Bicalutamide: A review

Female Pattern Hair Loss (FPHL)

The synthesis of testosterone is from glandular as well as extra-glandular sites. In males, the primary production of testosterone is from the testis, under the influence of the feedback loop of GnRH, luteinizing hormone (LH), and follicle-stimulating hormone secreted from the hypothalamic-pituitary axis.⁹ However, in females, the primary sources of testosterone synthesis are ovarian theca cells (regulated by LH) and the adrenal cortex. Androstenedione and dehydroepiandrosterone are likewise produced by the ovary and adrenal gland and are converted either to more potent androgens (e.g., testosterone and dihydrotestosterone [DHT]) or to estrogens in peripheral organs including skin.¹⁰

Serum testosterone concentration in women ranges from 15 to 65 ng/dL (0.5–2.3 nM). The average daily rate of testosterone production in women is approximately 0.25 mg, with about half of this daily output derived from the metabolic conversion of androstenedione to testosterone at extra-glandular sites, including the skin. Two peaks of androgen concentration parallel the peaks of plasma estrogens at the preovulatory and luteal phases of the menstrual cycle.¹¹ Nevertheless, both forms – testosterone and DHT – bind to the peripheral AR, inducing a conformational change in the receptor. This alteration enables the movement of the receptor-ligand complex into the nucleus. The activated ARligand complex acts as a transcription factor and regulates gene expression. There is an alteration of the Wnt/b-catenin transcription pathway and secretion of transforming growth factor b, ultimately causing a shortened anagen phase and miniaturization of hair follicles. In disorders of androgen excess, such as polycystic ovarian syndrome (PCOS), or in local androgen abnormalities at cutaneous sites, due to either 5-a reductase or AR abnormalities, clinical conditions such as FPHL, hirsutism, and acne can be induced through this mechanism.¹²

Based on the understanding of the pathogenesis of FPHL, the AR can serve as a better target than DHT to tackle patterned hair loss, especially in females with or without other signs of virilization. The non-steroidal AR antagonists with no other hormonal activity competitively block androgen action on accessory sex organs and skin, typically reversing hair loss by inducing anagen.¹³ Studies done by Fernandez-Nieto et al. and Ismail et al. with an oral non-steroidal anti-androgen, bicalutamide, have shown 27.5% and 20.2% reduction in hair loss, respectively, at 6 months follow-up [Table 1].^14,15 Fernandez-Nieto et al. studied a total of 44 patients with FPHL, who used doses of 25 mg/d in 15 patients and 50 mg/d in 29 patients. A total of 28 patients had coexisting comorbidities, namely, PCOS in 14 patients, seborrhea, acne, hirsutism, and alopecia (SAHA) syndrome in 6 patients, and hirsutism in eight patients. A total of 32 patients were evaluated after 6 months for response to treatment and showed a 27.5% reduction in the Sinclair scale. The side effects encountered in their study were a mild and transient increase of liver enzymes (<3 times the upper limit of normal) in five patients, hair shedding in 3, transient amenorrhea in 2, and endometrial hyperplasia, and headache in a single patient each.¹⁴

A more recent and potentially safer and more effective approach to treating this condition could involve the topical preparation of non-steroidal AR antagonists. These meso-solutions serve to target the scalp specifically, thus minimizing the risk of side effects in other parts of the body. In a study done by Gomez-Zubiaur et al., they used mesotherapy with 1 mL of 0.5% bicalutamide solution and noted a subtle improvement in hair density at 3 months [Table 1].¹⁶

Hirsutism

It is the presence of terminal coarse hairs in females in a male-pattern distribution. It is often part of PCOS along with acne, seborrhea, and patterned hair loss. Oral contraceptive pills (OCPs) are currently the primary treatment of choice in such patients. However, in a randomized control trial done by Moretti et al., they showed that OCPs combined with oral bicalutamide (50 mg/d) were more effective in treating severe hirsutism.¹⁷ Following this, Müderris et al. used low-dose oral bicalutamide (25 mg/d) as a standalone therapy for the treatment of hirsutism and found clinical improvement in the degree of hirsutism in all patients by a mean reduction in hirsutism scores of 41.2 ± 11.4% at 3 months and 61.6 ± 11.1% at 6 months.¹⁸

Notably, bicalutamide had also been shown to reverse minoxidil-induced hypertrichosis in FPHL by Moussa et al. in a case series of 35 patients. They commenced bicalutamide at a dose of 10 mg and gradually up-titrated it to a mean dose of 14.4 mg until no hypertrichosis was seen with concomitant oral minoxidil therapy.¹⁹ Therefore, oral bicalutamide may be useful for decreasing the risk of hypertrichosis as well, which is the most frequent adverse effect of oral minoxidil while improving Sinclair grading in FPHL patients.

The mechanism of bicalutamide in minoxidil-induced hypertrichosis is not entirely clear. However, there is a possibility that minoxidil might have an impact on the AR or its downstream signaling pathways, as mentioned by Moussa et al. in their paper.¹⁹ Another study reports that minoxidil suppresses AR-related functions, decreases AR transcriptional activity in reporter assays, and reduces the expression of AR targets at the protein level.²⁰ Ironically, these noted observations bring into doubt the prior assertion that hypertrichosis induced by minoxidil is not influenced by androgens but is due to the stimulation of dermal papilla cells by various growth factors.²¹ This view rather prompts a reconsideration of the differentiation between hypertrichosis and hirsutism and needs a better understanding of the mechanism of the same.

Acne and seborrhea

Hormonal acne and seborrhea can be constituents of polycystic ovary syndrome or as part of SAHA syndrome. Lowering androgen concentrations or controlling their effect at the tissue level is a priority in the therapeutic strategy for such patients. Oral anti-androgen like bicalutamide can be combined with other therapies for non-responders and more effective results.²²

Frontal Fibrosing Alopecia (FFA)

FFA is a patterned form of cicatricial alopecia, commonly encountered in postmenopausal females. The only report of bicalutamide use in FFA is published by Jerjen et al. They have mentioned the difficulty in determining if FFA represents androgenetic alopecia (AGA) with a lichenoid tissue reaction or patterned lichen planopilaris, hence the use of oral bicalutamide in their cohort along with low-dose oral minoxidil and other anti-androgens to clinically improve it.²³

Hidradenitis Suppurativa (HS)

HS/acne inversa is a post-pubertal, chronic, inflammatory disorder of the hair follicle presenting as painful, deep-seated, and inflamed lesions in the apocrine gland-bearing areas of the body. In a systematic review by Zouboulis et al., their literature search cumulated 452 HS-associated druggable genes which they proposed as targets in HS and postulated that they can be repurposed as drugs for controlling HS, including AR ligands like bicalutamide.²⁴

Feminization of transgender women

Anti-androgenic effects of bicalutamide can also form part of gender-affirming hormonal therapy along with a therapeutic armamentarium consisting of estrogens and progestins. This will add to the scope of practice for obstetricians and gynecologists with some modest expansion of the knowledge base required to prescribe this drug to their patients.²⁵

Precocious puberty in boys

Familial male-limited precocious puberty is a GnRH-independent form of isosexual precocious puberty driven by androgens which promote virilization and growth. At present, there is no established treatment. Steroidal as well as non-steroidal anti-androgens can be used. However, Reiter et al. used the effective and favorable tolerability profile of bicalutamide as an anti-androgen along with anastrozole in 14 patients of precocious puberty. They showed an overall decreased growth rate, bone maturation rate, and less aggressive behavior with minimal changes in the Tanner stage in the testes, scrotum, and pubic hair in their study.²⁶

Chemical castration

The role of testosterone in sexual offending is thought to be mediated by its effect on known risk factors for recidivism such as deviant sexual arousal and/or sexual preoccupation. Anti-androgenic effects of bicalutamide have been employed as chemical castration therapy along with psychosocial therapies in such patients.²⁷

Priapism

Priapism is a disorder in which the penis maintains a prolonged, rigid erection in the absence of appropriate stimulation. It is a potentially devastating condition and may lead to penile fibrosis if untreated. Dahm et al. reported the use of 50 mg of bicalutamide in three patients, who not only experienced no further episodes of sustained priapism but also reported maintained libido and the ability to achieve sustained rigid erections for intercourse.²⁸

Table 2 summarizes the comparative features of available AR blockers and their versatility of use in different indications, reported so far in the literature.^29-31