ABSTRACT: Female pattern hair loss (FPHL) is a biological process that is genetically mediated. Various medicines are used to treat it, few acting via a hormonal mechanism and few acting peripherally via non hormonal mechanisms. It is a difficult condition to treat due to its associated psychological impact and despite the advent of newer drugs, treatment options with proved efficacy in FPHL, are still minimal. Counselling is of utmost importance in this condition and minoxidil 2 % lotion topically still remains the mainstay in all grades of FPHL. Despite the fact that the role of androgen excess or genetic basis has still not been established, the role of antiandrogens in treatment of FPHL cannot be ignored. However, the treatment approach of FPHL is changing with the recent trends. There are various medical, semi-invasive, surgical and camouflage options also available now. Few of these are under trial; however for better understanding and classification, they have been discussed in this chapter. A newer approach combining all these modalities, will give a better patient compliance and more promising results.
Female pattern hair loss (FPHL) is one of the most challenging hair disorders to treat, due to its multifactorial aetiology and associated psychological impact. The role of genetic basis or androgenic nature has still not been clearly established and the impact of iron deficiency and hypothyroidism is still debatable.1,2,3 Multiple topical and oral medications targeting these aetiologies have been tried; however topical Minoxidil has remained the mainstay in FPHL treatment irrespective of the aetiology. Role of antiandrogens has been proved successful in recent studies, especially in patients with hyperandrogenism4,5and many newer modalities of treatment have also been introduced.
Treatment for FPHL can be widely divided as:
Counseling: Irrespective of the grade of alopecia, all females with hair loss need good counseling. Patients should be explained the nature of the hair loss, the necessity for long term treatment and adequate investigation and given realistic expectations. Stressing on these points helps in increasing the patient compliance too. Keeping the patient aware about options such as surgical modalities and camouflage techniques helps decrease the anxiety and depression, in severely affected women.
As the etiology of FPHL can be hormonal or non-hormonal, the medical management is divided into the following groups-
It is the only FDA approved topical agent for FPHL, and can be used in FPHL in normoandrogenic and hyperandrogenic women.
Mode of action: It has no androgenic action and its active molecule is minoxidil sulphate. This molecule acts on the potassium channels in cell membranes and causes peripheral vasodilatation. The exact mechanism by which minoxidil promotes hair growth is still unclear.
Other possible effects of minoxidil on the hair follicles include:
Due to these effects, minoxidil increases follicular vascularity, prolongs anagen, shortens telogen, and converts miniaturized (intermediate) hair to terminal hairs.
Dosage: 2% minoxidil applied twice daily is the US-FDA approved dosage for FPHL. Although studies have claimed better response to 5% lotion, chances of side-effects are higher with 5% lotion. Study done by Blume-Petyavi et al has shown that once daily application of 5% lotion causes lesser side effects and better compliance than 2% lotion.7
Side-effects:They are minimal with 2% lotion. However, non-virilizing hypertrichosis, irritant contact dermatitis(due to the propylene glycol vehicle), dryness and deposition of drug on the hair shaft mimicking dandruff are more with 5% lotion.8These effects are reversible on treatment break and reduction of concentration (within 4-6 months). The unsightly dandruff appearance can be reduced by using shampoos with salicylic acid and/or ZPTO.
Application: Since minoxidil is an over-the-counter product, it is widely used but patients are unaware about its practical aspects. While prescribing following instructions are of utmost importance:
Newer Formulations: Recently gel and foam form of minoxidil have been made available. Newer combinations, with:
1)Tretinoin 0.05% or 0.01%, increases the absorption by three times,11,12but the chance of irritation is greater with it13,14. Azelaic acid is also added to the combination occasionally.
2)Amnexil 1.5% (reverses perifollicular fibrosis) is known but its superiority over minoxidil alone in not proved.
3) Topical Finasteride (no additional benefit proven) 15
All antiandrogens act by inhibiting binding of 5α DHT to androgen receptor. Due to this central action all drugs in this category cause feminization of male fetus and oral contraceptive pills are necessary to give along with them. Nowadays many of these antiandrogens are synthetic progesterones and are given as combination oral contraceptive pills (OCPs)
I] ANTIANDROGENIC ORAL CONTRACEPTIVE PILLS:
These are the first line therapy for women suffering from hairloss associated with PCOS. PCOS being the most common cause of hormonal imbalance in pre-menopausal women these days, the importance of these drugs cannot be neglected. Additionally OCPs are also given along with antiandrogens, hence selecting the right one is of utmost importance. An OCP contains an estrogen and progesterone. The progesterone component can be proandrogenic or antiandrogenic. The third (Norgestimate and desogestrel) and fourth(drospirinone)generation progesterones are considered least androgenic. Since the 3rd generation ones have higher thromboembolic properties, Drospirinone is considered the safest and most antiandrogenic progesterone in combination OCPs.
The other newer synthetic progesterone with antiandrogenic properties is cyproterone acetate.
CYPROTERONE ACETATE (CPA): CPA is unavailable in USA but approved in Britain as treatment for acne and hirsuitism. There is sufficient evidence to support the use of CYA benefits FPHL in evidence of hyperandrogenism 16,17,18
Dosage Regimes: In Pre-menopausal women, cyclic antiandrogen therapy (CAT) is used globally, i.e. 100mg/day of CYA on day 5-15 and 50µg of ethinyl estradiol on day 16-25 of the cycle.19,20,21In India Diane35®(2mg CPA and 50µg ethinyl estradiol) is available as an OCP. It has been proved effective in FPHL along with additional 20mg CPA on day 5-20.22In post-menopausal women, 50mg/day of CYA daily is used.23 CYA has not been proved superior to spironolactone or topical minoxidil in FPHL but one study has claimed it to be the best treatment option in FPHL.24Side-effects: weight gain, menstrual irregularities, breast tenderness, nausea, depression, decreased libido and depression are few of the adverse effects. It is contraindicated in women with liver abnormalities due to its biliary secretion
DROSPIRINONE: is a 17α spironolactone derivative and has antiandrogenic, progestagenic and anti-aldosteronic activities. It is used as an OCP at 3mg/day with 30µg of ethinyl estradiol. Due to its anti-mineralocorticoid features, it has become the most widely used OCP as its dose does not cause any weight gain or fluid retention. However, theoretically use of drospirinone simultaneously with spironolactone can increase chances of hyperkalemia, though there are no studies to prove this theory.
II] FLUTAMIDE:is a pure non-steroidal antiandrogen and is approved in USA only for prostate cancer. It has been considered as the treatment of choice for hair loss and hirsuitism in PCOS25and results in greater reductionin hair loss than any other antiandrogen or finasteride.16,26
Dosage: one study has proven that 250mg/day for one year gives good results27, however to avoid the side-effects, low doses (125mg/day to 62.5mg/day) along with OCPs also give satisfactory results in women with PCOS.
Side-effects: At higher doses hepatotoxicity is seen in 13%24and monitoring of liver transaminase is essential. Increase in levels to more than twice the normal range, should be an indication to stop the drug.28 Since the hepatotoxicity is so common and very severe, this drug is not used frequently in the Indian scenario. Other common side effects are dry skin,lethargy, mood changes, decrease libido and feminization of male fetus.
III] SPIRONOLACTONE: is approved in USA for hypertension and in Australia for hirsuitism. It is anantagonist of aldosterone with antiandrogen action. Despite a lack of sufficient studies with an adequate cohort size, this drug is widely usedin FPHL. There is no minimally effective dosage proved in case of spironolactone.
Dosage: When used for 6 months at dose of 50-200mg/day it can reduce the total testosterone level substantially29. Improvement is seen after 6 months of treatment30
Side-effects: It is a category C drug for pregnancy. Adverse effect of hyperkalemia is very rare in healthy women but the physician must be aware of the risk and warn patient from consuming excessive amounts of bananas and/or coconut water. Other side-effects such as lethargy, menorrhagia and cutaneous side-effects can occur. It can occasionally precipitate lupus type eruptions and alopecia too.31
There are 2 main drugs in this category that act on 5α reductase enzyme and block the conversion of testosterone to dihydrotestosterone, Finasteride and Dutasteride
Finasteride exclusively acts on 5αreductase type II present in hair follicles and prostate, and reduces systemic as well as peripheral follicular androgenic activity. It is most commonly used oral drug in male androgenic alopecia at a dose of 1mg/day and is US-FDA approved for the same. It can be used in hyperandrogenic and normoandrogenic women too. Normoandrogenic women occasionally have high levels of 5αreductase, hence they tend to benefit with this drug.32
Dosage: In women, the dose requirement is higher. Studies have proved that a 5mg/day dose is required in post-menopausal women with or without hyperandrogenism. In pre-menopausal women it can be used along with an OCP at same dose.33. If the OCP is antiandrogenic, the dose of finasteride can be reduced to 2.5mg/day.34. Recently it is also available as a topical agent; however it did not have any advantage over minoxidil.35
Side-effects: It is a category X drug as it can cause feminization of the male fetus. It is generally well tolerated and the adverse effects such as breast tenderness and increased libido, decrease after first few months of therapy. It can be absorbed via the skin surface however the amount absorbed is too less to cause any effects, never the less it is advisable to inform the patient about this. Blood donations can be done after 1 month of stopping finasteride.
Dutasteride acts on both type I and Type II 5α reductase. There are fewer reports of dutasteride on women as it 3 times more potent inhibitor of type II enzyme than finasteride.36 It can cause serious side effects on the fetus if used in a pre-menopausal female. It is not US-FDA approved for hairloss.
Dosage: due to the lack of studies, the same dose used in men is used in women, i.e., 2.5md/day.
A topical preparation used in mesotherapy has given good results, it contains 0.5mg dutasteride, 20mg biotin, 200mg biotin, 500mg D-panthenol.37Side-effects: related to sexual performance and reproduction are higher in men, in women
MISCELLANEOUS NUTRITIONAL AND ADJUVANT DRUGS: Various new studies have focused on different modalities of approach to hair loss in women and men. Newer target molecules and bioengineering has also been adopted in this field due to the limited treatment options. All these modalities work only as adjuvants and are still being researched. Table 1 gives a brief list of few of them, used in androgenic alopecia in men and women. They surely give us hope for newer more efficient drugs in the near future
|Iron supplements||Extremely important in India, due to high prevalence of iron deficiency anemia and proved association with hair loss.38|
|Vitamin B12, Folic acid and Biotin||OCPs with CPA with ethinyl estradiol can worsen B12 deficiency24, hence supplementation is required along with them|
|Cysteine, histadine, copper and zinc||These amino acids and trace elements have been proved in a few studies to be beneficial. Copper peptides are now-a-days one of the most marketed supplemental therapy.|
|Alfatradiol 0.025% solution||Alfatradiol is a topical estrogens used in FPHL, but due to contrary results of the efficacy the studies are insufficient.40|
|Melatonin 0.1% solution topically||Known to cause hormone alteration in DHT and testosterone, has been tried in one study topically as 0.1% solution, leading to significant increase in anagen hair.41|
|Biomimetic peptides (Trifolium pratense flower extract combined with acetyl tetrapeptide-3) used topically||Its mode of action is by inhibition of 5-α-reductase activity, reduction of inflammatory reactions, and stimulation of ECM protein synthesis in the vicinity of the hair follicle.42|
|Stemoxydine 5% solution||A potent prolyl-4-hydroxylase competitive inhibitor, used topically to mimic hypoxic signally and maintain hair growth and cycling. In a single study stemoxydine was applied 1 time a day (6ml), and at the end of the 3 months of the trial, there was an increase of 4% in hair density. Currently, this molecule is patented by L’Oreal Research and Innovation, Clichy, France.43|
|Valproic acid solution 8.3% topically||Valproic acid (VPA), a widely used anticonvulsant, inhibits glycogen synthase kinase 3β and activates the Wnt/β-catenin pathway, which is associated with hair growth cycle and anagen induction.44|
|Roxithromycin 5% solution used topically||Roxithromycin increases hair elongation and inhibits catagen-like changes induced in vitro with IFN-gamma in murine and human hair follicles by its anti-apoptotic activity to keratinocytes.45|
NON-INVASIVE AND SEMI-INVASIVE MODALITIES:
SURGICAL MANAGEMENT: Now-a-day hair transplantsare being attempted in women with good donor area. Due to the chronicity of FPHL and scarce treatment options, most the patients may already be applying minoxidil 2% lotion for 2-3 years prior to their consult with no significant improvement and treatment failure. In such cases to avoid frustration and depression in patients, surgery can be offered during the first visit along with medical management. The Strip surgery is a better option in women rather than Follicular unit extraction, as the amount of shaving of hair required with strip surgery is less.53 This modality has been discussed in detail in the later chapters.
COSMETIC CAMOFLAGE: In severe cases, hair pieces and wigs aregood camouflaging and concealment options. Mild grades of alopecia can be concealed with hair fibres and micro-pigmentation.
Micro-pigmentation is a new technique involving tattooing of the scalp in pin points giving an illusion of increased hair density. It has been discussed in detail in later chapters.
Female pattern hair loss (FPHL) is a biological process that is genetically mediated. Various medicines are used to treat it, few acting via a biological response to hormonal mechanism and few acting peripherally via non hormonal mechanisms. Minoxidil 2 % lotion topically is the only treatment approved by US-FDA, and it remains the mainstay in all treatment protocols for FPHL. However, the treatment approach of FPHL is changing with the recent trends. There are various medical, semi-invasive, surgical and camouflage options also available now. A newer approach combining all these modalities, will give a better patient compliance and more promising results.