Spironolactone has antiandrogenic activity. For this reason, it is 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.[38] Spironolactone is used for the treatment of hirsutism in the United States.[39] 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.[40]
Heart failure
While loop diuretics remain first-line for most people with heart failure, spironolactone has been 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%.[41]
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 US Food and Drug Administration (FDA) 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.[44]
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.[45] There is no evidence of person-oriented outcome at any dose in this group.[45]
Because of the antiandrogenic activity of spironolactone, it can be quite effective in treating acne in women.[62][63][64] In addition, spironolactone reduces oil that is naturally produced in the skin and can be used to treat oily skin.[63][65][52] 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.[63][65] Oftentimes, for women treating acne, spironolactone is prescribed and paired with a birth control pill.[63][65] Positive results in the pairing of these two medications have been observed, although these results may not be seen for up to three months.[63][65] Spironolactone has been reported to produce a 50 to 100% improvement in acne at sufficiently high doses.[66] Response to treatment generally requires 1 to 3months in the case of acne and up to 6months in the case of hirsutism.[66] Ongoing therapy is generally required to avoid relapse of symptoms.[66] Spironolactone is commonly used in the treatment of hirsutism in women, and is considered to be a first-line antiandrogen for this indication.[67] Spironolactone can be used in the treatment of female-pattern hair loss (pattern scalp hair loss in women).[68] There is tentative low quality evidence supporting its use for this indication.[69] Although apparently effective, not all cases of female-pattern hair loss are dependent on androgens.[70]
Antiandrogens like spironolactone are male-specific teratogens which can feminize male fetuses due to their antiandrogenic effects.[60][71][72] For this reason, it is recommended that antiandrogens only be used to treat women who are of reproductive age in conjunction with adequate contraception.[60][71][72] Oral contraceptives, which contain an estrogen and a progestin, are typically used for this purpose.[60] 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.[60][73]
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.[68] As an example, spironolactone has been reported to reduce symptoms of acne in males.[74] An additional example is the usefulness of spironolactone as an antiandrogen in transgender women.[75][76][77]
Topical spironolactone is effective in the treatment of acne as well.[78] 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.[79][80] 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.[80]
Comparison
Spironolactone, the 5α-reductase inhibitorfinasteride, and the nonsteroidal antiandrogenflutamide all appear to have similar effectiveness in the treatment of hirsutism.[67][81][82] 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.[67] 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.[67] One study showed that spironolactone or the steroidal antiandrogencyproterone acetate both in combination with a birth control pill had equivalent effectiveness for hirsutism.[67] 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.[67] The nonsteroidal antiandrogen bicalutamide is an alternative option to flutamide with improved safety.[83][84]
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.[63] However, this was based on low- to very-low-quality evidence.[63] 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.[85] In addition, some clinical research has found that flutamide is more effective than spironolactone in the treatment of acne.[63] In one study, flutamide decreased acne scores by 80% within 3months, whereas spironolactone decreased symptoms by only 40% in the same period.[86][87][88] However, the use of flutamide for acne is limited by its liver toxicity.[89][90][91][92] Bicalutamide is a potential alternative to flutamide for acne as well.[93][94] 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.[85][61]
There is insufficient clinical evidence to compare the effectiveness of spironolactone with other antiandrogens for female-pattern hair loss.[95] 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.[85][96][97] However, higher doses also have greater side effects, such as menstrual irregularities.[63]
A potential side effect of spironolactone is hyperkalemia (high potassium levels), which, in severe cases, can be life-threatening.[8] Hyperkalemia can present as a normal anion-gap metabolic acidosis.[8] It has been reported that the addition of spironolactone to loop diuretics in people with heart failure was associated with a higher risk of hyperkalemia and acute kidney injury.[114] Spironolactone may put people at a heightened risk for gastrointestinal issues like nausea, vomiting, diarrhea, cramping, and gastritis.[8][115] In addition, there has been some evidence suggesting an association between use of the medication and bleeding from the stomach and duodenum,[8] though a causal relationship between the two has not been established.[116][117] Also, spironolactone is immunosuppressive in the treatment of sarcoidosis.[118]
Most of the side effects of spironolactone are dose-dependent.[62] Low-dose spironolactone is generally very well tolerated.[62] Even higher doses of spironolactone, such as 100mg/day, are well tolerated in most individuals.[62] Dose-dependent side effects of spironolactone include menstrual irregularities, breast tenderness, and enlargement, orthostatic hypotension, and hyperkalemia.[62] The side effects of spironolactone are usually mild and rarely result in discontinuation.[62]
Spironolactone can cause hyperkalemia, or high blood potassium levels.[111] Rarely, this can be fatal.[111] Of people with heart disease prescribed typical dosages of spironolactone, 10 to 15% develop some degree of hyperkalemia, and 6% develop severe hyperkalemia.[111] At a higher dosage, a rate of hyperkalemia of 24% has been observed.[119] 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.[111][119][120][35] However, another population-based study in Scotland failed to replicate these findings.[121][122] 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 antibiotictrimethoprim, and potassiumsupplements), and at higher dosages of spironolactone.[111][35][123][124]
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.[63][65][125] 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.[63] 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.[63][65][125] However, other sources have claimed that hyperkalemia can nonetheless also occur in people with more normal renal function and presumably without such risk factors.[35] Occasional testing on a case-by-case basis in those with known risk factors may be justified.[63] 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.[63] Notably, non-use of routine potassium monitoring with spironolactone in young women would reduce costs associated with its use.[63]
Among young gender-diverse individuals taking spironolactone, hyperkalemia is rare and (if present) transient and asymptomatic. Larger doses do not appear to increase risks in this population.[126] A broader retrospective study found that the rate of hyperkalemia in gender-diverse individuals is correlated with age, with those above 45 years old being more at risk. The finding suggests that patients below or at 45 years old without other conditions that affect potassium handling can be spared from routine monitoring.[127]
Breast changes
Spironolactone can cause breast pain and breast enlargement in women.[128][129] This is "probably because of estrogenic effects on target tissue."[111] 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.[130][62] Breast enlargement and tenderness may occur in 26% of women at high doses.[86] Some women regard spironolactone-induced breast enlargement as a positive effect.[63]
Spironolactone also commonly and dose-dependently produces gynecomastia (breast development) as a side effect in men.[110][129][131][132] At low doses, the rate is only 5 to 10%,[132] but at high doses, up to or exceeding 50% of men may develop gynecomastia.[110][129][131] In the RALES, 9.1% of men taking 25mg/day spironolactone developed gynecomastia, compared to 1.3% of controls.[133] Conversely, in studies of healthy men given high-dose spironolactone, gynecomastia occurred in 3 of 10 (30%) at 100mg/day, in 5 of 8 (62.5%) at 200mg/day, and in 6 of 9 (66.7%) at 400mg/day, relative to none of 12 controls.[134][135] The severity of gynecomastia with spironolactone varies considerably, but is usually mild.[110] As with breast enlargement caused by spironolactone in women, gynecomastia due to spironolactone in men is often although inconsistently accompanied by breast tenderness.[110] In the RALES, only 1.7% of men developed breast pain, relative to 0.1% of controls.[133]
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.[133] Gynecomastia induced by spironolactone usually regresses after a few weeks following discontinuation of the medication.[110] 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.[136][137]
Menstrual disturbances
Spironolactone at higher doses can cause menstrual irregularities as a side effect in women.[62] These irregularities include metrorrhagia (intermenstrual bleeding), amenorrhea (absence of menstruation), and breakthrough bleeding.[62] 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.[86][111] For example, about 20% of women experienced menstrual irregularities with 50 to 100mg/day spironolactone, whereas about 70% experienced menstrual irregularities at 200mg/day.[62] Most women taking moderate doses of spironolactone develop amenorrhea, and normal menstruation usually returns within two months of discontinuation.[111] Spironolactone produces an irregular and anovulatory pattern of menstrual cycles.[86] It is also associated with metrorrhagia and menorrhagia (heavy menstrual bleeding) in large percentages of women,[128] as well as with polymenorrhea (short menstrual cycles).[138][139] The medication reportedly has no birth control effect.[140]
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.[86][141][142] An alternative proposed cause is inhibition of 17α-hydroxylase and hence sex steroidmetabolism by spironolactone and consequent changes in sex hormone levels.[110] Indeed, CYP17A1genotype is associated with polymenorrhea.[143] 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.[86][144]
Mood changes
Research is mixed on whether antimineralocorticoids like spironolactone have positive or negative effects on mood.[145][146][147] In any case, it is possible that spironolactone might have the capacity to increase the risk of depressive symptoms.[145][146][147] However, a 2017 hybrid systematic review found that the incidence of depression in women treated with spironolactone for acne was less than 1%.[63] Likewise, a 10-year observational study found that the incidence of depression in 196transgender women taking high-dose spironolactone in combination with an estrogen was less than 1%.[148]
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
Spironolactone can cross the placenta.[128] It has been found to be present in the breast milk of lactating mothers.[8] However, only very small amounts of spironolactone and its metabolite canrenone enter breast milk, and the amount received by an infant during breastfeeding (<0.5% of the mother's dose) is considered to be insignificant.[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 (200mg/kg per day).[161][163] Another study found permanent, dose-related reproductive tract abnormalities rat offspring of both sexes at lower doses (50 to 100mg/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 2mg/day or high doses of 50 to 100mg/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]
There is no specific antidote for overdose of spironolactone.[8] Treatment may consist of induction of vomiting or stomach evacuation by gastric lavage.[8] The treatment of spironolactone overdose is supportive, with the purpose of maintaining hydration, electrolyte balance, and vital functions.[8] Spironolactone should be discontinued in people with impaired kidney function or hyperkalemia.[8]
Interactions
Spironolactone often increases serum potassium levels and can cause hyperkalemia, a very serious condition. Therefore, it is recommended that people using this medication avoid potassium supplements and salt substitutes containing potassium.[169] 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[125] and in healthy young gender-diverse individuals taking spironolactone for hormone therapy.[127] 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.[170]
Spironolactone has been reported to induce the enzymesCYP3A4 and certain UDP-glucuronosyltransferases (UGTs), which can result in interactions with various medications.[15][171][172] However, it has also been reported that metabolites of spironolactone irreversibly inhibit CYP3A4.[173] 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.[174] Spironolactone has also been found to inhibitUGT2B7.[175] Spironolactone can also have numerous other interactions, most commonly with other cardiac and blood pressure medications, for instance digoxin.[8]
Licorice, which has indirect mineralocorticoid activity by inhibiting mineralocorticoid metabolism, has been found to inhibit the antimineralocorticoid effects of spironolactone.[176][177][178] 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.[176][177] On the opposite end of the spectrum, spironolactone is useful in reversing licorice-induced hypokalemia.[179][180]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.[37][181]
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.[182][183] However, other research contradicts this hypothesis and has suggested that spironolactone might produce antidepressant effects. For instance, studies showing antidepressant-like effects of spironolactone in animals.[184]
7α-Thiomethylspironolactone, the major active form of spironolactone. It accounts for about 80% of the potassium-sparing effect of spironolactone.Canrenone, the second major active form of spironolactone. It accounts for around 10 to 25% of the potassium-sparing effect of spironolactone.
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.[109][134] 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.[202][203] 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.[204][205] 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.[202][206][207]
In response to the antimineralocorticoid activity spironolactone, and in an attempt to maintain homeostasis, the body increases aldosterone production in the adrenal cortex.[208][209][210] Some studies have found that levels of cortisol, a glucocorticoid hormone that is also produced in the adrenal cortex, are increased as well.[209][210][211] Spironolactone “acts at the basolateral side of the upper-distal tubule as well as in the collecting tubule,” and does not have glucocorticoid-like effects at these specific sites; it can sometimes be prescribed as an alternative to glucocorticoids for patients with Glucocorticoid-Remediable Aldosteronism characterized by aldosterone excess,[141][212][97][213] In patients “receiving spironolactone, there was a significant positive correlation between the change in cortisol and the change in HbA1c (r = 0.489, P = .003).”[214] Patients taking spironolactone must be monitored for side effects including dizziness, headache, fatigue, diarrhea, hypertriglyceridemia and elevated liver enzymes.[215][216]
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.[135] Nonetheless, much has been elucidated about the pharmacokinetics of spironolactone over the decades.[221][222][223][11][224][225][226][227]
Absorption
Levels of spironolactone and its major active metabolites after a single oral dose of 100mg spironolactone in humans.
The bioavailability of spironolactone when taken by mouth is 60 to 90%.[11][12][13] 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.[229][230][231] 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.[229][232][233] 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 200mg spironolactone.[195]Steady-state concentrations of spironolactone are achieved within 8 to 10days of treatment initiation.[186][234]
Little or no systemic absorption has been observed with topical spironolactone.[235]
Distribution
Spironolactone and its metabolite canrenone are highly plasma protein bound, with percentages of 88.0% and 99.2%, respectively.[11][14] Spironolactone is bound equivalently to albumin and α1-acid glycoprotein, while canrenone is bound only to albumin.[11][14] Spironolactone and its metabolite 7α-thiospironolactone show very low or negligible affinity for sex hormone-binding globulin (SHBG).[236][237] 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.[238] This is in contradiction with widespread statements that spironolactone increases free estradiol levels by displacing estradiol from SHBG.[97][239]
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][185] 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.[243] 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][185][186] Other known but more minor metabolites of spironolactone include 7α-thiospironolactone (7α-TS), which is an important intermediate to the major metabolites of spironolactone,[15] as well as the 7α-methyl ethyl ester of spironolactone and the 6β-hydroxy-7α-methyl ethyl ester of spironolactone.[20]
Spironolactone, also known as 7α-acetylthiospirolactone, is a steroidal17α-spirolactone, or more simply a spirolactone.[107] It can most appropriately be conceptualized as a derivative of progesterone,[133][249][234] 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-lactonering, and an acetylthio group has been substituted in at the C7α position.[250][251][252] These structural modifications of progesterone confer increased oralbioavailability and potency,[253] potent antiandrogenic activity, and strongly reduced progestogenic activity.[254] The C7α substitution is likely responsible for or involved in the antiandrogenic activity of spironolactone, as 7α-thioprogesterone (SC-8365), unlike progesterone,[255] is an antiandrogen with similar affinity to the AR as that of spironolactone.[256] 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.[255][257][258]
Names
Spironolactone is also known by the following equivalent chemical names:[250][251][252]
The natriuretic effects of progesterone were demonstrated in 1955, and the development of spironolactone as a synthetic antimineralocorticoid analogue of progesterone shortly followed this.[133][249][260][261] Spironolactone was first synthesized in 1957,[28][260][261] was patented between 1958 and 1961,[262][263] and was first marketed, as an antimineralocorticoid, in 1959.[264][265] Gynecomastia was first reported with spironolactone in 1962,[107][266] and the antiandrogenic activity of the medication was first described in 1969.[267] This shortly followed the discovery in 1967 that gynecomastia is an important and major side effect of AR antagonists.[268][269] Spironolactone was first studied in the treatment of hirsutism in women in 1978.[270][176][271][272][273] It has since become the most widely used antiandrogen for dermatological indications in women in the United States.[103][274][275][276] 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.[277][278][279]
Early oral spironolactone tablets showed poor absorption.[280] The formulation was eventually changed to a micronized formulation with particle sizes of less than 50μg, which resulted in approximately 4-fold increased potency.[280][281]
Society and culture
Generic names
Generic spironolactone for veterinary use
The English, French, and generic name of the medication is spironolactone and this is its INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, USPTooltip United States Pharmacopeia, BANTooltip British Approved Name, DCFTooltip Dénomination Commune Française, and JANTooltip Japanese Accepted Name.[105][106][250][282] Its name is spironolactonum in Latin, Spironolacton in German, espironolactona in Spanish and Portuguese, and spironolattone in Italian (which is also its DCITTooltip Denominazione Comune Italiana).[105][106][282]
Spironolactone is also known by its developmental code names SC-9420 and NSC-150339.[105][106][250]
Brand names
Spironolactone is marketed under various brand names throughout the world.[105][106] The original brand name of spironolactone is Aldactone.[105][106] Other 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.[105][106]
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.[106]
Availability
Spironolactone is marketed throughout the world.[105][106]
Research
Prostate conditions
Spironolactone has been studied at a high dosage in the treatment of benign prostatic hyperplasia (BPH; enlarged prostate).[283][284][285] It was found to be better than placebo in terms of symptom relief following three months of treatment.[283][284] However, this was not maintained after six months of treatment, by which point the improvements had largely disappeared.[283][284][285] Moreover, no difference was observed between spironolactone and placebo with regard to volume of residual urine or prostate size.[283][284] Gynecomastia was observed in about 5% of people.[284] On the basis of these results, it has been said that spironolactone has no place in the treatment of BPH.[284]
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.[288] This effect of spironolactone was determined to be independent of its antimineralocorticoid actions.[288]
Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of drugs that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. They act by blocking the androgen receptor (AR) and/or inhibiting or suppressing androgen production. They can be thought of as the functional opposites of AR agonists, for instance androgens and anabolic steroids (AAS) like testosterone, DHT, and nandrolone and selective androgen receptor modulators (SARMs) like enobosarm. Antiandrogens are one of three types of sex hormone antagonists, the others being antiestrogens and antiprogestogens.
Cimetidine, sold under the brand name Tagamet among others, is a histamine H2 receptor antagonist that inhibits stomach acid production. It is mainly used in the treatment of heartburn and peptic ulcers.
Potassium-sparing diuretics or antikaliuretics refer to drugs that cause diuresis without causing potassium loss in the urine. They are typically used as an adjunct in management of hypertension, cirrhosis, and congestive heart failure. The steroidal aldosterone antagonists can also be used for treatment of primary hyperaldosteronism. Spironolactone, a steroidal aldosterone antagonist, is also used in management of female hirsutism and acne from PCOS or other causes.
Drospirenone is a progestin and antiandrogen medication which is used in birth control pills to prevent pregnancy and in menopausal hormone therapy, among other uses. It is available both alone under the brand name Slynd and in combination with an estrogen under the brand name Yasmin among others. The medication is an analog of the drug spironolactone. Drospirenone is taken by mouth.
Flutamide, sold under the brand name Eulexin among others, is a nonsteroidal antiandrogen (NSAA) which is used primarily to treat prostate cancer. It is also used in the treatment of androgen-dependent conditions like acne, excessive hair growth, and high androgen levels in women. It is taken by mouth, usually three times per day.
A mineralocorticoid receptor antagonist or aldosterone antagonist, is a diuretic drug which antagonizes the action of aldosterone at mineralocorticoid receptors. This group of drugs is often used as adjunctive therapy, in combination with other drugs, for the management of chronic heart failure. Spironolactone, the first member of the class, is also used in the management of hyperaldosteronism and female hirsutism. Most antimineralocorticoids, including spironolactone, are steroidal spirolactones. Finerenone is a nonsteroidal antimineralocorticoid.
Eplerenone, sold under the brand name Inspra, is an aldosterone antagonist type of potassium-sparing diuretic that is used to treat chronic heart failure and high blood pressure, particularly for people with resistant hypertension due to elevated aldosterone. It is a steroidal antimineralocorticoid of the spirolactone group and a selective aldosterone receptor antagonist (SARA).
Canrenone, sold under the brand names Contaren, Luvion, Phanurane, and Spiroletan, is a steroidal antimineralocorticoid of the spirolactone group related to spironolactone which is used as a diuretic in Europe, including in Italy and Belgium. It is also an important active metabolite of spironolactone, and partially accounts for its therapeutic effects.
Feminizing hormone therapy, also known as transfeminine hormone therapy, is hormone therapy and sex reassignment therapy to change the secondary sex characteristics of transgender people from masculine or androgynous to feminine. It is a common type of transgender hormone therapy and is used to treat transgender women and non-binary transfeminine individuals. Some, in particular intersex people, but also some non-transgender people, take this form of therapy according to their personal needs and preferences.
Spirolactones are a class of functional group in organic chemistry featuring a cyclic ester attached spiro to another ring system. The name is also used to refer to a class of synthetic steroids, called steroid-17α-spirolactones, 17α-spirolactosteroids, or simply 17α-spirolactones, which feature their spirolactone group at the C17α position. They are antimineralocorticoids, or antagonists of the mineralocorticoid receptor, and have been employed clinically as potassium-sparing diuretics. Some also possess progestogenic and/or antiandrogen properties, which have both contributed to side effects and been utilized for medical indications. The spirolactones were developed by G. D. Searle & Company in the 1950s and thereafter and were denoted as "SC" compounds.
Cyproterone acetate (CPA), sold alone under the brand name Androcur or with ethinylestradiol under the brand names Diane or Diane-35 among others, is an antiandrogen and progestin medication used in the treatment of androgen-dependent conditions such as acne, excessive body hair growth, early puberty, and prostate cancer, as a component of feminizing hormone therapy for transgender individuals, and in birth control pills. It is formulated and used both alone and in combination with an estrogen. CPA is taken by mouth one to three times per day.
Benorterone, also known by its developmental code name SKF-7690 and as 17α-methyl-B-nortestosterone, is a steroidal antiandrogen which was studied for potential medical use but was never marketed. It was the first known antiandrogen to be studied in humans. It is taken by mouth or by application to skin.
A nonsteroidal antiandrogen (NSAA) is an antiandrogen with a nonsteroidal chemical structure. They are typically selective and full or silent antagonists of the androgen receptor (AR) and act by directly blocking the effects of androgens like testosterone and dihydrotestosterone (DHT). NSAAs are used in the treatment of androgen-dependent conditions in men and women. They are the converse of steroidal antiandrogens (SAAs), which are antiandrogens that are steroids and are structurally related to testosterone.
A steroidal antiandrogen (SAA) is an antiandrogen with a steroidal chemical structure. They are typically antagonists of the androgen receptor (AR) and act both by blocking the effects of androgens like testosterone and dihydrotestosterone (DHT) and by suppressing gonadal androgen production. SAAs lower concentrations of testosterone through simulation of the negative feedback inhibition of the hypothalamus. SAAs are used in the treatment of androgen-dependent conditions in men and women, and are also used in veterinary medicine for the same purpose. They are the converse of nonsteroidal antiandrogens (NSAAs), which are antiandrogens that are not steroids and are structurally unrelated to testosterone.
←
6β-Hydroxy-7α-thiomethylspironolactone (6β-OH-7α-TMS) is a steroidal antimineralocorticoid of the spirolactone group and a major active metabolite of spironolactone. Other important metabolites of spironolactone include 7α-thiospironolactone, 7α-thiomethylspironolactone, and canrenone (SC-9376).
7α-Thiospironolactone is a steroidal antimineralocorticoid and antiandrogen of the spirolactone group and a minor active metabolite of spironolactone. Other important metabolites of spironolactone include 7α-thiomethylspironolactone, 6β-hydroxy-7α-thiomethylspironolactone (6β-OH-7α-TMS), and canrenone (SC-9376).
The medical uses of bicalutamide, a nonsteroidal antiandrogen (NSAA), include the treatment of androgen-dependent conditions and hormone therapy to block the effects of androgens. Indications for bicalutamide include the treatment of prostate cancer in men, skin and hair conditions such as acne, seborrhea, hirsutism, and pattern hair loss in women, high testosterone levels in women, hormone therapy in transgender women, as a puberty blocker to prevent puberty in transgender girls and to treat early puberty in boys, and the treatment of long-lasting erections in men. It may also have some value in the treatment of paraphilias and hypersexuality in men.
Comparison of the nonsteroidal antiandrogen (NSAA) bicalutamide with other antiandrogens reveals differences between the medications in terms of efficacy, tolerability, safety, and other parameters. Relative to the other first-generation NSAAs, flutamide and nilutamide, bicalutamide shows improved potency, efficacy, tolerability, and safety, and has largely replaced these medications in clinical practice. Compared to the second-generation NSAAs, enzalutamide and apalutamide, bicalutamide has inferior potency and efficacy but similar tolerability and safety and a lower propensity for drug interactions.
The pharmacodynamics of spironolactone, an antimineralocorticoid and antiandrogen medication, concern its mechanisms of action, including its biological targets and activities, as well as its physiological effects. The pharmacodynamics of spironolactone are characterized by high antimineralocorticoid activity, moderate antiandrogenic activity, and weak steroidogenesis inhibition. In addition, spironolactone has sometimes been found to increase estradiol and cortisol levels and hence could have slight indirect estrogenic and glucocorticoid effects. The medication has also been found to interact very weakly with the estrogen and progesterone receptors, and to act as an agonist of the pregnane X receptor. Likely due to increased activation of the estrogen and/or progesterone receptors, spironolactone has very weak but significant antigonadotropic effects.
↑ Clark MA, Harvey RA, Finkel R, Rey JA, Whalen K (15 December 2011). Pharmacology. Lippincott Williams & Wilkins. pp.286, 337. ISBN978-1-4511-1314-3. Archived from the original on 7 October 2022. Retrieved 6 November 2016.
1 2 3 4 Takamura N, Maruyama T, Ahmed S, Suenaga A, Otagiri M (April 1997). "Interactions of aldosterone antagonist diuretics with human serum proteins". Pharmaceutical Research. 14 (4): 522–6. doi:10.1023/A:1012168020545. PMID9144743. S2CID13227538.
1 2 Los LE, Pitzenberger SM, Ramjit HG, Coddington AB, Colby HD (1994). "Hepatic metabolism of spironolactone. Production of 3-hydroxy-thiomethyl metabolites". Drug Metabolism and Disposition. 22 (6): 903–8. PMID7895608.
1 2 3 Burinkul S, Panyakhamlerd K, Suwan A, Tuntiviriyapun P, Wainipitapong S (July 2021). "Anti-Androgenic Effects Comparison Between Cyproterone Acetate and Spironolactone in Transgender Women: A Randomized Controlled Trial". The Journal of Sexual Medicine. 18 (7): 1299–1307. doi:10.1016/j.jsxm.2021.05.003. PMID34274044.
↑ World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl:10665/371090. WHO/MHP/HPS/EML/2023.02.
↑ Prior JC, Vigna YM, Watson D (1989). "Spironolactone with Physiological Female Steroids for Presurgical Therapy of Male-To-Female Transsexualism". Archives of Sexual Behavior. 18 (1): 49–57. doi:10.1007/BF01579291. PMID2540730.
↑ Loy R, Seibel MM (December 1988). "Evaluation and therapy of polycystic ovarian syndrome". Endocrinology and Metabolism Clinics of North America. 17 (4): 785–813. doi:10.1016/S0889-8529(18)30410-9. PMID3143568.
↑ Chatterjee S, Moeller C, Shah N, Bolorunduro O, Lichstein E, Moskovits N, etal. (August 2012). "Eplerenone is not superior to older and less expensive aldosterone antagonists". The American Journal of Medicine. 125 (8): 817–25. doi:10.1016/j.amjmed.2011.12.018. PMID22840667.
1 2 Batterink J, Stabler SN, Tejani AM, Fowkes CT (August 2010). "Spironolactone for hypertension". The Cochrane Database of Systematic Reviews (8): CD008169. doi:10.1002/14651858.CD008169.pub2. PMID20687095.
1 2 Katsambas AD, Dessinioti C (2010). "Hormonal therapy for acne: why not as first line therapy? facts and controversies". Clinics in Dermatology. 28 (1): 17–23. doi:10.1016/j.clindermatol.2009.03.006. PMID20082945.
↑ Giorgetti R, di Muzio M, Giorgetti A, Girolami D, Borgia L, Tagliabracci A (March 2017). "Flutamide-induced hepatotoxicity: ethical and scientific issues". European Review for Medical and Pharmacological Sciences. 21 (1 Suppl): 69–77. PMID28379593.
↑ Hassoun LA, Chahal DS, Sivamani RK, Larsen LN (June 2016). "The use of hormonal agents in the treatment of acne". Seminars in Cutaneous Medicine and Surgery. 35 (2): 68–73. doi:10.12788/j.sder.2016.027 (inactive 1 November 2024). PMID27416311.{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)
↑ Azarchi S, Bienenfeld A, Lo Sicco K, Marchbein S, Shapiro J, Nagler AR (June 2019). "Androgens in women: Hormone-modulating therapies for skin disease". Journal of the American Academy of Dermatology. 80 (6): 1509–1521. doi:10.1016/j.jaad.2018.08.061. PMID30312645. S2CID52973096.
↑ Brown J, Farquhar C, Lee O, Toomath R, Jepson RG (April 2009). "Spironolactone versus placebo or in combination with steroids for hirsutism and/or acne". The Cochrane Database of Systematic Reviews (2): CD000194. doi:10.1002/14651858.CD000194.pub2. hdl:2292/9640. PMID19370553.
↑ Wandelt-Freerksen E (July 1977). "[Aldactone in the treatment of sarcoidosis of the lungs (author's transl)]". Zeitschrift für Erkrankungen der Atmungsorgane. 149 (1): 156–9. PMID607621.
1 2 Lainscak M, Pelliccia F, Rosano G, Vitale C, Schiariti M, Greco C, etal. (December 2015). "Safety profile of mineralocorticoid receptor antagonists: Spironolactone and eplerenone". International Journal of Cardiology. 200: 25–9. doi:10.1016/j.ijcard.2015.05.127. PMID26404748.
1 2 Holsboer F (1999). "The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists to treat depression and anxiety". Journal of Psychiatric Research. 33 (3): 181–214. doi:10.1016/S0022-3956(98)90056-5. PMID10367986.
1 2 Armanini D, Castello R, Scaroni C, Bonanni G, Faccini G, Pellati D, etal. (March 2007). "Treatment of polycystic ovary syndrome with spironolactone plus licorice". European Journal of Obstetrics, Gynecology, and Reproductive Biology. 131 (1): 61–67. doi:10.1016/j.ejogrb.2006.10.013. PMID17113210.
↑ Salassa RM, Mattox VR, Rosevear JW (November 1962). "Inhibition of the "mineralocorticoid" activity of licorice by spironolactone". The Journal of Clinical Endocrinology and Metabolism. 22 (11): 1156–9. doi:10.1210/jcem-22-11-1156. PMID13991036.
↑ Lin SH, Yang SS, Chau T, Halperin ML (March 2003). "An unusual cause of hypokalemic paralysis: chronic licorice ingestion". The American Journal of the Medical Sciences. 325 (3): 153–6. doi:10.1097/00000441-200303000-00008. PMID12640291.
↑ Holsboer, F. The Rationale for Corticotropin-Releasing Hormone Receptor (CRH-R) Antagonists to Treat Depression and Anxiety. J. Psychiatr. Res. 33, 181–214 (1999).
↑ Otte C, Hinkelmann K, Moritz S, Yassouridis A, Jahn H, Wiedemann K, etal. (April 2010). "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. doi:10.1016/j.jpsychires.2009.10.006. PMID19909979.
↑ Mostalac-Preciado CR, de Gortari P, López-Rubalcava C (September 2011). "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. doi:10.1016/j.bbr.2011.04.008. PMID21515309. S2CID26986501.
1 2 3 Agusti G, Bourgeois S, Cartiser N, Fessi H, Le Borgne M, Lomberget T (January 2013). "A safe and practical method for the preparation of 7α-thioether and thioester derivatives of spironolactone". Steroids. 78 (1): 102–7. doi:10.1016/j.steroids.2012.09.005. PMID23063964. S2CID8992318.
1 2 3 International Agency for Research on Cancer, World Health Organization (2001). Some Thyrotropic Agents. World Health Organization. pp.325–. ISBN978-92-832-1279-9. Archived from the original on 7 October 2022. Retrieved 6 October 2016.
1 2 Satoh T, Itoh S, Seki T, Itoh S, Nomura N, Yoshizawa I (October 2002). "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. doi:10.1016/S0960-0760(02)00154-1. PMID12477487. S2CID9972497.
↑ Rose LI, Underwood RH, Newmark SR, Kisch ES, Williams GH (October 1977). "Pathophysiology of spironolactone-induced gynecomastia". Annals of Internal Medicine. 87 (4): 398–403. doi:10.7326/0003-4819-87-4-398. PMID907238.
↑ Poirier D (March 2003). "Inhibitors of 17 beta-hydroxysteroid dehydrogenases". Current Medicinal Chemistry. 10 (6): 453–77. doi:10.2174/0929867033368222. PMID12570693.
↑ Poirier D (July 2009). "Advances in development of inhibitors of 17beta hydroxysteroid dehydrogenases". Anti-Cancer Agents in Medicinal Chemistry. 9 (6): 642–60. doi:10.2174/187152009788680000. PMID19601747.
↑ Biggar RJ, Andersen EW, Wohlfahrt J, Melbye M (December 2013). "Spironolactone use and the risk of breast and gynecologic cancers". Cancer Epidemiology. 37 (6): 870–5. doi:10.1016/j.canep.2013.10.004. PMID24189467.
↑ Soubhye J, Alard IC, van Antwerpen P, Dufrasne F (2015). "Type 2 17-β hydroxysteroid dehydrogenase as a novel target for the treatment of osteoporosis". Future Medicinal Chemistry. 7 (11): 1431–56. doi:10.4155/fmc.15.74. PMID26230882.
↑ Abshagen U, Spörl S, L'age M (February 1978). "Non-interaction of spironolactone medication and cortisol metabolism in man". Klinische Wochenschrift. 56 (3): 135–8. doi:10.1007/BF01478568. PMID628197. S2CID30885047.
↑ Yamaji M, Tsutamoto T, Kawahara C, Nishiyama K, Yamamoto T, Fujii M, etal. (November 2010). "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. doi:10.1016/j.ahj.2010.04.024. PMID21095280.
↑ Sabbadin C, Andrisani A, Zermiani M, Donà G, Bordin L, Ragazzi E, etal. (September 2016). "Spironolactone and intermenstrual bleeding in polycystic ovary syndrome with normal BMI". Journal of Endocrinological Investigation. 39 (9): 1015–21. doi:10.1007/s40618-016-0466-0. PMID27072668. S2CID34201900.
↑ Overdiek HW, Merkus FW (1987). "The metabolism and biopharmaceutics of spironolactone in man". Reviews on Drug Metabolism and Drug Interactions. 5 (4): 273–302. doi:10.1515/DMDI.1987.5.4.273. PMID3333882. S2CID29482256.
↑ Kolkhof P, Borden SA (March 2012). "Molecular pharmacology of the mineralocorticoid receptor: prospects for novel therapeutics". Molecular and Cellular Endocrinology. 350 (2): 310–7. doi:10.1016/j.mce.2011.06.025. PMID21771637. S2CID36894459.
↑ Yang J, Young MJ (April 2016). "Mineralocorticoid receptor antagonists-pharmacodynamics and pharmacokinetic differences". Current Opinion in Pharmacology. 27: 78–85. doi:10.1016/j.coph.2016.02.005. PMID26939027.
↑ Kolkhof P, Jaisser F, Kim SY, Filippatos G, Nowack C, Pitt B (2017). "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. Vol.243. Springer. pp.271–305. doi:10.1007/164_2016_76. ISBN978-3-319-59658-7. PMID27830348.
↑ Jankowski A, Skorek-Jankowska A, Lamparczyk H (June 1996). "Simultaneous determination of spironolactone and its metabolites in human plasma". Journal of Pharmaceutical and Biomedical Analysis. 14 (8–10): 1359–65. doi:10.1016/S0731-7085(96)01767-0. PMID8818057.
↑ Overdiek HW, Merkus FW (November 1986). "Influence of food on the bioavailability of spironolactone". Clinical Pharmacology and Therapeutics. 40 (5): 531–6. doi:10.1038/clpt.1986.219. PMID3769384. S2CID32313529.
↑ Melander A, Danielson K, Scherstén B, Thulin T, Wåhlin E (July 1977). "Enhancement by food of canrenone bioavailability from spironolactone". Clinical Pharmacology and Therapeutics. 22 (1): 100–3. doi:10.1002/cpt1977221100. PMID872489. S2CID12827850.
↑ Saini-Chohan HK, Hatch GM (March 2009). "Biological actions and metabolism of currently used pharmacological agents for the treatment of congestive heart failure". Current Drug Metabolism. 10 (3): 206–19. doi:10.2174/138920009787846314. PMID19442083.
↑ Rey FO, Valterio C, Locatelli L, Ramelet AA, Felber JP (April 1988). "Lack of endocrine systemic side effects after topical application of spironolactone in man". Journal of Endocrinological Investigation. 11 (4): 273–8. doi:10.1007/BF03350151. PMID3411088. S2CID30535049.
↑ Rifka SM, Pita JC, Vigersky RA, Wilson YA, Loriaux DL (February 1978). "Interaction of digitalis and spironolactone with human sex steroid receptors". The Journal of Clinical Endocrinology and Metabolism. 46 (2): 338–44. doi:10.1210/jcem-46-2-338. PMID86546.
↑ Pugeat MM, Dunn JF, Nisula BC (July 1981). "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. doi:10.1210/jcem-53-1-69. PMID7195405.
↑ Kaulhausen H, Rohner HG, Siedek M, Lafosse M, Breuer H (February 1980). "[Binding capacity of sex hormone binding globulin and corticosteroid-binding globulin in serum of male patients with liver cirrhosis (author's transl)]". Journal of Clinical Chemistry and Clinical Biochemistry. Zeitschrift für klinische Chemie und klinische Biochemie (in German). 18 (2): 137–43. PMID7189544.
↑ Künzel HE (March 2012). "Psychopathological symptoms in patients with primary hyperaldosteronism--possible pathways". Hormone and Metabolic Research. 44 (3): 202–7. doi:10.1055/s-0032-1301921. PMID22351473. S2CID23273751.
1 2 Varin F, Tu TM, Benoît F, Villeneuve JP, Théorêt Y (February 1992). "High-performance liquid chromatographic determination of spironolactone and its metabolites in human biological fluids after solid-phase extraction". Journal of Chromatography. 574 (1): 57–64. doi:10.1016/0378-4347(92)80097-A. PMID1629288.
↑ Cutler GB, Pita JC, Rifka SM, Menard RH, Sauer MA, Loriaux DL (July 1978). "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. doi:10.1210/jcem-47-1-171. PMID263288.
↑ Hertz R, Tullner WW (November 1958). "Progestational activity of certain steroid-17-spirolactones". Proceedings of the Society for Experimental Biology and Medicine. 99 (2): 451–2. doi:10.3181/00379727-99-24380. PMID13601900. S2CID20150966.
↑ Larik FA, Saeed A, Shahzad D, Faisal M, El-Seedi H, Mehfooz H, etal. (February 2017). "Synthetic approaches towards the multi target drug spironolactone and its potent analogues/derivatives". Steroids. 118: 76–92. doi:10.1016/j.steroids.2016.12.010. PMID28041953. S2CID7003499.
↑ Neill JD, Johansson ED, Datta JK, Knobil, E (1968). "Endocrinology: Relationship Between the Plasma Levels of Luteinizing Hormone and Progesterone During the Normal Menstrual Cycle". Obstetrical & Gynecological Survey. 23 (3): 271–277. doi:10.1097/00006254-196803000-00006.
↑ Ober KP, Hennessy JF (November 1978). "Spironolactone therapy for hirsutism in a hyperandrogenic woman". Annals of Internal Medicine. 89 (5 Pt 1): 643–4. doi:10.7326/0003-4819-89-5-643. PMID717935.
↑ Boisselle A, Tremblay RR (September 1979). "New therapeutic approach to the hirsute patient". Fertility and Sterility. 32 (3): 276–9. doi:10.1016/s0015-0282(16)44232-9. PMID488407.
↑ Shapiro G, Evron S (September 1980). "A novel use of spironolactone: treatment of hirsutism". The Journal of Clinical Endocrinology and Metabolism. 51 (3): 429–32. doi:10.1210/jcem-51-3-429. PMID7410528.
↑ Dahl M, Feldman JL, Goldberg JM, Jaberi A (2006). "Physical Aspects of Transgender Endocrine Therapy". International Journal of Transgenderism. 9 (3–4): 111–134. doi:10.1300/J485v09n03_06. ISSN1553-2739. S2CID146232471.
↑ Prior JC, Vigna YM, Watson D, Diewold P, Robinow O. "Spironolactone in the presurgical therapy of male to female transsexuals: Philosophy and experience of the Vancouver Gender Dysphoria Clinic". Journal of Sex Information & Education Council of Canada (1): 1–7.
1 2 Castro JE, Griffiths HJ, Edwards DE (July 1971). "A double-blind, controlled, clinical trial of spironolactone for benign prostatic hypertrophy". The British Journal of Surgery. 58 (7): 485–9. doi:10.1002/bjs.1800580703. PMID4104441. S2CID27601630.
↑ Pelle MT, Crawford GH, James WD (October 2004). "Rosacea: II. Therapy". Journal of the American Academy of Dermatology. 51 (4): 499–512, quiz 513–4. doi:10.1016/j.jaad.2004.03.033. PMID15389184.
↑ Merticariu A, Marinescu L, Giurcăneanu C (2016). "Rosacea and its comorbidities". Journal of Translational Medicine and Research. 21 (1): 17. doi:10.21614/jtmr-21-1-68 (inactive 9 November 2024). ISSN2393-4999.{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)
↑ Wernze H, Herdegen T (April 2014). "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. doi:10.1016/j.sjpain.2013.12.003. PMID29913681. S2CID49305801.
This page is based on this Wikipedia article Text is available under the CC BY-SA 4.0 license; additional terms may apply. Images, videos and audio are available under their respective licenses.
