Spironolactone
Template:Short description Template:Distinguish Template:Use dmy dates Template:Cs1 config Template:Main other <templatestyles src="Infobox drug/styles.css"/> {{#invoke:Infobox|infobox}}Template:Template other{{#invoke:TemplatePar |check |template=Template:Infobox_drug |all= |opt= pronounce= pronounce_ref= pronounce_comment= ATC_prefix= ATC_suffix= ATC_supplemental= ATCvet= biosimilars= CAS_number_Ref= CAS_number= CAS_supplemental= ChEBI= ChEBI_Ref= ChEMBL_Ref= ChEMBL= ChemSpiderID= ChemSpiderID_Ref= chirality= class= container_only= DailyMedID= data_page= DrugBank_Ref= DrugBank= Drugs.com= duration_of_action= INN= INN_EMA= IUPAC_name= IUPHAR_ligand= KEGG_Ref= KEGG= MedlinePlus= NIAID_ChemDB= PDB_ligand= PubChemSubstance= PubChem= StdInChIKey_Ref= StdInChIKey= StdInChI_Ref= StdInChI_comment= StdInChI= UNII_Ref= UNII= DTXSID= Verifiedfields= Watchedfields= addiction_liability= alt2= altL= altR= alt= bioavailability= boiling_high= boiling_notes= boiling_point= captionLR= caption= caption2= charge= chemical_formula= chemical_formula_ref= chemical_formula_comment= class1= class2= class3= class4= class5= class6= component1= component2= component3= component4= component5= component6= density= density_notes= dependency_liability= drug_name= elimination_half-life= engvar= excretion= image2= imageL= imageR= image= image_class= image_class2= image_classL= image_classR= Jmol= legal_AU= legal_BR= legal_CA= legal_DE= legal_EU= legal_NZ= legal_UK= legal_UN= legal_US= legal_AU_comment= legal_BR_comment= legal_CA_comment= legal_DE_comment= legal_UK_comment= legal_NZ_comment= legal_US_comment= legal_UN_comment= legal_EU_comment= legal_status= licence_CA= licence_EU= licence_US= license_CA= license_EU= license_US= mab_type= melting_high= melting_notes= melting_point= metabolism= metabolites= molecular_weight= molecular_weight_round= molecular_weight_unit= molecular_weight_ref= molecular_weight_comment= onset= pregnancy_AU= pregnancy_AU_comment= pregnancy_category= protein_bound= routes_of_administration= SMILES= smiles= solubility= sol_units= source= specific_rotation= synonyms= target= tradename= type= vaccine_type= verifiedrevid= width2= widthL= widthR= width= AAN= BAN= JAN= USAN= source_tissues= target_tissues= receptors= agonists= antagonists= precursor= biosynthesis= gt_target_gene= gt_vector= gt_nucleic_acid_type= gt_editing_method= gt_delivery_method= sec_combustion= Ac=Ag=Al=Am=Ar=As=At=Au=B=Ba=Be=Bh=Bi=Bk=Br=C=Ca=Cd=Ce=Cf=Cl=Cm=Cn=Co=Cr=Cs=Cu= D=Db=Ds=Dy=Er=Es=Eu=F=Fe=Fl=Fm=Fr=Ga=Gd=Ge=H=He=Hf=Hg=Ho=Hs=I=In=Ir=K=Kr=La=Li=Lr=Lu=Lv= Mc=Md=Mg=Mn=Mo=Mt=N=Na=Nb=Nd=Ne=Nh=Ni=No=Np=O=Og=Os=P=Pa=Pb=Pd=Pm=Po=Pr=Pt=Pu=Ra=Rb=Re=Rf=Rg=Rh=Rn=Ru=S=Sb=Sc=Se=Sg=Si=Sm=Sn=Sr=Ta=Tb=Tc=Te=Th=Ti=Tl=Tm=Ts=U=V=W=Xe=Y=Yb=Zn=Zr= index_label= index2_label= index_comment= index2_comment= CAS_number2= CAS_supplemental2= ATC_prefix2= ATC_suffix2= ATC_supplemental2= PubChem2= PubChemSubstance2= IUPHAR_ligand2= DrugBank2= ChemSpiderID2= UNII2= KEGG2= ChEBI2= ChEMBL2= PDB_ligand2= NIAID_ChemDB2= SMILES2= smiles2= StdInChI2= StdInChIKey2= CAS_number2_Ref= ChEBI2_Ref= ChEMBL2_Ref= ChemSpiderID2_Ref= DrugBank2_Ref= KEGG2_Ref= StdInChI2_Ref= StdInChIKey2_Ref= UNII2_Ref= DTXSID2= QID= QID2=PLLR= pregnancy_US= pregnancy_US_comment= |cat=Pages using infobox drug with unknown parameters |format=0|errNS=0
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Spironolactone, sold under the brand name Aldactone among others, is classed as a diuretic medication.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It can be used to treat fluid build-up due to liver disease or kidney disease.<ref name=AHFS2015>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It is also used to reduce risk of disease progression, hospitalization and death due to some types of heart failure.<ref name=":0"/><ref>Template:Cite journal</ref> Other uses include acne and excessive hair growth in women, low blood potassium that does not improve with supplementation, high blood pressure that is difficult to treat and early puberty in boys.<ref name=AHFS2015/><ref>Template:Cite journal</ref><ref>Template:Cite book</ref><ref>Template:Cite journal</ref> It can also be used to block the effects of testosterone in transgender women and nonbinary people undergoing feminizing hormone replacement therapy.<ref name="WPATH2011" /> Spironolactone is usually available in tablets, taken by mouth, though topical forms are also available.<ref name=AHFS2015/>
Common side effects include electrolyte abnormalities, particularly high blood potassium, nausea, vomiting, headache, rashes, and a decreased desire for sex.<ref name=AHFS2015/> In those with liver or kidney problems, extra care should be taken.<ref name=AHFS2015/>
If taken during pregnancy, some animal studies suggest that spironolactone may affect the development of sex organs in babies.<ref name="pmid30352280" /> While this has not occurred in the few human studies available,<ref name="pmid30352280" /><ref name="pmid27156905" /><ref>Template:Cite journal</ref> women who are pregnant or considering pregnancy should discuss spironolactone use with their doctor due to the theoretical risk.<ref name="pmid27156905" />
Spironolactone is a steroid that blocks the effects of the hormones aldosterone and, to a lesser degree, testosterone, causing some estrogen-like effects.<ref name="Burinkul_2021">Template:Cite journal</ref>Template:Unreliable source?<ref name="Sehgal_2023">Template:Cite journal</ref><ref name="ineffectiveness in HRT">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>Template:Unreliable medical source<ref name="AHFS2015" /><ref name="Deedwania2014">Template:Cite book</ref> Spironolactone belongs to a class of medications known as potassium-sparing diuretics.<ref name="AHFS2015" />
Spironolactone was discovered in 1957, and was introduced in 1959.<ref name="OttowWeinmann2008">Template:Cite book</ref><ref name="Wermuth2008">Template:Cite book</ref><ref name="Sittig1988">Template:Cite book</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO23rd">Template:Cite book</ref> It is available as a generic medication.<ref name=AHFS2015/> In 2022, it was the 52nd most commonly prescribed medication in the United States, with more than 12Template:Nbspmillion prescriptions.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Spironolactone has a history of use in the trans community.<ref>Template:Cite journal</ref> Its use continues despite the rise of various accessible alternatives such as bicalutamide and cyproterone acetate with more precise action and less side effects.<ref name="Burinkul_2021" /><ref name="Sehgal_2023" /> Template:TOC limit
Medical usesEdit
Spironolactone is primarily used in the treatment of heart failure with reduced ejection fraction (HFrEF), where it has demonstrated significant benefits in reducing mortality and hospitalizations when added to standard therapy.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
Multiple studies show that spironolactone improves left ventricular diastolic function and reduce heart failure hospitalisations in patients with heart failure with preserved ejection fraction (HFpEF), though without benefits in all-cause death or overall hospitalisation rates.<ref>Template:Cite journal</ref> There is also evidence suggesting spironolactone may be effective in HFpEF with resistant hypertension (defined as blood pressure >130/80 mmHg) refractory to an ACE inhibitor/ARB, calcium channel blocker, and diuretic.<ref>Template:Cite journal</ref>
It is also used to treat 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).Template:Medical citation needed The most common use of spironolactone is in the treatment of heart failure.<ref name="RoncoBellomo2017" /> 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.Template:Medical citation needed The classification of spironolactone as a "potassium-sparing diuretic" has been described as obsolete.<ref name="pmid10760075">Template:Cite journal</ref> Spironolactone is also used to treat Bartter's syndrome due to its ability to raise potassium levels.<ref name="EndouHosoyamada1995">Template:Cite book</ref>
Spironolactone, which has antiandrogenic effects, may help improve acne in adult women, with modest benefits demonstrated in recent clinical trials. Its use is limited by short-term outcome data and minimal reporting of side effects. It is considered a possible alternative to antibiotics for hormonal acne.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> It is also used to manage other androgen-related conditions such as hirsutism, seborrhoea, and female pattern hair loss <ref name="pmid2969259">Template:Cite journal</ref> Spironolactone is used for the treatment of hirsutism in the United States.<ref name="Preedy2012">Template:Cite book</ref> 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.<ref name="pmid3143568">Template:Cite journal</ref>
Heart failureEdit
Although loop diuretics helps to treat acute symptoms of heart failure,<ref>Template:Cite journal</ref> the role of diuretics in the mineralocorticoid receptor antagonists’ class such as spironolactone is to reduce mortality and morbidity associated with certain types of chronic heart failure.<ref name=":0">Template:Cite journal</ref><ref>Template:Cite journal</ref> One randomised control trial in 1999 found that the addition of spironolactone to standard therapy reduced all-cause mortality in patients with HF by 30%.<ref name=":0" /> 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%.<ref name="Yancy e147-239">Template:Cite journal</ref>
Spironolactone improves left ventricular diastolic function in patients with heart failure with preserved ejection fraction, however it has no effect on mortality and hospitalization.<ref name="Li_2018">Template:Cite journal</ref><ref name="Kosmas_2018">Template:Cite journal</ref>
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. While Mineralocorticoid Receptor Antagonist (MRA) as a class (including spironolactone, eplerenone, and canrenone), is likely to be beneficial in heart failure patients, the precise comparative magnitude of effect on mortality between spironolactone and eplerenone remains subject to some clinical uncertainty, with limited comparative data available for canrenone.<ref name="pmid22840667">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
High blood pressureEdit
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.<ref name=Bat2010>Template:Cite journal</ref> There is no evidence of person-oriented outcome at any dose in this group.<ref name=Bat2010/>
High aldosterone levelsEdit
Spironolactone is used in the treatment of hyperaldosteronism (high aldosterone levels or mineralocorticoid excess), for instance primary aldosteronism (Conn's syndrome).<ref name="pmid30854950">Template:Cite journal</ref> Antimineralocorticoids like spironolactone and eplerenone are first-line treatments for hyperaldosteronism.<ref name="pmid30854950" /> They improve blood pressure and potassium levels, as well as left ventricular hypertrophy, albuminuria, and carotid intima-media thickness, in people with primary aldosteronism.<ref name="pmid30854950" /> In people with hyperaldosteronism due to unilateral aldosterone-producing adrenocortical adenoma, adrenalectomy should be preferred instead of antimineralocorticoids.<ref name="pmid30854950" /> Spironolactone should not be used to treat primary aldosteronism in pregnancy due to its antiandrogen-related risk of teratogenicity in male fetuses.<ref name="pmid35536535">Template:Cite journal</ref><ref name="pmid27156905">Template:Cite journal</ref><ref name="pmid25163723">Template:Cite journal</ref><ref name="pmid32586668">Template:Cite journal</ref>
Skin and hair conditionsEdit
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).<ref name="pmid15507105">Template:Cite journal</ref><ref name="pmid28979664">Template:Cite journal</ref> 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.<ref name="ShalitaRosso2011">Template:Cite book</ref><ref name="ZouboulisKatsambas2014">Template:Cite book</ref> 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.<ref name="pmid16985920">Template:Cite journal</ref><ref name="Sloane2002">Template:Cite book</ref><ref name="HannoGuzzo2014">Template:Cite book</ref><ref name="Harper2007">Template:Cite book</ref><ref name="Blume-PeytaviWhiting2008">Template:Cite book</ref> 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.<ref name="pmid15507105" /> In accordance with the preceding, antiandrogens are highly effective in the treatment of the aforementioned androgen-dependent skin and hair conditions.<ref name="pmid9420861" /><ref name="pmid20082945" />
Because of the antiandrogenic activity of spironolactone, it can be quite effective in treating acne in women.<ref name="pmid22468178">Template:Cite journal</ref><ref name="pmid28155090" /><ref>Template:Cite journal</ref> In addition, spironolactone reduces oil that is naturally produced in the skin and can be used to treat oily skin.<ref name="pmid28155090" /><ref name="pmid26897386" /><ref name="pmid28979664" /> 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.<ref name="pmid28155090" /><ref name="pmid26897386" /> Oftentimes, for women treating acne, spironolactone is prescribed and paired with a birth control pill.<ref name="pmid28155090" /><ref name="pmid26897386" /> Positive results in the pairing of these two medications have been observed, although these results may not be seen for up to three months.<ref name="pmid28155090" /><ref name="pmid26897386" /> Spironolactone has been reported to produce a 50 to 100% improvement in acne at sufficiently high doses.<ref name="pmid9238337" /> Response to treatment generally requires 1 to 3 months in the case of acne and up to 6 months in the case of hirsutism.<ref name="pmid9238337" /> Ongoing therapy is generally required to avoid relapse of symptoms.<ref name="pmid9238337" /> Spironolactone is commonly used in the treatment of hirsutism in women, and is considered to be a first-line antiandrogen for this indication.<ref name="pmid24889738" /> Spironolactone can be used in the treatment of female-pattern hair loss (pattern scalp hair loss in women).<ref name="pmid21413648">Template:Cite journal</ref> There is tentative low quality evidence supporting its use for this indication.<ref>Template:Cite journal</ref> Although apparently effective, not all cases of female-pattern hair loss are dependent on androgens.<ref name="pmid20128792">Template:Cite journal</ref>
Antiandrogens like spironolactone are male-specific teratogens which can feminize male fetuses due to their antiandrogenic effects.<ref name="pmid9420861" /><ref name="IswaranImai1997">Template:Cite journal</ref><ref name="Smith2013">Template:Cite book</ref> For this reason, it is recommended that antiandrogens only be used to treat women who are of reproductive age in conjunction with adequate contraception.<ref name="pmid9420861" /><ref name="IswaranImai1997" /><ref name="Smith2013" /> Oral contraceptives, which contain an estrogen and a progestin, are typically used for this purpose.<ref name="pmid9420861" /> 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.<ref name="pmid9420861" /><ref name="Ostrzenski2002">Template:Cite book</ref>
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.<ref name="pmid21413648" /> As an example, spironolactone has been reported to reduce symptoms of acne in males.<ref name="pmid9557251">Template:Cite journal</ref> An additional example is the usefulness of spironolactone as an antiandrogen in transgender women and nonbinary individuals.<ref name="WPATH2011">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="pmid19509099">Template:Cite journal</ref><ref name="pmid2540730">Template:Cite journal</ref>
Topical spironolactone is effective in the treatment of acne as well.<ref name="pmid1387779">Template:Cite journal</ref> 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.<ref name="pmid8112074">Template:Cite journal</ref><ref name="Benvenga2009">Template:Cite book</ref> 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.<ref name="Benvenga2009" />
ComparisonEdit
Spironolactone, the 5α-reductase inhibitor finasteride, and the nonsteroidal antiandrogen flutamide all appear to have similar effectiveness in the treatment of hirsutism.<ref name="pmid24889738">Template:Cite journal</ref><ref name="pmid25918921">Template:Cite journal</ref><ref name="pmid29522176">Template:Cite journal</ref> 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.<ref name="pmid24889738" /> 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.<ref name="pmid24889738" /> One study showed that spironolactone or the steroidal antiandrogen cyproterone acetate both in combination with a birth control pill had equivalent effectiveness for hirsutism.<ref name="pmid24889738" /> 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.<ref name="pmid24889738" /> The nonsteroidal antiandrogen bicalutamide is an alternative option to flutamide with improved safety.<ref name="pmid24455796">Template:Cite journal</ref><ref name="pmid29211888">Template:Cite journal</ref>
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.<ref name="pmid28155090" /> However, this was based on low- to very-low-quality evidence.<ref name="pmid28155090" /> 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.<ref name="pmid22994662" /> In addition, some clinical research has found that flutamide is more effective than spironolactone in the treatment of acne.<ref name="pmid28155090" /> In one study, flutamide decreased acne scores by 80% within 3 months, whereas spironolactone decreased symptoms by only 40% in the same period.<ref name="pmid10495361" /><ref name="ShelleyShelley2001">Template:Cite book</ref><ref name="BalenFranks2010">Template:Cite book</ref> However, the use of flutamide for acne is limited by its liver toxicity.<ref name="pmid28379593">Template:Cite journal</ref><ref name="pmid28492054">Template:Cite journal</ref><ref name="YasaDural2016">Template:Cite journal</ref><ref name="pmid28274354">Template:Cite journal</ref> Bicalutamide is a potential alternative to flutamide for acne as well.<ref name="pmid27416311">Template:Cite journal</ref><ref name="pmid30312645">Template:Cite journal</ref> 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.<ref name="pmid22994662" /><ref name="pmid20082945">Template:Cite journal</ref>
There is insufficient clinical evidence to compare the effectiveness of spironolactone with other antiandrogens for female-pattern hair loss.<ref name="pmid27225981">Template:Cite journal</ref> 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.<ref name="pmid22994662">Template:Cite journal</ref><ref name="pmid19370553">Template:Cite journal</ref><ref name="Hammerstein1990">Template:Cite book</ref> However, higher doses also have greater side effects, such as menstrual irregularities.<ref name="pmid28155090" />
Transgender hormone therapyEdit
Template:See also Despite paradoxical reactions, spironolactone is used off-label as a component of feminizing hormone therapy in transgender women, especially in the United States (where cyproterone acetate is not available), usually in addition to an estrogen.<ref name="Paradoxical reactions">Template:Cite journal</ref>Template:Unreliable source?<ref name="WPATH2011" /><ref name="pmid19509099" /><ref name="pmid2540730" /> Alternatives like bicalutamide do not have a similar level of popularity.<ref>Template:Cite journal</ref> As spironolactone's antiandrogenic effect appears only in high doses, it can have a wide array of side effects not found in antiandrogens working more exclusively on the androgen receptor.<ref name="Burinkul_2021" /><ref name="Sehgal_2023" /><ref name="ineffectiveness in HRT" />Template:Unreliable medical source When coupled with estradiol, effects in transgender women include decreased male pattern body hair, induction of breast development and of feminization in general, and reduced spontaneous erections.<ref name="pmid2540730" />
FormsEdit
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.<ref name="Muller1998">Template:Cite book</ref><ref name="LeeDesai2007">Template:Cite book</ref><ref name="Niazi2016">Template:Cite book</ref><ref name="WakelinMaibach2002">Template:Cite book</ref><ref name="Drugs@FDA">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>Template:Failed verification 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.<ref name="FARIDDiamanti-Kandarakis2009">Template:Cite book</ref><ref name="IndexNominum2000" /> The medication is also available in combination with other medications, such as hydrochlorothiazide (brand name Aldactazide, others).<ref name="Drugs@FDA" />Template:Failed verification<ref name="Drugs.com" /> 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.<ref name="pmid15947888">Template:Cite journal</ref> The only antimineralocorticoid that is available as a solution for parenteral use is the related medication potassium canrenoate.<ref name="pmid28634268" />
ContraindicationsEdit
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.<ref name="Aldactone label" /><ref name="GoldsmithCovic2014">Template:Cite book</ref> It should also be used with caution in people with certain neurological disorders, as well as those who experience or have experienced anuria (lack of urine production), acute kidney injury, or significant impairment of kidney excretory function with risk of hyperkalemia.<ref name="Aldactone label" />
Side effectsEdit
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),<ref name="pmid10495361" /> ataxia (muscle incoordination), drowsiness, dizziness,<ref name="pmid10495361" /> dry skin, and rashes. Because of its antiandrogenic activity, spironolactone can 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.<ref name="pmid984618" /> 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 cis men.<ref name="SeldinGiebisch1997" /><ref name="Aronson2009" /> However, such doses of spironolactone are rarely used clinically.<ref name="Aronson2009" /> In cis women, spironolactone can cause menstrual irregularities, breast tenderness, and breast enlargement.<ref name="pmid2969259"/><ref name="pmid28155090" /><ref name="CarrellPeterson2010">Template:Cite book</ref> Aside from these adverse effects, the side effects of spironolactone in women taking high doses are minimal, and it is well tolerated.<ref name="pmid28155090" /><ref name="pmid10495361" /><ref name="PescovitzEugster2004">Template:Cite book</ref>
A potential side effect of spironolactone is hyperkalemia (high potassium levels), which, in severe cases, can be life-threatening.<ref name="Aldactone label" /> Hyperkalemia can present as a normal anion-gap metabolic acidosis.<ref name="Aldactone label" /> 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.<ref>Template:Cite journal</ref> Spironolactone may put people at a heightened risk for gastrointestinal issues like nausea, vomiting, diarrhea, cramping, and gastritis.<ref name="Aldactone label" /><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> In addition, there has been some evidence suggesting an association between use of the medication and bleeding from the stomach and duodenum,<ref name="Aldactone label" /> though a causal relationship between the two has not been established.<ref>Template:Cite journal</ref><ref name="pmid18507655">Template:Cite journal</ref> Also, spironolactone is immunosuppressive in the treatment of sarcoidosis.<ref>Template:Cite journal</ref>
Most of the side effects of spironolactone are dose-dependent.<ref name="pmid22468178" /> Low-dose spironolactone is generally very well tolerated.<ref name="pmid22468178" /> Even higher doses of spironolactone, such as 100 mg/day, are well tolerated in most individuals.<ref name="pmid22468178" /> Dose-dependent side effects of spironolactone include menstrual irregularities, breast tenderness, and enlargement, orthostatic hypotension, and hyperkalemia.<ref name="pmid22468178" /> The side effects of spironolactone are usually mild and rarely result in discontinuation.<ref name="pmid22468178" />
Template:Side effects of spironolactone in women in clinical studies for acne
High potassium levelsEdit
Spironolactone can cause hyperkalemia, or high blood potassium levels.<ref name="Aronson2009">Template:Cite book</ref> Rarely, this can be fatal.<ref name="Aronson2009" /> Of people with heart disease prescribed typical dosages of spironolactone, 10 to 15% develop some degree of hyperkalemia, and 6% develop severe hyperkalemia.<ref name="Aronson2009" /> At a higher dosage, a rate of hyperkalemia of 24% has been observed.<ref name="pmid26404748">Template:Cite journal</ref> 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.<ref name="Aronson2009" /><ref name="pmid26404748" /><ref name="pmid15295047">Template:Cite journal</ref><ref name="RoncoBellomo2017">Template:Cite book</ref> However, another population-based study in Scotland failed to replicate these findings.<ref name="pmid22942339">Template:Cite journal</ref><ref name="pmid20483947">Template:Cite journal</ref> 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 inhibitor|Template:Abbr inhibitor]]s, angiotensin II receptor blockers, nonsteroidal anti-inflammatory drugs, the antibiotic trimethoprim, and potassium supplements), and at higher dosages of spironolactone.<ref name="Aronson2009" /><ref name="RoncoBellomo2017" /><ref name="pmid21911446">Template:Cite journal</ref><ref name="pmid25646289">Template:Cite journal</ref>
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.<ref name="pmid28155090">Template:Cite journal</ref><ref name="pmid26897386">Template:Cite journal</ref><ref name="pmid25796182">Template:Cite journal</ref> 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.<ref name="pmid28155090" /> 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.<ref name="pmid28155090" /><ref name="pmid26897386" /><ref name="pmid25796182" /> However, other sources have claimed that hyperkalemia can nonetheless also occur in people with more normal renal function and presumably without such risk factors.<ref name="RoncoBellomo2017" /> Occasional testing on a case-by-case basis in those with known risk factors may be justified.<ref name="pmid28155090" /> 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.<ref name="pmid28155090" /> Notably, non-use of routine potassium monitoring with spironolactone in young women would reduce costs associated with its use.<ref name="pmid28155090" />
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.<ref name="pmid31065620">Template:Cite journal</ref> 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.<ref name="pmid36267595">Template:Cite journal</ref>
Breast changesEdit
Spironolactone can cause breast pain and breast enlargement in women.<ref name="Becker2001">Template:Cite book</ref><ref name="TsioufisSchmieder2016" /> This is "probably because of estrogenic effects on target tissue."<ref name="Aronson2009" /> 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.<ref name="ConnJacobs1998">Template:Cite journal</ref><ref name="pmid22468178" /> Breast enlargement and tenderness may occur in 26% of women at high doses.<ref name="pmid10495361">Template:Cite journal</ref> Some women regard spironolactone-induced breast enlargement as a positive effect.<ref name="pmid28155090" />
Spironolactone also commonly and dose-dependently produces gynecomastia (breast development) as a side effect in men.<ref name="SeldinGiebisch1997">Template:Cite book</ref><ref name="TsioufisSchmieder2016">Template:Cite book</ref><ref name="Elsevier2014">Template:Cite book</ref><ref name="McInnes2008">Template:Cite book</ref> At low doses, the rate is only 5 to 10%,<ref name="McInnes2008" /> but at high doses, up to or exceeding 50% of men may develop gynecomastia.<ref name="SeldinGiebisch1997"/><ref name="TsioufisSchmieder2016"/><ref name="Elsevier2014"/> In the RALES, 9.1% of men taking 25 mg/day spironolactone developed gynecomastia, compared to 1.3% of controls.<ref name="pmid15134800" /> 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.<ref name="pmid8094898">Template:Cite journal</ref><ref name="Wilcox2008">Template:Cite book</ref> The severity of gynecomastia with spironolactone varies considerably, but is usually mild.<ref name="SeldinGiebisch1997" /> As with breast enlargement caused by spironolactone in women, gynecomastia due to spironolactone in men is often although inconsistently accompanied by breast tenderness.<ref name="SeldinGiebisch1997" /> In the RALES, only 1.7% of men developed breast pain, relative to 0.1% of controls.<ref name="pmid15134800" />
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.<ref name="pmid15134800" /> Gynecomastia induced by spironolactone usually regresses after a few weeks following discontinuation of the medication.<ref name="SeldinGiebisch1997" /> 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.<ref name="pmid18983216">Template:Cite journal</ref><ref name="pmid11546925">Template:Cite journal</ref>
Menstrual disturbancesEdit
Spironolactone at higher doses can cause menstrual irregularities as a side effect in women.<ref name="pmid22468178" /> These irregularities include metrorrhagia (intermenstrual bleeding), amenorrhea (absence of menstruation), and breakthrough bleeding.<ref name="pmid22468178" /> 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.<ref name="pmid10495361" /><ref name="Aronson2009" /> 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.<ref name="pmid22468178" /> Most women taking moderate doses of spironolactone develop amenorrhea, and normal menstruation usually returns within two months of discontinuation.<ref name="Aronson2009" /> Spironolactone produces an irregular and anovulatory pattern of menstrual cycles.<ref name="pmid10495361" /> It is also associated with metrorrhagia and menorrhagia (heavy menstrual bleeding) in large percentages of women,<ref name="Becker2001" /> as well as with polymenorrhea (short menstrual cycles).<ref name="pmid16076921">Template:Cite journal</ref><ref name="pmid10792338">Template:Cite journal</ref> The medication reportedly has no birth control effect.<ref name="RabeGrunwald2009">Template:Cite journal</ref>
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.<ref name="pmid10495361" /><ref name="pmid8144871">Template:Cite journal</ref><ref name="pmid2744183">Template:Cite journal</ref> An alternative proposed cause is inhibition of 17α-hydroxylase and hence sex steroid metabolism by spironolactone and consequent changes in sex hormone levels.<ref name="SeldinGiebisch1997" /> Indeed, CYP17A1 genotype is associated with polymenorrhea.<ref name="pmid32038990">Template:Cite journal</ref> 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.<ref name="pmid10495361" /><ref name="JemecRevuz2006">Template:Cite book</ref>
Mood changesEdit
Research is mixed on whether antimineralocorticoids like spironolactone have positive or negative effects on mood.<ref name="pmid25459896">Template:Cite journal</ref><ref name="Schultebraucks2016">Template:Cite thesis</ref><ref name="pmid10367986">Template:Cite journal</ref> In any case, it is possible that spironolactone might have the capacity to increase the risk of depressive symptoms.<ref name="pmid25459896" /><ref name="Schultebraucks2016" /><ref name="pmid10367986" /> However, a 2017 hybrid systematic review found that the incidence of depression in women treated with spironolactone for acne was less than 1%.<ref name="pmid28155090" /> 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%.<ref name="BassonPrior1997">Template:Cite book</ref>
Lipid changesEdit
Spironolactone has been found to increase LDL ("bad") cholesterol and decrease HDL ("good") cholesterol levels at the relatively high doses used in women with polycystic ovary syndrome (PCOS).<ref name="pmid28944709">Template:Cite journal</ref><ref name="pmid19843067">Template:Cite journal</ref> As such, it may have unfavorable effects on the blood lipid profile in this context.<ref name="pmid28944709" /><ref name="pmid19843067" /> Heightened LDL cholesterol levels are a potential risk factor for cardiovascular disease such as atherosclerosis or coronary heart disease.<ref name="pmid30586774">Template:Cite journal</ref> Consequently, it has been said that spironolactone should not be given to women with dyslipidemia (e.g., high cholesterol).<ref name="pmid28944709" /><ref name="pmid19843067" /> Unfavorable lipid changes have also been seen with other antiandrogens, like cyproterone acetate<ref name="WPATH-SOC8">Template:Cite journal</ref><ref name="pmid3318361">Template:Cite journal</ref> and bicalutamide.<ref name="pmid33334002">Template:Cite journal</ref><ref name="pmid29211888"/>
Rare reactionsEdit
Aside from hyperkalemia, spironolactone may rarely cause adverse reactions such as anaphylaxis, kidney failure,<ref name="pmid19006114">Template:Cite journal</ref> hepatitis (two reported cases, neither serious),<ref name="ThaiSinclair2001">Template:Cite journal</ref> agranulocytosis, DRESS syndrome, Stevens–Johnson syndrome or toxic epidermal necrolysis.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7699#f_adverse-reactions</ref> Five cases of breast cancer in patients who took spironolactone for prolonged periods of time have been reported.<ref name="Aronson2009"/><ref name="McInnes2008" />
Spironolactone bodiesEdit
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.<ref name="pmid7195152">Template:Cite journal</ref>
Pregnancy and breastfeedingEdit
Spironolactone can cross the placenta.<ref name="Becker2001" /> It has been found to be present in the breast milk of lactating mothers.<ref name="Aldactone label" /> 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.<ref name="Ainsworth2014" />
A study found that spironolactone was not associated with teratogenicity in the offspring of rats.<ref name="Little2006">Template:Cite book</ref><ref name="RubinRamsey2008">Template:Cite book</ref><ref name="BriggsFreeman2011">Template:Cite book</ref> Because it is an antiandrogen, however, spironolactone could theoretically have the potential to cause feminization of male fetuses at sufficient doses.<ref name="Little2006" /><ref name="RubinRamsey2008" /> 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).<ref name="Little2006" /><ref name="BriggsFreeman2011" /> Another study found permanent, dose-related reproductive tract abnormalities rat offspring of both sexes at lower doses (50 to 100 mg/kg per day).<ref name="BriggsFreeman2011" />
In practice however, although experience is limited, spironolactone has never been reported to cause observable feminization or any other congenital defects in humans.<ref name="Little2006" /><ref name="RubinRamsey2008" /><ref name="ElkayamGleicher1998">Template:Cite book</ref><ref name="Schaefer2001">Template:Cite book</ref> Among 31 human newborns exposed to spironolactone in the first trimester, there were no signs of any specific birth defects.<ref name="Schaefer2001" /> 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.<ref name="Schaefer2001" /> 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.<ref name="Ainsworth2014">Template:Cite book</ref><ref name="Little2006"/> 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).<ref name="Schaefer2001" /> 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.<ref name="Little2006" /><ref name="Upfal2006">Template:Cite book</ref>
A 2019 systematic review found insufficient evidence that spironolactone causes birth defects in humans.<ref name="pmid30352280">Template:Cite journal</ref> However, there was also insufficient evidence to be certain that it does not.<ref name="pmid30352280" />
OverdoseEdit
Spironolactone is relatively safe in acute overdose.<ref name="Aldactone label" /> Symptoms following an acute overdose of spironolactone may include drowsiness, confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, and diarrhea.<ref name="Aldactone label" /> In rare cases, hyponatremia, hyperkalemia, or hepatic coma may occur in individuals with severe liver disease.<ref name="Aldactone label" /> However, these adverse reactions are unlikely in the event of an acute overdose.<ref name="Aldactone label" /> Hyperkalemia can occur following an overdose of spironolactone, and this is especially so in people with decreased kidney function.<ref name="Aldactone label" /> Spironolactone has been studied at extremely high oral doses of up to 2,400 mg per day in clinical trials.<ref name="pmid28634268" /><ref name="pmid15134797">Template:Cite journal</ref> Its oral median lethal dose (LD50) is more than 1,000 mg/kg in mice, rats, and rabbits.<ref name="Aldactone label" />
There is no specific antidote for overdose of spironolactone.<ref name="Aldactone label" /> Treatment may consist of induction of vomiting or stomach evacuation by gastric lavage.<ref name="Aldactone label" /> The treatment of spironolactone overdose is supportive, with the purpose of maintaining hydration, electrolyte balance, and vital functions.<ref name="Aldactone label" /> Spironolactone should be discontinued in people with impaired kidney function or hyperkalemia.<ref name="Aldactone label" />
InteractionsEdit
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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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<ref name="pmid25796182"/> and in healthy young gender-diverse individuals taking spironolactone for hormone therapy.<ref name="pmid36267595"/> 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.<ref>Template:Cite journal</ref>
Spironolactone has been reported to induce the enzymes CYP3A4 and certain UDP-glucuronosyltransferases (UGTs), which can result in interactions with various medications.<ref name="Parkinson2001" /><ref name="Davis2009">Template:Cite book</ref><ref name="pmid1826112">Template:Cite journal</ref> However, it has also been reported that metabolites of spironolactone irreversibly inhibit CYP3A4.<ref name="Wolverton2007">Template:Cite book</ref> 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.<ref name="pmid29756046">Template:Cite journal</ref> Spironolactone has also been found to inhibit UGT2B7.<ref name="JhajraRamesh Varkhede2012">Template:Cite book</ref> Spironolactone can also have numerous other interactions, most commonly with other cardiac and blood pressure medications, for instance digoxin.<ref name="Aldactone label">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
Licorice, which has indirect mineralocorticoid activity by inhibiting mineralocorticoid metabolism, has been found to inhibit the antimineralocorticoid effects of spironolactone.<ref name="pmid27450358" /><ref name="pmid17113210">Template:Cite journal</ref><ref name="pmid13991036">Template:Cite journal</ref> 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.<ref name="pmid27450358" /><ref name="pmid17113210" /> On the opposite end of the spectrum, spironolactone is useful in reversing licorice-induced hypokalemia.<ref name="pmid23185686">Template:Cite journal</ref><ref name="pmid12640291">Template:Cite journal</ref> 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.<ref name="EndouHosoyamada1995" /><ref name="pmid17362671">Template:Cite journal</ref>
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.<ref>Holsboer, F. The Rationale for Corticotropin-Releasing Hormone Receptor (CRH-R) Antagonists to Treat Depression and Anxiety. J. Psychiatr. Res. 33, 181–214 (1999).</ref><ref name="pmid19909979">Template:Cite journal</ref> 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.<ref name="pmid21515309">Template:Cite journal</ref>
PharmacologyEdit
PharmacodynamicsEdit
{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}}
The pharmacodynamics of spironolactone are characterized by high antimineralocorticoid activity, moderate antiandrogenic activity, and weak steroidogenesis inhibition, among other more minor activities.<ref name="pmid28634268" /><ref name="pmid984618" /><ref name="pmid8094898" /> Spironolactone is a prodrug, so most of its actions are actually mediated by its various active metabolites.<ref name="pmid28634268" /> The major active forms of spironolactone are 7α-thiomethylspironolactone (7α-TMS) and canrenone (7α-desthioacetyl-δ6-spironolactone).<ref name="pmid15947888"/><ref name="pmid28634268" />
Spironolactone is a potent antimineralocorticoid.<ref name="pmid15947888"/> That is, it is an antagonist of the mineralocorticoid receptor (MR), the biological target of mineralocorticoids like aldosterone and 11-deoxycorticosterone.<ref name="pmid15947888"/> By blocking the MR, spironolactone inhibits the effects of mineralocorticoids in the body.<ref name="pmid15947888"/> The antimineralocorticoid activity of spironolactone is responsible for its therapeutic efficacy in the treatment of edema, high blood pressure, heart failure, hyperaldosteronism, and ascites due to cirrhosis.<ref name="Feldman2008">Template:Cite book</ref><ref name="Health2015">Template:Cite bookTemplate:Dead link</ref> It is also responsible for many of the side effects of spironolactone, such as urinary frequency, dehydration, hyponatremia, low blood pressure, fatigue, dizziness, metabolic acidosis, decreased kidney function, and its risk of hyperkalemia.<ref name="pmid24456327">Template:Cite journal</ref> Due to the antimineralocorticoid activity of spironolactone, levels of aldosterone are significantly increased by the medication, probably reflecting an attempt of the body to maintain homeostasis.<ref name="pmid9420861">Template:Cite journal</ref><ref name="pmid10495361" />
Spironolactone is a moderate antiandrogen.<ref name="pmid984618">Template:Cite journal</ref><ref name="pmid8144871" /><ref name="pmid1826112" /> That is, it is an antagonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT).<ref name="pmid984618" /><ref name="pmid8144871" /><ref name="pmid1826112" /> By blocking the AR, spironolactone inhibits the effects of androgens in the body.<ref name="pmid984618" /><ref name="pmid8144871" /><ref name="pmid1826112" /> The antiandrogenic activity of spironolactone is mainly responsible for its therapeutic efficacy in the treatment of androgen-dependent skin and hair conditions like acne, seborrhea, hirsutism, and pattern hair loss and hyperandrogenism in women, precocious puberty in boys with testotoxicosis, and as a component of feminizing hormone therapy for transgender women.<ref name="pmid8144871" /><ref name="pmid29756046" /><ref name="pmid11322868">Template:Cite journal</ref> It is also primarily responsible for some of its side effects, like breast tenderness, gynecomastia, feminization, and demasculinization in men.<ref name="SeldinGiebisch1997" /><ref name="pmid11322868" /> Blockade of androgen signaling in the breast disinhibits the actions of estrogens in this tissue.<ref name="StraussIII2013">Template:Cite book</ref> Although useful as an antiandrogen in women, who have low testosterone levels compared to men,<ref name="pmid2941190">Template:Cite journal</ref><ref name="GregoryTravis2015">Template:Cite book</ref> spironolactone is described as having relatively weak antiandrogenic activity.<ref name="Wu2012">Template:Cite book</ref><ref name="pmid11322868" /><ref name="BenniVemer1990">Template:Cite book</ref><ref name="pmid8915726">Template:Cite journal</ref>
Spironolactone is a weak steroidogenesis inhibitor.<ref name="pmid984618" /><ref name="pmid8094898"/><ref name="pmid8144871" /><ref name="pmid6786868">Template:Cite journal</ref> That is, it inhibits steroidogenic enzymes, or enzymes involved in the production of steroid hormones.<ref name="pmid984618" /><ref name="pmid8094898" /><ref name="pmid8144871" /><ref name="pmid6786868" /> Spironolactone and/or its metabolites have been found in vitro to weakly inhibit a broad array of steroidogenic enzymes including cholesterol side-chain cleavage enzyme, 17α-hydroxylase, 17,20-lyase, 5α-reductase, 3β-hydroxysteroid dehydrogenase, 11β-hydroxylase, 21-hydroxylase, and aldosterone synthase (18-hydroxylase).<ref name="pmid8144871" /><ref name="pmid6786868" /><ref name="pmid26001184">Template:Cite journal</ref><ref name="pmid18819053">Template:Cite journal</ref> However, although very high doses of spironolactone can considerably decrease steroid hormone levels in animals, spironolactone has shown mixed and inconsistent effects on steroid hormone levels in clinical studies, even at high clinical doses.<ref name="pmid28155090" /><ref name="pmid984618" /><ref name="pmid8094898" /><ref name="pmid8144871" /><ref name="pmid1826112" /> In any case, the levels of most steroid hormones, including testosterone and cortisol, are usually unchanged by spironolactone in humans, which may in part be related to compensatory upregulation of their synthesis.<ref name="pmid984618" /><ref name="pmid8094898" /><ref name="WattsFaingold2009">Template:Cite book</ref> The weak steroidogenesis inhibition of spironolactone might contribute to its antiandrogenic efficacy to some degree and may explain its side effect of menstrual irregularities in women.<ref name="pmid984618" /><ref name="SeldinGiebisch1997" /> However, its androgen synthesis inhibition is probably clinically insignificant.<ref name="pmid9238337">Template:Cite journal</ref>
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.<ref name="pmid984618" /><ref name="pmid8094898" /> 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.<ref name="pmid12477487">Template:Cite journal</ref><ref name="pmid907238">Template:Cite journal</ref> 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.<ref name="pmid12570693">Template:Cite journal</ref><ref name="pmid19601747">Template:Cite journal</ref> 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.<ref name="pmid12477487" /><ref name="pmid24189467">Template:Cite journal</ref><ref name="pmid26230882">Template:Cite journal</ref>
In response to the antimineralocorticoid activity spironolactone, and in an attempt to maintain homeostasis, the body increases aldosterone production in the adrenal cortex.<ref name="Adams2014">Template:Cite book</ref><ref name="pmid22836869" /><ref name="pmid17035932">Template:Cite journal</ref> Some studies have found that levels of cortisol, a glucocorticoid hormone that is also produced in the adrenal cortex, are increased as well.<ref name="pmid22836869">Template:Cite journal</ref><ref name="pmid17035932" /><ref name="pmid27519144">Template:Cite journal</ref> 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,<ref name="pmid8144871" /><ref name="FalconeHurd2007">Template:Cite book</ref><ref name="Hammerstein1990"/><ref name="pmid628197">Template:Cite journal</ref> 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)."<ref name="pmid21095280">Template:Cite journal</ref> Patients taking spironolactone must be monitored for side effects including dizziness, headache, fatigue, diarrhea, hypertriglyceridemia and elevated liver enzymes.<ref name="KuntzKuntz2009">Template:Cite book</ref><ref name="MelmedPolonsky2011">Template:Cite book</ref>
Other activities of spironolactone may include very weak interactions with the estrogen and progesterone receptors and agonism of the pregnane X receptor.<ref name="Hammerstein1990" /><ref name="pmid12372848">Template:Cite journal</ref> These activities could contribute to the menstrual irregularities and breast side effects of spironolactone and to its drug interactions, respectively.<ref name="pmid27072668">Template:Cite journal</ref><ref name="Delyani2000">Template:Cite journal</ref><ref name="pmid9727070">Template:Cite journal</ref>
PharmacokineticsEdit
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.<ref name="Wilcox2008" /> Nonetheless, much has been elucidated about the pharmacokinetics of spironolactone over the decades.<ref name="pmid363379">Template:Cite journal</ref><ref name="pmid6369882">Template:Cite journal</ref><ref name="pmid3333882">Template:Cite journal</ref><ref name="pmid15947888"/><ref name="pmid22099505">Template:Cite journal</ref><ref name="pmid21771637">Template:Cite journal</ref><ref name="pmid26939027">Template:Cite journal</ref><ref name="pmid27830348">Template:Cite book</ref>
AbsorptionEdit
The bioavailability of spironolactone when taken by mouth is 60 to 90%.<ref name="pmid15947888"/><ref name="pmid18729003" /><ref name="CaroneOxberry2017" /> 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.<ref name="DeinumRiksen2015" /><ref name="pmid3769384">Template:Cite journal</ref><ref name="pmid872489">Template:Cite journal</ref> 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.<ref name="DeinumRiksen2015">Template:Cite journal</ref><ref name="Saini-ChohanHatch2009">Template:Cite journal</ref><ref name="Al-HadiyaBelal2002">Template:Cite journal</ref> The relationship between a single dose of spironolactone and plasma levels of canrenone, a major active metabolite of spironolactone, has been found to be linear across a dose range of 25 to 200 mg spironolactone.<ref name="Wu2012" /> Steady-state concentrations of spironolactone are achieved within 8 to 10 days of treatment initiation.<ref name="CancerOrganization2001">Template:Cite book</ref><ref name="Elsevier2019">Template:Cite book</ref>
Little or no systemic absorption has been observed with topical spironolactone.<ref name="pmid3411088">Template:Cite journal</ref>
DistributionEdit
Spironolactone and its metabolite canrenone are highly plasma protein bound, with percentages of 88.0% and 99.2%, respectively.<ref name="pmid15947888"/><ref name="TakamuraMaruyama1997" >Template:Cite journal</ref> Spironolactone is bound equivalently to albumin and α1-acid glycoprotein, while canrenone is bound only to albumin.<ref name="pmid15947888"/><ref name="TakamuraMaruyama1997" /> Spironolactone and its metabolite 7α-thiospironolactone show very low or negligible affinity for sex hormone-binding globulin (SHBG).<ref name="pmid86546">Template:Cite journal</ref><ref name="pmid7195405">Template:Cite journal</ref> 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.<ref name="pmid7189544">Template:Cite journal</ref> This is in contradiction with widespread statements that spironolactone increases free estradiol levels by displacing estradiol from SHBG.<ref name="Hammerstein1990" /><ref name="BlandIII2009">Template:Cite book</ref>
Spironolactone appears to cross the blood–brain barrier.<ref name="pmid25376974">Template:Cite journal</ref><ref name="pmid22351473">Template:Cite journal</ref>
MetabolismEdit
Spironolactone is rapidly and extensively metabolized in the liver upon oral administration and has a very short terminal half-life of 1.4 hours.<ref name="pmid15947888"/><ref name="pmid18729003" /> The major metabolites of spironolactone are 7α-thiomethylspironolactone (7α-TMS), 6β-hydroxy-7α-thiomethylspironolactone (6β-OH-7α-TMS), and canrenone (7α-desthioacetyl-δ6-spironolactone).<ref name="pmid15947888"/><ref name="pmid18729003" /><ref name="AgustiBourgeois2013">Template:Cite journal</ref> 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.<ref name="pmid15947888"/><ref name="pmid18729003" /> As such, spironolactone is a prodrug.<ref name="Oxford2003">Template:Cite book</ref> 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.<ref name="pmid15947888"/><ref name="AgustiBourgeois2013" /><ref name="CancerOrganization2001" /> Other known but more minor metabolites of spironolactone include 7α-thiospironolactone (7α-TS), which is an important intermediate to the major metabolites of spironolactone,<ref name="Parkinson2001" /> as well as the 7α-methyl ethyl ester of spironolactone and the 6β-hydroxy-7α-methyl ethyl ester of spironolactone.<ref name="SzaszBudvari-Barany1990">Template:Cite book</ref>
Spironolactone is hydrolyzed or deacetylated at the thioester of the C7α position into 7α-TS by carboxylesterases.<ref name="Parkinson2001">Template:Cite book</ref><ref name="AnzenbacherZanger2012">Template:Cite book</ref> Following formation of 7α-TS, it is S-oxygenated by flavin-containing monooxygenases to form an electrophilic sulfenic acid metabolite.<ref name="Parkinson2001" /> This metabolite is involved in the CYP450 inhibition of spironolactone, and also binds covalently to other proteins.<ref name="Parkinson2001" /> 7α-TS is also S-methylated into 7α-TMS, a transformation catalyzed by thiol S-methyltransferase.<ref name="Parkinson2001" /> Unlike the related medication eplerenone, spironolactone is said to not be metabolized by CYP3A4.<ref name="SmithPh.D.2014">Template:Cite book</ref> However, hepatic CYP3A4 is likely responsible for the 6β-hydroxylation of 7α-TMS into 6β-OH-7α-TMS.<ref name="Klaassen2007">Template:Cite book</ref><ref name="Montellano2015">Template:Cite book</ref> 7α-TMS may also be hydroxylated at the C3α and C3β positions.<ref name="pmid7895608">Template:Cite journal</ref> Spironolactone is dethioacetylated into canrenone.<ref name="BlackElliott2006">Template:Cite book</ref> Finally, the C17 γ-lactone ring of spironolactone is hydrolyzed by the paraoxonase PON3.<ref name="pmid14579013">Template:Cite journal</ref><ref name="AcademicPress2012">Template:Cite book</ref> It was originally thought to be hydrolyzed by PON1, but this was due to contamination with PON3.<ref name="pmid14579013" />
Template:Pharmacokinetics of 100 mg per day spironolactone and its metabolites
EliminationEdit
The majority of spironolactone is eliminated by the kidneys, while minimal amounts are handled by biliary excretion.<ref name="Brittain2002">Template:Cite book</ref>
ChemistryEdit
Spironolactone, also known as 7α-acetylthiospirolactone, is a steroidal 17α-spirolactone, or more simply a spirolactone.<ref name="pmid28634268">Template:Cite journal</ref> It can most appropriately be conceptualized as a derivative of progesterone,<ref name="pmid15134800" /><ref name="JamesonGroot2010" /><ref name="Elsevier2019" /> itself also a potent antimineralocorticoid, in which a hydroxyl group has been substituted at the C17α position (as in 17α-hydroxyprogesterone), the acetyl group at the C17β position has been cyclized with the C17α hydroxyl group to form a spiro 21-carboxylic acid γ-lactone ring, and an acetylthio group has been substituted in at the C7α position.<ref name="Elks2014" /><ref name="PubChem" /><ref name="ChemSpider" /> These structural modifications of progesterone confer increased oral bioavailability and potency,<ref name="pmid8616985">Template:Cite journal</ref> potent antiandrogenic activity, and strongly reduced progestogenic activity.<ref name="pmid16101407">Template:Cite journal</ref> The C7α substitution is likely responsible for or involved in the antiandrogenic activity of spironolactone, as 7α-thioprogesterone (SC-8365), unlike progesterone,<ref name="pmid16112947">Template:Cite journal</ref> is an antiandrogen with similar affinity to the AR as that of spironolactone.<ref name="pmid263288">Template:Cite journal</ref> 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.<ref name="pmid16112947" /><ref name="pmid13601900">Template:Cite journal</ref><ref name="Butterworth1961">Template:Cite book</ref>
NamesEdit
Spironolactone is also known by the following equivalent chemical names:<ref name="Elks2014" /><ref name="PubChem">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="ChemSpider">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
- 7α-Acetylthio-17α-hydroxy-3-oxopregn-4-ene-21-carboxylic acid γ-lactone
- 7α-Acetylthio-3-oxo-17α-pregn-4-ene-21,17β-carbolactone
- 3-(3-Oxo-7α-acetylthio-17β-hydroxyandrost-4-en-17α-yl)propionic acid lactone
- 7α-Acetylthio-17α-(2-carboxyethyl)androst-4-en-17β-ol-3-one γ-lactone
- 7α-Acetylthio-17α-(2-carboxyethyl)testosterone γ-lactone
AnaloguesEdit
Template:Spirolactone structures
Spironolactone is closely related structurally to other clinically used spirolactones such as canrenone, potassium canrenoate, drospirenone, and eplerenone, as well as to the never-marketed spirolactones SC-5233 (6,7-dihydrocanrenone; 7α-desthioacetylspironolactone), SC-8109 (19-nor-6,7-dihydrocanrenone), spiroxasone, prorenone (SC-23133), mexrenone (SC-25152, ZK-32055), dicirenone (SC-26304), spirorenone (ZK-35973), and mespirenone (ZK-94679).<ref name="pmid28634268" />
SynthesisEdit
Chemical syntheses of spironolactone and its analogues and derivatives have been described and reviewed.<ref name="pmid28041953">Template:Cite journal</ref>
HistoryEdit
The natriuretic effects of progesterone were demonstrated in 1955, and the development of spironolactone as a synthetic antimineralocorticoid analogue of progesterone shortly followed this.<ref name="pmid15134800">Template:Cite journal</ref><ref name="JamesonGroot2010">Template:Cite book</ref><ref name="pmid13486053">Template:Cite journal</ref><ref name="pmid13486054">Template:Cite journal</ref> Spironolactone was first synthesized in 1957,<ref name="OttowWeinmann2008" /><ref name="pmid13486053" /><ref name="pmid13486054" /> was patented between 1958 and 1961,<ref name="EngelKleemann2014">Template:Cite book</ref><ref name="LandauAchilladelis1999">Template:Cite book</ref> and was first marketed, as an antimineralocorticoid, in 1959.<ref name="Jugdutt2014">Template:Cite book</ref><ref name="Wermuth2011">Template:Cite book</ref> Gynecomastia was first reported with spironolactone in 1962,<ref name="pmid28634268" /><ref name="Smith1962">Template:Cite journal</ref> and the antiandrogenic activity of the medication was first described in 1969.<ref name="pmid5344274">Template:Cite journal</ref> This shortly followed the discovery in 1967 that gynecomastia is an important and major side effect of AR antagonists.<ref name="pmid148431">Template:Cite journal</ref><ref name="NeillJohansson1968">Template:Cite journal</ref> Spironolactone was first studied in the treatment of hirsutism in women in 1978.<ref name="pmid6205409">Template:Cite journal</ref><ref name="pmid27450358">Template:Cite journal</ref><ref name="pmid717935">Template:Cite journal</ref><ref name="pmid488407">Template:Cite journal</ref><ref name="pmid7410528">Template:Cite journal</ref> It has since become the most widely used antiandrogen for dermatological indications in women in the United States.<ref name="WakelinMaibach2002" /><ref name="Curtis2014">Template:Cite book</ref><ref name="ShahBhathena2004">Template:Cite book</ref><ref name="Hillard2013">Template:Cite book</ref> 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.<ref name="DahlFeldman2006">Template:Cite journal</ref><ref name="PriorVigna1986">Template:Cite journal</ref><ref name="FisherMaggi2015">Template:Cite book</ref>
Early oral spironolactone tablets showed poor absorption.<ref name="Dorfman2016">Template:Cite book</ref> The formulation was eventually changed to a micronized formulation with particle sizes of less than 50 μg, which resulted in approximately 4-fold increased potency.<ref name="Dorfman2016" /><ref name="GlázVecsei2017">Template:Cite book</ref>
Society and cultureEdit
Generic namesEdit
The English, French, and generic name of the medication is spironolactone and this is its Template:Abbrlink, Template:Abbrlink, Template:Abbrlink, Template:Abbrlink, Template:Abbrlink, and Template:Abbrlink.<ref name="IndexNominum2000">Template:Cite book</ref><ref name="Drugs.com">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Elks2014">Template:Cite book</ref><ref name="MortonHall1999">Template:Cite book</ref> Its name is {{#invoke:Lang|lang}} in Latin, {{#invoke:Lang|lang}} in German, {{#invoke:Lang|lang}} in Spanish and Portuguese, and {{#invoke:Lang|lang}} in Italian (which is also its Template:Abbrlink).<ref name="IndexNominum2000" /><ref name="Drugs.com" /><ref name="MortonHall1999" />
Spironolactone is also known by its developmental code names SC-9420 and NSC-150339.<ref name="IndexNominum2000"/><ref name="Drugs.com" /><ref name="Elks2014" />
Brand namesEdit
Spironolactone is marketed under various brand names throughout the world.<ref name="IndexNominum2000"/><ref name="Drugs.com" /> The original brand name of spironolactone is Aldactone.<ref name="IndexNominum2000"/><ref name="Drugs.com" /> Other brand names include Aldactone-A, Berlactone, CaroSpir, Espironolactona, Espironolactona Genfar, Novo-Spiroton, Prilactone (veterinary), Spiractin, Spiridon, Spirix, Spiroctan, Spiroderm (discontinued),<ref name="FARIDDiamanti-Kandarakis2009" /> Spirogamma, Spirohexal, Spirolon, Spirolone, Spiron, Spironolactone Actavis, Spironolactone Orion, Spironolactone Teva, Spirotone, Tempora (veterinary), Uractone, Uractonum, Verospiron, and Vivitar.<ref name="IndexNominum2000"/><ref name="Drugs.com" />
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.<ref name="Drugs.com" />
AvailabilityEdit
Spironolactone is marketed throughout the world.<ref name="IndexNominum2000"/><ref name="Drugs.com" />
ResearchEdit
Prostate conditionsEdit
Spironolactone has been studied at a high dosage in the treatment of benign prostatic hyperplasia (BPH; enlarged prostate).<ref name="Springer2012">Template:Cite book</ref><ref name="pmid1702565">Template:Cite journal</ref><ref name="pmid4104441">Template:Cite journal</ref> It was found to be better than placebo in terms of symptom relief following three months of treatment.<ref name="Springer2012" /><ref name="pmid1702565" /> However, this was not maintained after six months of treatment, by which point the improvements had largely disappeared.<ref name="Springer2012" /><ref name="pmid1702565" /><ref name="pmid4104441" /> Moreover, no difference was observed between spironolactone and placebo with regard to volume of residual urine or prostate size.<ref name="Springer2012" /><ref name="pmid1702565" /> Gynecomastia was observed in about 5% of people.<ref name="pmid1702565" /> On the basis of these results, it has been said that spironolactone has no place in the treatment of BPH.<ref name="pmid1702565" />
Spironolactone has been studied and used limitedly in the treatment of prostate cancer.<ref name="pmid29603164">Template:Cite journal</ref><ref name="pmid3540320">Template:Cite journal</ref><ref name="EndouHosoyamada1995" />
Epstein–Barr virusEdit
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.<ref name="Verma2016">Template:Cite journal</ref> This effect of spironolactone was determined to be independent of its antimineralocorticoid actions.<ref name="Verma2016" />
Other conditionsEdit
Spironolactone has been studied in the treatment of rosacea in both males and females.<ref name="pmid15389184">Template:Cite journal</ref><ref name="GiurcăneanuMarinescu2016">Template:Cite journal</ref><ref name="Wollina2014">Template:Cite book</ref><ref name="pmid9557251" /><ref name="pmid23594595">Template:Cite journal</ref>
Spironolactone has been studied in fibromyalgia in women.<ref name="WernzeHerdegen2014">Template:Cite journal</ref><ref name="Kalso2014">Template:Cite journal</ref> It has also been studied in bulimia nervosa in women, but was not found to be effective.<ref name="pmid22946772">Template:Cite journal</ref>
ReferencesEdit
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