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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 1  |  Page : 1-11

A bird's eye view of common antiandrogens used by dermatologists


Department of Dermatology, IQ City Medical College, Durgapur, West Bengal, India

Date of Submission01-Feb-2019
Date of Decision23-Sep-2019
Date of Acceptance18-Nov-2019
Date of Web Publication06-Jan-2020

Correspondence Address:
Aditya Kumar Bubna
Department of Dermatology, IQ City Medical College, Sovapur, Bijra Road, Jemua, Durgapur - 713 206, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CDR.CDR_5_19

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  Abstract 


The use of antiandrogens is gaining significance in dermatology practice these days. Though once considered a domain of endocrinologists and gynecologists, these drugs now constitute an important category while treating a number of dermatologic conditions. A thorough knowledge of these drugs, as well as their applications in dermatology would therefore be of immense value for the practicing dermatologist. This review will throw a bird's eye view on the salient aspects of these drugs and their importance in those conditions, where their usage in applicable.

Keywords: Cyproterone acetate, dutasteride, finasteride, flutamide, spironolactone


How to cite this article:
Bubna AK. A bird's eye view of common antiandrogens used by dermatologists. Clin Dermatol Rev 2020;4:1-11

How to cite this URL:
Bubna AK. A bird's eye view of common antiandrogens used by dermatologists. Clin Dermatol Rev [serial online] 2020 [cited 2020 Jun 4];4:1-11. Available from: http://www.cdriadvlkn.org/text.asp?2020/4/1/1/275247




  Introduction Top


Antiandrogens are a class of drugs that have found to be useful in treating a number of dermatologic conditions. They are broadly classified into three categories.

  • Androgen receptor antagonists: These include spironolactone (SPL), flutamide (FD), cyproterone acetate (CA), and cimetidine. These drugs act on androgen receptors and block effects of circulating androgens
  • Androgen synthesis inhibitors: These include drugs such as finasteride (FT) and dutasteride (DT). They act by lowering androgen levels by other mechanisms
  • Antigonadotrophins: These include gonadotropin-releasing hormone (GnRH) modulators, estrogens, and progestogens.[1]


There are a number of dermatologic conditions where these drugs have been utilized and include hirsutism, acne (particularly the hormonal variant), androgenetic alopecia, hidradenitis suppurativa, and frontal fibrosing alopecia (FFA).


  Hirsutism Top


Hirsutism presents as excessive terminal hair growth in women at locations where hair is normally minimal or absent. Hirsutism can be androgenic or non-androgenic. Polycystic ovarian syndrome (PCOS) is a major contributor of androgenic hirsutism. Other causes include androgen-secreting tumors, non-classic adrenal hyperplasia, and syndromes of severe insulin resistance. However, in some patients, no etiology is identifiable, and these patients are labeled to have idiopathic hirsutism.[1]

Various drugs have been utilized by dermatologists to treat this condition and include SPL, FD, cyproterone acetate, FT, and GnRH analogs.

Spironolactone

SPL in hirsutism acts as a competitive antagonist for cytosolic androgenic receptors and causes reduction in the concentration of cytochrome P450 in the gonads. Further, at higher doses, it also inhibits 17-β hydroxylase and 17, 20 desmolase adrenal activities.[2]

Prior to starting SPL, the cause of hirsutism needs to be ascertained. In those cases of hirsutism secondary to PCOS, congenital adrenal hyperplasia (CAH) or idiopathic hirsutism; SPL can be considered.

SPL can be given either at low dosing or high dosing for this indication and the decision is best left to the treating dermatologist.

For the high dosing schedule, a daily dose of 100–200 mg of SPL is administered. In most cases, the duration of treatment generally extends for 9-12 months. Combining SPL with oral contraceptives (OCs) or with dexamethasone may also prove beneficial here.[3]

In low-dose therapy, SPL given at a dose of 50 mg from day 4 to day 22 of the menstrual cycle, over 12 consecutive cycles, has demonstrated to reduce the concentration of total and free levels of testosterone.[4]

On comparing FT with SPL in treating hirsutism, SPL proved superior. However, FD was more efficacious than SPL for treating hirsutism.[5],[6]

Flutamide

FD is a pure anti-androgen, with little or no measurable interaction with any of the other steroid hormone receptors. Although not commonly employed in the dermatological set up for treating hirsutism owing to its toxicity profile, it is indeed a very valuable drug for this indication. Various guidelines have been proposed for the use of FD in hirsutism and have been tabulated in [Table 1].
Table 1: Guidelines for flutamide in hirsutism

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Though the standard recommended dose of FD in hirsutism ranges from 62.5 to 500 mg/day,[7],[8],[9] de Zegher and Ibáñez [10] have suggested that FD dosed at 1 mg/kg/day could be a better alternative because this dosing could help balance between its antiandrogenic efficacy and hepatic safety for women and adolescent girls with hirsutism or other androgen-related symptoms. Therapy is generally long term ranging from 6 months to 1 year, and therefore, careful monitoring of the drug is mandated.[11]

Although other antiandrogens are considered a safer alternative than FD, Cusan et al.[6] in their study demonstrated that FD is more effective than SPL in hirsute women treated with OC pills (OCPs) plus antiandrogens.

Cyproterone acetate

CA is a strong progestin, resulting in a decrease in circulating testosterone and androstenedione levels through a decrease in circulating luteinizing hormone levels. It further antagonizes the effect of androgens at the peripheral level and is an effective agent for treating hirsutism. CA has been utilized in various dosing schedules for treating hirsutism, the details of which have been elaborated in [Table 2].
Table 2: Studies demonstrating the efficacy of cyproterone acetate in hirsutism

Click here to view


Finasteride

In some cases of hirsutism, FT has also been of benefit. It has been suggested that increase in 5α reductase activity in hair follicles of hirsute women may be responsible for this clinical outcome, and thus the role of FT.[15] It has been clearly demonstrated that FT at a dose of 5 mg/day taken for 6 months is equally effective as SPL (100 mg/day) and FD (250 mg/day).[15]

The efficacy of 5 mg/day of FT in idiopathic hirsutism and hirsutism secondary to PCOS has further been elaborated by Faloia et al.[16] and Lakrye et al.[17]

Gonadotropin-releasing hormone agonists

GnRH agonists like leuprolide given parenterally as a depot (3.75 mg/month), has been of value in those severe hirsute patients not responding to OCs and antiandrogens.[18] Two to three months of treatment may be required for the full suppressive effect of the agonist to occur. Long-acting GnRH analogs decrease gonadotropin secretion and therefore reduce ovarian stimulation and hence testosterone. However, estrogen production is also reduced with this therapy and therefore concomitant usage of OCPs containing estrogen and progestin is recommended.[19]


  Acne Top


Antiandrogens are of particular value in treating acne when faced with the following presentations:[20]

  • In females with late-onset or persistent acne with or without signs of hyperandrogenism
  • In females not responding to conventional therapy and unwilling to take or cannot take oral isotretinoin (ISO)
  • In females where acne flares coincide with menses
  • In females where OCs cannot be used but require antiandrogens as part of their acne regimen
  • Women with acne tarda or sudden onset acne vulgaris after 25 years of age
  • Women also presenting with clinical signs like hirsutism, androgenic alopecia and seborrhea with acne vulgaris (SAHA syndrome)
  • The predominance of inflammatory papules concentrated along the lower half of the cheeks, jawline, chin, and lateral neck.


In most patients presenting with the above quality of acne, other associations like menstrual irregularities, hirsutism, and androgenetic alopecia may also be observed. Though these features correlate with a high androgenic state in many patients, the circulating levels of androgens may be normal. Nevertheless, it is mandatory to evaluate the hormonal profile in all such patients to rule out the two most important disorders associated with excess levels of circulating androgens, namely PCOS and CAH.[20]

Spironolactone

SPL, in this setting, decreases 5α reductase activity via increased clearance of testosterone secondary to augmented liver hydroxylase activity. Furthermore, SPL increases the level of sex hormone-binding globulin (SHBG), thereby providing a sink that reduces free testosterone as more of it gets bound to SHBG. This facilitates in reducing free testosterone in the circulation and an increased estrogenic state thus. In addition, SPL also competes with dihydrotestosterone (DHT) for cutaneous androgen receptors thereby antagonizing the binding of testosterone and DHT to these receptors.[21],[22],[23]

For hormonal acne (HA), SPL can be used as monotherapy or in combination with OCs, oral antibiotics, and ISO.[24]

SPL is preferred as monotherapy in those women who are intolerant to OCs and are at an increased risk of developing thromboembolism or stroke following intake of OCs, or in those women who do not want OC induced melasma to occur.[24]

The dose of SPL employed ranges from 25 to 200 mg/day. The author feels, it is best to start at a lower dosing, generally 50–100 mg/day, and if mandated, the dose could be escalated depending upon the clinical requirement. Even at lower doses, SPL is effective in reducing seborrhea, which in turn heralds reduction in the number and size of acne lesions. The response to therapy with SPL is usually evident after 3 months of initiation of treatment with SPL.[25],[26],[27]

Apart from its beneficial role in facial acne SPL has also shown to be effective in truncal acne.[28]

Once the desired endpoint of control of acne lesions has been obtained, maintenance dosing of SPL ranging from 25 to 50 mg/day maybe particularly beneficial in those women who tend to have sporadic outbreaks of inflammatory or isolated nodulocystic lesions.[29]

When SPL is used with OCs there usually is an added benefit in improving acne lesions along with alleviating concerns about unwanted pregnancy while taking SPL. Use of OCs along with SPL also reduces menstrual-related side effects like irregular menses and breast tenderness both of which is commonly seen with SPL monotherapy, especially in high doses. Further, combining OCs with SPL enables lower doses of SPL to be dispensed without compromising its efficacy.[30]

OCs containing EE (20 mcg or 30 mcg) with drosiperone 3 mg or EE (35 mcg) with CA 2 mg can be used along with SPL. A 3 mg dose of drosiperone has been reported to be equivalent to 25 mg of SPL, and therefore, regular monitoring of serum potassium maybe required when administering SPL along with drosiperone containing OCs. However, no significant adverse effects have ever occurred with this combination, and this combination has a good safety profile.

SPL can also be combined with most antibiotics for acne, namely minocycline, tetracycline, and erythromycin.[29] The combination definitely is associated with better overall clinical outcome. It must be however be remembered that topical benzoyl peroxide is of value in these combinations to reduce the risk of emergence of antibiotic-resistant strain of Propionibacterium acnes. Other antibiotics combined with SPL include amoxicillin and co-trimoxazole.[31] However, co-trimoxazole has been associated with hyperkalemia, and therefore, its combination with SPL should be used with caution and only as a last resort if at all necessary.[32],[33]

In severe cases of nodulocystic acne, not responding to oral ISO alone, addition of SPL at an initial dose of 100 mg/day and gradually escalating the dose to 200 mg/day if needed has demonstrated beneficial effects in bringing about regression of acne lesions. Once the desired benefit is obtained, the dose of SPL is generally reduced to 50 mg/day as a maintenance dosing.[24]

Also, topical 5% SPL has been used in Europe for grade II acne with a similar efficacy compared to topical therapy with antibiotic agents.[34] Further, topical SPL gel when used along with topical corticosteroids has been found effective in limiting glucocorticoid-induced epidermal activity by blocking mineralocorticoid receptors.[35] However, this concept needs further exploration.

Flutamide

FD has been purported as a potential therapy for HA owing to its antiandrogenic effects. Few studies have indicated the beneficial properties of FD in HA. Carmina and Lobo [36] in 2002 demonstrated that FD has similar efficacy to ethinyl estradiol and CA in 48 hyperandrogenic women.

Similarly, in 2011, Paradisi et al.[37] demonstrated the clinical efficacy of low dose FD over a 6-years period. However, FD needs to be cautiously used given its potential for hepatotoxicity.[37]

Cyproterone acetate

CA 2 mg along with EE 35 mcg has been used in the management of HA. In adult females, when acne is resistant to conventional therapy, a possible existing hormonal etiology requires evaluation. Treatment needs to be continued for at least 1 year with periodicc assessments.[38] Improvement of acne is noticeable within 3 months of initiation of therapy.

It can also be combined with ISO in some cases.

If CA is being used alone in acne without being combined with EE, it should begin on the 1st or 5th day of the menstrual cycle and should be stopped on day 14 just before ovulation.[39] When used alone, the recommended dose of CA is 50–100 mg/day. Studies have shown that overall improvement of acne can be witnessed in 75%–90% cases.[40],[41]

CA inhibits conversion of DHEA to androstenedione by 3 β-hydroxysteroid dehydrogenase, decreasing the production of adrenal androgens. CA also inhibits the production of follicle stimulating hormone and luteinizing hormone which blocks ovarian function and reduces serum levels of androgens. Further, CA also reduces comedones indirectly by an increase in the sebaceous linolenic acid concentration.[42]

Gruber et al.[43] have utilized topical CA in a liposomal lotion consisting of soyabean oil, lecithin, glycerol, and oleic acid containing 20 mg of CA in 10 ml of the liposomal lotion used. They found that after 3 months of topical usage, the lesion counts had decreased from a mean of 35.9 to 9.1, thereby suggesting this to be a valuable modality of treating HA. Whether topical CA acts directly on the skin or whether serum levels of CA (though low with topical therapy), are responsible for the effect needs to be determined in future studies.

Finasteride

In some women with hormonal acne having normal levels of free serum testosterone, no clinical improvements can be reached with classical antiandrogens and ISO. In some of these women, there could be an underlying excessive activity of the enzyme 5α reductase making the use of FT, a valuable option in these cases. The dose of FT here is 5 mg/day.[44]


  Androgenetic Alopecia Top


AGA is a common genetically determined disorder affecting both men and women and is characterized by the gradual conversion of terminal hairs into indeterminate and finally into vellus hairs. There are a number of drugs used in its treatment and have been described below.

Finasteride

Oral FT (1 mg/day) has been approved by the US FDA since December 1997 for the treatment of AGA in males. Regarding the use of FT in women for AGA, its efficacy has not been established and is used as an off label treatment with doses ranging from 2.5 to 5 mg/day.[45],[46],[47]

In AGA in males, it has been concluded that:

  • The daily use of oral FT increases hair count and improves patient and investigator assessment of hair appearance [48]
  • Long term use of FT for up to 5 years has shown to decrease the likelihood of developing further invisible hair loss [49]
  • If FT is started at a younger age, responses obtained are superior [50]
  • In cases where adequate responses are not observed even after 1 year of FT therapy, long term continuation of the drug is associated with a positive trend in bringing about hair growth [51]
  • Combination therapy of oral FT with minoxidil and ketoconazole shows a better response than either drugs being used as monotherapy.[52]


The efficacy of topical FT has also been documented in AGA. Tanglertsampan [53] has compared the efficacy of 3% minoxidil versus 3% minoxidil and 0.1% FT in AGA. A significant improvement was demonstrable in the group obtaining both topical drugs.

Hajheydari et al.[54] have also demonstrated the beneficial properties of topical 1% FT gel applied twice daily.

Topical FT therefore could be considered a valuable maintenance option once initial improvement with oral FT occurs, because of its property of maintaining hair density. This would also prevent in the indefinite use of oral FT.[55]

Evidence, however, for topical formulations of FT is scanty, requiring more systematic documentation in further studies.

In patients who are apprehensive about the side effects of FT, it could be worthwhile considering administration of lower/staggered doses of FT to enhance patient compliance. As the t1/2 of FT is 6–8 h and its tissue binding remains for 4–5 days,[56] a dose of 0.2 mg is adequate enough to suppress DHT levels. It has been seen that while 0.2 mg caused 55% suppression of DHT, 5 mg achieved 69% suppression.[57],[58] Therefore, in such patients, the drug maybe started at 0.5 mg/day for a short term period. This would enable gaining patient confidence, following which 1 mg/day of FT can be started once the patient is comfortable. However, this suggestion of stepping up the dose of FT is only an opinion of experts.[59]

In female pattern hair loss (FPHL) the mechanism of FT is still unclear. In those patients who fail minoxidil therapy or cannot tolerate minoxidil therapy, FT can be tried. Although data is sparse, menopausal status, circulating androgen concentrations, and concomitant symptoms of hyperandrogenism do not appear to predict a response to FT.

FT is generally well-tolerated in women. However, in women with childbearing potential, owing to the teratogenic effects of FT, adherence to a reliable method of contraception is mandatory.[60] Price et al.[61] in 2000, demonstrated that FT given at 1 mg/day for FPHL was ineffective in increasing hair growth or improving the appearance of hair. Given the lack of clinical efficacy with this dosing, higher dosing of FT ranging from 2.5 to 5 mg/day have been advocated. This dosing has demonstrated clinical efficacy in postmenopausal women in the absence of clinical or laboratory signs of hyperandrogenism.[62],[63] However, there is limited evidence for the use of FT at higher dosages for treating FPHL in postmenopausal women. FT is usually a useful option in those cases of FPHL which have failed other therapies.

Spironolactone

There have been no randomized trials in evaluating the efficacy of SPL in FPHL, but case reports and series have been described.

Adamopoulos et al.[64] demonstrated that SPL at a daily dose of 200 mg reduced hair loss by 60% and also increased the number of anagen hairs.

Sinclair et al.[65] in an open-label comparative study of 80 women with biopsy-proven FPHL using either SPL 200 mg/day or CA 50mg/day depicted both therapies to be equally effective.

Further, when SPL 200 mg once daily is combined with 5% topical minoxidil twice daily application, for FPHL, it acts as an effective adjunct to stimulate hair growth if a plateau has been reached with topical minoxidil monotherapy.[66]

Dutasteride

DT (0.5 mg/day) though not approved by the FDA for AGA, has shown to be more superior than FT (1 mg/day) in men. In various studies, the positive effects of DT have been demonstrated. Some of them have been summarized in [Table 3].
Table 3: Various studies demonstrating the beneficial effects of systemic dutasteride in androgenic alopecia

Click here to view


Further, DT has also been utilized as mesotherapy in AGA. Mesotherapy schedules require frequent treatment sessions and that could be a limiting factor in patient adherence. Various studies utilizing DT mesotherpay for AGA has been summarized in [Table 4].
Table 4: Various studies utilizing dutasteride mesotherapy for androgenetic alopecia

Click here to view


The reason why DT mesotherapy has been considered to be as efficacious as oral therapy is because systemic absorption after mesotherapy is almost similar to oral DT because of the highly vascular scalp.

Flutamide

FD has been shown to be effective in treating FPHL in women who have associated hyperandrogenism. The dose of FD for this indication is 250 mg/day. Carmina and Lobo [73] demonstrated that FD led to greater improvements in stemming hair loss after 1 year of treatment when compared to FT and CA.

Similarly, Sinclair et al.[65] found a significant treatment advantage for FD over SPL with regard to slowing or halting hair loss, reduction of total acne and seborrhea and also in treating hirsutism.

Further, Paradisi et al.[37] noticed in 80% of their study patients with FPHL after 2 years of therapy with FD that most of them were satisfied or highly satisfied regardless of whether they were consuming OCPs or not.

Cyproterone acetate

A number of studies have suggested the role of CA in AGA with some suggesting that this role is greater in patients with evidence of hyperandrogenism.

Brzezińska-Wcisło [74] in a study of 25 subjects aged between 31 and 35 years where CA 2 mg and EE 35 mcg was administered for FPHL, clearly demonstrated reduction in hair loss, hair thinning and seborrhea.

Lucky et al.[75] in 20 patients with FPHL, administered 50 mcg of EE and 2 mg of CA along with an additional 20 mg of CA on days 5–20 of the menstrual cycle. The authors concluded that though reduction in hair shedding was noticed, actual increased hair growth was not appreciated.

Vexiau et al.[76] in a 12-month randomized comparative trial of 2% minoxidil and combined OCPs in 33 patients; and 52 mg of CA along with 35 mcg of EE for 20 days of every 28 days in another 33 patients, found that CA was more effective in those patients who demonstrated features of hyperandrogenism along with an elevated body mass index, whereas 2% minoxidil was effective in those patients without evidence of clinical and biochemical hyperandrogenism.

Futterweit et al.[77] compared SPL with CA in 80 women with biopsy-confirmed FPHL. It was found that in 88% of individuals, there was improvement with no progression of hair loss and no significant difference in the efficacy of both medications.

However, in a randomized study by Carmina and Lobo,[36] CA failed to demonstrate therapeutic benefit in FPHL.

However, given the balance of evidence, CA does have a role in FPHL associated with hyperandrogenism.

Though doses utilized vary, it appears that CA 100 mg/day on days 5–15 of the menstrual cycle supplemented with EE 50 mcg/day on days 5–25 of the cycle appears to be the most effective dosing schedule of CA for AGA.[78]


  Hidradenitis Suppurativa Top


HS is an inflammatory disease of the skin occurring as a reaction pattern of the skin dependant on the patients inherent and specific risk factors in a setting of predisposing genetic factors and inflammation.[79] It is commonly seen in postpubertal young adults and has a diverse spectrum of presentation including comedones, folliculitis, abscesses, scars and disfiguring tracts and fistulas. Currently, HS is considered to be a disease of follicular pathology rather than apocrinitis.

Finasteride

In HS, FT is employed owing to its ability to reduce local concentrations of DHT at the level of hair follicles by altering end-organ sensitivity rather than a systemic effect on circulating androgens.[80]

As HS is now identified to be a disorder secondary to inflammation of the terminal follicular epithelium, inhibition of 5α reductase brings about reduction of local concentrations of DHT at the level of the hair follicles and thereby reducing target tissue concentrations of androgens.[81] The precise mechanism of FT in HS, however is speculative, since it has not been confirmed conclusively in any study, and confounded by the difficulty of measuring tissue and intercellular levels DHT, as circulating levels may not be an accurate assessment.[82]

FT has been employed at a dose of 5 mg/day with dramatic improvement in HS. Some of the published reports have been elucidated in [Table 5].
Table 5: Some reports demonstrating the valuable effects of finasteride in hidradenitis suppurativa

Click here to view


It has been clearly seen that FT in HS has been effective both as monotherapy and as adjunctive therapy. In most cases, however, FT was advocated in more advanced disease where multiple regimens were unsuccessful. No documented cases have been found where FT was introduced early in disease management in adults. However, in a 7-year-old girl FT was employed within a year of disease onset with excellent outcomes. It has been postulated that if an effective drug is used early in HS, presumably during puberty, the disease-modifying effect would be superior, and could be a potential avenue for further evaluation.[81]

Both finite and continuous regimens of FT for HS have been reported. Joseph et al.[80] used a finite regimen discontinuing the drug within a month of healing. Recurrences did occur following a month of drug cessation. This could be explained on the grounds of the chronic nature of HS.

Continuous therapy exceeding 6 years have also been utilized. Both finite and continuous regimens with FT have demonstrated benefits. Finite regimens have been associated with prolonged remissions whereas the continuous regimens demonstrate reduced intensity and frequency of recurrences.[80],[81] Owing to the limited data available for the use of FT, the exact regimen and duration of treatment still cannot be completely ascertained.

Spironolactone

SPL has been effective at a dose of 100–125 mg daily after 3–6 months of therapy in patients with mild to moderate HS.[85]


  Frontal-Fibrosing Alopecia Top


Georgala et al.[86] have reported a positive response with oral DT (0.5 mg/day) on a daily basis for a year in 13 patients with FFA. FFA is considered to be an anatamoclinical form of lichen planopilaris with selective topography.[87],[88] FFA has been treated earlier with FT (2.5 mg/day) combined with 2% minoxidil, and there was a halt in disease progression as demonstrated by Tosti et al.[88]

Further, Katoulis et al.[89] have also demonstrated significant re-growth of eyebrows and axillary hair in postmenopausal patients with FFA and a moderate improvement in frontotemporal scalp hair in postmenopausal women following treatment with DT (0.5 mg/day) and topical 1% pimecrolimus cream for 3 months.

Given the tendency of FFA for spontaneous stabilization some of the apparent responses may be considered to be the natural course of the disease process. Therefore DT needs to be further evaluated with more randomized controlled trials for the same.


  Conclusion Top


Through this review we do observe the utility of antiandrogens in a variety of dermatologic conditions. Certain side effects like hepatotoxicity and hyperkalemia associated with FD and SPL respectively should be carefully monitored to ensure patient safety while on these drugs. Other drugs like FT, DT, and CA are relatively safer. With a change in the profile of a number of disorders, for example, acne, it would be prudent for any dermatologist to have a fairly good knowledge regarding these drugs.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Hirsutism
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