Standing to the pathogenesis of this type of alopecia the most effective solution would be the topical application of estrogens. Even if reports about the use of these molecules exist, we do not recommend them because of their possible oncogenic effects if they enter the cardiovascular system and/or because they could favor skin metastasis when topically administered. It is important to remember that HT is administered in patients with hormone-sensitive breast cancer, and higher blood levels of estrogens could enhance tumor growth.

17β-estradiol is a hormone to all effects, able to bind estrogen receptors, so it should not be used in this kind of patient. 17α-estradiol is an isoform of 17β-estradiol which is incapable of binding estrogen receptor, and for this reason, it was considered suitable for the treatment of alopecia induced by HT [10]. It has been demonstrated that 17α-estradiol is able to increase testosterone transformation in 17β-estradiol and androstenedione in estrone, probably by increasing aromatase activity [16]. So even this isoform, although unable to bind hormonal receptors, could be indirectly dangerous.

Since it was clear that no estrogens could be employed, it was proposed to use anti-androgen molecules, such as spironolactone [10]. It competes for the binding site of the aldosterone receptor in the kidney, but it is also able to bind the DHT receptor so that it also has anti-androgen activity. Anyway, by binding the DHT receptor, spironolactone could activate a series of events that end with an increased estrogen production (Figure 2). Theoretically, spironolactone would increase DHT concentration with a consequently delayed transformation of testosterone, which would accumulate. Moreover, it has been demonstrated that high levels of DHT lead to an increased synthesis of prostaglandin D2 (PGD2), which has a negative effect on hair follicle growth [17] (Figure 2).

Finasteride has also been proposed [10], but even this molecule could provoke an increased estrogen production. The block of 5α-reductase would lead to a higher testosterone concentration (Figure 3).

An increased quantity of testosterone could have different effects depending on the HT agent in use. In the case of treatment with SERMs aromatase is able to transform testosterone to 17β-estradiol, and if its concentration grows, it could compete with SERM’s binding to the receptor. If the patient is taking LHRH analogs, the greater quantity of testosterone would be transformed to 17β-estradiol and it would bind its receptors if treatment with SERMs is not also given. In the case of the patient receiving AI, testosterone transformation into 17β-estradiol is theoretically blocked, but it cannot be excluded that testosterone could compete with binding to the enzyme and, having a better affinity for it, it could be transformed anyway.

For these reasons all the molecules which increase testosterone concentration (spironolactone and finasteride) should be avoided in the case of HT with LHRH analogs. In the case of HT with AI or SERMs, they could be used in reserve, even if the authors discourage their use until their safety is demonstrated.

If it is accepted that hormonal agents are best not employed, other molecules can be considered.

Topical minoxidil 2% and 5% is commonly utilized. It induces vasodilatation by opening potassium channels localized on smooth muscle cells of peripheral arteria, slowing down circulation. Minoxidil, in addition, induces angiogenesis and activates prostaglandin-endoperoxides synthase 1 which stimulates hair growth [18]. The final minoxidil effect is to extend the anagen phase. The association with topical hydrocortisone could help follicular growth.

Freites-Martinez et al. [11] reported a moderate to significant improvement in alopecia in 80% of patients using topical minoxidil.

Bimatoprost 0.03%, a prostaglandin analog, could also be utilized [19]. It protects follicles in the anagen phase and improves follicular growth in anagen I. For these reasons, it should be utilized with the same indications of minoxidil. In addition, the costs and the availability of the molecule should be considered.

Minoxidil and prostaglandin analogs are not recommended in preventing alopecia induced by cytotoxic agents [20], but in the case of HT, they could be useful. Probably because, differently from classic chemotherapeutic drugs, HT does not have a direct toxic effect on hair follicles, but it creates an unfavorable condition for hair growth. Moreover, even if minoxidil and prostaglandin analog increases drug concentration around the hair follicle, it is possible that beyond a certain concentration, HT molecules are not able to bind their receptor sites over more, because receptor saturation would be reached.

Lastly, another promising molecule is cetirizine. It is an antihistamine anti-H1 receptor, which is able to increase prostaglandin prostaglandine E (PGE) and prostaglandine F2alpha (PGFα) synthesis, with an action similar to bimatoprost, and to reduce inflammation and prostaglandin PGD2 synthesis. This action seems to be independent of its antihistamine one. Available studies evaluated cetirizine efficacy for the treatment of AGA and other types of alopecia with good results. Recently, it has also been proposed for the treatment of alopecia induced by palbociclib [21]. For this reason and the absence of hormonal influence, cetirizine could be a good option for alopecia induced by HT [22].

In light of what is described above, we propose the use of topical formulations containing minoxidil 2%, cetirizine 0.5%, and hydrocortisone butyrate in alcohol, applied once a day alongside HT duration or minoxidil 5% + hydrocortisone butyrate 0.1% in the most severe cases and/or when a previous FAGA was present.