Female Androgenetic Alopecia: An Update on Diagnosis and Management

Michela Starace; Gloria Orlando; Aurora Alessandrini; Bianca Maria Piraccini

Disclosures

Am J Clin Dermatol. 2020;21(1):69-84. 

In This Article

Treatments

FAGA is a slowly progressive disease.[1] The goal of therapy is to stop the progression and to induce a cosmetically acceptable hair regrowth.[32] It is essential to discuss with the patient the therapeutic options, their costs and side effects, the importance of the use of and adherence to treatments, always remembering to set realistic expectations. An objective method to evaluate hair regrowth is the global photographic assessment, which is a standardized and reproducible method to estimate the severity of the disease in each patient.[32]

Minoxidil

Topical Minoxidil. Topical minoxidil is the first-line treatment for FAGA approved by the US FDA. Its efficacy has been proved in double-blind placebo-controlled trials.[54–56] Minoxidil is a potassium channel blocker originally used as an oral hypotensive, whose peculiar side effect was an increase in hair regrowth. Topical minoxidil is available in 2% and 5% solutions and in a 5% foam. The precise mechanism of action is not yet known; some hypotheses include enhanced vasodilatation and proliferative, anti-androgenic and anti-inflammatory effects.[57] The final result is to prolong the anagen phase of the hair follicle and induce an enlargement of miniaturized follicles, obtaining the conversion of miniaturized hair follicles to terminal hair follicles.[55] Minoxdil 2% solution applied twice daily shows similar efficacy to minoxidil 5% solution or foam applied once daily.[56] Topical minoxidil should be applied as 1 mL of solution with a pipette directly on the dry scalp. It doesn't need massage and it is advisable to apply it 2 h before bed to allow adequate time for drying and to avoid it spreading on the face during sleep. Its efficacy could be observed after 6–12 months of treatment.[32] If successful, it should be continued indefinitely. Its withdrawal will lead to a TE because of the simultaneous transition to hair telogen with a minoxidil-dependent prolonged anagen phase. Patients should be informed about a transitory increase in telogen hair shedding during the first months of treatment.[55] The most disturbing side effect in women is hypertrichosis.[54] It can be the result of the personal sensitivity, or, more often, due to incorrect application with local spreading. Irritant or allergic contact dermatitis may occur, commonly related to the solution vehicle propylene glycol.[32] If patch testing confirms a contact dermatitis, a switch can be made to 5% foam—that doesn't contain propylene glycol—or to oral minoxidil.

Oral Minoxidil. Patients are considered eligible for oral minoxidil if their hair loss does not respond to topical minoxidil or if they don't tolerate it.[58] Oral minoxidil is used at much lower doses than those used to treat high blood pressure; indeed, doses range from 0.25 to 2.5 mg/day.[58] It can cause a significant reduction in blood pressure if it is given with other anti-hypertensive treatments. Other side effects include fluid retention and hypertrichosis.

Hormone-modulating Treatments

The hormone-modulating treatments used for FAGA include antiandrogen receptor antagonists, which avoid testosterone and DHT binding to their receptor, and real antiandrogens, which alter androgen levels at the hair follicle.

It must be remembered that 5-α-reductase inhibitors or antiandrogens are forbidden in pregnant women. Abnormalities of external male genitalia, namely feminization of the male foetus, were reported in animal studies. Strict contraception should be used during and for at least 30 days after discontinuation of these drugs.[1]

They are mainly prescribed off-label for the treatment of FAGA and their use is still contested. Indeed, several studies including a metanalysis did NOT evidence any improvement with either antiandrogens or 5-alfa-reductase inhibitors.[59] Due to their teratogen potential, many antiandrogen studies have been conducted in post-menopausal women. More studies are needed to assess the real potential of antiandrogens in different ages and biochemical situations. Their administration is advisable, in association with Minoxidil, in cases of poor response to the latter or in patients with hyperandrogenism.[1]

Finasteride. Finasteride is a 5-α-reductase type II inhibitor that blocks the conversion of testosterone in DHT, stopping hair loss and increasing hair growth.[60] Finasteride is approved by the US FDA for the treatment of benign prostatic hypertrophy and male AGA; it is used off-label for the treatment of FAGA.

A study including 137 post-menopausal women with normal androgen levels and treated with 1 mg of finasteride for 12 months did not show significant improvements.[61] However, finasteride has shown its effectiveness both in normo-androgenic and in hyperandrogenic patients in some studies utilizing higher doses (2.5–5 mg per day).[62–65]

In our clinical practice, we usually prescribe 2.5–5 mg daily. It requires at least 6–12 months of treatment to achieve hair regrowth. Responding patients need to continue the treatment to maintain obtained results.[32]

Besides the teratogenic effect, finasteride has been associated with estrogen-mediated malignancies such as breast cancer, because it can generate estrogen excess.[66] Therefore, finasteride should not be prescribed if the patient has a family history of breast cancer.

It is generally well tolerated; side effects include headaches, depression, nausea, hot flushes and decreased libido.[60,67]

Dutasteride. Dutasteride is an inhibitor of 5-α-reductase types I and II. It has demonstrated more efficacy than finasteride in male patients with AGA.[68] It is approved for benign prostatic hypertrophy, while it is used off label for male AGA and FAGA.[60] It has been reported to successfully treat FAGA at doses that range from 0.25 to 0.5 mg/day.[69] It is well tolerated but due to its long half-life, women of childbearing potential should continue to use effective contraception for at least 6 months post-discontinuation.[1]

Spironolactone. Spironolactone is a potassium-sparing diuretic primarily used for the treatment of hypertension, hyperaldosteronism and heart failure. It is also approved for the treatment of hirsutism.[60] The mechanisms of action of spironolactone are complex, since they are mediated not only by the direct antagonist of aldosterone on androgen receptors, but also indirectly through the reduction of hyperandrogenism and systemic inflammation.[70] This molecule partially inhibits ovarian and adrenal steroidogenesis, blocks 5-α-reductase and 17-hydroxysteroid dehydrogenase at the ovarian and adrenal level, activates aromatase and increases SHBG.[70] The initial dose is usually 50 mg per day for 1 month, then 100–200 mg/day thereafter. It should be continued for at least 6–9 months to assess its efficacy. There are limited data about the efficacy of spironolactone in FAGA. A study included 80 women aged between 12 and 79 years with FAGA receiving a minimum of 12 months of oral antiandrogen therapy. Forty women received spironolactone 200 mg daily and 40 women received cyproterone acetate (50 mg daily if post-menopausal or 100 mg for 10 days per month if premenopausal). There were no significant differences in the results between spironolactone and cyproterone acetate. Thirty-five (44%) women had hair regrowth, 35 (44%) had no clear change in hair density before and after treatment and 10 (12%) experienced continuing hair loss during the treatment period. In conclusion, 88% of women receiving oral antiandrogens can experience a halt of progression of their FAGA, or even a clinical improvement.[71]

Spironolactone is generally well tolerated and its side effects include headaches, decreased libido, menstrual irregularities, orthostatic hypotension, breast tenderness and hyperkalaemia. However, some studies have evidenced that patients younger than 50 years without renal diseases have no risk of hyperkalaemia, thus monitoring is not required.[72]

In women who complain of orthostatic hypotension, it can be useful to take some pastilles of pure liquorice because liquorice can reduce the side effects related to the diuretic activity of spironolactone. In cases of intermenstrual bleeding, the addition of 2.5 mg nomegestrol for 4–5 days from the 14th day of the menstrual cycle can block the bleeding and, after some cycles of treatment, the bleeding could disappear.[70]

Spironolactone is a valid alternative to finasteride in patients that show FAGA associated with hirsutism or acne.[73]

Cyproterone Acetate. Cyproterone acetate (CPA) is an antiandrogen that acts by blocking androgen receptors and decreasing testosterone levels by suppressing luteinizing hormone and follicle-stimulating hormone release. It is approved in Europe and Canada to treat hirsutism, acne and female alopecia, but it is not approved in the United States.[60] As mentioned above, its efficacy is similar to spironolactone.[71] In a 1-year trial, CPA was compared with minoxidil 2% in 66 women with FAGA. While minoxidil showed an improvement, statistically significant hair regrowth did not occur in the CPA group.[74] However, even if not statistically significant, women with irregular menstrual cycles seem to respond better than those with regular menstrual cycles. CPA is generally prescribed in combination with an estrogen in oral contraceptive pills. The suggested regimens for the treatment of FAGA in premenopausal women are 100 mg/day on days 5–15 of the menstrual cycle alongside ethinyl estradiol 50 μg on days 5–25, or 50 mg/day on days 1–10 and ethinyl estradiol 35 μg on days 1–21. Postmenopausal women may be treated with 50 mg daily.

Side effects include menstrual cycle irregularities, weight gain, breast tenderness, reduced libido, depression and nausea. Moreover, it should not be prescribed to patients with liver diseases. There is an increased risk of venous thromboembolism in patients taking oral contraceptives containing estrogen, which can then be enhanced in patients taking CPA contraceptives.[32]

Flutamide. Flutamide antagonises the receptor to which testosterone and DHT bind. US FDA approved it for the treatment of prostate cancer.[60]

Flutamide is usually administered at doses that range from 62.5 to 250 mg daily for FAGA.

Although it has shown to be more efficient than finasteride and spironolactone in FAGA,[75] it is not habitually prescribed due to the risk of hepatotoxicity, which can lead, in rare cases, to hepatic failure. Physicians who prescribe flutamide should monitor serum transaminase at baseline, monthly for the first 4 months and periodically thereafter.[60] Flutamide should not be prescribed in patients with impaired hepatic function at baseline. Other minor side effects include decreased libido and hot flushes.

Other Treatments

Prostaglandin Analogues. Latanoprost and bimatoprost are anti-glaucoma drugs with the well known side effects of eyelash growth caused by the stimulation of the anagen phase, and periocular skin pigmentation. Topical latanoprost 0.1% led to increased hair density in a small placebo-controlled trial including 16 male patients,[76] whereas bimatoprost 0.03% injections were not effective in a case report of a post-menopausal woman with FAGA.[77] Moreover, some studies link the inflammation in the scalp to an increased level of PG-D2, with a consequent miniaturization of hair follicles, and the topical application of PG-D2 has been shown to inhibit hair growth.[24] Actually, research is being carried out to verify if drugs able to block the PG-D2 receptor (GPR44) could have a potential application in patients with AGA.

Light Therapy. After the first published report of paradoxical hair growth in patients treated with intense pulsed light (IPL) for removal of unwanted hair, an interest has grown for the potential effects and applications of low-level laser light therapy (LLLT) to treat alopecia.[78] This phenomenon has been called 'paradoxical hypertrichosis' and is widely acknowledged to occur with an incidence rate ranging from 0.6 to 10% with low fluences of all laser types.

The mechanism of LLLT on hair growth is not yet known; it is hypothesized that the light enhances mitochondrial respiratory activity and production of adenosine triphosphate.[79] The treatment is usually performed at home and there are many devices designed such as brushes, combs, hoods and helmets.

The FDA has approved different LLLT devices for use in AGA: for example, the HairMax LaserComb and the TOPHAT 665. They are usually well tolerated; side effects include scalp dryness, itching, tenderness and a warm sensation. A recent paper compared the use of LLLT for adult androgenetic alopecia with a review and meta-analysis of randomized controlled studies.[80]

The majority of studies found an overall improvement in hair regrowth, thickness and patient satisfaction following LLLT therapy. Further controlled randomized clinical studies are required to establish the efficacy of these devices.[81–83]

Platelet-rich Plasma. Platelet-rich plasma (PRP) is obtained by centrifuging patient's own blood and concentrating the platelets. Platelets, often with added growth factor, chemokines and cytokines, are then injected in the affected areas.[84]

PRP has begun to be used in many specialties, such as orthopaedics, aesthetics and plastic surgery, because platelet activation promotes wound healing and induces tissue regeneration, with the release of various growth factors and cytokines such as platelet-derived growth factor, transforming growth factor beta (TGF-β), vascular endothelial growth factor, epidermal growth factor and insulin-like growth factor.[85]

The efficacy of PRP during hair transplants has been evaluated, and a considerable improvement in the density and regrowth of the transplanted hair follicles has been observed after the growth factors' stimulation.[85]

The mechanisms of action on hair follicles are still under debate. In vitro PRP induces the proliferation of dermal papilla cells and prevents apoptosis by inducing an increase in Akt and Bcl-2 expression. Furthermore, PRP contributes to the formation of hair epithelium and stem cell differentiation into hair follicle cells, thanks to an upregulation of β-catenin, which is expressed in the bulge area of the follicle. The increased expression of FGF-7 (fibroblast growth factor- 7) determines an extended anagen phase of hair cycle. Moreover, in androgenetic alopecia, PRP increases proliferation of bulge cells with release of Ki-67. Finally, thanks to the suppression of inflammatory cytokines, PRP appears as a potent anti-inflammatory agent.[85]

According to recent studies, PRP proved to be a promising option for the treatment of FAGA.[85–87] A placebocontrolled, randomized, half-head trial that included 12 men and 13 women with AGA found a greater increase in hair density in sites treated with PRP compared with control sites 6 months after the first of three monthly PRP treatments.[88]

Moreover, three studies assessing the efficacy of PRP in female patients were included in the evidence-based evaluation of the last European Guidelines for AGA.[32,89–91] Based on these studies, it was concluded that there was insufficient evidence to support the use of PRP in FAGA.[32]

Although studies may differ in methodology, patient selection and treatment technique, regrowth rates have been reported after five local treatments of 3 mL of PRP at 2- to 3-week intervals.[92]

The main side effects of PRP include pain and transient post-treatment oedema and tenderness, persistent trichodynia, psoriasiform scalp reactions, telogen effluvium, secondary infections and scarring.[32]

Even though further studies are needed to confirm its efficacy and to define standardized protocols for treatments, PRP can represent a viable option in patients in whom standard treatments do not produce satisfactory results.[85]

Microneedling. Microneedling is a minimally invasive procedure that involves the use of a skin roller with small needles that cause minor skin injuries. It has become initially popular for the management of acne scars and facial rejuvenation.[92] Recently, the use of microneedling has been investigated as a potential therapeutic option for the treatment of hair disorders due to its capacity to enhance growth factor production, facilitate hair follicle development and cycling, amplify collagen and elastin production and create microchannels that allow transdermal delivery of medications, such as minoxidil or PRP, through the stratum corneum.[93]

In our experience, we recommend microneedling treatment three times a month, for at least 6 months. For the procedure, the patients are anaesthetized with a local mixture of lidocaine and prilocaine/tetracaine cream 1 h before the procedure. Rolling is done with a dermaroller with a needle length of 1.5 mm over affected areas until mild erythema and point–point bleeding is noted. Patients are recommended to resume the application of topical treatments after 24 h.[93]

Microneedling is usually well tolerated. Reported side effects are pain or discomfort at the site of treatment, bleeding, infections and enlargement of the lateral cervical lymph nodes.[93]

There is evidence that this technique may be effective in male AGA, based on the results of a 12-week, randomized, evaluator-blinded study on 100 patients.[94] Single case reports, case series, or small randomized controlled trials have shown promising results in FAGA, suggesting the effectiveness of microneedling in combination with other validated treatments of AGA.[93,95,96] In particular, a case series studying the association of microneedling with topical minoxidil in FAGA showed that the frontal area, the typical androgenetic affected area in females, has the most improvement with the microneedling technique.[93]

To date, it is considered a valid method to be paired with the existing techniques.[92] Future large controlled clinical trials exploring the utility of microneedling are imperative to prove its validation as an evidence based therapeutic option.

Ketoconazole. Ketoconazole is an antifungal drug used to treat seborrheic dermatitis. Oral administration has proven to be effective in reversing the biochemical and clinical abnormalities of ovarian hyperandrogenism. In FAGA, ketoconazole shampoo has proved its utility, especially if used in combination with other treatments.[97] This effect could be due to its anti-inflammatory power, reducing Malassezia, and to its ability to decrease DHT in the skin acting as an androgen receptor antagonist.[97] It is recommended in women with FAGA associated with seborrheic dermatitis or sebopsoriasis.

Topical Hormonal Treatments. The anti-androgen fluridil and the anti-estrogen fulvestrant are not recommend for FAGA therapy.[32]

Hair Transplant

Hair transplant is a valid option in patients who do not achieve a cosmetically satisfying response to topical and systemic agents.[98] It is a minimally invasive technique in which hair follicles from the occipital area, called the 'donor site', are transplanted to the bald area. It is indicated in women with a high hair density in the donor site and no overlying diffuse TE. Final results can be assessed after 9–12 months. In many cases, multiple surgical sessions are needed and the potential transplant failure should not be excluded.[32] After the transplant, patients should continue previous treatment with minoxidil or antiandrogens. Side effects include early temporary hair loss, pain and infections.

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