Endocrine consequences of antifungal therapy: A missed entity

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.

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