Minoxidil is known to be an effective treatment for decreasing the rate of hair loss and promoting hair regrowth by increasing both hair diameter and density, but its mechanism of action is not yet fully understood [6, 7]. Minoxidil can also promote premature anagen entry to resting hair follicles and prolong the anagen phase [8, 9]. Thus, shortening of the telogen phase and acceleration of the telogen–exogen phase lead to synchronization of the hair cycle and increased hair shedding after the initiation of minoxidil therapy .
Low-dose oral minoxidil has been used in many Asian countries for > 30 years to treat male AGA, albeit there have been very few case reports. In 2018, a pilot study demonstrated the effectiveness of oral minoxidil 0.25–1.25 mg once daily and spironolactone 25 mg for the treatment of Sinclair stage 2–5 female pattern hair loss. One hundred women completed the study, with a mean reduction in hair shedding score (range 1–6) of 2.3 at 6 months and 2.6 at 12 months.  In addition, a recent retrospective review showed that low-dose minoxidil (2.5–5 mg once daily), given either as monotherapy or as an additional therapy for 6–12 months, was both effective and safe in 41 male patients with AGA [12, 13]. Therianou et al. also reported the effectiveness of using oral minoxidil in patients allergic to topical minoxidil .
The results of our study showed that oral minoxidil improved hair growth in men with AGA according to all of the assessments applied. Compared to baseline, total hair count at the vertex increased by 14.25% at 12 weeks of treatment (from 182.5 to 208.5 hairs/cm2) and by 19.23% at 24 weeks of treatment (from 182.5 to 217.6 hairs/cm2). Non-vellus hair counts were even more improved: compared to baseline there was an increase of + 17.07% (from 152.3 to 178.1 hairs/cm2) at week 12 and an increase of + 23.5% (from 152.3 to 188.1 hairs/cm2) at week 24. As expected, the younger patients (< 41 years) showed better response to treatment than the older ones (≥ 41 years). Compared to baseline, at 24 weeks, total hair counts were significantly different in these two groups in favor of the younger patients, with an increase of + 40.7 hairs/cm2 in the younger patients versus + 25.4 hairs/cm2 in the older ones. This difference is likely due to the shorter duration of hair loss, the lower classification of AGA severity and the larger hair diameter in the younger group at baseline, although the baseline hair counts were not significantly different in the two groups. In addition, the aging process also contributes to the treatment outcomes: hair density and diameter decrease with advancing age, due not only to androgen-mediated processes but also to the systemic senescence process, such as oxidative stress and stem cell apoptosis, found in those aged > 50 years . The authors of a previous study reported that finasteride is also unlikely to stimulate significant hair regrowth in older men, and older men who take finasteride 5 mg for prostate gland hypertrophy show no significant hair growth .
Hair growth in patients on oral minoxidil was clearly observed in the global photographic assessment, with a 100% improvement (score > + 1 or + 1–40% improvement) on the vertex area at 24 weeks. An improvement scale score of + 2 (moderate increase, + 41–70% improvement) and 3 (large increase, > + 70–100% improvement) were reported in 93.3% of patients in the vertex and 73.3% of patients in the frontal area. The frontal area also showed a significant response, but less than that of the vertex, which is consistent with many previous reports [17, 18]. In previous studies, the vertex type of AGA showed a more rapid and obvious improvement with oral 1 mg finasteride compared with the other areas [18, 19].
Although we did make a direct comparison of oral minoxidil 5 mg once daily to other standard medications for AGA, our results suggest that oral minoxidil at this dose is superior to a 2–5% minoxidil solution, 5% minoxidil foam, finasteride 1 mg, and dutasteride 0.5 mg daily in all measurements (Table 4). Our global photographic assessment illustrates distinctive results in the oral minoxidil group, with all patients showing positive response. A comparison of total hair counts in patients treated with oral minoxidil in our study with those in other studies (see Table4) showed a 19.2% increase among the patients in our study, followed by those treated with 5% minoxidil foam (13.4% increase), dutasteride (11.67%), and oral finasteride (7.2–9%).
In terms of safety, the results of physical examinations, laboratory evaluations, and imaging were assessed in our study. The common side effects of oral minoxidil were hypertrichosis (93%) and pedal edema (10%). Hypertrichosis is a well-recognized adverse effect of either oral or topical minoxidil, and the extent of this AE has been suggested to be dose dependent . This condition is typically reversible within 3–5 months and does not always require discontinuation of therapy [21, 22]. However, for patients with marked hypertrichosis or psychosocial disturbances, laser hair removal is an option to get rid of unwanted hairs . All patients in this study were able to accept the hypertrichosis, which usually resolves within 2–3 weeks after stopping the medication . We observed pedal edema in patients with obesity and poorly controlled hypertension. This condition is caused by sodium and water retention, with blood flow redistributed from the outer to the inner cortex of the kidney [1, 25]. Therefore, a low salt diet should be recommended to patients who are taking oral minoxidil. However, the prevalence of edema in patients on low-dose oral minoxidil is far less than that in patients taking the standard dose (10–40 mg/day), which ranges from 7 to 100% of patients .
Regarding the hemodynamic effects, the first case of orthostatic hypotension was found in two patients, with a drop in systolic BP of + 2.5 mm/Hg. Based on this observation, we recommend that the first dose of oral minoxidil be administrated before bedtime to avoid this side effect [1, 26]. At low dosage, there was no significant change in BP and PR at 24 weeks after treatment, with a mean systolic BP decrease of − 3.8 mmHg, mean diastolic BP decrease of − 1.1 mmHg and a PR increase of + 0.6/min. The most serious side effects of minoxidil reported to date are cardiovascular complications, with ischemic heart disease, pericarditis, pericardial effusion and tamponade, pulmonary hypertension, and high output cardiac failure reported . Angina may worsen or appear for the first time during minoxidil treatment, probably due to the increased oxygen demands associated with increased heart rate and cardiac output [27, 28]. In one study, pericardial effusion caused by minoxidil occurred in approximately 3–5% of patients, but the mechanism remained unknown . An association between pericardial effusion and renal status is assumed. In some studies, pericardial effusion was often associated with renal disease, uremic syndrome, a connective tissue disease, congestive heart failure, or marked fluid retention [2, 3, 29]. When pericardial effusion is suspected, EKG should be performed. In earlier studies, EKG changes, such as ST-segment depression and T-wave flattening and inversion, were reported in up to 90% of patients in the first 2 weeks of minoxidil treatment for hypertension [26, 30]; basic blood chemistry and chest X-rays were largely within normal range. In our study, no SAEs were found and low-dose oral minoxidil was generally well-tolerated. From the safety point of view, we recommend not prescribing oral minoxidil to elderly patients with an increased risk for myocardial infarction, heart failure, chronic renal failure, or severe hypertension; oral minoxidil should be considered only in healthy subjects.
To our knowledge, this is the first prospective clinical trial studying the therapeutic effects of oral minoxidil in male AGA using a standardized hair count method, hair mass index, global photographic assessment, and patient satisfaction. The strength of our study is the comprehensive investigations on safety the profile of oral minoxidil, which is the main concern of most physicians. A limitation of the current study is that it was neither randomized nor controlled but rather an open-label clinical trial. A study population of 30 patients can be considered to be a relatively small sample. In the future, randomized, double-blind, placebo-controlled studies with longer study period are required to accurately identify the efficacy and long-term safety of low-dose oral minoxidil for the treatment of AGA.