REPORTS AND RECOMMENDATIONS

Female Pattern Hair Loss and Androgen Excess: A Report

From the Multidisciplinary Androgen Excess and Downloaded from https://academic.oup.com/jcem/article-abstract/104/7/2875/5342938 by Endocrine Society Member Access 2 user on 24 June 2019 PCOS Committee

Enrico Carmina,1 Ricardo Azziz,2 Wilma Bergfeld,3,4 Héctor F. Escobar-Morreale,5,6,7 Walter Futterweit,8 Heather Huddleston,9 Rogerio Lobo,10 and Elise Olsen11,12

1Department of Health Sciences and Mother and Child Care, University of Palermo, 90121 Palermo, Italy; 2Department of Health Policy, Management, and Behavior, School of Public Health, University at Albany, State University of New York, Albany, New York 12144; 3Department of Dermatology, Cleveland Clinic, Cleveland, Ohio 44195; 4Department of Pathology, Cleveland Clinic, Cleveland, Ohio 44195; 5Department of Endocrinology and Nutrition, Hospital Universitario Ramon ´ y Cajal, Universidad de Alcala, ´ 28801 Madrid, Spain; 6Centro de Investigacion ´ Biomedica ´ en Red Diabetes y Enfermedades Metabolicas ´ Asociadas, 28029 Madrid Spain; 7Instituto Ramon ´ y Cajal de Investigacion ´ Sanitaria, 28034 Madrid, Spain; 8Mount Sinai School of Medicine, New York, New York 10029; 9Department of Obstetrics and Gynecology, University of California at San Francisco, San Francisco, California 94143; 10Department of Obstetrics and Gynecology, Columbia University, New York, New York 10032; 11Department of Dermatology, Duke University Medical Center, Durham, North Carolina 27710; and 12Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710

ORCiD numbers: 0000-0001-7336-7610 (E. Carmina); 0000-0002-6890-1644 (H. F. Escobar-Morreale).

Objective: To determine the current state of knowledge and provide evidence-based recommendations that could be valid for all specialists taking care of female pattern hair loss (FPHL), a common form of hair loss in women that is characterized by the reduction of hair density in the central area of the scalp, whereas the frontal hairline is generally well conserved.

Participants: An expert task force appointed by the Androgen Excess and PCOS Society, which included specialists from dermatology, endocrinology, and reproductive endocrinology.

Design: Levels of evidence were assessed and graded from A to D. Peer-reviewed studies evaluating FPHL published through December 2017 were reviewed. Criteria for inclusion/exclusion of the published papers were agreed on by at least two reviewers in each area and arbitrated by a third when necessary.

Conclusions: (i) The term “female pattern hair loss” should be used, avoiding the previous terms of alopecia or androgenetic alopecia. (ii) The two typical patterns of hair loss in FPHL are centrifugal expansion in the mid scalp, and a frontal accentuation or Christmas tree pattern. (iii) Isolated FPHL should not be considered a sign of hyperandrogenism when androgen levels are normal. (iv) The assessment of patients with FPHL is primarily clinical. (v) In all patients with FPHL, assessment of a possible androgen excess is mandatory. Measurement of vitamin D, iron, zinc, thyroid hormones, and prolactin are optional but recommended. (vi) Treatment of FPHL should start with minoxidil (5%), adding 5a-reductase inhibitors or antiandrogens when there is severe hair loss or hyperandrogenism. (J Clin Endocrinol Metab 104: 2875–2891, 2019)

ISSN Print 0021-972X ISSN Online 1945-7197 Abbreviations: AE-PCOS Society, Androgen Excess and PCOS Society; AR, androgen Printed in USA receptor; CCCA, central centrifugal cicatricial alopecia; CTE, chronic telogen effluvium; Copyright © 2019 Endocrine Society DHEA, dehydroepiandrosterone; DHEAS, DHEA sulfate; FAPD, fibrosing alopecia in a Received 27 November 2018. Accepted 15 February 2019. pattern distribution; FFA, frontal fibrosing alopecia; FPHL, female pattern hair loss; LC/MS, First Published Online 20 February 2019 liquid chromatography/mass spectrometry; LLL, low-intensity light laser; MPHL, male pattern hair loss; PCOS, polycystic ovary syndrome; PRP, platelet-rich plasma; T, tes- tosterone; TMF, topical minoxidil foam; TMS, topical minoxidil solution.

doi: 10.1210/jc.2018-02548 J Clin Endocrinol Metab, July 2019, 104(7):2875–2891 https://academic.oup.com/jcem 2875 2876 Carmina et al FPHL and Androgen Excess J Clin Endocrinol Metab, July 2019, 104(7):2875–2891

air loss in women is common and may have different excess, and to provide evidence-based recommendations. All causes. A specific and particularly common subtype members of the task force declared no conflicts of interest or H financial interests that might interfere with their objectivity and is characterized by reduction of hair density in the central duty. area of the scalp whereas the frontal hairline is generally

well conserved. In the 1950s, Hamilton (1) noted that this Downloaded from https://academic.oup.com/jcem/article-abstract/104/7/2875/5342938 by Endocrine Society Member Access 2 user on 24 June 2019 form of hair loss shares certain characteristics with male Process pattern baldness [also called male pattern hair loss Each section of this review was prepared by at least two investigators and then reviewed by all members of the task (MPHL)] and considered it androgen-dependent. Further force. Analyzed papers included individual studies, systematic studies specifically related MPHL to increased DHT reviews, and abstracts published in the English scientific liter- production in skin (2). However, similar evidence for ature. Criteria for inclusion/exclusion of the published papers a relationship between DHT overproduction and this relating to each section were agreed on by at least two reviewers pattern of hair loss in women has not been produced. in each area and arbitrated by a third when necessary. Levels of evidence were assessed and graded from A to D (16, 17). This phenotype of hair loss in women has been given The final manuscript was reviewed and approved by the AE- various names, although in the endocrine and gyneco- PCOS Society Board of Directors. Institutional Review Board logic literature it is most frequently referred to as an- approval was not obtained because the study reviewed publicly drogenetic alopecia, under the assumption that is available medical literature. androgen related (3). Recent guidelines on the diagnosis of polycystic ovary syndrome (PCOS) continue using the Systematic review of the literature more general term “alopecia” and consider the finding and meta-analysis diagnostic for the presence of hyperandrogenism (4–7). Peer-reviewed studies evaluating FPHL published through Overall, the relationship of hair loss and androgen December 2017 were reviewed. Multiple databases were excess in women is neither consistent nor clear. Most searched, including MEDLINE, Embase, Cochrane, ERIC, affected women with the frontal–central pattern of hair EBSCO, Dissertation Abstracts International, and Current Contents. This review focuses on the epidemiology, patho- loss have normal circulating androgen concentrations (8, physiology, diagnosis, and treatment of the disorder. Some 9) and an absence of other androgen-related signs or studies were eliminated because the data were either not related symptoms, such as hirsutism or irregular periods/ovulation to the focus of the systematic review, insufficient for epide- (10). The presence of this phenotype of hair loss has been miological analysis, or reported in previous publications. All reported also in women with total absence of circulating data sources were analyzed while recognizing positive publi- cation bias. androgens, deficiency of postpubertal androgenization A meta-analysis was also performed to obtain pooled (11), or lacking an androgen receptor (AR) (12). Because prevalence estimates on FPHL in subjects with PCOS. The terms of this, the term female pattern hair loss (FPHL) has of the MEDLINE search for this meta-analysis were: (alopecia become the most common name used in the dermatologic OR androgenetic OR female pattern hair loss OR mid scalp OR literature for this common condition in women (10, Ludwig OR frontal accentuation OR Olsen OR male pattern 13–15), without immediately stressing a link to androgen OR Hamilton) AND prevalence AND (PCOS OR polycystic ovary OR polycystic ovarian OR polycystic ovaries). The excess. Consequently, we use the term FPHL in the search was completed by examining the references listed in the present publication. articles identified. As many women with hyperandrogenism also exhibit After study identification, screening, selection, and in- or complain of scalp hair loss, the Androgen Excess and clusion, a quality-effects model was applied considering the PCOS (AE-PCOS) Society appointed an expert task force heterogeneity of the studies in terms of age, race, and ethnicity of the populations being described. Double arcsine trans- to determine the current state of knowledge concerning formations were applied to stabilize the variance (18). Pub- the relationship of these two conditions. This publication lication bias was assessed by a funnel plot representing the provides evidence-based recommendations for the eval- double arcsine transformation of the prevalence against the uation, diagnosis, and treatment of FPHL, as well as its SE (19). MetaXL 3.0 software was used for the meta- association with hyperandrogenism for use by the many analysis (18). different specialties of health professionals that are called upon to evaluate and treat these women. Results and Discussion

Clinical presentation of FPHL Methods A shortened anagen phase and miniaturization of hair AE-PCOS Society task force follicles in the affected scalp are key features of pattern The AE-PCOS Society Board appointed an expert task force hair loss, a condition with distinct patterns of hair loss in of varying medical disciplines to determine the current state of men and women (14). However, hair loss in women with knowledge concerning FPHL and its relationship to androgen FPHL exhibits several important differences from that of doi: 10.1210/jc.2018-02548 https://academic.oup.com/jcem 2877 men with MPHL, including patterns and density in af- women (23, 24), patients with androgen excess who fected areas. develop FPHL (i.e., hyperandrogenic FPHL) usually There are typically two patterns of hair loss in FPHL: present during young adulthood. The role of hyper- centrifugal expansion in mid scalp with preservation of androgenism in postmenopausal women with FPHL

the frontal hair line (Ludwig pattern) (20) and a frontal remains unclear, and further studies are needed to un- Downloaded from https://academic.oup.com/jcem/article-abstract/104/7/2875/5342938 by Endocrine Society Member Access 2 user on 24 June 2019 accentuation or Christmas tree pattern (Olsen pattern) derstand the hormonal mechanisms involved in FPHL (21). The latter pattern is distinctive for FPHL and helps during this period of life. to distinguish FPHL from other hair loss conditions that favor the central scalp. Hamilton (1) concurred that Conclusions women with pattern hair loss generally do not develop Hair loss in women presents differently than that in the vertex baldness seen in men but may have bitemporal males and three typical patterns (Ludwig, Olsen, and recession; this recession is usually not baldness but rather Hamilton) may be distinguished (level of evidence B). thinner, shorter, less dense hair. There are, however, women with significant androgenization that may de- Psychological consequences of FPHL velop typical MPHL (Hamilton pattern) that includes Hair loss in women has a substantial psychological vertex thinning. In Fig. 1, the two main patterns of FPHL impact, and several studies have noted that it may result are presented and compared with MPHL (22). in depression symptoms and reduced quality of life (25, Women with FPHL do not experience the degree of 26). Interestingly, hyperandrogenic disorders, but mainly baldness that men with MPHL do, largely because the PCOS, may be associated with mood disorders and de- miniaturization process is not as profound and not all hairs pression symptoms per se (27, 28), but to our knowledge are affected equally in the involved areas. Many women no study has specifically addressed the impact of hyper- with FPHL may also display parietal thinning, but this androgenism on depression symptoms and quality of life should not dissuade against making the diagnosis of FPHL. in women with FPHL. FPHL may first present in adolescence/early adult- hood and/or in the perimenopause or postmenopause age Conclusions range. Considering the peak age-related incidence of this Pattern hair loss in women has significant impact on type of hair loss and the possible role of androgens in at psychological well-being and quality of life (level of ev- least some of these patients, the following classification of idence C). FPHL has been suggested (14): Pathophysiology of FPHL 1. FPHL: early onset Molecular mechanisms a. With androgen excess The maintenance of a healthy hair follicle cycle re- b. Without androgen excess quires well-coordinated progression and timing through 2. FPHL: late onset/postmenopausal the different phases of growth (anagen), regression (catagen), quiescence (telogen), and regeneration. Mul- a. With androgen excess tiple genes, growth factors, and hormones govern this b. Without androgen excess cycle. However, because androgen secretion decreases during Molecular processes that regulate the different phases thelatereproductiveageinnormal and hyperandrogenic have been extensively studied in animals (29–31). The

Figure 1. The two main patterns of FPHL (patterns 2 and 3) compared with MPHL. 2878 Carmina et al FPHL and Androgen Excess J Clin Endocrinol Metab, July 2019, 104(7):2875–2891 major pathway influencing the normal sequence of events the scalp (37) with a clear effect of androgens in altering is the activation of the wingless (Wnt) ligand system. Wnt expression (38). However, data in FPHL are less Through Wnt and the production of b-catenin, a down- clear. In fact, many women with FPHL present normal stream effector of the Wnt pathway, a regular sequence androgen levels (see below), and it has been shown that

of events is occasioned. Activation of the Wnt system in FPHL may present also in subjects with no ARs (8). Downloaded from https://academic.oup.com/jcem/article-abstract/104/7/2875/5342938 by Endocrine Society Member Access 2 user on 24 June 2019 the dermal papilla promotes hair follicle growth and Additionally, in the scalp, AR content is higher in the induces the switch from telogen to anagen by stimu- frontal vs occipital scalp in both men and women, higher lating the proliferation and differentiation of bulge stem in men than in women (39), and higher in the balding vs cells. The vitamin D receptor, independent of circulating nonbalding scalp (40). vitamin D3, also plays an important role in anagen In women with FPHL, enhanced androgen action in initiation. Data from animal models demonstrate that the scalp may occur due to alterations in 5a-reductase the vitamin D receptor and b-catenin act together, and enhanced DHT formation locally, or in androgen forming a complex important for anagen activation. binding to the AR (39). In fact, the 5a-reductase mRNA The catagen phase, alternatively, seems to be linked to levels of all three isozymes (I, II, and III) were observed to increased expression of bone morphogenetic proteins be increased in the hair follicles of some, albeit not all, during the late anagen phase. Many other factors women with hair loss (41). Consistent with an increased participate in the process of hair regeneration, including formation of DHT in the scalp, elevated circulating levels several growth factors. Follicular growth factors (Fgf7 of 5a-reductase–derived C19 androgen conjugates have and Fgf10) and bone morphogenetic protein inhibitors been found in women with hyperandrogenic hair loss produced from the dermal papilla activate stem cells to (42, 43). Legro et al. (43) observed a shift favoring pe- regrow a new follicle during hair regeneration (30, 31). ripheral formation of C19 androgen sulfate conjugates vs In both MPHL and FPHL, the same pathologic pro- glucuronide conjugates. cess appears to be present and is characterized by a re- Recently, using more sensitive mass spectrometry/ duction in the duration of the anagen phase and an chromatographic analyses, 11-oxo androgens of adre- increase in percentage of hairs in the telogen phase. There nal origin have been found to be quantitatively greater in is an increasing delay in the onset of the next anagen the circulation than levels of the usual androgens assessed phase, leading to prolongation of the latent phase (also (44). These 11-oxo testosterone (T) and DHT metabo- termed kenogen) that follows the telogen phase in pattern lites have great affinity for the AR. It is possible that these hair loss (32). Follicles then also undergo a process of steroids or their converted conjugates could be involved miniaturization that will determine a progressive scalp in the pathogenesis of FPHL, but no data in this regard hair loss (33). are yet available. Polygenic susceptibility and increased androgen action The role of androgen excess in the FPHL of post- in the scalp seem to be the main drivers of scalp hair loss menopausal women is more difficult to establish. An- in both MPHL and FPHL. The possible role of chronic drogen levels start decreasing several years before low-grade inflammation in the scalp may represent an menopause, and in normal women plasma T decreases by additional or different driver of hair loss in FPHL. 50% moving from the age of 20 to the age of 40 (45). In hyperandrogenic women, this decline in plasma T Genetic susceptibility in FPHL is also present but the degree of the decrease appears to In MPHL, large genome-wide association studies have be somewhat less (23), which may reflect continued been performed and several genetic loci linked to scalp ovarianandrogenexcessaftermenopause. Postmenopausal hair loss have been identified (34). However, the can- women with FHPL who have had evidence of PCOS didate genes that have been identified in MPHL [genes may have relatively higher circulating androgens and a encoding the AR, the histone deacetylases 4 and 9, and low estrogen/androgen ratio, but no data support this the Wnt molecule Wnt10A (34)] have not shown any hypothesis. association with FPHL (35). Although not all genetic loci A possible protective effect of estrogens on human hair associated with MPHL [.60 (36)] have been studied in growth has been suggested, and it is supported by indirect FPHL, these data suggest that the genetic components of evidence, including increased prevalence of FPHL fol- MPHL and FPHL may be different (35). lowing menopause, prolongation of anagen during preg- nancy (46), and reports of hair loss in women taking Possible role of androgens in FPHL tamoxifen or aromatase inhibitors for treatment of breast In MPHL, the role of androgen action on the scalp has cancer (47). Additionally, genome-wide association studies been extensively studied demonstrating elevated ex- have shown an association between polymorphisms of the pression of ARs and/or exaggerated formation of DHT in aromatase gene and FPHL (48). Alternatively, there is no doi: 10.1210/jc.2018-02548 https://academic.oup.com/jcem 2879 clear effect of estrogen supplementation on human hair rising to 14% to 28% in postmenopausal women in their growth, and in many animal species estrogens have an 50s and further increasing to 29% to 56% in women inhibitory effect on hair growth (49). aged $70 years of age (59–61). In a study conducted in the United Kingdom, Birch Chronic low-grade inflammation in FPHL

et al. (59) examined 377 women presenting to a general Downloaded from https://academic.oup.com/jcem/article-abstract/104/7/2875/5342938 by Endocrine Society Member Access 2 user on 24 June 2019 Several data suggest that chronic low-grade in- dermatology clinic with complaints not related to hair flammation in the scalp may be an important factor and found that FPHL was present in 6% of women ,50 favoring hair loss in women (34, 50, 51). This hypothesis years of age and 38% of those $70 years of age. In is supported by the finding that many inflammatory another study, investigators examined a large sample of peptides, including TGF-b1, TNF-a, and IL-1, are in- white women (n = 1006), including patients in a der- volved in the catagen phase (34, 52). Several studies have matology clinic as well as individuals from the sur- also found that inflammation is more common in biopsy rounding community, none of which specifically sought samples from patients with pattern hair loss compared help for hair loss and found a rate of FPHL of 19% for with those of control subjects (53–55). Additionally, the overall population, ranging from 3% for women in minoxidil downregulates the genetic expression of IL-1 in their 20s, 17% for women in their 30s, and 23% for human keratinocytes (56). those in their 50s (60). The possible role of chronic inflammation in the A 2005 community-based study of women in Aus- pathogenesis of hair loss is reinforced by data indicating tralia assessed the self-reporting of hair loss using a that prostaglandin D2 is elevated in bald scalp and in- mailed survey with a 34% response rate followed by hibits hair growth in explanted human hair follicles (57). examination of 193 women (61). Using a photographic Transgenic mice, who have elevated prostaglandin D2 in scale with a progressive decrease in density in the central the skin, develop hair loss and miniaturization of hair scalp and an assignment of FPHL for those with score $2, follicles (57). Because prostaglandins are not only able to the investigators found an overall prevalence of FPHL of induce acute inflammation but also convert short-lived 32%. Notably, the survey also observed underreporting inflammatory responses to long-lasting chronic in- of hair loss by many of the respondents with FPHL, even flammation (58), it is possible that their greater con- those with most pronounced hair loss. centration in the scalp is one of the mechanisms involved The prevalence of pattern hair loss in East Asian in the inflammatory process that may be associated with women is also related to age but seems to be overall lower hair loss. However, no data on prostaglandins in FPHL than in white women (62–64). The largest study was are available, and their role in FPHL remains unclear. conducted by Su et al. (62) in Taiwan, where it was Additionally, treatment with classic anti-inflammatory observed that there was a prevalence of FPHL of 11.8% agents or immunosuppressive drugs does not seem to overall, ranging from 7% to 15% with aging. A study in improve FPHL, and the relationships between scalp in- Korean women (n = 4601) found an overall prevalence of flammation and other possible causal factors of FPHL 5.6% (63), similar to the rate observed in a 2010 study of have not been clarified (34). Chinese women (64). Differences in the prevalence of FPHL between ethnic Conclusions groups may depend on genetic differences in molecular FPHL seems to be related to several factors, including action and biochemistry of several factors that regulate genetic influences (level of evidence B), androgen sensi- hair growth. Consistent with this hypothesis, in East Asia tivity and concentrations (level of evidence C), and populations, hirsutism is less common. For example, in possibly inflammation in the scalp (level of evidence C). hyperandrogenic Japanese women, despite similarly el- In many patients, FPHL may be present in the absence of evated T levels, hirsutism scores and serum levels of 3a- any detectable signs of androgen excess (level of evidence hydroxy-androstanediol-glucuronide, a marker of 5a- B). Overall, further research on the pathogenesis of FPHL reductase activity, are significantly lower than in white is critically needed. populations (65).

Epidemiology of FPHL in the general population Conclusions In the general population, the prevalence of FPHL Available data suggest a relatively low prevalence of increases with age and is higher in older women. Al- FPHLinyoungwomenaged20to30years,increasing though there are different prevalence figures due to with age to one-third to one-half of women $70 years old varying study designs and differences in ethnicity, in (level of evidence C). In East Asian women a similar age- white women the prevalence of FPHL ranges from 3% to related trend is observed, although the overall prevalence of 12% in young women in their third to fourth decade, FPHL is lower than in white women (level of evidence C). 2880 Carmina et al FPHL and Androgen Excess J Clin Endocrinol Metab, July 2019, 104(7):2875–2891

Prevalence of hyperandrogenism in women The initial search identified 86 articles (Fig. 2, left panel). with FPHL Review of article abstracts led totheexclusionof62articles, In studies of consecutive women with FPHL, the with 24 studies remaining, whose text was fully assessed for prevalence of clinical (hirsutism) or biochemical (increased eligibility (Fig. 2, left panel). Of these, 15 were subsequently

circulating androgen levels) hyperandrogenism has varied excluded because of several reasons (Figure 2, left panel). Downloaded from https://academic.oup.com/jcem/article-abstract/104/7/2875/5342938 by Endocrine Society Member Access 2 user on 24 June 2019 widely. In one retrospective study of 187 women with Consequently, nine articles (72–80) were included in the FPHL and 21 healthy control women, 67% of the patients quantitative synthesis and meta-analysis of the prevalence of with hair loss alone (n = 110) and 84% of patients FPHL in patients with PCOS (Fig. 2, left panel). The char- with hair loss plus other symptoms of androgen excess acteristics of the patients included in these studies are had hyperandrogenemia (66). In another retrospective summarized in Table 1. Most of the patients in these studies study of 53 consecutive female patients with isolated were in their third decade of life, important when comparing FPHL (without hirsutism or other clinical sign of en- the data derived from these studies with those obtained in the docrine disturbance), only 26% demonstrated hyper- general population. androgenemia (67). In a retrospective study of 166 Applying a quality-effects model, the pooled preva- female patients diagnosed with FPHL, 8.2% of patients lence of FPHL in patients with PCOS was 28% (95% CI, had increased total T, 2% increased free T, and 8.9% 22% to 34%) (Fig. 2, top right panel). A funnel plot increased dehydroepiandrosterone (DHEA) sulfate (Fig. 2, bottom right panel) representing the double (DHEAS) concentrations (68). In a prospective study, arcsine transformation of the prevalence against the Futterweit et al. (9) assessed 109 women with FPHL and SE demonstrated minimal asymmetry, thereby ruling out observed that 38.5% had increased androgen levels; publication bias. Of note, only one study (79) compared 26.1% of those with hyperandrogenemia had no asso- PCOS to non-PCOS controls, finding a prevalence of FPHL ciated hirsutism or menstrual dysfunction. of 23.1% vs 8.8% in age-matched controls in China.

Conclusions Conclusions Although hyperandrogenism appears to be associated Although the available data are few and the results with FHPL, the strength and nature of this association highly variable, it may be concluded that evidence of remains unclear (level of evidence C). FPHL is found in 20% to 30% of patients with PCOS (level of evidence C). Prevalence of FPHL in women with PCOS: results of a systematic review and meta-analysis Diagnosis of FPHL In retrospective studies including female patients with The diagnosis of FPHL is primarily made clinically, different forms of androgen excess, the prevalence of hair although laboratory analyses play an important role in loss has been reported to range from 1.9% to 8% identifying specific underlying causes that may contribute (69–71). To address the relationship of the most common to the development of hair loss in affected women. androgen excess disorder in women, namely PCOS, with FPHL, the task force undertook a systematic review and a Medical history meta-analysis to obtain pooled prevalence estimates of Women with potential FPHL should be queried about FPHL in patients with PCOS. age of onset and evolution of their hair loss. Sharing with

Table 1. Characteristics of the Studies Included in the Meta-Analysis of Prevalence of FPHL in Patients With PCOS

Ascertainment of Alopecia Age of Patients Sample Patients With Study by a Dermatologist Ethnicity With PCOS (y) Size (n) FPHL (n) Ozdemir¨ et al., 2010 (72) Yes Turkish 23 (16–40) 115 40 Wang et al., 2013 (73) Yes White plus Asian 28 6 6 123 25 Quinn et al., 2014 (74) Yes Multiethnic 28 6 6 254 56 Gowri et al., 2015 (75) Yes Indian (21–30) 40 12 Hong et al., 2015 (76) Yes Korean 25 6 7405 Leerasiri et al., 2016 (77) No Thai 26 6 7 145 63 Schmidt et al., 2016 (78) Yes Multiethnic 28 6 6 237 53 Feng et al., 2018 (79) Yes Chinese 30 6 6 186 61 Keen et al., 2017 (80) Yes Indian 25 6 4 100 31

All of these studies applied the European Society of Human Reproduction and Embryology/American Society of Reproductive Medicine criteria for the diagnosis of PCOS. Data are counts, means 6 SD, or medians (range). doi: 10.1210/jc.2018-02548 https://academic.oup.com/jcem 2881 Downloaded from https://academic.oup.com/jcem/article-abstract/104/7/2875/5342938 by Endocrine Society Member Access 2 user on 24 June 2019

Figure 2. PRISMA flowchart (A) and funnel plot (B) of the studies included in the meta-analysis of the prevalence of FPHL among patients presenting with PCOS. For the calculations of SEs and of double arcsine in the funnel plot, prevalences were introduced as per unit. patients the Sinclair scale for FPHL (81, 82) or the Instead, there will be hairs having a variety of diameters modified Hamilton–Norwood scale for MPHL (83) may and lengths in affected areas. This can be appreciated be helpful for determining family history of MPHL or using a piece of black or white fabric (depending on hair FPHL. Symptoms related to hyperandrogenism such as color) placed behind the hairs or by dermatoscopy. hirsutism, menstrual irregularities, difficulty conceiving, or severe cystic acne should be sought. Use of medica- Absence of diffuse shedding tions that are related to hyperandrogenism, such as Although by histological examination there is an in- valproic acid and androgen supplementation or prior use creased percentage of hairs in the telogen phase in af- of 13-cis retinoic acid, should be also investigated. fected areas of FPHL compared with normal (85), a history of increased shedding is inconstant. Hair shed- Clinical presentation ding should not be global, but only in affected areas, if it The following clinical features are characteristic of does occur at all. An increase in the percentage of hairs in FPHL (10, 14, 21). the telogen phase can be determined by performing several hair pulls in the affected area of FPHL and three Pattern of hair loss/decreased hair density on the top to four other areas of the scalp, including at least one of the scalp from the occiput. A hair pull is a simple bedside test Usually scalp hair loss will be either central loss or performed by gently pulling on a group of 50 to 60 hairs frontal accentuation, rarely the vertex/male pattern of from the scalp surface to the ends of the hair: it should hair loss (10). A decrease in hair follicle density can be normally generate 0 to 2 hairs per pull (86). If there is an confirmed by comparing the density in the occiput, which increase in the number of hairs removed with each pull in is not under androgen control and not involved in FPHL, multiple areas of the scalp, this suggests another path- with that of the top of the scalp. This is best demonstrated ophysiologic process in addition to FPHL such as telogen by parting the hair vertically in both areas and comparing effluvium (84). the part widths (84). The parietal scalp may be involved. Preservation of follicular ostia (follicular opening) Miniaturization of hairs in the affected areas of on the scalp in affected areas the scalp The presence of ostia implies potential regrowth. Loss In FPHL, the degree of miniaturization is never as of ostia implies loss of the follicular unit and sebaceous profound as in men, so true baldness is rare (10, 85). gland and a scarring or cicatricial process (84). 2882 Carmina et al FPHL and Androgen Excess J Clin Endocrinol Metab, July 2019, 104(7):2875–2891

Presence of focal atrichia infiltrate of lymphocytes, mast cells, macrophages, and Focal atrichia are small (;4 mm) areas of the central large Arao bodies (dense aggregates of elastin fibers) (33). scalp devoid of hair. They are observed in 44% of women In late MPHL, streamers may present as fibrotic tracts with FPHL compared with 2% of subjects with other hair with some follicles obliterated by the inflammatory

disorders, and they are more common in late onset (67%) process (95). Downloaded from https://academic.oup.com/jcem/article-abstract/104/7/2875/5342938 by Endocrine Society Member Access 2 user on 24 June 2019 than early onset (15%) FPHL (87). Differential diagnosis Dermatoscopic findings Some common causes of female hair loss must be A dermatoscopic examination offers a means of con- distinguished from FPHL, including chronic telogen ef- firming the presence of follicular ostia and the variety of fluvium (CTE), central centrifugal cicatricial alopecia diameter hairs involved in the miniaturization process in (CCCA), frontal fibrosing alopecia (FFA), and fibrosing FPHL (88). Also seen in FPHL is an increase in single alopecia in a pattern distribution (FAPD), as detailed hair units in the frontal scalp compared with normal, below. yellow dots indicative of empty follicles and peripilar hyperpigmentation (89), with the latter seen in 86% of CTE women with FPHL (90). The most common condition requiring differentiation from FPHL is CTE. This condition is defined as diffuse Scalp biopsy scalp hair thinning, generally in middle-aged women, To be most useful, a 4-mm punch scalp biopsy in- which is accompanied by generalized persistent shedding volving the dermis should be performed, followed by (53). There is no frontoparietal or central pattern of hair horizontal sections to establish the number of hairs per loss as in FPHL, but frequently there may be bitemporal unit area (91). Much of our knowledge about histological recession. A hair pull is usually positive from multiple findings in FPHL and potential explanations for the areas of the scalp, including the occiput. A biopsy may be clinical findings have been extrapolated from biopsies of helpful in distinguishing CTE from FPHL, as the men with MPHL. In one study, biopsies of MPHL terminal-to-vellus hair ratio in CTE is generally 9:1, demonstrated a terminal-to-vellus hair ratio of ,1.7:1 indicating a lack of miniaturization. An algorithm using (,3:1 considered diagnostic) and an increased percent- the amount of total and #3-cm hairs (considered telogen age of telogen hairs (.10%) (91). Vellus hairs are defined vellus hairs) shed per day, alone or in combination, has as ,0.03 mm in diameter and have no attached arrector been suggested as a noninvasive method to help distin- pili muscle (92). For comparison, in a sample of control guish the two conditions (96). male and female patients without hair loss, a terminal-to- vellus hair ratio of 7:1 and 7% telogen hairs were ob- CCCA served (91). There are ethnic variabilities in the density of CCCA is a scarring type of hair loss, with lymphocytic hair follicles. The total number of hairs reported in 4-mm infiltration predominant on biopsy, primarily seen in punch biopsies in normal white (91, 93), African Amer- African American women who present with central, ican (93), and Asian subjects (94) was 36 to 40, 22, and frontal, or vertex predominant loss (97–99). With time, 16, respectively. the hair loss leads to frank baldness and lack of follicular In FPHL, there is a greater variability in the number of ostia in the involved areas. Many of these women have miniaturized hairs in each follicular unit in an area of hair signs and symptoms of hyperandrogenism (98), but no loss, supporting the concept that each hair follicle may large-scale evaluation of their androgen status has been have a different susceptibility to the responsible factors. done. Olsen (99) has hypothesized that these women may One of the most notable changes in pattern hair loss is the have underlying FPHL that becomes inflammatory with histopathologic presence of concomitant inflammation, the use of some hair care practices, such as hot combs, highlighted by the presence of lymphocytic infiltrates. relaxers, or occlusive ointments, leading to a cicatricial Mild inflammation is observed in about one-third of type of hair loss. controls and in men with MPHL, but moderate in- flammation is far more common in patients with MPHL FFA and FAPD than in controls (36% to 9%) (94). FFA was only first described in 1994 (100) but has Stelae (or streamers) are the collapsed connective become one of the most frequent causes of cicatricial tissue sheath that is left behind as a telogen hair moves alopecia. Most subjects with FFA are women, primarily upward in the scalp to the level of the bulge area. In white and primarily postmenopausal, although men, MPHL, and possibly FPHL, the stelae are hypertrophic, premenopausal women, and affected patients from all excessively vascularized, and have a mixed inflammatory races have been reported with FFA. Key clinical features doi: 10.1210/jc.2018-02548 https://academic.oup.com/jcem 2883 are a receding hairline with perifollicular erythema and Alternatively, it may also be useful to perform con- eyebrow loss. A scalp biopsy shows a lymphocytic in- comitant measurement of SHBG along with the total T filtrate typical of the patchy scarring alopecia called li- measurement, permitting the calculation of free T (106). chen planopilaris. Many women have central scalp hair This estimate of free T has good concordance and cor-

loss as well, and a biopsy is critical to do in this area in relation with free T measured by equilibrium dialysis, Downloaded from https://academic.oup.com/jcem/article-abstract/104/7/2875/5342938 by Endocrine Society Member Access 2 user on 24 June 2019 addition to that in the frontal scalp. provided that an accurate method is used for the total T FAPD presents with central hair loss in a Ludwig measurement (106). pattern, albeit typically with perifollicular erythema. Testing for androgens or androgen metabolites, other FAPD also demonstrates on biopsy lichen planopilaris than total and free T, such as androstenedione, DHEA, (101). Both FFA and FAPD, similar to FPHL, show some and DHEAS, does not appear to add much to the de- improvement with 5a-reductase inhibitors. tection of hyperandrogenism in women with PCOS and FPHL (72, 74). The potential value of 11-oxo androgens, as described above (44), in the evaluation of androgen Laboratory evaluation in women with FPHL excess in women with FPHL remains to be determined. Circulating androgen measures The most common androgens measured in the cir- Other hormone analyses culation include total and free T, androstenedione, and The frequency of thyroid disorders in patients with the DHEA metabolite DHEAS. When considering total T FPHL does not appear to be significantly higher than in measures, it is generally best to avoid those immunoas- the general population. It was 0% in the prospective says that do not use extracted and otherwise purified series of 109 women with alopecia reported by Futterweit blood samples, because of their recognized unreliability et al. (9). In a survey study of 64 patients (ages 20 to 88) (102). Consequently, many commercial diagnostic lab- with FPHL who were being seen at a hair clinic, 31.25% oratories in the United States have begun to measure total indicated they were hypothyroid; however, there was no T (and other related steroids) using mass spectrometry, significant association between FPHL severity and thy- following either gas or, more commonly, liquid chro- roid disease (68). In a retrospective study of 210 patients matography (LC/MS) (103). These assays have a high (ages 68 to 86 years) with FPHL, 12% (n = 26) had a degree of sensitivity and specificity, and they generally preexisting history of thyroid disease (and presumably provide accurate results. LC/MS is used as the reference were being treated), and thyroid screening identified only method at centers such as the US National Institute of one more affected individual (109). However, subclinical Standards and Technology and is the “gold standard” for hypothyroidism is common in older women, and prev- measurement of serum T (103). A few commercial ra- alence up to 18% in women in their 80s has been re- dioimmunoassays (104) and chemiluminescent immu- ported (110). Hypothyroidism, similar to nutritional noassay (105) that do not include prior extraction and deficiencies, should be sought in FPHL, although not purification of the sample may be as accurate as LC/MS necessarily as a causative factor, but as a condition that assays in patients with PCOS, and even at very low T itself can cause a telogen effluvium and make hair concentrations such as those from prepubertal and regrowth difficult in FPHL. postpubertal children (104). However, more studies are The utility of measuring serum prolactin in patients needed to confirm these observations. with FPHL is unclear. In the prospective series of 109 Circulating free T concentrations are more sensitive women with FPHL examined by Futterweit et al. (9), 7.2% than the measurement of total T for establishing the of patients had elevated prolactin and two (1.8%) had a presence of androgen excess (102). Accurate techniques prolactinoma. The possible link between high prolactin for the estimation of free T include equilibrium dialysis and pattern hair loss is unclear and further studies are and ultracentrifugation assays, which determine the needed. Increased prolactin levels may be secondary to percentage of free T, and ammonium sulfate precipitation hypothyroidism or to hyperestrogenism (102). techniques, which determine bioavailable T by pre- cipitation of the SHBG-bound T fraction (106). In any of Mineral and vitamin deficiency assessment these free T assays, a high-quality total T measurement is Recently, there has been much interest on the possible needed (102, 106). However, these assays are cumber- role of nutrient deficiency in FPHL (111, 112). Many some, and most commercial laboratories use direct radio- studies have been dedicated to the possibility that iron immunoassay or chemiluminescent immunoassay assays deficiency contributes to hair loss in FPHL (113). In a that rely on the competitive binding of a nontestosterone retrospective study of 100 multiethnic patients with FPHL analog for measuring free T, which are notoriously in Vancouver (BC, Canada), deficiency in ferritin was inaccurate (107, 108). observed in 29% at the first consultation (113). In a 2884 Carmina et al FPHL and Androgen Excess J Clin Endocrinol Metab, July 2019, 104(7):2875–2891 prospective, case-controlled study of 38 women (18 to 45 equilibrium dialysis, ultracentrifugation, or am- years of age), mean ferritin levels were lower in patients monium sulfate precipitation, or estimated using with FPHL than in controls; serum ferritin levels were SHBG (level of evidence C). lowest in those patients with the severest degrees of hair 6. Measurements of blood iron studies, vitamin D,

loss (114). However, in another case-controlled study that zinc, thyroid profile, and prolactin may be useful to Downloaded from https://academic.oup.com/jcem/article-abstract/104/7/2875/5342938 by Endocrine Society Member Access 2 user on 24 June 2019 included 170 women with FPHL, 58 with CTE, and 47 rule out and treat other conditions that may affect control subjects, there was no statistically significant in- hair regrowth in FPHL (level of evidence C). crease in the incidence of iron deficiency in premenopausal or postmenopausal women with FPHL or CTE vs con- Treatment of FPHL in hyperandrogenic women , m trols, regardless of whether a definition of ferritin 15 g/ A recent Cochrane review noted that most studies of , m Lor 40 g/L was used as the definition of iron deficiency therapy in women with FPHL were of low quality, (115). Other investigators have reported that serum fer- mainly due to bias in design (e.g., no blinding) or a small ritin is lower in premenopausal, but not in postmeno- sample size and were only able to detect enough evidence pausal, patients, compared with controls (116). In the to support the use of topical minoxidil in women with same study supplementation with iron in patients with FPHL, although even then the effect size was small (119). low-normal serum ferritin (,70 mg/L) did not improve the hair loss (116). Overall, there remains an uncertain re- Topical minoxidil lationship of iron deficiency and FPHL, given the frequent Topical minoxidil is considered the first-line treatment occurrence in the general premenopausal population of of FPHL. Minoxidil is a potassium channel opener hy- iron deficiency and a lack of well controlled studies on pothesized to enhance angiogenesis and vasodilation, whether correction of iron deficiency affects FPHL. and to have anti-inflammatory and antiandrogenic ef- Mean vitamin D levels were reported to be reduced in fects (14, 120). In animal studies, minoxidil shortens the many patients with hair loss (109, 116, 117). In the telogen phase, resulting in premature entry of resting hair Vancouver study, 62% of patients with FPHL presented follicles into the anagen phase (120). The anagen phase is low serum levels of 25-hydroxyvitamin D (109). In a also prolonged and miniaturized follicles are enlarged prospective study, mean zinc levels, but not mean copper with minoxidil, resulting in increased hair counts, weight, levels, were lower in 77 women with FPHL vs 32 controls and density (120). (118). In the Vancouver study, 15% of patients with FPHL Topical minoxidil is available in 2% and 5% solution presented with low zinc levels (109). Well-controlled (TMS) or in 5% foam (TMF). In both MPHL and FPHL studies are needed to establish the relatedness of these there is evidence of greater efficacy of the 5% vs 2% TMS deficiencies to FPHL and whether correction of the de- (121, 122). The 5% TMF applied once a day has been ficiency specifically improves hair growth. shown to be equivalent to 2% TMS applied twice a day in FPHL (123), and both 5% preparations are used most Conclusions frequently in clinical practice (14). During the initial treatment period of 2 to 8 weeks, there can be a transient 1. The diagnosis of FPHL is mainly clinical and increase in scalp hair shedding, which results from the requires a careful medical history and physical shedding of telogen hairs in preparation for new anagen examination, including evaluation of the scalp, and growth (14, 120). Scalp pruritus and flaking may occur assessment for the presence of other immune or with therapy, more common with TMS, which contains endocrine disorders (level of evidence B). propylene glycol, vs TMF (121, 123). Facial hyper- 2. The differentiation of FPHL from other causes of trichosis may also occur and is more common with 5% hair loss in women may require a dermatoscopic than 2% formulations (14, 121). Topical minoxidil examination and/or a scalp biopsy (level of evi- should be used for at least 12 months for optimal re- dence C). sults (14). 3. Clinicians taking care of patients with FPHL should be able to recognize the different clinical Antiandrogen therapy alterations that may be present in female hair loss. When the patient has severe hair loss or hyper- 4. In women with FPHL circulating androgens should androgenism, a combination of skin-directed and sys- be evaluated (level of evidence C). temic therapy with an antiandrogen or 5a-reductase 5. Androgen measures should include measuring total inhibitor may enhance results (3). Although one meta- T using a high-quality assay, preferably by LC/MS analysis suggested no significant improvement with or by an immunoassay including sample extrac- either a 5a-reductase inhibitor or antiandrogen (119), tion and purification, and free T, either using multiple small studies, case reports, and general prescribing doi: 10.1210/jc.2018-02548 https://academic.oup.com/jcem 2885 practices suggest otherwise. More data with out- 5 mg daily. However, the task force recognizes that most comes stratified by age, hair loss severity, and hyper- finasteride studies have been conducted in postmenopausal androgenism are needed to better understand the efficacy women because of the higher prevalence of FPHL in this of these agents. age range and to avoid the potential for women of a

When adding an antiandrogen or 5 -reductase in- childbearing age becoming pregnant while on the drug. Downloaded from https://academic.oup.com/jcem/article-abstract/104/7/2875/5342938 by Endocrine Society Member Access 2 user on 24 June 2019 hibitor, it must be remembered that these products have Consequently, although current data support the use of teratogenic potential for feminization of a male fetus and finasteride for FPHL primarily in postmenopausal patients should be counseled accordingly, and strict women, various clinical reports suggest that it may also contraception should be used during and for at least be effective in selected premenopausal women with 30 days after discontinuation of these drugs. FPHL. Large unbiased prospective controlled studies are needed to determine the efficacy and best approach Finasteride for the use of finasteride in FPHL. Finasteride is often used in women with FPHL, es- pecially when hyperandrogenism is present. However, Dutasteride clear-cut evidence of its effectiveness is less clear, and a Dutasteride, an inhibitor of both type I and type II 5a- meta-analysis evaluation failed to demonstrate a signif- reductase, has been found to be more effective than icant effect of finasteride in FPHL (119). However, as finasteride in men with MPHL (135, 136). In patients previously observed, interpretation of data by meta- with FPHL, data on dutasteride are almost absent. In the analysis is difficult because of inclusion of patients retrospective study of 30 women ,50 years of age and 30 with FPHL with different age and inflammatory and women .50 years of age, 3 years of therapy with 0.15 mg androgen status. of dutasteride was similarly effective to 1.25 mg of Differences in age and in finasteride doses may be finasteride in improving hair density and thickness but important. Differently from what has been reported in more effective in the central and vertex sites in women ,50 men (124, 125), in postmenopausal women with FPHL years old (131). Dutasteride has a much longer half-life 1 mg daily of finasteride did not appear to be any more than finasteride, and women of child-bearing potential effective than placebo (85, 124, 126). Higher doses of should avoid its use without effective contraception for finasteride (2.5 or 5 mg) have been associated with im- at least 6 months after discontinuation owing to its provement of FPHL, but it has been shown mainly in potential teratogenic effect. postmenopausal nonhyperandrogenic patients. In fact, a retrospective study of premenopausal and postmenopausal Spironolactone patients with FPHL prescribed finasteride 2.5 mg/d Spironolactone, a potassium-sparing diuretic that is found that of 112 patients studied 30% demonstrated commonly used in hirsutism treatment because of its slight and 65% significant improvement using global antiandrogen activity, represents a possible alternative to photographs, whereas 5% had no change. In this study, finasteride in patients with FPHL (68, 137, 138). Doses finasteride had a better effect on hair growth when of 100 to 200 mg/d and prolonged treatments (at least patients had a lower Ludwig score and an older age at 12 months) are needed. Hair regrowth or stabilization of onset (126). Similar results have been reported in other hair loss is observed in a variable number of patients studies (127–130) that found improvement of FPHL in ranging from 44% (136) to 74% (68). Patients with postmenopausal normoandrogenic women with both FPHL and hirsutism or acne have a significantly better 2.5- and 5-mg doses of finasteride. response to spironolactone (68) than do women with Few data are available in young women with FPHL. only FPHL. In a retrospective study including 30 women ,50 years of age and 30 women .50 years of age, 1.25 mg/d Flutamide finasteride administered for 3 years was found to be Flutamide is a pure antiandrogen that has been suc- effective in both age groups (131). No data on andro- cessfully used in FPHL, but that bears the risk of im- genic status of these patients are available. Instead, in a portant, albeit rare, hepatotoxicity. Because of this, few group of hyperandrogenic young women with FPHL, studies have evaluated the efficacy of flutamide in women finasteride treatment did not result in significant changes with FPHL. In a randomized open-label trial in 36 in the Ludwig score (132). Alternatively, several case hyperandrogenic young women with FPHL, 250 mg/d studies have shown that low doses (1 or 1.25 mg) may be flutamide resulted in a significant reduction (221%) in also effective in treatment of FPHL (133, 134). Ludwig scores (132). In a prospective nonblinded cohort These data suggest that finasteride may be useful for study, 101 women diagnosed with FPHL received yearly the treatment of FPHL in some patients in doses of 2.5 or reducing doses of flutamide (250, 125, and 62.5 mg/d) 2886 Carmina et al FPHL and Androgen Excess J Clin Endocrinol Metab, July 2019, 104(7):2875–2891 for 4 years (139). The cohort included 33 patients treated Topical ketoconazole with flutamide alone and 68 treated with flutamide and In men with MPHL, ketoconazole shampoo has been an oral contraceptive. Both groups demonstrated marked shown to increase hair density, hair size, and percentage decrease in alopecia scores after 12 months of flutamide of hairs in the anagen phase (149), and topical ketoco-

therapy, compared with baseline values; the maximum nazole has been found to increase hair growth (150). Downloaded from https://academic.oup.com/jcem/article-abstract/104/7/2875/5342938 by Endocrine Society Member Access 2 user on 24 June 2019 drug effect occurred after 2 years and was maintained However, data in women with FPHL are lacking. during the subsequent 2 years of therapy (139). In conclusion, although flutamide may be more effective Conclusions than spironolactone or finasterideintreatmentofhyper- androgenic FPHL, its use is not recommended because 1. Topical minoxidil is an effective treatment of FPHL of the risk of hepatotoxicity. and should be used as the first-line treatment (level of evidence B). Cyproterone acetate 2. Therapeutic results of minoxidil may be enhanced Cyproterone acetate is an antiandrogen product that is with the addition of 5a-reductase inhibitors or not available in United States. This product has been used antiandrogen therapy. The 5a-reductase inhibitor at high doses (50 to 100 mg/d) for hyperandrogenic finasteride, in doses of 2.5 or 5 mg/d, and the AR- women with FPHL with mixed results (132, 140). blocker spironolactone, in doses of 100 to 200 mg/ d, may be used with the lowest risk (level of evi- Alternative treatments for FPHL dence C). Dutasteride may be useful, but clinical evidence is limited (level of evidence D). Flutamide Low-level laser light therapy is potentially effective, although its use is associated Red or near-infrared laser light has been reported to with significant, albeit rare, hepatotoxicity (level of promote tissue repair and regeneration and, more re- evidence C), and consequently use in patients with cently, low-intensity light laser (LLL) therapy has been FPHL is not encouraged. Cyproterone acetate demonstrated to stimulate hair growth, probably by appears to have unclear effectiveness (level of ev- increasing the mitotic rate of the hair follicle stem cells or idence C). follicular keratinocytes (141). Additionally, LLL may 3. Note that most of the data generated with the use of modulate inflammation by increasing TGF-b1 and IL-10 5a-reductase inhibitors and antiandrogen for while reducing proinflammatory cytokines and prosta- FPHL therapy are in postmenopausal women. In glandin E (141). Usually wavelengths between 600 and 2 women of reproductive age, 5a-reductase inhibitor 1550 nm (in red/infrared spectrum), emitted by helium- and antiandrogen treatment should be used con- neon and fractional erbium glass lasers, are used. Several comitant with secure contraception to minimize the studies have shown that LLL may improve FPHL teratogenic risk of these medications (level of evi- (141–144) but the effect is generally modest and, in a dence B). male study, although hair count increased, no differences 4. LLL therapy may be of modest benefit for FPHL with global photographs were observed (145). Adverse (evidence level C). Scalp injections of PRP are a effects are few but may include headache, erythema, promising emerging therapy, although evidence is pruritus, burning, pain, and mild paresthesia (141). limited (level of evidence C). Hair transplantation is a possible therapy to assist in hair recuperation Platelet-rich plasma (level of evidence B), although it should be used in Platelet-rich plasma (PRP) is produced by centrifuging conjunction with continued medical therapy (level apatient’s own blood, concentrating the platelets, and of evidence D). injecting the concentrate into the patient’s scalp in affected areas. In addition to platelets, PRP contains numerous growth factors, chemokines, and cytokines (146). Results Summary Recommendations are promising; however, evidence is very limited and studies that have been performed have used different 1. The term “female pattern hair loss” should be used, protocols without sufficient follow-up (147). avoiding the previous terms of alopecia or an- drogenetic alopecia. Hair transplantation 2. The two typical patterns of hair loss in FPHL are In women with FPHL, hair transplantation may also centrifugal expansion in mid scalp or a frontal be useful (148) although the hair loss process, as in men, accentuation or Christmas tree pattern. will continue outside of the transplant areas, so contin- 3. Isolated FPHL should not be considered a sign ued use of medical treatment after surgery is necessary. of hyperandrogenism when androgen levels are doi: 10.1210/jc.2018-02548 https://academic.oup.com/jcem 2887

normal and no other clinical signs of hyper- 8. Miller JA, Darley CR, Karkavitsas K, Kirby JD, Munro DD. Low androgenism are present. sex-hormone binding globulin levels in young women with diffuse hair loss. Br J Dermatol. 1982;106(3):331–336. 4. The assessment of patients with FPHL is primarily 9. Futterweit W, Dunaif A, Yeh HC, Kingsley P. The prevalence of clinical and requires differentiation from other hyperandrogenism in 109 consecutive female patients with diffuse alopecia. J Am Acad Dermatol. 1988;19(5 Pt 1):831–836.

forms of hair loss in women. Downloaded from https://academic.oup.com/jcem/article-abstract/104/7/2875/5342938 by Endocrine Society Member Access 2 user on 24 June 2019 10. Olsen EA. Female pattern hair loss. J Am Acad Dermatol. 2001; 5. In all patients with FPHL, assessment of a possible 45(3, Suppl):S70–S80. androgen excess is mandatory. Measurement of 11. Orme S, Cullen DR, Messenger AG. Diffuse female hair loss: are vitamin D, iron, zinc, thyroid hormones, and androgens necessary? Br J Dermatol. 1999;141(3):521–523. prolactin are optional but recommended. 12. Cousen P, Messenger A. Female pattern hair loss in complete androgen insensitivity syndrome. Br J Dermatol. 2010;162(5): 6. Treatment of FPHL should begin with minoxidil 1135–1137. (5%), adding 5a-reductase inhibitors or anti- 13. Birch MP, Lalla SC, Messenger AG. Female pattern hair loss. Clin androgens when there is severe hair loss or asso- Exp Dermatol. 2002;27(5):383–388. 14. 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