Each hair strand is formed in a hair follicle that goes through three phases divided didactically into anagen (growth phase), catagen (involution phase), and telogen (latent or resting phase). At the end of the telogen phase, the hair follicle restarts the anagen phase and a new shaft begins to be produced, even before the previous one is detached. The detachment of the shaft is also known as teloptosis or exogenous phase.

Exceptionally, the follicle may enter a period of inactivity, in which it is empty for a period of time (kenogen phase). This phase may be present physiologically, but it becomes more common and longer in older patients or those with advanced androgenetic alopecia (Fig. 1).13

Fig. 1.

Scalp follicular cycle: anagen phase (cell proliferation), catagen (involution) and telogen (resting). After successive cycles, the kenogen phase (without hair production) may occur.

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In MAA, there is a reduction in the anagen phase with premature entry into the catagen phase and a reduction in the anagen-telogen ratio. With a greater predominance of telogen hairs, the patient may notice an increase in hair loss. Some studies suggest that entry into the catagen phase is a consequence of decreased expression of factors that maintain the anagen phase, such as insulin-like growth factor (IGF-1), basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) and increased expression of cytokines that promote cell apoptosis, such as transforming growth factor beta 1 (TGF-β1), interleukin-1 alpha (IL-1α) and tumor necrosis factor alpha (TNF-α).14

In addition to the change in the follicular cycle, there is also a morphological change in the follicles and, consequently, in the hair shafts: miniaturization. The miniaturized hair is very similar to a vellus hair, with a thickness of less than 0.03 mm.15

Miniaturization probably occurs at some point between the catagen phase and the beginning of the next anagen phase, when the dermal papilla is moving and, therefore, more susceptible to external influences.16 The hair shaft diameter is determined by the size of the dermal papilla, and the reduction in papillary volume, by mechanisms involving the loss of regulation between pro- and anti-apoptotic agents, may be related to this miniaturization process.17

Because it is such a common disease, it is difficult to establish a genetic inheritance pattern for MAA.12 Evidence of the importance of the hereditary factor in the development of MAA is supported by the fact that, rarely the disease has already been identified in prepubertal children and these cases of early onset have a strong positive family history for the condition.18 Moreover, there is greater concordance of MAA in monozygotic twins, compared to dizygotic ones.19

Alterations in the androgen receptor (AR) gene on chromosome Xq12 can lead to increased expression of this receptor and a consequent tendency towards MAA,20 but they are not sufficient to cause baldness. The local and systemic presence of androgens also exerts an influence and can be genetically determined, indicating a probable polygenic inheritance in disease development.21

This polygenic inheritance model and variable expressivity can explain the different phenotypes and the variation in their age of onset.22 There are two important studies in the field of the MAA genome, with currently 10 susceptibility loci identified: 2012;8.1p36.22, 2q37.3, 7p21.1, 7q11.22, 17q21.31, 18q21.123, 2q35, 3q25.1, 5q33.3 and 12p12.1.23,24

Estrogen, thyroid hormones, glucocorticoids, retinoids, prolactin and growth hormone interfere with hair growth, but androgens are the most important hormones.25

The skin and the pilosebaceous unit have the capacity to metabolize and convert sex steroids26 and in the hair follicle the enzyme 5-alpha reductase type 2 (5-αR2) converts testosterone into dihydrotestosterone (DHT), which binds to intracellular AR, initiating a signaling cascade that culminates in hair thinning14 (Fig. 2). Compared to testosterone, DHT has approximately five times more affinity for AR.14

Fig. 2.

Androgen-dependent signaling pathway in the dermal papilla cells.

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Men with 5-αR deficiency do not develop MAA, regardless of serum testosterone levels, so DHT, and consequent gene activation, is one of the main causes of the disease. The relative efficacy of 5-αR2 inhibitors in the treatment of MAA helps to corroborate this hypothesis.27

The limited success of therapies with androgen modulators and hair growth promoters suggests that other mechanisms may be involved in MAA.12

The term microinflammation is currently used to refer to the milder and more superficial inflammation that affects the follicles in MAA, in comparison with the inflammation in cicatricial alopecia.28

An important issue is the origin of this inflammation. The fact that it is more superficial may indicate an origin in the infundibulum and, in this case, colonization by Propionibacterium sp, Staphylococcus sp and Malassezia sp, among other microorganisms, could contribute with toxins and/or antigens to the initiation of the inflammatory process.29 Environmental factors such as irritants, pollutants, ultraviolet radiation, smoking and oxygen-free radicals can also activate the inflammatory response in follicular keratinocytes through the release of IL-1α.30 Adjacent fibroblasts respond to this inflammatory signal, perpetuating the cascade until the antigens are destroyed.31 Through DHT influence, an increase in the sebaceous gland activity could provide a more favorable microenvironment for the development of the aforementioned pro-inflammatory microorganisms.28

Finally, other receptors may be involved in microinflammation, such as the vitamin D receptor and retinoid receptors, as it has been shown that these have antagonistic actions on IL-8 expression and may be part of a delicate balance in the complex inflammatory cascade of hair growth.32,33 However, it is worth noting that it remains controversial whether microinflammation in MAA is the initial trigger for its development or, even, whether it is relevant in the disease pathogenesis.34

The most frequent findings in trichoscopy are based on studies in Caucasians:

• •

  Variation in hair thickness due to progressive miniaturization, typical of MAA. This occurs because terminal hairs are gradually replaced by finer and shorter hairs (vellus hairs), except in the occipital region;

• •

  Presence of thicker and longer hairs than typical vellus hairs, but shorter and finer than terminal hairs with a wavy appearance (wavy hair);

• •

  The number of hairs emerging from the follicular unit decreases to one or two, characterizing a decrease in hair volume. The scalp has follicular units with two to five hair shafts and the proportion of units with only one hair is less than 30% in individuals without MAA. This information is very useful for early diagnosis;

• •

  Yellow spots can be found in advanced cases, corresponding to keratin and sebum accumulated in the dilated ostia of the follicles;

• •

  Presence of the peripilar sign (or perifollicular hyperpigmentation), which corresponds to the presence of a perifollicular lymphocytic infiltrate. It is observed in 22% to 60% of the patients, but it is not pathognomonic;

• •

  Honeycomb pigmentation in Caucasian individuals with advanced MAA who have had their scalp exposed to the sun. It can be found in Caucasians with any type of non-scarring alopecia and in the healthy scalp of patients with higher phototypes.

After hypertrichosis was observed in patients using oral minoxidil as an antihypertensive drug, a 2% topical formulation was developed and received approval from the US Food and Drug Administration (FDA) for the treatment of MAA in 1988. Later, in 1991, studies reported the superiority of the 5% solution when compared to the 2% solution and placebo.44

The mechanism of action of minoxidil in the hair follicle is not fully known and probably it’s not solely due to its vasodilatory effect. Possible effects include increased vascular endothelial growth factor in the dermal papilla, indicating that the drug induces angiogenesis; activation of prostaglandin-1-synthetase, an enzyme that promotes follicular activity; and increased expression of the hepatocyte growth factor, which promotes cell activity in the follicle.45

Recent data suggest that minoxidil may act on gene expression and activation of signaling pathways, leading to the upregulation of some genes. Possible antiandrogenic mechanisms have also been reported, interfering not only with AR, but also acting on two different targets related to steroid biosynthesis.46

In its topical presentation, it is recommended that men use the 5% solution twice a day, and for the obtained results to be maintained, treatment must be continued indefinitely.47 It is a safe, well-tolerated drug with few adverse effects. Among the most common are pruritus and desquamation of the scalp. Although minoxidil can cause contact dermatitis, it is propylene glycol, present in the vehicle, that most frequently causes dermatitis. In these cases, symptoms are resolved by switching to topical minoxidil without propylene glycol.

After the topical application, the enzyme sulfotransferase (SULT1A1) in the human scalp converts minoxidil to minoxidil sulfate, which is the active form of the molecule. Differences in SULT1A1 activity between individuals may affect the efficacy of the medication, leading to inconsistencies in the response to treatment.48 In its oral form, minoxidil also needs to be converted to its active form, this time by hepatic sulfotransferase (SULT1A2) (Fig. 6).

Fig. 6.

Conversion of Minoxidil into its active form, Minoxidil Sulfate.

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Studies have demonstrated the clinical efficacy of both minoxidil 5% solution, twice daily49 and low-dose oral minoxidil (LDOM) with doses of 1 to 5 mg per day.49,50 However, adherence over one year is greater with the oral medication,51 which may explain the perception of greater efficacy of LDOM in the dermatology office.52

Oral minoxidil may cause systemic side effects in a small percentage of patients, such as increased heart rate, headache, fluid retention, hypertrichosis, and edema of the lower extremities. The most commonly observed event is hypertrichosis in approximately 15% of the patients.53 The adverse events of oral minoxidil, however, are typically dose-dependent and reversible upon drug discontinuation. Rare and idiosyncratic, i.e., dose-independent, side effects include pericardial effusion, congestive heart failure, and allergic reactions. LDOM is likely to have a safety profile similar to the general population in patients with hypertension or arrhythmia,54 but cardiologic evaluation is necessary in this group.

At the beginning of use of the oral or topical forms, some patients may experience effluvium, the mechanism of which is immediate telogen release. This shedding may last from two to eight weeks and resolves spontaneously. During the first two months of treatment, an incidence of telogen effluvium of 16% was observed in the group treated with topical minoxidil, while in the group treated with oral minoxidil, this incidence was significantly lower, at only 9%.55

Considered to be drugs that modify male pattern baldness, finasteride 1 mg/day and dutasteride 0.5 mg/day are approved for use.56 The literature shows they are effective in the treatment of patients with MAA and long-term use has shown hair growth and baldness stabilization.57 Their efficacy is greater in the treatment of vertex baldness than in the frontoparietal region and it is recommended that they be continued indefinitely to preserve the recovered hair.58 Although potentially reversible because it is a non-cicatricial alopecia, MAA in patients with significant follicle miniaturization constitutes a therapeutic challenge, and 5αR inhibitors alone have not been shown to be capable of fully reversing the disease.

Despite the well-established efficacy and mechanism of action in the treatment of MAA, including a sustained response over the years, the biggest obstacle to the oral use of 5αR inhibitors is mens insecurity about possible side effects such as decreased libido and impotence.59 Cohort studies report an increased risk of depression in patients treated for benign prostatic hyperplasia, especially in the first eighteen months of medication use.60 This is partially justified because DHT and 5αR participate in the production of several neuroactive steroids. Moreover, testosterone and DHT modulate the neuroendocrine response to stress and are inversely related to depression rates.61 On the other hand, the nocebo effect, that is, when a person develops symptoms and side effects from a medication simply because they have read or been warned about such a possibility, has been well documented in men using 5αR inhibitors.62 The choice of treatment should involve careful evaluation, avoiding the prescription in individuals with recent episodes of depression or sexual dysfunction complaints. Other adverse effects of this class of medication include orthostatic hypotension, dizziness, gynecomastia, and reduced sperm volume.63

Suppression of circulating DHT levels during pregnancy may inhibit the development of the external genitalia of a male fetus; therefore, pregnant women and children should avoid contact with the capsules. Men undergoing treatment with finasteride and dutasteride should not donate blood for one and six months, respectively, after the last dose to prevent administration to a pregnant transfusion recipient.64

Some studies have addressed the effects of 5αR inhibitors on sperm motility, morphology and volume. One study assessed the effects of daily therapy with finasteride (5 mg) and dutasteride (0.5 mg) for one year, examining serum and semen samples before and after treatment, and concluded that neither treatment had an impact on sperm morphology.65 There is no need to discontinue medication in men attempting to impregnate their partners or who are sexually active with pregnant partners, since the excretion of finasteride and dutasteride in semen is minimal and unlikely to cause teratogenic effects.66

There is a concern that 5αR inhibitors may cause or worsen underlying male infertility. There are insufficient data in the literature to categorically state their role in male fertility.

In this context, it is important to define infertility, which is a condition characterized by the inability of a couple to achieve a clinical pregnancy after 12 months of regular, unprotected sexual intercourse. Therefore, evaluating isolated male infertility outside the context of the couple attempt to become pregnant is not an approach that involves requesting a single test. In fact, male infertility is multifactorial and its incidence has been increasing over time.67 Requesting a spermogram may document semen characteristics below the established lower limits but does not necessarily imply infertility, and values ​​considered “normal” do not guarantee fertility.68

There is no standardization in the request for laboratory tests for the prescription of 5αR inhibitors. Laboratory monitoring is not necessary in patients without comorbidities.69 In patients over 45 years of age, after six months of treatment, it is recommended to establish a new baseline level of prostate-specific antigen (PSA).70,71 Continuous increases in PSA during treatment may indicate prostate cancer or non-adherence to therapy. Treatment with this class of medications does not interfere with the use of PSA for the diagnosis of prostate cancer after the new baseline has been established. After stopping treatment, PSA levels return to baseline values ​​in approximately six months.

5αR inhibitors are considered by the World Anti-Doping Agency (WADA) as potential confounding factors in the assessment of athletes steroid profiles since they can interfere with the urinary excretion of several diagnostic compounds.72 However, given the advances in doping diagnostics, they are not included in the list of prohibited drugs by WADA.73

Finasteride is a 5αR-2 inhibitor, which decreases the conversion of testosterone to DHT with a plasma half-life of 5–8 hours. After the initial peak of improvement, long-term follow-up studies demonstrate the progression of alopecia in 10.3% of cases of vertex MAA; 16.2% of the frontal type, and disease control in the biphasic or diffuse types.58

Recent reports of a post-finasteride syndrome, a controversial condition that can include sexual problems, depression and anxiety, have created fear among patients seeking treatment. While studies neither confirm nor refute the syndrome as a valid disease, the safe long-term use of oral finasteride over a period of ten years has been documented.74

Dutasteride is an inhibitor of 5αR-1 and 2, with a half-life of five weeks, which is three times more potent in inhibiting 5αR-2 than finasteride and 100 times more potent in inhibiting 5α-1.75 These characteristics justify the superior effect of dutasteride 0.5 mg/day when compared to finasteride 1 mg/day in the treatment of MAA,76 without showing, to date, significant differences in adverse effects (Table 2).

In an attempt to mitigate its systemic effects, finasteride in topical preparations has been studied and has shown the ability to reduce DHT levels in both plasma and scalp.77 The lack of standardized concentrations and vehicles makes it unpredictable to determine the efficacy of this route of administration.

Due to the large molecular size of dutasteride, it is difficult to formulate and administer it as a topical agent. On the other hand, its large size and lipophilic nature may contribute to its persistence on the scalp, with reduced systemic absorption. At present, however, there is insufficient data in the literature to support its usefulness in the treatment of MAA.78