples from Russia lacked detectable residues of canrenone. This led to the conclusion that the TOPCAT trial results in Russia do not reflect actual clinical experience with spironolactone in patients with preserved ejection fraction.[37] The TOPCAT study results are now considered to have been invalidated. The study's prime investigator and other prominent research cardiologists are now advising physicians treating heart failure with preserved ejection fraction to consider prescribing spironolactone pending outcome of two multicenter trials of newer medications.[38]
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.[39]
The clinical benefits of spironolactone as a diuretic are typically not seen until 2–3 days after dosing begins. Likewise, the maximal antihypertensive effect may not be seen for 2–3 weeks.[medical citation needed]
Unlike with some other diuretics, potassium supplementation should not be administered while taking spironolactone, as this may cause dangerous elevations in serum potassium levels resulting in hyperkalemia and potentially deadly abnormal heart rhythms.[medical citation needed]
High blood pressure[edit]
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.[40] There is no evidence of person-oriented outcome at any dose in this group.[40]
High aldosterone levels[edit]
Spironolactone is used in the treatment of hyperaldosteronism (high aldosterone levels or mineralocorticoid excess), for instance primary aldosteronism (Conn's syndrome).[41] Antimineralocorticoids like spironolactone and eplerenone are first-line treatments for hyperaldosteronism.[41] They improve blood pressure and potassium levels, as well as left ventricular hypertrophy, albuminuria, and carotid intima-media thickness, in people with primary aldosteronism.[41] In people with hyperaldosteronism due to unilateral aldosterone-producing adrenocortical adenoma, adrenalectomy should be preferred instead of antimineralocorticoids.[41] Spironolactone should not be used to treat primary aldosteronism in pregnancy due to its antiandrogen-related risk of teratogenicity in male fetuses.[42][43][44][45]
Skin and hair conditions[edit]
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).[46][47] 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.[48][49] 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.[50][51][52][53][54] 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.[46] In accordance with the preceding, antiandrogens are highly effective in the treatment of the aforementioned androgen-dependent skin and hair conditions.[55][56]
Because of the antiandrogenic activity of spironolactone, it can be quite effective in treating acne in women.[57] In addition, spironolactone reduces oil that is naturally produced in the skin and can be used to treat oily skin.[58][59][47] 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.[58][59] Oftentimes, for women treating acne, spironolactone is prescribed and paired with a birth control pill.[58][59] Positive results in the pairing of these two medications have been observed, although these results may not be seen for up to three months.[58][59] Spironolactone has been reported to produce a 50 to 100% improvement in acne at sufficiently high doses.[60] Response to treatment generally requires 1 to 3 months in the case of acne and up to 6 months in the case of hirsutism.[60] Ongoing therapy is generally required to avoid relapse of symptoms.[60] Spironolactone is commonly used in the treatment of hirsutism in women, and is considered to be a first-line antiandrogen for this indication.[61] Spironolactone can be used in the treatment of female-pattern hair loss (pattern scalp hair loss in women).[62] There is tentative low quality evidence supporting its use for this indication.[63] Although apparently effective, not all cases of female-pattern hair loss are dependent on androgens.[64]
Antiandrogens like spironolactone are male-specific teratogens which can feminize male fetuses due to their antiandrogenic effects.[55][65][66] For this reason, it is recommended that antiandrogens only be used to treat women who are of reproductive age in conjunction with adequate contraception.[55][65][66] Oral contraceptives, which contain an estrogen and a progestin, are typically used for this purpose.[55] 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.[55][67]
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.[62] As an example, spironolactone has been reported to reduce symptoms of acne in males.[68] An additional example is the usefulness of spironolactone as an antiandrogen in transgender women.[69][70][71]
Topical spironolactone has been found to be effective in the treatment of acne as well.[72] 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.[73][74] 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.[74]
Comparison[edit]
Spironolactone, the 5α-reductase inhibitor finasteride, and the nonsteroidal antiandrogen flutamide all appear to have similar effectiveness in the treatment of hirsutism.[61][75][76] 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.[61] 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.[61] One study showed that spironolactone or the steroidal antiandrogen cyproterone acetate both in combination with a birth control pill had equivalent effectiveness for hirsutism.[61] 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.[61] The nonsteroidal antiandrogen bicalutamide is an alternative option to flutamide with improved safety.[77][78]
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.[58] However, this was based on low- to very-low-quality evidence.[58] 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.[79] In addition, some clinical research has found that flutamide is more effective than spironolactone in the treatment of acne.[58] In one study, flutamide decreased acne scores by 80% within 3 months, whereas spironolactone decreased symptoms by only 40% in the same time period.[80][81][82] However, the use of flutamide for acne is limited by its liver toxicity.[83][84][85][86] Bicalutamide is a potential alternative to flutamide for acne as well.[87][88] 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.[79][56]
There is insufficient clinical evidence to compare the effectiveness of spironolactone with other antiandrogens for female-pattern hair loss.[89] 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.[79][90][91] However, higher doses also have greater side effects, such as menstrual irregularities.[58]
Alternative Spironolactone Use[edit]
Spironolactone medication is not approved for use as an antiandrogen by the Food and Drug Administration; instead, it is used off-label for such purposes.[92]
Doses and forms[edit]
Spironolactone is typically used at a low dosage of 25 to 50 mg/day in the treatment of heart failure,[93][94][95][96] while it is used at low to high dosages of 25 to 200 mg/day in the treatment of essential hypertension,[93][96] and at high dosages of 100 to 400 mg/day for hyperaldosteronism and ascites due to cirrhosis.[97][98][99][100] The medication is typically used at high dosages of 100 to 200 mg/day in the treatment of skin and hair conditions in women,[101][102][103][104][105] and at high dosages of 100 to 400 mg/day in feminizing hormone therapy for transgender women.[106][107][108] Spironolactone can be used to treat symptoms of hyperandrogenism, such as polycystic ovary syndrome, in women, dose of 50-100mg in 1 or 2 doses.[32]
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.[109][110][111][112][113] 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][114] The medication is also available in combination with other medications, such as hydrochlorothiazide (brand name Aldactazide, others).[113][115] 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.[6] The only antimineralocorticoid that is available as a solution for parenteral use is the related medication potassium canrenoate.[116]
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.[117][118] It should also be used with caution in people with some neurological disorders, no urine production, acute kidney injury, or significant impairment of kidney excretory function with risk of hyperkalemia.[117]
Side effects[edit]
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),[80] ataxia (muscle incoordination), drowsiness, dizziness,[80] 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.[119] 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.[120][121] However, such doses of spironolactone are rarely used clinically.[121] In women, spironolactone can cause menstrual irregularities, breast tenderness, and breast enlargement.[30][58][101] Aside from these adverse effects, the side effects of spironolactone in women taking high doses are minimal, and it is well tolerated.[58][80][122]
The most important potential side effect of spironolactone is hyperkalemia (high potassium levels), which, in severe cases, can be life-threatening.[117] Hyperkalemia in these people can present as a normal anion-gap metabolic acidosis.[117] 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).[123] Spironolactone may put people at a heightened risk for gastrointestinal issues like nausea, vomiting, diarrhea, cramping, and gastritis.[117][124] In addition, there has been some evidence suggesting an association between use of the medication and bleeding from the stomach and duodenum,[117] though a causal relationship between the two has not been established.[125][126] Also, spironolactone is immunosuppressive in the treatment of sarcoidosis.[127]
Most of the side effects of spironolactone are dose-dependent.[57] Low-dose spironolactone is generally very well tolerated.[57] Even higher doses of spironolactone, such as 100 mg/day, are well tolerated in most individuals.[57] Dose-dependent side effects of spironolactone include menstrual irregularities, breast tenderness and enlargement, orthostatic hypotension, and hyperkalemia.[57] The side effects of spironolactone are usually mild and rarely result in discontinuation.[57]
High potassium levels[edit]
Spironolactone can cause hyperkalemia, or high blood potassium levels.[121] Rarely, this can be fatal.[121] Of people with heart disease prescribed typical dosages of spironolactone, 10 to 15% develop some degree of hyperkalemia, and 6% develop severe hyperkalemia.[121] At a higher dosage, a rate of hyperkalemia of 24% has been observed.[128] 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.[121][128][129][27] However, another population-based study in Scotland failed to replicate these findings.[130][131] 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.[121][27][132][133]
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.[58][59][134] 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.[58] 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.[58][59][134] However, other sources have claimed that hyperkalemia can nonetheless also occur in people with more normal renal function and presumably without such risk factors.[27] Occasional testing on a case-by-case basis in those with known risk factors may be justified.[58] 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.[58] Notably, non-use of routine potassium monitoring with spironolactone in young women would reduce costs associated with its use.[58]
Breast changes[edit]
Spironolactone frequently causes breast pain and breast enlargement in women.[105][135] This is "probably because of estrogenic effects on target tissue."[121] 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.[136][57] Breast enlargement and tenderness may occur in 26% of women at high doses.[80] Some women regard spironolactone-induced breast enlargement as a positive effect.[58]
Spironolactone also commonly and dose-dependently produces gynecomastia (breast development) as a side effect in men.[120][135][137][138] At low doses, the rate is only 5 to 10%,[138] but at high doses, up to or exceeding 50% of men may develop gynecomastia.[120][135][137] In the RALES, 9.1% of men taking 25 mg/day spironolactone developed gynecomastia, compared to 1.3% of controls.[139] 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.[140][141] The severity of gynecomastia with spironolactone varies considerably, but is usually mild.[120] As with breast enlargement caused by spironolactone in women, gynecomastia due to spironolactone in men is often although inconsistently accompanied by breast tenderness.[120] In the RALES, only 1.7% of men developed breast pain, relative to 0.1% of controls.[139]
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.[139] Gynecomastia induced by spironolactone usually regresses after a few weeks following discontinuation of the medication.[120] 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.[142][143]
Menstrual disturbances[edit]
Spironolactone at higher doses can cause menstrual irregularities as a side effect in women.[57] These irregularities include metrorrhagia (intermenstrual bleeding), amenorrhea (absence of menstruation), and breakthrough bleeding.[57] 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.[80][121] 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.[57] Most women taking moderate doses of spironolactone develop amenorrhea, and normal menstruation usually returns within two months of discontinuation.[121] Spironolactone produces an irregular and anovulatory pattern of menstrual cycles.[80] It is also associated with metrorrhagia and menorrhagia (heavy menstrual bleeding) in large percentages of women,[105] as well as with polymenorrhea (short menstrual cycles).[144][145] The medication reportedly has no birth control effect.[146]
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.[80][147][148] An alternative proposed cause is inhibition of 17α-hydroxylase and hence sex steroid metabolism by spironolactone and consequent changes in sex hormone levels.[120] Indeed, CYP17A1 genotype is associated with polymenorrhea.[149] 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.[80][150]
Mood changes[edit]
Research is mixed on whether antimineralocorticoids like spironolactone have positive or negative effects on mood.[151][152][153] In any case, it is possible that spironolactone might have the capacity to increase the risk of depressive symptoms.[151][152][153] However, a 2017 hybrid systematic review found that the incidence of depression in women treated with spironolactone for acne was less than 1%.[58] 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%.[154]
Rare reactions[edit]
Aside from hyperkalemia, spironolactone may rarely cause adverse reactions such as anaphylaxis, kidney failure,[155] hepatitis (two reported cases, neither serious),[156] agranulocytosis, DRESS syndrome, Stevens–Johnson syndrome or toxic epidermal necrolysis.[157][158] Five cases of breast cancer in patients who took spironolactone for prolonged periods of time have been reported.[121][138]
Spironolactone bodies[edit]
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.[159]
Pregnancy and breastfeeding[edit]
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.[105] 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.[117] 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.[160]
A study found that spironolactone was not associated with teratogenicity in the offspring of rats.[161][162][163] Because it is an antiandrogen, however, spironolactone could theoretically have the potential to cause feminization of male fetuses at sufficient doses.[161][162] 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).[161][163] Another study found permanent, dose-related reproductive tract abnormalities rat offspring of both sexes at lower doses (50 to 100 mg/kg per day).[163]
In practice however, although experience is limited, spironolactone has never been reported to cause observable feminization or any other congenital defects in humans.[161][162][164][165] Among 31 human newborns exposed to spironolactone in the first trimester, there were no signs of any specific birth defects.[165] 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.[165] 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.[160][161] 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).[165] 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.[161][166]
A 2019 systematic review found insufficient evidence that spironolactone causes birth defects in humans.[167] However, there was also insufficient evidence to be certain that it does not.[167]
Overdose[edit]
Spironolactone is relatively safe in acute overdose.[117] Symptoms following an acute overdose of spironolactone may include drowsiness, confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, and diarrhea.[117] In rare cases, hyponatremia, hyperkalemia, or hepatic coma may occur in individuals with severe liver disease.[117] However, these adverse reactions are unlikely in the event of an acute overdose.[117] Hyperkalemia can occur following an overdose of spironolactone, and this is especially so in people with decreased kidney function.[117] Spironolactone has been studied in fibromyalgia in women.[293][294] It has also been studied in bulimia nervosa in women, but was not found to be effective.[295]