Figure 1.1

The hair follicle growth cycle. Hair follicles possess the ability, unique among mammalian tissues, to be partially regenerated in a process termed the hair follicle growth cycle. Hair follicles go through repeated cycles of development and growth (anagen), regression (catagen), and rest (telogen) to enable the replacement of hairs. Reproduced from Escobar-Morreale et al. [1], by permission of Oxford University Press.

Because androgens play a definite role in the transformation of vellus into terminal hair during puberty, and in the growth of terminal hair in androgen-dependent areas of the female body, hirsutism is considered to be a clinical marker of androgen excess [3]. However, some hirsute patients do not show any other evidence of androgen excess, such as hyperandrogenemia or ovarian dysfunction, and often receive a diagnosis of “idiopathic” hirsutism [4].

To understand this apparent paradox, it is important to know some facts about female androgen metabolism. In women, the adrenals and the ovaries secrete androgens into the circulation, because these are the only organs in the female body expressing the biosynthetic enzymes needed for the synthesis of androgens. Peripheral tissues, such as fat, also contribute to circulating androgen levels by converting other steroid precursors. Testosterone is the most important androgen and circulates mostly bound to serum albumin (low affinity, but large capacity) and to sex-hormone-binding globulin (SHBG) (high affinity, but small capacity). Given its high affinity for testosterone, SHBG actually regulates the amount of testosterone that reaches target tissues, even if its binding capacity is much less than that of albumin. Therefore, the lower the SHBG concentration, the larger the fraction of free or unbound testosterone that may reach target tissues.

However, testosterone is a prohormone that undergoes conversion into dihydrotestosterone in target cells before entering the cell nucleus and binding the androgen receptor. Both the conversion rate of testosterone – mediated by 5α-reductase – and the binding of dihydrotestosterone to the androgen receptor are subject to individual variation, and current hypotheses explain idiopathic hirsutism as the result of increased 5α-reductase activity and/or increased sensitivity of the androgen receptor to normal amounts of testosterone [4]. An alternate hypothesis is that women with idiopathic hirsutism have mild steroidogenic abnormalities that go undetected by the relatively insensitive biochemical tests applied in routine clinical practice [5]. Considering the well-known limitations of the assays of serum androgens currently available for clinical practice [6], it is my personal opinion that the presence of hirsutism should be considered an accurate marker of androgen excess, irrespective of serum androgen concentrations. In other words, most if not all hirsute patients are hyperandrogenic, and our limitation in detecting androgen excess is the actual culprit that we cannot confirm this diagnosis by analytical tools.

Quantification and epidemiology of hirsutism

The definition of hirsutism implies that the amount of terminal hair must be quantified before establishing such a diagnosis. After the initial attempts to standardize the quantification of body hair made by S. M. Garn (who developed his score to assess male hairiness) [7], D. Ferriman and J. D. Gallwey [8], and E. Moncada Lorenzo [9], in 1981, Hatch and colleagues [10] published the modification of the original Ferriman–Gallwey score that is currently the “gold-standard” for the quantification of hirsutism. The modified Ferriman–Gallwey score (mFG) estimates the presence of terminal hair in nine areas of the female body – upper lip, chin, chest, abdominal region above and below the navel, upper and lower back, arms and thighs – and assigns a score from 0 (absent) to 4 (complete cover) to each of these areas for a total score ranging from 0 to 36 [10]. Most clinicians and researchers use a cut-off value of 8 or above to diagnose hirsutism, and grade it as mild up to a score of 15, moderate from 16 to 25, and severe above 25.

The broad application of this scoring system provided researchers with a common language for the definition of hirsutism and was followed by significant advances in the study of hirsutism and related conditions, such as polycystic ovary syndrome (PCOS). However, the mFG score has evident limitations, the most notable being the subjective nature of the assessment – yet, it appears that inter-observer variation is acceptable [11] – the possibility that substantial terminal hair in one or two areas may yield total normal scores, and the lack of population-based and uniform cut-off values.

The prevalence of hirsutism varies according to the mFG score cut-off value and the population under study [12–21]. This prevalence is relatively homogeneous across the world with the exception of women of Asian ancestry, in whom hirsutism is much less frequent (Table 1.1). In American women, 7.6%, 4.6%, and 1.9% demonstrated a score of 6 or more, 8 or 10, and there was no significant racial difference, with hirsutism prevalences of 8.0%, 2.8%, and 1.6% in white women, and 7.1%, 6.1%, and 2.1% in black women, respectively, according to the chosen cut-off [22]. Similarly, we found that 7.1% of unselected blood donors in Spain had hirsutism as defined by an mFG score above 7 [13]. These and other studies addressing the prevalence of hirsutism, as defined by a pre-defined mFG score cut-off value in different populations according to their race and ethnicity, are summarized in Table 1.1. However, because race and ethnicity greatly influence the amount of body hair, ideally the cut-off values of the mFG score should be obtained from the particular population under study. Table 1.2 includes proposed mFG score cut-off values based on the 95th percentile of selected female populations of fertile age [11,13,15–18,20,23–26]. Broad application of these cut-off values would render a uniform 5% worldwide prevalence of hirsutism.

Table 1.1 Summary of studies addressing the prevalence of hirsutism in women

Author, year	Country	Race	Ethnicity	Score	Cut-off	Method of sample selection	Sample size	Prevalence (95% CI)	Comments
Diamanti-Kandarakis et al., 1999 [12]	Greece	White	Mediterranean	FG	≥6	Invitation of free medical examination	192	38% (31–45)	Possible selection self-referred bias^a
Asuncion et al., 2000 [13]	Spain	White	Mediterranean	mFG	≥8	Unselected female blood donors from general population	154	7.1% (3.0–11.1)
Zargar et al., 2002 [14]	India	Asian	Kashmir Dardic	FG	≥6	Hospital outpatient clinic	4780	10.5% (9.6–11.4)	Includes postmenopausal women
Sagsoz et al., 2004 [15]	Turkey	White	Middle Eastern	mFG	≥8	Regular check-up in outpatient clinic	204	8.3% (4.5–12.1)
Cheewadhanaraks et al., 2004 [16]	Thailand	Asian	Thai and Chinese	mFG	≥3	Regular cervical smear check	531	2% (0.8–3.2)
DeUgarte et al., 2006 [17]	USA	White Black	Caucasian and Hispanic African American	mFG	≥8	Pre-employment physical exam	293 350	5.4% (2.8–8.0) 4.3% (2.2–6.4)	Possible selection self-referred bias^b 97.5% reproductive age
Noorbala and Kefaie, 2010 [18]	Iran	White	Middle Eastern	mFG	≥8	Randomized cluster sampling proportionate to population size	900	10.8% (8.8–12.8)	Included only teenagers
March et al., 2010 [19]	Australia	White	Caucasian	mFG	8	Unselected population cohort	728	21.2% (18.2–24.2)	Possible selection self-referred bias^c 3% were not white
Sanchón et al., 2012 [20]	Spain	White	Mediterranean	mFG	≥8	Unselected female blood donors from general population	393	11.7% (8.5–14.9)
Sanchón et al., 2012 [20]	Italy	White	Mediterranean	mFG	≥8	Unselected female blood donors from general population	199	13.1% (8.4–17.7)
Gabrielli and Aquino, 2012 [21]	Brazil	Mixed	Mixed	mFG	≥6	Premenopausal women during cervical cancer screening	859	12.5% (10.4–14.8)	88.5% were black

FG, Ferriman–Gallwey score; mFG, modified Ferriman–Gallwey score.

^a Invitation of free medical examination.

^b Only 66% of invited women participated.

^c Only 53% of invited women participated, and patients self-assessed their hirsutism scores.

Modified from Escobar-Morreale et al. [1], by permission of Oxford University Press.

Table 1.2 Suggested cut-offs for the modified Ferriman–Gallwey hirsutism score (mFG) according to the 95th percentile in different unselected populations of premenopausal women

Author, year	Year	Country	Race	Ethnicity	Sample size	Suggested mFG cut-off^a
Asuncion et al., 2000 [13]	2000	Spain	White	Mediterranean	154	≥8
Sagsoz et al., 2004 [15]	2004	Turkey	White	Middle Eastern	204	≥9
Cheewadhanaraks et al., 2004 [16]	2004	Thailand	Asian	Thai and Chinese	531	≥3
Tellez and Frenkel, 1995 [23]	2005	Chile	White	Hispanic	236	≥6
DeUgarte et al., 2006 [17]	2006	United States	White Black	Caucasian and Hispanic African American	283 350	≥8 ≥8
Zhao et al., 2007 [24]	2007	China	Asian	Chinese Han	623	≥2
Api et al., 2009 [11]	2009	Turkey	White	Middle Eastern	121	≥11
Moran et al., 2010 [25]	2010	Mexico	White	Hispanic	150	≥10
Noorbala and Kefaie, 2010 [18]	2010	Iran	White	Middle Eastern	900	≥10
Kim et al., 2011 [26]	2011	Korea	Asian	Korean	1010	≥6
Sanchón et al., 2012 [20]	2011	Spain and Italy	White	Mediterranean	592	≥10

^a As defined by the 95th percentile of an unselected population of premenopausal women.

Modified from Escobar-Morreale et al. [1], by permission of Oxford University Press.

Diagnosis of hirsutism

After establishing the presence of hirsutism by an increased mFG score, or if a history of hirsutism is strongly suggested by the finding of some evidence of terminal hair in androgen-dependent areas in women successfully treated for this condition, the most likely etiology should be established in all patients.

Functional causes account for most cases [27–31]: PCOS, as defined by the combination of hyperandrogenism with ovarian dysfunction (oligo-ovulation or polycystic ovarian morphology), is the most frequent diagnosis, accounting for approximately 60% of cases, followed by idiopathic hyperandrogenism (when there is no evidence of ovarian dysfunction) in approximately 25% of cases, idiopathic hirsutism (when there is no evidence of hyperandrogenemia or ovarian dysfunction) in approximately 10% of cases, and nonclassic congenital adrenal hyperplasia in approximately 3–5% of cases (Table 1.3). Exceptionally, hirsutism derives from benign or malignant adrenal or ovarian tumors, from hyperplasia of ovarian cells, from androgenic medications or drugs that interfere with ovarian steroidogenesis such as valproate, or from gestational hyperandrogenism secondary to placental aromatase deficiency or Krukenberg tumors.

Table 1.3 Frequencies of the etiologies of androgen excess in large clinical series

Author, year	Sample size (n)	PCOS (n)	Idiopathic hyperandrogenism (n)	Idiopathic hirsutism (n)	NCCAH (n)	Tumors (n)	Miscellaneous (n)
Azziz et al., 2004 [27]	873	749^a	59^b	39	18	2	6
Glintborg et al., 2004 [28]	340	134	86^b	115	2	1	2
Unluhizarci et al., 2004 [29]	168	96	29^b	27	12	3	1
Carmina et al., 2006 [30]	950	685^c	150	72	41	2	0
Escobar-Morreale et al., 2008 [31]	270	171	61^b	24	6	0	8
Total no. (%)	2601 (100)	1835 (71)	385 (15)	277 (10)	79 (3)	8 (0.3)	17 (0.7)