Gender Differences in Adverse Effects and Dosing Practices of Low-Dose Oral Minoxidil for Androgenetic Alopecia: A Retrospective Analysis of 310 Patients

Minoxidil is US Food and Drug Administration-approved for treatment of androgenetic alopecia (AGA) topically and hypertension orally. Off-label low-dose oral minoxidil (LDOM), defined as ≤5 mg/day, has been studied for AGA treatment [1], with limited safety data in this patient population. A dose-dependent association between LDOM and the risk of several adverse effects (AEs), including dizziness/lightheadedness, hypertrichosis, lower extremity edema, and other cardiovascular AEs, has been described [2‒5]. However, there is a paucity of literature on LDOM dosing practices and AE management. Therefore, we examined AEs and their management in AGA patients treated with LDOM, stratified by age, gender, and dose, to provide guidance for dermatologists in risk/benefit discussions.

After Institutional Review Board approval, patients with AGA diagnosis (International Classification of Diseases [ICD]-9 codes 704.00/704.09, ICD-10 L64/L65.8/L65.9) taking oral minoxidil were queried from Weill Cornell Medicine Epic, January 1, 2010–December 31, 2022. AGA diagnoses were confirmed via chart review, and unconfirmed AGA cases and patients without follow up were excluded. AEs and management were recorded from follow-up and emergency room visits. Fisher’s exact test and logistic regression determined statistical significance (p ≤ 0.05) and odds ratios (ORs). The Benjamini-Hochberg procedure was applied for multiple hypotheses testing with false discovery rate set at 0.05.

A total of 310 patients were included, with 53.2% females, mean age 47.5 years (range: 18–89 years), and 54.2% white (Table 1). The mean dose was lower in females than males (1.8 mg/day vs. 2.2 mg/day, respectively, p < 0.001). Forty-five patients (14.9%) experienced AEs, most commonly dizziness/lightheadedness (4.5%), hypertrichosis (3.5%), and extremity edema (2.6%). Higher dosages predicted dizziness/lightheadedness likelihood (β = 0.4183, aOR: 1.52, p = 0.04) in a multivariate logistic regression model controlling for age and gender. Overall AE frequency was similar between patients ≥50 years old and <50 years old (p = 0.63), but higher for females compared to males (22.4% vs. 5.5%, respectively, p < 0.001). This difference did not persist upon age subgroup analysis between genders for each AE (Table 2). Of those with AEs, 11.1% adjusted dose and 22.2% discontinued treatment, with similar regimen changes between genders (13 females [35.1%] and two males [25.0%]) (p = 0.47) (Table 3).

We found that LDOM AEs were fairly common (∼15%) in both genders, with a higher dose increasing risk of dizziness/lightheadedness. Females had higher risk of having any AE, which did not persist upon AE subgroup analysis. A meta-analysis of six studies reported that increasing the dosage of LDOM by 1 mg significantly increased hypertrichosis and cardiovascular AE (hypotension, edema, increased heart rate, palpitations, and abnormal electrocardiogram) risk by 17.6% (p = 0.0057) and 4.8% (p = 0.00382), respectively [2]. In a retrospective study of 1,404 hair loss patients (82.4% AGA) on LDOM [3], dosage increased risk for hypertrichosis (aOR: 1.26, p < 0.001), but not lightheadedness, contrary to our findings. This may be explained by differences in study populations and AE reporting. A retrospective study of 435 patients on LDOM for AGA reported that hypertrichosis in men (OR 1.03, p < 0.001) and headache in women (OR 1.09, p = 0.014) were associated with dose/weight [4]. In a systematic review including 442 patients on LDOM for hair loss, hypertrichosis was associated with dose (6.7% on 0.25 mg to 56.1% on 5 mg [p < 0.001]), as was lower extremity edema (p = 0.009) [5]. Together, these findings suggest that several AEs of LDOM including dizziness/lightheadedness, hypertrichosis, lower extremity edema, and other cardiovascular AEs may be dose-dependent.

We also found that approximately one-third of patients who experienced AEs required dose adjustment or discontinued treatment, suggesting that starting doses are often too high. Women were started at an average dose of 1.8 mg/day vs. 2.2 mg/day for males. A retrospective study of 1,404 hair loss patients treated with LDOM analyzed the mean dose of LDOM that induced AEs by gender [3]. In females, the mean doses that induced hypertrichosis, lightheadedness, leg edema, tachycardia, and headache were 1.42 mg, 0.93 mg, 0.97 mg, 0.73 mg, and 1.28 mg, respectively. In males, the corresponding mean doses were 4.10 mg for hypertrichosis, 3.90 mg for lightheadedness, 3.25 mg for leg edema, 2.52 mg for tachycardia, and 1.25 mg for headache. Of the 479 patients who experienced these AEs, 131 (27.3%) adjusted their dose or discontinued treatment, including 29.9% of females and 14.8% of males. Together, these findings reflect a trend in current clinical practice toward prescribing inappropriately high doses, particularly for females, which may contribute to treatment discontinuation or dose modification due to AEs.

In a review of 17 studies including 634 patients treated with LDOM for hair loss, LDOM was generally well tolerated, with only minor AEs reported [6]. Hypertrichosis was the most common AE, affecting approximately 20% of patients. In patients taking 5 mg daily, hypertrichosis occurred in over 50% of cases [7, 8]. However, similar to our findings, hypertrichosis was almost never a cause for discontinuation as many patients regarded it as mild and manageable [6]. Lower doses were associated with a much lower incidence of hypertrichosis, with 0.25 mg LDOM associated with hypertrichosis in less than 10% of patients [9, 10]. Cardiovascular side effects were rare and relatively mild, with minor changes in blood pressure and a slight increase in heart rate noted in some patients [6]. However, we have previously found that LDOM does not lead to clinically significant changes in blood pressure [11]. Postural hypotension or dizziness occurred in about 2% of patients, and lower limb edema was reported in approximately 3%, mostly in those on the higher 5 mg dose [6]. In this review, the authors concluded that 0.25–1.25 mg LDOM is safe and effective for females, while 2.5–5 mg LDOM is required to be effective for men [6].

Limitations include retrospective single-center design, few patients of color, not controlling for other causes of these AEs, and limited sample size. We performed subgrouping allowing for risk stratification by age and gender, which is a strength of our study compared to prior analyses.

In sum, we found that a higher LDOM dose increased risk of lightheadedness/dizziness and that females were more likely to experience any AE. Our findings suggest that LDOM may be prescribed at inappropriately high doses, particularly in women, leading to dose adjustments or medication discontinuation in many patients. Therefore, we recommend a nuanced approach to mitigating LDOM AEs, by starting AGA patients on lower doses (i.e., 0.25–1.25 mg for women and 2.5–5 mg for men) and titrating up as tolerated and counseling female patients on their overall increased risk of AEs.

This study protocol was reviewed and approved by Weill Cornell Medicine IRB, approval #22-10025335 on 11/29/2022. Weill Cornell Medicine IRB has determined that the criteria which permit a waiver of written informed consent are satisfied.

The authors have no conflicts of interest to declare. Dr. Shari Lipner has served as a consultant for Moberg Pharmaceuticals, BelleTorus Corporation, Eli Lilly, and Ortho Dermatologics.

This study was not supported by any sponsor or funder.

Conceptualization and methodology: M.M.O. and S.R.L.; data curation: H.D. and B.H.; formal analysis: M.M.O.; investigation: M.M.O., H.D., and B.H.; supervision: S.R.L.; writing – original draft: M.M.O.; writing – review and editing: H.D., B.H., and S.R.L.

The data that support the findings of this study are not publicly available due to their containing information that could compromise the privacy of research participants but are available from the corresponding author S.R.L. or the data sharing committee [email protected] upon reasonable request.