Endocrine consequences of antifungal therapy: A missed entity

Abstract

With fungal infections rising worldwide, the use of azoles, polyenes, and echinocandins, the mainstay of antifungal therapy has expanded markedly. With broader use, uncommon adverse effects are increasingly being identified. Azoles, the most widely prescribed class of antifungal agents, inhibit several cytochrome P450-dependent steps in human steroidogenesis, leading to disruption of endocrine pathways. Adrenal and gonadal dysfunctions with ketoconazole, and mineralocorticoid excess with posaconazole and itraconazole, are well-documented. Uncommon manifestations, such as voriconazole-induced syndrome of inappropriate antidiuretic hormone secretion or salt-losing nephropathy, and fluoride-related periostitis associated with voriconazole and itraconazole, have also been reported. The adverse reactions may be further influenced by drug interactions with enzyme inducers or inhibitors. Amphotericin B is known to cause electrolyte disturbances due to tubular damage. Echinocandins differ from azoles and polyenes in that they rarely affect endocrine pathways, making them a safer option when endocrine toxicity is a concern. Clinicians must remain vigilant to the endocrine adverse effects and pharmacological interactions of antifungal agents to enable timely recognition and management.

Key Words: Voriconazole; Posaconazole; Adrenal insufficiency; Apparent mineralocorticoid excess; Ketoconazole; Amphotericin B; Antifungal therapy

Core Tip: Antifungal drugs can interfere with key endocrine pathways by inhibiting steroidogenic enzymes or through drug interactions that alter glucocorticoid and mineralocorticoid metabolism. Ketoconazole, fluconazole, itraconazole, posaconazole, and voriconazole demonstrate distinct endocrine adverse effects, ranging from adrenal insufficiency and apparent mineralocorticoid excess to reproductive dysfunction, hyponatremia, and fluoride-related periostitis. Amphotericin B primarily induces renal tubular injury and associated electrolyte disturbances, whereas echinocandins rarely affect endocrine function. Recognizing these effects, especially in patients receiving multiple interacting medications, is essential for timely diagnosis and safe therapeutic decision-making.

INTRODUCTION

Fungi are a group of ubiquitous organisms that cause superficial and systemic human infections. Most of the superficial fungal infections are caused by dermatophytes and Candida. These infections are frequent and often extensive in diabetes and immunocompromised states[1]. Superficial infections respond to topical therapy, but prolonged oral therapy is often necessary in an immunocompromised state[2].

Systemic fungal infections are categorized into two broad groups: Endemic and opportunistic mycoses. The endemic mycoses represent a diverse group of systemic fungal infections usually acquired by inhalation and prevalent in specific geographic regions. Opportunistic mycoses, the other group of systemic fungal diseases, are a growing health problem. Bone marrow transplant, solid organ transplant, hematological malignancies, immunosuppressive therapy or chemotherapy, prolonged use of corticosteroids, long-term intensive care unit admission, acquired or congenital immunodeficiency, and diabetes predispose to opportunistic fungal diseases[3].

The rising burden of fungal diseases has increased the usage of antifungal drugs. Furthermore, their widespread use has led to the emergence of resistance, necessitating long-term and sometimes complex regimens. Patients infected with fungi are often receiving multiple medications related to intensive care, organ transplantation, diabetes, etc., raising the possibility of pharmacokinetic interactions[4]. Additionally, new pathogens such as Candida auris are getting identified that pose diagnostic challenges and often exhibit resistance to standard antifungal agents, leading to the need for prolonged or combination therapy[5]. Although antifungal drugs can adversely affect the functioning of various organs, the endocrine system is especially vulnerable[3].

Managing fungal infections in the presence of endocrine disorders or compromised immune function necessitates a thorough understanding of endocrine effects and drug interactions. Choosing appropriate antifungals and promptly identifying and managing endocrine adverse effects is crucial for optimal outcomes. This narrative review outlines the endocrine effects of antifungal drugs and aims to improve their recognition.

LITERATURE SEARCH STRATEGY

We searched PubMed, EMBASE, MEDLINE, Cochrane Library, ClinicalTrials.gov, and Google Scholar to identify articles published until September 2024 using the following search strategy. The terms “adverse effects”, “side effects”, “endocrine disorders”, “adrenal insufficiency”, “pseudohyperaldosteronism”, “male gonadal dysfunction”, “female sexual dysfunction”, “hyponatremia”, “fluoride-induced periostitis”, “hypokalaemia”, “diabetes insipidus”, and “side-effects” were searched in combination with “triazoles”, “imidazoles”, “amphotericin B”, “echinocandins”, and “antifungal agents”. The references to these articles were scanned and reviewed.

AZOLE-INDUCED ADRENAL INSUFFICIENCY

The azoles inhibit the cytochrome P450 (CYP) enzyme lanosterol 14-α-demethylase that blocks the conversion of lanosterol to ergosterol, a critical constituent of the fungal cell wall[6]. Though the lanosterol 14-α-demethylase enzyme is absent in mammals, azoles interfere with several other structurally related CYP enzymes in human steroid synthesis[6,7]. Figure 1 depicts the enzymes in the steroidogenic pathway that are blocked by different azoles. The practice guidance and precautions to prevent azole-induced adrenal insufficiency (AI) are summarized in Table 1.

Figure 1 Adrenal steroidogenesis and enzymes blocked by azoles. SCC: Side-chain cleavage enzyme; STAR: Steroidogenic acute regulatory; HSD: Hydroxysteroid dehydrogenase. The figures were created using BioRender (Supplementary material).

Table 1 Strategies to minimize azole-induced adrenal insufficiency.

	Clinical findings and evidence	Strategies
1	AI is a recognized adverse effect of oral ketoconazole	Oral ketoconazole use for antifungal effect should be avoided
2	Abrupt fluconazole withdrawal after concomitant long-term glucocorticoid use can trigger adrenal insufficiency by removing CYP3A4 inhibition and accelerating steroid metabolism	Monitor for AI after discontinuing fluconazole in individuals on long-term glucocorticoids
3	Drugs inhibiting CYP3A4 enzyme, like ritonavir and fluconazole itself, can impede the metabolism of steroids, including those administered via inhalation thereby causing exogenous CS. AI after cessation of steroid can occur	Monitor for CS when fluticasone and fluconazole are being taken together, especially with concurrent use of ritonavir. Monitor for AI after withdrawal of inhaled steroids
4	Posaconazole, like fluconazole, can inhibit the metabolism of steroids, such as dexamethasone, metabolized by CYP3A4 enzymes	Monitor for CS and subsequent AI on withdrawal of steroids when these combinations are used
5	Itraconazole inhibits hepatic CYP3A4, increasing glucocorticoid levels, particularly methylprednisolone. Prednisolone is unaffected due to differences in metabolism	Prednisolone is preferred with itraconazole, if methylprednisolone is necessary, dose reduction should be considered
6	Concurrent use of itraconazole and inhaled glucocorticoids can lead to exogenous CS and secondary AI	Monitor closely when inhaled steroids like fluticasone or budesonide and itraconazole are concurrently used
7	Voriconazole inhibits CYP2C9, CYP2C19, and CYP3A4, reducing glucocorticoid metabolism (fluticasone or budesonide) potentially causing iatrogenic CS and subsequent secondary AI	Alternatives such as beclomethasone or flunisolide may be preferred with voriconazole

CYP: Cytochrome P450; AI: Adrenal insufficiency; CS: Cushing’s syndrome.

Ketoconazole

Ketoconazole, in addition to its antifungal role, is used for medical management of endogenous Cushing’s syndrome[8]. It inhibits the CYP steroidogenic enzymes in the adrenals and gonads, including the cholesterol side-chain cleavage complex, 17,20-lyase, 11β-hydroxylase, and 17α-hydroxylase[9]. The dosage typically ranges from 200 mg to 1200 mg per day. However, in most cases, a dosage of 600 mg to 800 mg per day is necessary to achieve normalization of cortisol[8].

AI is an expected adverse effect of ketoconazole. However, overt hypocortisolism is uncommon, and individuals receiving oral formulations for fungal infections usually do not require glucocorticoid replacement[10,11]. A case series of ten prepubertal children receiving 3 months to 52 months of high-dose (10 mg/kg/day to 23 mg/kg/day) ketoconazole for coccidioidomycosis, demonstrated a partial reduction in cortisol and aldosterone synthesis, but none required adrenal steroid replacement[11]. Another series of nine children who received ketoconazole for coccidioidal meningitis did not have any clinical evidence of long-term AI. However, transient AI was observed at four hours which settled down by 24 hours[10]. Rare cases of prolonged AI have been described even after exposure to low doses (400 mg/day) of ketoconazole[12]. Systemic ketoconazole use has declined with the availability of safer antifungals.

Fluconazole

Inhibition of steroidogenic enzymes: Fluconazole dose-dependently inhibits adrenal steroidogenesis in vitro. In cultures of human adrenocortical tissues or adrenocortical carcinoma cell lines, pharmacological concentrations of fluconazole blocked the activity of 11β-hydroxylase and 17-hydroxylase, albeit with less potency than ketoconazole[13]. Despite the blockade of adrenal enzymes in vitro, fluconazole does not usually cause AI. Fluconazole-induced AI was not apparent in a group of preterm infants (n = 37) compared to controls (n = 40)[14]. AI has been reported with fluconazole after allogeneic hematopoietic stem cell transplant[15], high-dose cyclophosphamide for peripheral blood stem-cell harvest[16], acquired immunodeficiency syndrome (AIDS)[17], and critically ill patients[18]. AI can occur after abrupt withdrawal of fluconazole in individuals on long-term steroids. Fluconazole is a moderate inhibitor of the CYP3A4 enzyme, and the increased metabolism of steroids resulting from the release of inhibitory effects can precipitate AI[19].

Drug interactions: Discontinuation of inhaled fluticasone in an individual with acquired immunodeficiency syndrome receiving ritonavir and fluconazole precipitated AI[20]. Ritonavir, a potent inhibitor of the CYP3A4 enzyme, can elevate the systemic concentration of fluticasone to cause exogenous Cushing’s syndrome[21]. The authors hypothesized that the secondary AI after the sudden discontinuation of fluticasone could be potentiated by fluconazole, as both the drugs block CYP3A4 enzyme[20]. Exogenous Cushing’s syndrome and consequent AI have also been reported from a combination of fluconazole and fluticasone in a case of cystic fibrosis[22].

Posaconazole

Posaconazole use longer than six months was associated with AI in phase III clinical trials[23]. Primary AI occurred in an individual with type 1 diabetes mellitus and rhino-cerebral mucormycosis receiving posaconazole for 2 months[24]. Like fluconazole, posaconazole is an inhibitor of the CYP3A4 enzyme and can interact with the drugs metabolized by the CYP3A4 enzyme, such as dexamethasone (Table 1).

Itraconazole

Itraconazole and its metabolites inhibit CYP450 enzymes, especially CYP3A4, leading to increased levels of glucocorticoids such as methylprednisolone[25]. In a double-blinded cross-over trial of healthy volunteers, itraconazole reduced clearance of methylprednisolone, thereby increasing the risk of AI after withdrawal[26]. In another cross-over trial involving healthy volunteers, itraconazole increased methylprednisolone concentrations and suppressed endogenous cortisol secretion. No effect on prednisolone pharmacokinetics was noted and could be related to the differential metabolism of the two glucocorticoids by hepatic CYP3A4[27]. Prednisolone may be preferred over methylprednisolone when itraconazole is used (Table 1).

Exogenous Cushing’s syndrome, followed by secondary AI, has been reported with itraconazole and inhaled fluticasone[28]. Similar findings were observed with simultaneous use of budesonide and itraconazole[29]. In a study by Skov et al[30], 11 of the 25 participants receiving both itraconazole and budesonide developed AI, as determined by tetracosactide (0.25 mg) stimulation. In contrast, none of the 12 individuals receiving itraconazole alone showed a diminished adrenocorticotropic hormone response.

Voriconazole

Voriconazole acts as a potent substrate as well as an inhibitor of liver microsomal enzymes like CYP2C9, CYP2C19, and CYP3A4[31]. The interaction can lead to reduced metabolism of glucocorticoids and development of iatrogenic Cushing’s syndrome and secondary AI. Iatrogenic Cushing’s syndrome has been reported in a patient receiving oral budesonide for Crohn’s disease and voriconazole for fluconazole-resistant Candida albicans esophagitis[32]. Secondary AI occurred in a patient with granulomatous aspergillus pneumonia and bullous emphysema who was on intranasal mometasone, inhaled fluticasone, and voriconazole 200 mg twice daily. However, no relationship has been documented between voriconazole plasma levels and the degree of CYP3A4 inhibition[33]. An alternative corticosteroid like beclomethasone or flunisolide may be advisable when using potent CYP3A4 inhibitors like voriconazole.

AZOLES AND APPARENT MINERALOCORTICOID EXCESS

Apparent mineralocorticoid excess (AME) or pseudohyperaldosteronism refers to a condition where features of hyperaldosteronism are present without actual production of excess aldosterone. The condition usually results from genetic mutations or inappropriate stimulation of mineralocorticoid receptors precipitated by drug interaction[34].

Posaconazole

Triazoles such as posaconazole and itraconazole are associated with the syndrome of AME, manifesting as low-aldosterone, low-renin hypertension, and hypokalemia. AME results from either the inhibition of 11β-hydroxylase or 11β-hydroxysteroid dehydrogenase type 2[35].

Inhibition of 11β hydroxylase: 11β-hydroxylase is a mitochondrial enzyme encoded by CYP11B1 that converts 11-deoxy-corticosterone and 11-deoxy-cortisol to corticosterone and cortisol, respectively. Reduced cortisol synthesis triggers increased adrenal steroidogenesis due to the loss of negative feedback of the hypothalamic-pituitary-adrenal axis, leading to the accumulation of 11-deoxy-corticosterone and 11-deoxy-cortisol. Despite having lower receptor binding affinity and higher plasma protein binding, markedly high levels of 11-deoxy-corticosterone lead to mineralocorticoid receptor activation, causing hypertension and hypokalemia[35].

Inhibition of 11β hydroxysteroid dehydrogenase type 2: Posaconazole inactivates 11β-hydroxylase or 11β-hydroxysteroid dehydrogenase type 2 and prevents the conversion of cortisol to cortisone in the distal convoluted tubule[36]. Increased levels of cortisol induce activation of mineralocorticoid receptors in the distal convoluted tubule, resulting in hypertension and hypokalemia. An elevated ratio of urinary tetrahydrocortisol and allotetrahydrocortisol to tetrahydrocortisone is diagnostic. Additionally, an elevated ratio of cortisol to cortisone can corroborate[37].

17α-hydroxylase inhibition: Inhibition of CYP17A1 17α-hydroxylase by posaconazole may not directly induce AME, but a subsequent decrease in cortisol production and the feedback activation of steroid biosynthetic pathway can drive excess mineralocorticoid generation[38].

Clinical scenario: In 69 patients on posaconazole, 23.2% had AME, predicted by age, hypertension, and elevated serum drug levels[39]. An analysis of the Food and Drug Administration adverse event reporting system database linked posaconazole [reporting odds ratio (OR) of 865.37] and itraconazole (reporting OR = 556.21) to AME risk, while fluconazole, voriconazole, and isavuconazole showed no such risk. Among 66 cases (mean age 55.5 years), AME was dose-dependent, mainly occurring at posaconazole levels > 3 μg/mL, with a median onset of 11.5 weeks. Prevention strategies include dose reduction or switching to fluconazole, isavuconazole, or voriconazole[40]. Elevated 11-deoxycorticosterone and 11-deoxycortisol, with an increased cortisol-to-cortisone ratio, indicate a dual pathogenic mechanism. The cortisol response to the short synacthen test was frequently inadequate[37,41]. A combined presentation of AI and AME has been reported[42]. Atypical manifestations with nephrotic-range proteinuria and AME occurring concurrently are also described[43].

Itraconazole

Current molecular modeling and clinical data indicate that itraconazole primarily causes AME due to 11β-hydroxysteroid dehydrogenase 2 inhibition, whereas for posaconazole, the predominant effect could be inhibition of 11β hydroxylase (CYP11B1). Itraconazole-induced AME is associated with a high urinary cortisol: Cortisone ratio[44]. AME has been observed across doses ranging from 100 mg/day to 600 mg/day[40,44].

AZOLE-INDUCED REPRODUCTIVE DYSFUNCTION

Male gonadal dysfunction

Imidazoles inhibiting testosterone synthesis contain a phenylated side chain in the imidazole molecule. Typical examples include ketoconazole, miconazole, and clotrimazole[45].

Ketoconazole: Ketoconazole exerts its anti-androgenic effects through several mechanisms (Table 2). Oligospermia, azoospermia, reduced libido, gynecomastia, and impotence have been noted in studies using high-dose ketoconazole (800-1200 mg/day)[46]. In a multicentric trial in cases of coccidioidomycosis, 21% developed reversible gynecomastia, and 13% complained of decreased libido. The effects were dose-dependent. The majority (14 out of 25) developed it within the first 6 months and were reversible[47].

Table 2 Proposed mechanisms of azole-induced male hypogonadism.

Drugs	Mechanism	Clinical manifestation
Ketoconazole[46,54]	Inhibition of 17-alpha hydroxylase and 17,20 lyase	Decreased libido
	Increased estrogen: Testosterone ratio	Gynecomastia
	Binding to androgen receptor	Oligospermia; azoospermia
Posaconazole[52]	Inhibition of 11-β hydroxylase	Gynecomastia
	Compensatory increase in steroidogenesis
	Peripheral aromatization of testosterone to estrogen
	Inhibition of CYP3A4 and CYP3A7 slows down the hepatic metabolism of estrogen
Itraconazole[49]	Unknown	Gynecomastia
		Loss of libido

Fluconazole and itraconazole: Fluconazole has a negligible effect on circulating testosterone in clinical and in-vitro studies[48]. Two case series have reported decreased libido and impotence with itraconazole[49,50]. The symptoms occur in < 1% of recipients. Caution should be exercised in those with pre-existing risk factors, where fluconazole may be preferred[51].

Posaconazole: Posaconazole caused gynecomastia and hypertension in a 38-year-old male treated for pulmonary coccidioidomycosis. The elevated serum estradiol normalized after switching to voriconazole. The proposed mechanism involves the inhibition of CYP11B1 11β-hydroxylase, leading to a compensatory increase in steroidogenesis and subsequent peripheral aromatization of testosterone to estrogen[52]. Although a decrease in androgen synthesis in the testes and adrenal gland due to inhibition of CYP17A1 17,20-lyase activity may be responsible, serum testosterone levels usually remain normal[36]. Moreover, posaconazole-induced inhibition of CYP3A4 and CYP3A7 slows down the hepatic metabolism of estrogen, which could increase circulating estradiol levels[52].

Female reproductive dysfunction

Ketoconazole: Ketoconazole reduces serum estrogen levels transiently, the primary mechanism being deprivation of precursors due to androgen blockade[53]. Ovarian progesterone production may be also affected by ketoconazole[54].

Itraconazole: Iatrogenic metrorrhagia has been reported with co-administration of itraconazole and simvastatin. CYPA34 inhibition by simvastatin leads to itraconazole accumulation and estradiol synthesis inhibition. The altered estrogen: Progesterone ratio results in estrogen breakthrough bleeding[55]. Inadvertent pregnancies have been reported as itraconazole interferes with the efficacy of oral contraceptive pills (OCPs) by enhancing estrogen metabolism[56].

Other azoles: Fluconazole inhibits estrogen metabolism, increasing ethinyl estradiol levels in women using OCPs. The concurrent long-term use of OCPs and fluconazole may trigger hyperestrogenic symptoms[57]. Similar interactions may occur with voriconazole[58].

AZOLE AND HYPONATREMIA - VORICONAZOLE

Voriconazole-induced hyponatremia commences after 6 days to 26 days[59]. Both syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and salt-losing nephropathy have been described, with SIADH being the predominant pathology[7].

SIADH has been described in a 75-year-old man with chronic pulmonary aspergillosis, receiving 400 mg of voriconazole, who developed euvolemic hyponatremia with elevated urinary sodium 21 days into therapy[60]. In another report, somnolence, malaise, low blood pressure, and decreased skin turgor, indicating volume depletion, occurred in a male being treated with voriconazole. Laboratory tests showed hyponatremia and liver dysfunction. After discontinuing voriconazole and administering normal saline, his symptoms improved. Elevated antidiuretic hormone and plasma renin activity, along with high urine sodium despite volume depletion and low serum osmolality, were suggestive of salt-losing nephropathy[61].

There is a marked interindividual variability in blood concentrations of voriconazole secondary to non-linear saturation pharmacokinetics, drug interactions, hepatic metabolism, and CYP2C19 genetic polymorphisms. Hence, therapeutic drug monitoring can be used to avoid adverse effects[62]. Higher concentrations (> 5-6 μg/mL) increase the risk of toxicity[59,60,62].

Voriconazole undergoes hepatic metabolism mediated primarily by CYP2C19 followed by CYP2C9 and CYP3A4[63]. Blood concentrations of voriconazole are influenced by genetic polymorphisms of CYP2C19[64]. Non-functioning alleles CYP2C19*2, CYP2C19*3, and CYP2C19*4 with poor metabolizing capacity are observed more frequently among Asians, increasing the risk of toxicity[65]. Isobe et al[60] reported the first case of voriconazole-induced SIADH secondary to CYP2C19*2 G681A mutation. Additional heterozygous and homozygous mutations associated with reduced metabolizing capacity have also been described[62,66].

FLUORIDE-INDUCED PERIOSTITIS WITH AZOLES - VORICONAZOLE

Epidemiology

Data from the Food and Drug Administration adverse event reporting system suggests a strong association between periostitis and voriconazole in 143 patients, with a reporting OR of 1831.7. No signals were found for other triazoles[67]. Voriconazole-induced fluorosis and subsequent periostitis with exostoses are described in cases of solid-organ transplant and hematological malignancy[68,69]. The true prevalence is unknown but may occur in up to 15% of long-term recipients[70].

Pathogenesis

Voriconazole contains three fluorine atoms, constituting 16.25% of its molecular weight[71]. A dose of 400 mg of voriconazole contains 65 mg of fluorine. Oxidative defluorination is the primary pathway for metabolism and excretion of voriconazole[72]. Fluoride has an anabolic effect on bone, encouraging osteoblasts to produce excessive unmineralized bone, leading to osteomalacia. The unmineralized bone accumulates in the periosteal and endosteal regions. Additionally, the deposition of fluorapatite can result in a denser but brittle bone matrix that is resistant to resorption[73]. Fluoride-independent mechanisms can also stimulate osteogenesis and enhance the expression of cytokines[74].

Clinical profile and predictors

The presentation resembles fluorosis, with skeletal pain and, at times, painless bony swellings due to periostitis deformans can occur[75]. Fluoride is concentrated in mineralized tissues and mainly excreted by the kidneys, with renal clearance dependent on the glomerular filtration rate and urinary pH[73]. The condition is more common in the presence of moderate-to-severe chronic kidney disease, including cases of cyclosporine-induced nephrotoxicity. Elevated fluoride and serum alkaline phosphatase normalize after discontinuing voriconazole[76].

Diagnosis and treatment

The daily and cumulative dosage of voriconazole is the best predictor of toxicity instead of serum drug levels. While serum fluoride levels rise significantly during therapy, the relationship to skeletal disease is unpredictable and may not be helpful for monitoring[70]. In symptomatic cases, a serum fluoride level can still be obtained. A bone scan can confirm periostitis. Discontinuation of voriconazole usually reduces pain rapidly, but dose reduction is an option if discontinuation is not feasible[7].

OTHER ENDOCRINE ABNORMALITIES WITH AZOLES

Azoles and calcium metabolism

Ketoconazole inhibits CYP27B1 (1-alpha-hydroxylase) enzyme, leading to reduced 1,25-dihydroxycholecalciferol levels though significant changes in serum 25-hydroxycholecalciferol, calcium, phosphate, parathyroid hormone (PTH), or alkaline phosphatase levels do not occur[77].

Azoles and hypoglycemia

Voriconazole and ketoconazole-induced hypoglycemia in individuals without diabetes have been documented. The etiology could be hyperinsulinemia resulting from reduced degradation of insulin in chronic kidney disease or hepatic dysfunction[78]. Fluconazole can affect the pharmacokinetics of sulfonylureas by inhibiting the CYP2C9 enzyme, thereby increasing the plasma concentration and prolonging elimination. Hence, co-administration of fluconazole and glimepiride may lead to hypoglycemia[79].

POLYENES: AMPHOTERICIN B

Amphotericin B leads to renal tubular injury, with deoxycholate compounds exerting higher toxicity than lipid compounds. Its liposomal formulations have been linked to nephrogenic diabetes insipidus (NDI)[80]. Clinical manifestations include acute kidney injury, urinary potassium wasting and hypokalemia, magnesium wasting and hypomagnesemia, distal renal tubular acidosis, and polyuria secondary to NDI[81,82]. Risk factors are male gender, higher average daily dose (> 35 mg/day), diuretic use, and concomitant nephrotoxic drug usage[83]. A decrease in the aquaporin-2 expression induced by the drug in the renal medulla leads to decreased collecting tubule sensitivity to antidiuretic hormone[81]. Hypokalemia itself can cause NDI. Despite a better safety profile with liposomal compounds, hypokalemia is a known effect and correlates with baseline estimated glomerular filtration rate[84,85].

Amphotericin B-induced acute kidney injury occurs due to vasoconstriction and direct toxic actions on tubule. Renal hypoperfusion and nephrotoxins induce synergistic tubular damage, leading to tubular cell necrosis[86]. Renal magnesium wasting and hypomagnesemia mandate routine monitoring of serum magnesium. Hypocalcemia due to hypomagnesemia-induced impaired PTH secretion and PTH resistance have been reported[87,88]. Monitoring and replacement of potassium and magnesium is recommended[89].

ECHINOCANDINS

Echinocandins are a novel class of parenterally administered semi-synthetic lipopeptides, which include caspofungin, micafungin, and anidulafungin. These drugs, unlike azoles, do not usually cause any endocrine adverse effects.

Hypercalcemia and hypokalemia from capsofungin

Caspofungin has been reported to induce hypercalcemia by unknown mechanisms[90,91]. Caspofungin causes hypokalemia in 2%-11% of patients, and studies have suggested a dose-dependent hypokalemic effect. However, the mechanism is not clearly understood[91].

CONCLUSION

Azoles, the most commonly administered antifungal medications, are associated with a spectrum of endocrine adverse effects ranging from AI, AME, gonadal dysfunction, hyponatremia, and fluorosis. These effects are often influenced by drug interactions and individual susceptibility, necessitating careful monitoring and treatment. Amphotericin B, especially non-lipid formulations, commonly causes electrolyte imbalance from renal tubular damage. In contrast, newer antifungals like echinocandins have a more favorable endocrine safety profile. Understanding the adverse effects of different antifungal drugs on the endocrine system is crucial for optimizing treatment outcomes and ensuring patient safety in clinical practice.