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Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2016) 1e21

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Androgen excess: Investigations andmanagement

Daria Lizneva, MD, PhD a, b, c, Larisa Gavrilova-Jordan, MD a,Walidah Walker, MS a, Ricardo Azziz, MD, MPH a, d, *

a Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta State University, 1120 15thStreet, 30912 Augusta, GA, USAb Medical Company IDK, ul. Entuziastov 29, 443067 Samara, Russian Federationc Department of Reproductive Health Protection, Scientific Center of Family Health and HumanReproduction, ul. Timiryazeva 16, 664003 Irkutsk, Russian Federationd Department of Medicine, Medical College of Georgia, Augusta State University, 1120 15th Street, 30912Augusta, GA, USA

Keywords:hyperandrogenismhirsutismacnefemale pattern hair lossPCOS

* Corresponding author. Department of ObstetriGA 30912, USA. Tel.: þ1 706 721 2304.

E-mail address: [email protected] (R. Azziz).

http://dx.doi.org/10.1016/j.bpobgyn.2016.05.0031521-6934/© 2016 Published by Elsevier Ltd.

Please cite this article in press as: LiznevBest Practice & Research Clinical Obsj.bpobgyn.2016.05.003

Androgen excess (AE) is a key feature of polycystic ovary syn-drome (PCOS) and results in, or contributes to, the clinicalphenotype of these patients. Although AE will contribute to theovulatory and menstrual dysfunction of these patients, the mostrecognizable sign of AE includes hirsutism, acne, and androgenicalopecia or female pattern hair loss (FPHL). Evaluation includesnot only scoring facial and body terminal hair growth usingthe modified FerrimaneGallwey method but also recordingand possibly scoring acne and alopecia. Moreover, assessmentof biochemical hyperandrogenism is necessary, particularly inpatients with unclear or absent hirsutism, and will includeassessing total and free testosterone (T), and possibly dehydro-epiandrosterone sulfate (DHEAS) and androstenedione, althoughthese latter contribute limitedly to the diagnosis. Assessment ofT requires use of the highest quality assays available, generallyradioimmunoassays with extraction and chromatography ormass spectrometry preceded by liquid or gas chromatography.Management of clinical hyperandrogenism involves primarilyeither androgen suppression, with a hormonal combinationcontraceptive, or androgen blockade, as with an androgen re-ceptor blocker or a 5a-reductase inhibitor, or a combinationof the two. Medical treatment should be combined withcosmetic treatment including topical eflornithine hydrochloride

cs and Gynecology, Augusta University, 1120 15th Street, CB-2209, Augusta,

a D, et al., Androgen excess: Investigations and management,tetrics and Gynaecology (2016), http://dx.doi.org/10.1016/

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and short-term (shaving, chemical depilation, plucking, thread-ing, waxing, and bleaching) and long-term (electrolysis, lasertherapy, and intense pulse light therapy) cosmetic treatments.Generally, acne responds to therapy relatively rapidly, whereashirsutism is slower to respond, with improvements observed asearly as 3 months, but routinely only after 6 or 8 months oftherapy. Finally, FPHL is the slowest to respond to therapy, if itwill at all, and it may take 12 to 18 months of therapy for anobservable response.

© 2016 Published by Elsevier Ltd.

Androgen biosynthesis and metabolism in women

Androgens are produced de novo from cholesterol in the ovarian theca and the adrenal cortex(zonae reticularis). Additionally, circulating androgen precursors can be metabolized into more potentandrogens in peripheral tissues such as the liver, adipose tissue, and the pilosebaceous unit (PSU)(Fig. 1).

Baseline androgen synthesis is regulated via the alteration of gene transcription by luteinizinghormone (LH) and adrenocorticotropic hormone (ACTH) of the anterior pituitary gland. The in-crease in androgen production in women observed after the mid-cycle LH surge is regulated bycholesterol access to the mitochondria via activation of steroidogenic acute regulatory protein(StAR) [1].

Androgen production in ovaries and adrenals employ a relatively small number of enzymes;however, tissue-specific expression of steroidogenic enzymes results in a variety of steroid pre-cursors and final active products [2]. The adrenal zonae reticularis and gonadal tissue preferen-tially convert pregnenolone to precursor sex steroids via a single enzyme, P450c17, whichexhibits dual 17a-hydroxylase and 17, 20-lyase activity. Furthermore, the zonae reticularis hasabundant cytochrome b5, which fosters the production of androgens by P450c17 [3]. Therefore,most biosynthetic pathways of sex steroids proceed through dehydroepiandrosterone (DHEA).The adrenal zonae reticularis expresses more sulfotransferase than steroid sulfatase, with conse-quently augmented dehydroepiandrosterone sulfate (DHEAS) production [4]. DHEAS is not anandrogen per se, but a pro-androgen or androgen metabolite, depending on how it is itselfmetabolized. It can serve as a significant reservoir for DHEA, and eventually, the biosynthesis ofmany other androgens.

The ovarian theca cells are stimulated to produce androgens via LH-mediated activation of anumber of regulatory enzymes, including StAR, P450scc, 3a-HSD-II, and P450c17. DHEA is the precursorfor the majority of ovarian androgens. LH stimulates theca cells, which in turn induces androgenproduction; however, a robust feedback mechanism for androgen regulation is absent [5]. Tissue-specific expression is generally in the form of one of three types of 17a-hydroxysteroid de-hydrogenases (17a-HSDs) that interconvert 17-ketosteroids with their corresponding 17-hydroxysteroids [6]. Moreover, testosterone (T) can be converted to a five times more potentandrogen e dihydrotestosterone (DHT) e by one of two isoforms of 5a-reductase (5a-RA), which areexpressed in multiple organs [2,7]. Thus, PSUs express both 5a-reductase-I and 5a-reductase-II, andplay a significant role in the metabolism of androgens [8e10].

Androgens can act systemically in classic endocrine fashion, or locally in a paracrine and autocrinemanner (e.g., DHT action in PSU). Androgens exert their genomic effects through interaction with thenuclear androgen receptor, thereby regulating the transcription of target genes. Moreover, androgensact via non-genomic mechanisms through cell membrane-located steroid receptors as well asnonreceptor-mediated actions [10,11].

In women, the major circulating androgens or pro-androgens (in descending order of serum con-centration) are DHEAS, DHEA, androstenedione (A4), T, and DHT. However, only T and DHT have strong

a D, et al., Androgen excess: Investigations and management,tetrics and Gynaecology (2016), http://dx.doi.org/10.1016/

Fig. 1. Principal pathways of androgen synthesis and catabolism (modified from Azziz et al, 1989 [21]). Enzymatic activities: (1)3b-hydroxysteroid dehydrogenase (3b-HSD)c; (2) 17a-hydroxylased; (3) 17,20-lyased; (4) 17b-hydroxysteroid dehydrogenasee;(5) aromatasef; (6) 5a-reductaseg; (7) 5b-reductaseh; (8) 3b-oxoreductasei; and (9) 3a-oxoreductasej. a In the gonads, the 17b-hydroxysteroid dehydrogenase reaction predominantly produces 17b-dehydrogenated products (androstenediol and testos-terone), whereas the reverse is true in peripheral tissues. bAldosterone, etiocholanolone, and DHEA are the principal urinarymetabolites of androgens. cIn humans there are two isozymes of 3b-hydroxysteroid dehydrogenase/D5-4 isomerase (3b-HSD) (EC1.1.1.145), 3b-HSD type I, expressed in placenta and peripheral tissues, and 3b-HSD type II, expressed in the adrenal gland, ovary,and testis, encoded by HSD3B1 and HSD3B2, resp. In androgen biosynthesis, HSD3B2 dominates. dBoth 17a-hydroxylase and 7,20-lyase activities are determined by cytochrome P450c17A1 (EC 1.14.14.19), an enzyme that in humans is encoded by CYP17A1. Notethat, in humans, D417,20-lyase activity (catalyzing the direct interconversion of androstenedione and testosterone) is almostnonexistent under normal conditions; D517,20-lyase (catalyzing the interconversion of DHEA and androstenediol) is the domi-nant activity and, thus, determines the preferred pathway to testosterone synthesis from cholesterol. e 17b-dehydrogenase (EC1.1.1.239) is an enzyme that in humans has a number of isozymes, although in androstenedioneetestosterone and estro-neeestradiol interconversion, the types 1 and 2, encoded by HSD17B1 and HSD17B2, are the most predominant. f Aromataseactivity is determined by cytochrome P450c19 or P450arom (EC 1.14.14.1), encoded by the CYP19A1. g 5a-reductase activity (EC1.3.99.5) is determined by three isozymes, whose content varies in different tissues with age: steroid 5a-reductase type 1, 2, and3, encoded by SRD5A1, SRD5A2 and SRD5A3, respectively. Androgen 5a-reductase activity is primarily determined by 5a-reductase types 1 and 2. h5b-reductase activity is determined byD4-3-oxosteroid 5b-reductase (EC 1.3.1.3), encoded by AKR1D1(previously SRD5B1). i3a-oxoreductase activity is determined 3a-hydroxysteroid dehydrogenase (3a-HSD) (EC 1.1.1.50) is encodedby AKR1C4. j3b-oxoreductase activity is determined by 3b-hydroxy-5a-steroid:NADPþ 3-oxidoreductase (EC 1.1.1.278) encoded byAKR1D1.

D. Lizneva et al. / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2016) 1e21 3

affinity and potency for the androgen receptor (AR), as DHEAS, DHEA, and A4 have little to no capacityto bind to the AR and require conversion to T to exert androgenic effects. A4 is the most importantprecursor of T, whereas DHEAS and DHEA account for only 5% and 13% of circulating Tamongwomen ofreproductive age, respectively [12].

The bioactive portion of circulating T is free T and a portion of albumin-bound T, which differsamong tissues [13]. In healthy women, 80% of T is bound with a high affinity to sex hormone-binding

Please cite this article in press as: Lizneva D, et al., Androgen excess: Investigations and management,Best Practice & Research Clinical Obstetrics and Gynaecology (2016), http://dx.doi.org/10.1016/j.bpobgyn.2016.05.003


globulin (SHBG), 19% is bound to albumin, and only 1% circulates as a free fraction [12,14]. In contrast,DHEAS, DHEA, and A4 are bound to albumin with low affinity and, thus, available for peripheralconversion [15,16].

The clearance of androgens is accomplished by hepatic extraction and peripheral metabolism,which are highly dependent upon the unbound portion of circulating steroid [12]. Most of circulating Tis metabolized via hepatic conjugationwith glucuronic or sulfuric acids or voided as 17-ketosteroids inurine [17]. Only a small fraction of T and half of A4 are metabolized peripherally. Approximately 15% ofandrogen sulfates are excreted in bile, of which 80% are reabsorbed into the gut. The metabolism andclearance of circulating androgens may be altered by age, presence of obesity, medical conditions, andmedications.

Androgen excess in PCOS

The terms androgen excess (AE) and hyperandrogenismwill be used interchangeably in this article.The differential diagnosis of the hyperandrogenic patient includes idiopathic hirsutism, the hyper-androgenic insulin-resistant acanthosis nigricans (HAIRAN) syndrome, 21-hydroxylase-deficient non-classic congenital adrenal hyperplasia, classic congenital adrenal hyperplasia, and androgen-secretingneoplasms [18]. Rare causes include side effects from medication, hypothyroidism, hyper-prolactinemia, and Cushing's disease [19]. However, in women, the most common cause of AE (i.e.,hyperandrogenism) is the polycystic ovary syndrome (PCOS) and, in this disorder, gonadotropin-dependent functional ovarian AE is the major source of the hyperandrogenemia [20,21]. Ovariantheca cells increase androgen production in response to chronically elevated LH and insulin levels[22,23]. Hyperinsulinemia promotes androgen biosynthesis via the insulin receptor and, to a lesserextent, the insulin-like growth factore1 (IGF-1) receptor on theca cells, and increases levels of circu-lating free T by suppressing hepatic production of SHBG [24,25]. ACTH-dependent overproduction offunctional adrenal androgens further contributes to hyperandrogenemia [26,27].

Clinically evident hyperandrogenism results in various symptoms resulting from the impact of AEon the PSU activity in gender-specific skin areas: hirsutism, acne, and androgenic alopecia [10]. Theresponse of the PSU to androgens in regard to sebum production and the transformation of vellus toterminal hair (ie, hair terminalization) vary considerably across skin areas and between individuals[28,29]. The PSU sensitivity to androgens is, in part, determined by the local action of androgensthemselves: 5a-RA activity, which converts T to DHT; and the subsequent binding of DHT locally to PSUARs with high affinity [7,29,30]. Consequently, not all patients with hirsutism have demonstrablehyperandrogenemia, and not all patients with elevated circulating androgen levels will be hirsute[2,18,31].

Hirsutism, or the presence of male pattern terminal hair growth inwomen, is themost common andrecognizable sign of female AE. Half of the women with mild hirsutism and the majority of those withmoderate to severe hirsutism have elevated plasma total and free T levels [18,32,33]. One-third of PCOSwomen have elevated levels of adrenal androgen precursors [34]. Hirsute women commonly have lowlevels of SHBG that leads to increased concentrations of free T [14].

Androgens play significant role in the development of acne vulgaris, as AE is associated withincrease in sebum production and ameliorated shedding of hyperkeratinized epithelium, whichcauses occlusion of the hair follicle and proliferation of Propionibacterium acnes [28,30]. Bacteriametabolize sebum triglycerides to glycerol and free fatty acids that cause further inflammation ofthe PSU. Sebum production markedly increases during adrenarche, a time of maximal DHEASserum levels, and acne in PCOS women in part resembles an exaggerated form of adrenarche[10,27,28,34]. A majority of nonhirsute acneic patient, regardless of age, have variable degrees ofhyperandrogenemia [35].

Androgenic alopecia, also known as female pattern hair loss (FPHL), is characterized by thinning ofthe sagittal scalp hair growth with modest recession of the frontal and frontoparietal hair lines. It is ahighly prevalent disorder with an incidence that increases with age [36]. As a clinical sign of hyper-androgenemia, androgenic alopecia was reported in 67% of women with PCOS [37]. Elevated metab-olites of T and corticosterone, along with enhanced local 5a-RA activity, were also reported in womenwith androgenic alopecia [17].



Diagnosis of AE in women

Hyperandrogenism or AE in women can be evident clinically (by the presence of hirsutism and/orandrogenic alopecia) or biochemically, through the measurement of androgens, total, free, or in pre-cursor/metabolite forms, in the circulation or other body fluids (eg, urine, saliva, etc.).

Hirsutism

Objective and subjective methods are available for the diagnosis of hirsutism. Objective methodsof evaluation (i.e., photographic evaluations, weighing of extracted hairs) are generally time-consuming and are mainly used for research purposes [38]. More applicable to the clinical settingare the visual, albeit more subjective, scoring system widely used for the evaluation of hair growth.Several scales have been proposed; however, the modified FerrimaneGallwey scoring system (mFG)is currently considered the “gold” standard for the clinical evaluation of hirsutism [38] (Fig. 2). Inorder to improve the quality of assessment, patients should be advised to avoid use of electrolysis orlasers for at least 3 months, depilation or waxing for 4 weeks, and cautioned not to shave at least 5days prior to evaluation [38].

Establishing the cut-off score for determining an abnormal score (ie, one indicating hirsutism) hasgenerally relied on establishing the 95th percentile of a “normal,” or “control population,” with cut-offscores ranging from 3 to 8, and even as high as 10 [39e41]. However, these cut-off values do not takeinto account the type of control populations used (i.e., super-controls, who have been assessed care-fully; individuals from potentially medically biased population; or unscreened women from the gen-eral population) nor consider that the 95th percentile as a definition of “normal” has little clinical

Fig. 2. Modified FerrimaneGallwey (mFG) scoring system for facial and body terminal hair (copyright 2005 by Ricardo Azziz,reproduced with permission). Nine body areas are scored from 0 (no terminal hairs in the area observed and the score sheet is notmarked), to 1 (minimal terminal hairs are observed), 2 (more terminal hairs in the area are observed, but less than those of a normalmale), 3 (terminal hair growth in the area is similar to that seen in a lesser hirsute male), to 4 (terminal hair growth in the area issimilar to that seen in a hirsute male). Note: Terminal hairs can be recognized as those hairs that grow >5 mm in length if un-disturbed, are generally pigmented, and have a central core of compacted hairs (medulla), which may give them denser color,coarser feel, and shape.



validity. Imagine that we considered only 5% of those who are overweight as being obesee the averagebody mass index (BMI) to diagnose obesity would then be 40 kg/m2 [42].

A bettermethod of defining the degree of hirsutism, and that of any other continuous parameter in apopulation that one suspects detects an “abnormal” subset, is to use cluster analysis or similar ap-proaches to identify natural breaks in the data that would suggest the presence of these distinctivepopulations. Using this approach in a large population of unselected women seeking an employmentphysical assessment, consisting of Black (African-American, n¼ 350) and White (North-AmericanCaucasians, n¼ 283) women, we found that a cut-off of 3 or more clearly detected a population thatwas abnormal or different [39].

The population with a score of >3 comprised 22.1% of all subjects. Of these subjects, 69.3% com-plained of hirsutism, compared with 15.8% of womenwith anmFG score <3, and this was similar to theproportion of womenwith an mFG score of at least 8 who considered themselves to be hirsute (70.0%).Additionally, of women with an mFG score of at least 3, 60.7% used some form of treatment for un-wanted hair, not different from the proportion of women with an mFG score of at least 8 whoconsidered themselves to be hirsute or used some form of hair treatment (36.7%). Overall, there wereno significant differences between Black and White women [39]. Using a similar analysis, Zhao andcolleagues studying 2988 women aged 20e45 years from the general population of Southern Chinaobserved that an mFG score of �5 indicates hair growth above the norm [43]. In a separate study, weobserved that more than 50% of individuals with mFG scores of between 3 and 5 had a tangible AEdisorder [44].

Overall, the cut-off mFG score value indicating “abnormal” seems to be closer to 3e5, less than thehigher values reported previously. Thus, while an mFG score of 6e8 may be used as evidence ofpathologic “hirsutism,” this definition is much more severe than how patients perceive their hairgrowth. Finally, current data suggests relatively little difference in the cut-off mFG score betweenMongoloid Asians, Caucasians, and Blacks [39,43,45,46], although further studies are needed.

Acne vulgaris

There is no universally accepted classification currently in use for evaluation of acne severity.Several global assessment scales have been developed to incorporate the clinical manifestation ofacne vulgaris into a single category. They have focused on quantity and quality of acne elements:noninflammatory lesions (NIL) e closed and/or open comedons, and inflammatory lesions (IL) e

papules, pustules, and nodules. Recently, various professional associations proposed such scales,including The Global Alliance to Improve Outcomes in Acne [47] and the European DermatologyForum Guidelines group 2011 [48]. We have attempted to summarize these two grading systems inTable 1, although they have limited comparability. Regardless, current guidelines suggest thatdocumentation of acne during the evaluation of a potentially hyperandrogenic patient is recom-mended [19].

Female pattern hair loss

Female pattern hair loss (FPHL) is a thinning of hair, primarily in the sagittal area of the scalp, causedby miniaturization of the hair follicles (a process whereby the scalp terminal hairs become smaller and

Table 1Summary of 2 different acne assessment scales.

Reference Minimal Mild Moderate Severe

Gollnick 2003 [47] Comedonal Papulopustular, moderatemapulopustular

Nodular Nodular/conglobate

EuropeanDermatologyForum 2011 [48]

Comedonalacne

Moderate papulopustular acne Severe papulopustular acne,moderate nodular acne;severe nodular acne,conglobate acne


Fig. 3. Ludwig classification of female pattern of hair loss (androgenic alopecia) (reproduced with permission [50]).


eventually become short vellus hairs). There are two common pattern types of FPHL inwomen. Ludwigdescribed diffuse hair thinning in the centroparietal regionwith a preserved frontal line [49] (Fig. 3). Incontrast, the “Christmas tree” pattern is associated with diffuse centroparietal thinning of the hair inconjunctionwith branching of the frontal hair line [50]. FPHL is a process generally characterized by anincrease in the proportion of scalp hairs that are in telogen (i.e. lying unattached from the follicularbulb within the hair shaft ready to be extracted/shed), a finding that can be assessed by the “hair-pulltest” (Fig. 4). In the early stages of FPHL, hair-pull tests may be positive; however, in women withlongstanding, non-scarring hair shedding, a positive hair-pull test is more suggestive of telogen ef-fluvium [51].

FPHL is clinically diagnosed and represents a diagnosis of exclusion. Evaluation should include anassessment of pattern distribution, the hair-pull test (for which the patient should have beeninstructed to not brush or wash her hair for at least 48 hours prior to the exam), an mFG score,assessment for the presence of acne or acanthosis nigricans (see below), and for any defect in nailgrowth [52]. Exclusion of other causes of alopecia should be undertaken including tests to rule-out

Fig. 4. Hair pull test for the detection of hairs in telogen (photo courtesy of Dr. Daria Lizneva). The patient should not have washed orbrushed her hair for at least 24e48 hours before the test. Approximately 50 hairs are grasped and gently tugged outward by theexaminer. The easy extraction of more than six (i.e., >10% of hairs grasped) suggests the presence of excess numbers of hairs intelogen. Note: There are three phases of hair growth: Anagen, which represents the phase of active growth; catagen, which rep-resents the involution and rest phase of the hairs, as active growth ceases; and telogen, in which the hairs are now dead and liewithin the hair shaft separated from their follicle, readily extracted or shed. It is this latter population of hairs that the hair pull testassesses, and which normally comprises less than 10% of all hairs.



scalp fungal infections, autoimmune disorders, hematologic or nutritional defects, and systemichyperandrogenism.

The pattern of hair on the scalp is usually assessed using the Ludwig scale (grades IeIII) orChristmas tree (grades IeIII) classification [52]. It should be noted that there is no specific definitionfor FPHL based on the grade of these scales and all measures are highly subjective. Therefore, the useof photography of the affected area should be considered a better option, at least for follow-up, ifavailable [52].

Biochemical hyperandrogenism

Most of the measurements used clinically today are measurements obtained in blood, either fromserum or plasma. Althoughmeasures can be obtained in saliva, these tend to be highly variable and lessreliable [53] Previously, the measurement of androgen metabolites in urine, such as 17-ketosteroids[54], was widely used. However, as assays for measuring androgens in blood have improved, thesehave been relegated to history. Nonetheless, we should note that androgen measurements in bloodcapture amoment in time, subject to the knownpulsatility of these hormones, whereas urinemeasurescapture a broader picture of androgen biosynthesis.

Because androgens circulate in small amounts and are small steroidal molecules that differ inonly the most minute of ways from other steroids, such as estrogens, progesterones, glucocorti-coids, or even mineralocorticoids, and their myriad metabolites, it is extremely important thatthe assays used for their detection are of the highest quality possible. This is especially true forthe measurement of T [55] and, in general, means using a high-quality radioimmunoassay (RIA)following sample extraction and chromatography, or the use of mass spectrometer with sampleseparation by liquid or gas chromatography. Currently used enzyme-linked immunosorbent orchemiluminescent assays have demonstrated poor sensitivity and specificity in females [55]Levels of serum androgens in females vary depending on age, day of menstrual cycle, and timeof sampling, and no standardization is provided based on these parameters [55]. Anotherissue related to the use of these assay kits lie in their cross-reactivity with similar steroid sub-stances [56].

Overall, total T levels are found to be elevated in 22% to 85% of PCOS patients as defined by theNational Institutes of Health (NIH) 1990 criteria, although most demonstrate that only one-third ofsamples demonstrate an abnormal value [57]. Approximately 70% of samples from PCOSwomen by theNIH 1990 criteria have elevated serum concentration levels of free T [57], which is the single mostsensitive test for hyperandrogenemia. Therefore, elevation of either total T or free T levels is a keydiagnostic feature of biochemical hyperandrogenism. Further, other androgens may be useful to thediagnosis of biochemical hyperandrogenism. The measurement of DHEAS, an androgenmetabolite andpro-androgen levels, reflects primarily adrenal androgen production. It is elevated in approximately25% of PCOS patients, although the diagnosis requires using age-related cut-off values, as DHEAS levelsdecrease with age. Furthermore, only 10% of PCOS patients demonstrate isolated DHEAS elevation [33].Androstenedione is elevated in 18% of PCOS women; however, in only 9% of cases were isolated ele-vations observed [18]. DHEAS circulates in abundance and is easily detected, because of its sulfatedgroup, by most commercial assays. Alternatively, A4 measurement has the same issues as T mea-surement. Overall, the addition of DHEAS and A4 measurement values when assessing patients withpossible hyperandrogenism increases the proportion of patients deemed “hyperandrogenic” by 10%each.

Of note, defining “abnormal” for the measurement of androgens has the same issues as whendefining the same for hirsutism (see earlier). Thus, the use of appropriate controls and the currentepidemiologic statistical testing is necessary to define a truly “normal” range and, therefore, whatis “abnormal” or excessive. Unfortunately, few laboratories do this, although we have reportedsuch an effort for the measurement of total T and free T by a high-quality RIA and a tandemmass spectrometry assay [58]. A final word on androgen measures in the circulation. Androgenmeasures are not a substitute for the clinical assessment of hyperandrogenism and, in fact,androgen measures are most useful in patients without overt or obvious clinical signs ofhyperandrogenism.



Management of androgen excess

The management of AE in women generally focuses on treating the clinical consequences of theunderlying disorder. For example, patients need to be assessed and treated for anovulation andanovulatory bleeding or resultant infertility. Furthermore, patients may need to be evaluated andtreated for associated metabolic dysfunction, particularly those with PCOS. This section focuses ontreating dermatologic aspects of AE, including hirsutism, acne, and FPHL. One key fact regarding thetreatment of AE is that patients generally require combination therapy, combining not just medicationsbut mechanical approaches. Rare is the single agent that will treat a patient with clinical hyper-androgenism adequately.

Hirsutism

Our approach to managing hirsutism is based on the recommendations of the Androgen Excess andPCOS Society (AE-PCOS) [59] and the Endocrine Society [60], suitably modified by our extensiveexperience [18]. Initiation of treatment should be based on the patient's perception of the problem,rather than quantitative characteristics of hirsutism [60]. As noted earlier, approximately 70% of pa-tients with hirsutism defined by anmFG score >3 complain of being hirsute [39], and about one-half ofwomen with minimal hair growth (mFG 3e5) have PCOS [44]. The hirsutism score correlates poorlywith serum androgens [33]; therefore, monitoring of T and other androgens is generally unnecessary[61]. The choice of specific intervention depends on the patient's plan for pregnancy and the severity ofhirsutism [59].

Hirsutism is a sign, not a disease in and of itself; therefore, the underlying cause should beconsidered. PCOS is the most common etiology and is found in 72% to 82% of patients with AE [18].Treatment of clinical signs of hyperandrogenism primarily centers around the suppression of androgenproduction and/or action. The most useful medical treatment includes oral contraceptives (OCPs) andantiandrogen therapy, preferably in combination. Other useful therapies include topical and systemictreatments for acne (antibiotics, topical retinoids, isotretinoin, phototherapy, etc), topical treatmentsfor androgenic alopecia (minoxidil), and topical treatments for hirsutism (eflornithine). Finally,treatment of these hyperandrogenic signs necessities understanding and incorporating cosmeticmeans of treatment, including shaving, depilating, hair bleaching, electrolysis, laser hair removal, hairtransplantation, and others. Smoking cessation is strongly recommended for hirsute patients as many ofthe undesirable side effects of the medications prescribed to treat hirsutism are exacerbated whenpatients indulge this habit [59].

Androgen suppressionSuppression of androgen biosynthesis may be achieved by the use of hormonal contraceptives,

GnRH analogues, glucocorticoids, insulin sensitizers, and lifestyle modification.

Hormonal combination contraceptives. Progestins in hormonal combination contraceptives (HCCs) cau-ses suppression of LH levels and inhibition of LH-mediated ovarian androgen synthesis (Fig. 5) [62]. Theethinylestradiol in HCCs leads to a significant increase in SHBG, thereby contributing to a reduction offree T [63]. Moreover, HCCs modestly affect adrenal steroidogenesis by decreasing the synthesis andrelease of androgens [64]. Several progestins have antiandrogenic properties that can antagonize theAR and/or inhibit the activity of 5a-RA [64], although the amount found in HCCs alone is generallyinsufficient to mount a robust therapeutic response [60]. HCCs aremore effective than no treatment forhirsutism [65]. Therefore, approximately 60e100% of women with hirsutism demonstrate improve-ment on oral contraceptives [66]. This provides sufficient evidence to consider HCCs as monotherapyfor the treatment of hirsutism.

Several studies have demonstrated the superior efficiency of HCC monotherapy compared to fi-nasteride after 9 months of treatment [67], and this is comparable to GnRHa [68] and insulinsensitizer [69] therapy. There is some evidence that cyclical oral contraception (i.e., 21-day active/7-day placebo) provides better ovarian suppression (smaller ovarian volume and serum estrogens)


Fig. 5. Action of hormonal contraceptives on the secretion and action of androgens. 1 Androgen action blockade can be the result ofeither competitive binding for the androgen receptor (AR) or inhibition of 5a-reductase activity.


compared to a continuous regimen (i.e., 168-day active pill) [70]. To date, there is no universalagreement on the specific type of HCC for the treatment of hirsutism, and likely the type of HCCmatters little.

Oral vs. transdermal forms of HCCs. The vast majority of data concerning the effect of HCCs onhyperandrogenism is with oral HCCs. In one study, a transdermal form of HCC demonstrated alarger induction in hepatic SHBG production and a similar reduction in free T and DHEAS levels,compared to an oral HCC, suggesting that patch HCCs are likely as effective for reducing AE as oralforms of HCCs [72].

Effect of estrogen type. Current evidence regarding the effect of dose and type of estrogen on hir-sutism is limited. Modern HCCs contain 20e35 mg of ethinylestradiol (EE). Preparations containingestradiol valerate and 17b-estradiol are also available for contraception. A systematic review demon-strated that HCCs containing 20e25 mg EE were comparable with HCCs containing 30e35 mg EE in theireffects on total and free T suppression [73]. However, HCCs containing lower (20e25 mg) EE concen-trations have less pronounced effect on SHBG concentrations [73]. However, the resulting effect onhirsutism is not known and further investigation is needed. Likewise, the effectiveness of HCCs con-taining estradiol valerate or 17b-estradiol for hirsutism has yet to be established. The transdermalcontraceptive patch and vaginal contraceptive ring could also be used; however, their effectiveness forhirsutism has not been studied. The use of the transdermal contraceptive patch was associated with a1.6 increase in SHBG levels as compared to standard HCCs, but the decrease in free androgens wascomparable to oral formulations [72]. Data on the use of contraceptive rings for hyperandrogenicconditions are limited.

Second- vs. third-generation HCCs. Low-dose HCCs containing third-generation progestins areassociated with beneficial effects on metabolic profile in PCOS [74,75]. However, the use ofthird-generation HCCs is associated with some increased risk of venous thromboembolism vs.levonorgestrel (LNG)-containing pills. Third-generation HCC users, when compared with second-generation HCC users, showed significantly higher rates of developing this condition [76].



Therefore second-generation HCCs could also be used for these purposes. A small randomizedcontrolled trial (RCT) of 47 women demonstrated that HCCs containing LNG were clinicallyeffective for the treatment of hirsutism [77]. However, there is limited data to demonstratethat second-generation HCCs are less effective in the reduction of serum androgens and the hir-sutism score [77]. Furthermore, HCCs containing LNG could worsen the metabolic profile in PCOSpatients [78].

HCCs with antiandrogenic progestins. Cyproterone acetate (CPA), chlormadinone acetate (CMA),drospirenone (DRSP), and dienogest (DNG) can be considered progestins with antiandrogenic prop-erties. HCCs containing DNG are available in combinationwith two types of estrogens, EE and estradiolvalerate. Comparative studies of HCCs containing progestins with antiandrogenic properties, however,are limited. Batukan et al. demonstrated comparable effects of HCCs containing CPA and DRSP withregard to the clinical signs of hirsutism after 12 months of therapy [79]. In contrast, another RCTdemonstrated that HCCs with DRSP were more effective in the reduction of clinical hyperandrogenismas compared to CMA-containing HCCs [80]. Yet, in a relatively recent RCT, Bhattacharya et al.demonstrated that after 12 months of treatment, use of HCCs containing CPA was associated with asignificant decrease in the mFG score as compared with HCCs containing both desogestrel (DSG) andDSP [81]. Another prospective RCT of 2 HCCs with DSG and CPA showed comparable effectiveness forhirsutism in adolescents with PCOS [82]. It is worthmentioning that these studies were relatively smallin size.

Risks and side effects of HCCs. Commonly reported side effects of HCCs include nausea, bloating,and mood changes, but these may decrease after several months of treatment [83]. Breakthroughbleeding is another significant side effect of HCCs leading to discontinuation. Data based on 1small RCT showed that third-generation progestogens demonstrate better bleeding patterns incomparison to second-generation preparations [84]. Third-generation HCCs and DRSP-containingHCCs are associated with an increased risk of thromboembolic events compared to second-generation HCCs within the general population [85,86]. These data are supported by recent asystematic review [87]. Reportedly, the use of HCCs increased the risk of developing venousthrombosis (relative risk [RR] 3.5, 95% confidence interval [CI] 2.9e4.3) [87]. The RR of venousthrombosis for low-dose third-generation HCCs containing progestins, or drospirenone, or CPAwere similar, and approximately 50% to 80% higher than for HCCs containing LNG. Higher doses ofEE in HCCs were associated with higher thrombosis risk [87]. Yet, the absolute risk of thrombo-embolism is low [86].

Gonadotropin-releasing hormone agonists (GnRH-a). Administration of GnRH-a leads to suppression ofgonadotropin secretion and, as a result, decreased ovarian androgen secretion. The use of GnRH-a isoften associated with estrogen deficiency and is usually prescribed in combination with estrogens.Data on the efficacy of GnRH-a in comparison with other methods of treatment are mixed. In twostudies, the use of GnRH-a in combination with estrogen was associated with better clinical out-comes compared to HCCs [88,89]. The use of a GnRH-a in combination with HCCs is less effectivethan in combination of antiandrogen and HCCs [90]. Given the cost of therapy and a wide range ofside effects, GnRH-a along with the necessity to combine it with estrogen therapy should bereserved for patients who cannot tolerate other treatments, or for those patients with theHyperandrogenic-insulin resistant-acanthosis nigricans (HAIRAN) syndrome [91].

Glucocorticoids. Glucocorticoids (GCs) are traditionally used for the treatment of hyperandrogenism inwomen with congenital adrenal hyperplasia. Two studies have demonstrated that GCs were moreeffective than HCCs or androgens in suppressing levels of adrenal androgens, but less effective for thetreatment of hirsutism. Therefore, routine treatment of hirsutism with GCs is not recommended [92].Even in patients with congenital adrenal hyperplasia, treatment of associated hirsutism should includethe use of an antiandrogen.

Insulin sensitizers and lifestyle modification. Insulin sensitizers and lifestyle modification may reducehair growth by indirectly reducing circulating insulin levels, which in turn will reduce ovarian theca



stimulation. However, the overall effect is relatively modest. Overall, spironolactone and flutamide,and likely all antiandrogens, are superior to insulin sensitizers alone in the treatment of hirsutism[93].

Metformin. Metformin is an insulin sensitizer that not only has a favorable effect on insulin sensi-tivity, but also may reduce serum androgens [94e96]. However, a meta-analysis of 16 trials did notreveal a clinically significant difference in the reduction of the mFG score compared to placebo, andmetforminwas less effective compared to spironolactone and flutamide [94]. Althoughmetforminmayinfluence biochemical hyperandrogenism, it has a little effect on hirsutism and is not recommended forthe routine clinical treatment of hirsutism [59].

Troglitazone. The thiazolidinediones (TZDs) are a separate class of drugs that act to improve insulinresistance by acting on the PPARgamma receptor. Troglitazone, a TZD, was evaluated for its effect onhirsutism. Four hundred and ten PCOS women in a multicenter, double-blinded trial received placeboor troglitazone in different doses (150, 300, or 600 mg/day). There was a significant decrease in themFG score with 600 mg troglitazone as compared to placebo [97]. However, data on the use of TZDs inPCOS is limited [97,98] and, currently, these therapies are not recommended for the routine treatmentof hirsutism.

Weight loss. The prevalence and degree of hirsutism is higher among obese women with PCOS[99]. Abdominal obesity, associated with PCOS, leads to increased insulin levels, and reduced hepaticsynthesis of the SHBG [100]. This, in turn, causes an increase in free androgens concentration[99,101]. Insulin, moreover, has a direct impact on ovarian action [102,103] and functions as a co-gonadotropin [104], all of which contribute to biochemical hyperandrogenism. Some evidencesuggests that obesity itself may negatively impact the effects of pharmacologic treatments forhirsutism.

A systematic review of RCTs has shown that the effect of treatment was negatively associated withBMI in PCOS patients [105]. However, data regarding the effect of lifestyle modification on hirsutismare limited. A systematic review of six small RCTs observed that lifestyle modificationwas beneficial inthe reduction of serum androgens and increased SHBG, along with some improvement in hirsutism asevaluated by the mFG score [106].

Bariatric surgery is commonly used as a treatment modality in the advanced stages of obesity. In alongitudinal prospective non-randomized evaluation, a significant reduction in hirsutism score, serumandrogens, as well as improvement in insulin resistance (IR) and ovulatory function were observedafter surgery [107]. In some cases, obese womenwith PCOS were clinically cured after bariatric surgery[108]. However, the data regarding this approach are limited and this treatment option should bestrictly reserved for morbidly obese patients [109].

Androgen blockade

Antiandrogens in use generally include three AR blockers, spironolactone, flutamide and cyprot-erone acetate, and one 5a-RA inhibitor, finasteride. While there are other AR blockers and 5a-RA in-hibitors available, these have not been used with any regularity in women. Although the side effects ofantiandrogens vary somewhat, there are two side effects and risks that are common to all. First, allantiandrogens are teratogenic, in that they may cause feminization of the genitalia in a male fetus. Forthis reason, the use of antiandrogens alone is generally discouraged, unless they are used in a patientwith very secure contraception.

Second, they all have the potential to cause side effects related to their antiandrogenic properties,including some muscle weakness and decreased libido, although this varies greatly from patient topatient. In general, because efficacy is generally higher when using a combination of HCC and anti-androgens (see further), and because HCCs minimize the risk of teratogenicity, we generally begintherapy with a combination of HCCs and antiandrogens.

Antiandrogen monotherapyThe antiandrogens currently available for clinical use are spironolactone, CPA, finasteride, and

flutamide. RCTs using antiandrogens therapies were summarized in a systematic review [93]. In fivestudies, antiandrogen therapy (spironolactone, finasteride, and flutamide) was associated with a



reduction in mFG scores by 3.9 (95% CI, 2.3e5.4) as compared to placebo [96]. The comparative effi-ciency of antiandrogens is controversial. Some studies have not shown significant differences betweenantiandrogens on mFG scores [110e112], whereas other data demonstrated flutamide to be superior tospironolactone and CPA [90] and still other studies showed CPA and spironolactone to bemore effectivethan finasteride [67,113,114].

Combined treatment of antiandrogen with HCCsFour RCTs demonstrated that antiandrogens in combination with contraceptives were more

effective than monotherapy with HCCs [93]. These data were consistent with other publicationsdemonstrating that CPA, spironolactone, and flutamide when combined with HCCs showed a signifi-cant effect on hirsutism [105]. Of note, the addition of CPA to CPA-containing HCCs did not provideadditional benefit [93]. As indicated earlier, because efficacy is generally higher when using a com-bination of HCCs and antiandrogens, than with either HCC or antiandrogen monotherapy, and becauseHCCs minimize the risk of teratogenicity, we generally begin therapy with a combination of HCCs andantiandrogens.

Combined treatment of antiandrogen with metforminIn a relatively small RCT, flutamide in combination with metformin (4.6; CI, 1.3e7.9) appeared to be

superior to monotherapy [105].

Combined antiandrogensThe combined use of spironolactone and finasteride appears to be more clinically effective then

monotherapy with spironolactone [115], however, data on this are limited.

Cosmetic approaches

Cosmetic methods are widely used and can be categorized as short and long term [60]. Short-termmechanical methods include shaving, chemical depilation, plucking (threading), waxing, and bleach-ing; long-termmethods include electrolysis, laser therapy, and intense pulse light (IPL) therapy [60]. Inaddition, a 13.9% topical solution of eflornithine hydrochloride (HCL) can be used to reduce facial hairgrowth, although its effect is short term and requires daily use.

Eflornithine hydrochlorideDepending on accessibility and availability, in some countries, the topical use of 13.9% eflornithine

hydrochloride (HCL) is available for the treatment of facial hirsutism. This medication acts as per-manent inhibitor of enzyme ornithine decarboxylase, which is required for the growth and differ-entiation of cells in the hair follicle [116]. Topical administration of eflornithine HCL was shown toslow facial hair growth [116]. This action is reversible and hirsutism relapsed after 8 weeks ofcessation of treatment [116]. Percutaneous absorption of eflornithine is less than 1% [116]. Thegeneral use of eflornithine HCL is not approved for large surface areas of the skin due to systemiceffects; therefore, its use should be restricted to the removal of facial hair only. Treatment witheflornithine HCL has been found to significantly reduce the level of anxiety associated with hirsut-ism, as evaluated by the Bother Assessment in Skin Conditions (BASC) scale [71]. Two RCTsdemonstrated that eflornithine promotes a more rapid response to therapy when combined withlaser treatment [117,118].

Short-term cosmetic methods of hair removalDepilation is the removal of the hair shaft from the skin's surface and includes shaving and chemical

depilation. Conversely, epilation is the extraction of hair above the bulb (e.g., plucking, waxing) [60].Between these two methods, epilation provides the most long-lasting action on hair regrowth, withhair absent for 6e8 weeks [119]. If epilation is performed during the anagen phase, it could possiblydestroy the dermal papilla [120]. However, this effect is subtle and, compared with electrolysis,plucking is not as effective [121]. These methods are relatively safe and affordable. Side effects are rareand may include dermatitis with chemical epilation and bleaching; skin irritation with shaving and



scarring; and folliculitis with epilation [60]. Despitewidespread opinion, shaving does not cause excesshair growth [60].

Long-term cosmetic methods of hair removal

Electrology. Electrolysis has been commonly used for the treatment of unwanted hair since 1875 [122].Galvanic electrolysis facilitates chemical destruction of the dermal papilla resulting in the long-termreduction of hirsutism. Thermolytic electrolysis induces heat injury of the hair follicle in the treatedarea. Currently available Blended electrolysis includes the synergetic application of both energies.

Data on the clinical effectiveness of electrolysis are limited. The blended effect of electrolysis wasshown to be more effective than plucking, and long-term hair removal was achieved in 9.9 sessions[122]. It is worth mentioning that shaving a few days before the procedure proved helpful as it allowedselective destruction of growing anagen hair [121]. Side effects associated with electrolysis includediscomfort, erythema, skin discoloration, and scarring. Application of local anesthetics has shown to beeffective in reducing the discomfort associated with this procedure [123]. However, electrolysis is lesssatisfactory as compared to intense pulsed light (IPL) [124]. A comparative study of 25 women un-dergoing hair removal at an NHS hospital showed patient satisfaction rates were 8.3 out of 10 for IPLand 5.4 out of 10 for electrolysis [124].

Laser therapy. Laser therapy is based on selective photothermolysis, wherein melanin of hairfollicles accumulate the light energy, which in turn destroys the hair bulb [125]. Several laserswith varying wavelengths are available for hair removal: ruby, alexandrite, diode, and the neo-dymium:yttriumealuminiumegarnet (Nd:YAG) [125]. Darker skin types are usually more difficultto treat using photoepilation. In this case, light energy is absorbed by the surrounding epidermis ofthe hair follicle, which makes the procedure less effective and could be associated with skindiscoloration and burns [126]. Therefore, the Nd-YAG laser, which has a longer wavelength, is thepreferred treatment for patients with darker skin [127]. A Cochrane systematic review showed analmost 50% hair reduction in a period of 6 months after treatment with alexandrite and diode lasersand limited evidence of effectiveness with other lasers [128]. However, in another systematic re-view, conducted by Haedersdal and Wulf, efficacy was shown to extend beyond 6 months aftertreatment with alexandrite, diode lasers and possibly with ruby and Nd:YAG lasers [129]. The dataon the long-term (9 months) efficacy after treatment are available only for alexandrite lasers [130].Typically, four to six treatments are required to achieve a desired effect. Use of the alexandrite lasershowed 55% hair reduction after the third treatment [130]. Maintenance therapy is recommendedevery 6 to 12 months. Lasers are associated with local complications such as scarring and skindiscoloration, and also can cause reticulate erythema and uveitis [126,127,129]. In rare cases, thistreatment has been associated with paradoxical hypertrichosis [131].

Intense pulsed light. Data regarding IPL efficacy are limited [129]. It is shown to be superior to the rubylaser, similar to the Nd:YAG laser, and less effective as compared to diode laser therapy [132e134] IPLswith radiofrequency can be used inwomenwith blond hair and light skin, when lasers are not effective.In addition, IPLs are associated with less risk of burning in patients with darker skin types. However, fordarker skin in an assessor-blinded comparison, the Nd:YAG laser was more effective than the IPL [135].Evidence of the long-term effects of IPL treatment are lacking [128,129]. Side effects of IPL are similar tothose in lasers.

Acne

As discussed earlier, acne secondary to AE will benefit from androgen suppression. The EndocrineSociety recommends the use of HCCs as the first-line intervention in the acneic hyperandrogenic pa-tient [19]. HCCs are more effective than placebo, as shown in 9 RCTs included in the Cochrane sys-tematic review [136]. In addition, HCCsmay contain antiandrogenic progestins (chlormadinone acetateor CPA), which appears to be more effective than LNG-containing HCCs for the treatment of acne [136].Alternatively, the use of progestin-only contraception: pills, devices, or injectable forms could



aggravate the development of acne and are, therefore, not recommended [137]. In acneic patients withadrenal hyperplasia, treatment of GCs also improves their acne. Alternatively, there are conflicting dataregarding the efficacy of antiandrogens on acne [138e140].

Several studies, including an RCT, demonstrated the efficiency of topical agents (i.e., topical benzoylperoxide and retinoids) in the treatment of inflammatory acne [141,142]. Oral antibiotics are alsoeffective for moderate to severe inflammatory acne, or for truncal location of lesions [143]. Oral iso-tretinoin is the only agent that has demonstrated maximum clinical effectiveness for all forms of acne[144]. It is currently reserved for severe, nodular acne, in cases of scarring, and for milder formsresistant to other treatments [48].

Female pattern hair loss

The mainstay or first-line treatment of FPHL is 2% topical minoxidil [52]. The use of 1 mL minoxidiltopically to the scalp skin and hair twice daily is recommended for FPHL. A Cochrane systematic reviewand meta-analysis observed superior efficacy for minoxidil as compared to placebo for FPHL [145].Despite some evidence of greater efficiency for a 5% solution of minoxidil, its use is associated with anincreased rate of side effects, including facial hypertrichosis [146]. Treatment efficacy should be re-evaluated after 6 months and patients should be cautioned against possible increased shedding dur-ing the first 2 months of therapy [52].

Other treatment modalities include the use of androgen suppression in combinationwith androgenblockade, laser and light treatments, the use of prostaglandin analogs, and hair transplantation. Dataon the use of systemic antiandrogens (chlormadinone acetate, drosperinone, spironolactone, andflutamide) in women with FPHL is insufficient for routine use [145]. However, in one study, the use oforal CPA was associated with improved androgenic alopecia in a subgroup of female patients withhyperandrogenism [147] and may be reserved as second-line treatment for FPHL in these women [52].In case medical therapy is not sufficiently effective, follicular unit transplantation is a possible optionfor female patients with sufficient residual hair [148].

Follow-up and prognosis

The effectiveness of therapy should be monitored at least 6 months after treatment [92]. For hir-sutism, effective treatment is associated with a reduction in the frequency of cosmetic hair removal(e.g., waxing, depilation, shaving) as well as a lowered mFG score [92]. As hirsutism scores do notcorrelate well with androgen levels [61], monitoring of serum androgens during treatment is notrecommended [60,92].

Treatment of hirsutism takes time and an absolute cure is rarely possible, whereas cessation ofmedical therapy may lead to a relapse in symptoms [149].

Therapies for most causes of androgen excess are lifelong [150]. However, we should note that themajority of studies assessing the efficacy of medical treatment for clinical hyperandrogenism havebeen of only 6 or 12 months duration; therefore, it is unclear how long treatment should or can beused [151]. The majority of experts recommend lifelong treatment [59]. However, we tend to try andtreat patients with maximum suppression for approximately 2 years and then, depending on pro-gression of hair growth and amelioration in the mFG score, we may suggest decreasing or evenstopping antiandrogen use, while continuing oral contraceptive use. In our experience, approxi-mately 50% of patients so treated are able to remainwell controlled by oral contraceptive suppressionalone.

Generally, acne responds to therapy relatively rapidly, and improvements can be observedwithin the first month of effective therapy. Hirsutism, alternatively, is slower to respond, due tothe longer growth cycle of the hair, and improvements may be observed as early as 3 months, butgenerally only after 6 or 8 months of therapy. Finally, FPHL is the slowest to respond to therapy,if it will at all, and it may take 12 to 18 months of therapy before a response is begun to beobserved.

Once medical therapy begins, a follow-up visit should be scheduled at least 1 month after the initialtreatment visit to evaluate for side effects and reinforce the treatment plan. Follow-up thereafter can be



every 3 to 6 months until the patient's condition is stable. Once treatment responses are stable, annualvisits are appropriate. If the patient has PCOS, then monitoring and treatment for metabolic compli-cations is also necessary. Thus, the burden of care for the treating physician has increased beyond thatof solely treating the presenting complaint to include the detection and, if possible, prevention of thesemetabolic consequences [2,152].

Practice points

� Clinically evident hyperandrogenism results in hirsutism, acne, and androgenic alopecia.� The modified FerrimaneGallwey visual scoring system is currently considered the “gold”standard for the clinical evaluation of hirsutism.

� There is no universally excepted evaluation system for acne; several global assessmentscales have been offered.

� The pattern of hair loss on the scalp is usually assessed using the Ludwig scale; however,there is no universally accepted evaluation tool.

� Biochemical hyperandrogenism should be assessed by measuring total T and free T using ahigh-quality RIA or a tandem mass spectrometry assay.

� Treatment of hirsutism includes:✓ Topical eflornithine hydrochloride for mild facial hirsutism✓ Electrolysis for localized hirsutism in combination with pharmacological suppression✓ Lasers for generalized hirsutism in combination with pharmacological suppression✓ Low-dose neutral or antiandrogenic HCCs as first-line monotherapy for women with mild

hirsutism, or in combination with antiandrogens for women with moderate or severehirsutism

✓ Metformin or other insulin sensitizers, glucocorticoids, and GnRH analogues for thetreatment of clinical hyperandrogenism is not routinely recommended.

� Treatment of acne due to hyperandrogenism includes:✓ Topical astringents, or topical or oral antibiotics, as a first-line intervention✓ Topical retinoids✓ HCCs✓ Phototherapy✓ Oral isotretinoin, currently reserved for severe nodular acne, in cases of scarring, and for

milder forms proven resistant to other treatments� Treatment of FPHL includes:✓ 2% Topical minoxidil, as first-line therapy✓ 5a-reductase inhibition, as adjunct therapy✓ Other treatment modalities, including androgen suppression in combination with

androgen blockade, laser and light treatments, the use of prostaglandin analogs✓ Hair transplantation

� Therapies for most causes of androgen excess require lifelong intervention.

Research agenda

� Validated methods for acne evaluation� Validated methods for FPHL evaluation� Well-designed studies to evaluate the best medical therapy for hirsutism, acne, and alopeciain hyperandrogenic patient

� Well-designed studies to compare the effect of different HCC formulations on signs andfeatures of clinical hyperandrogenism

� Duration and prognosis of pharmacological interventions for androgen excess



Conflict of interest statement

DL, LGJ, and WW, have no conflicts of interest to declare. RA is a consultant for KinDexPharmaceuticals.

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