Hirsutism: managing the basics

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 ortwo 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 [1221]. 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 [11,13,1518,20,2326]. 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 biasa


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 biasb


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 biasc


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-offa


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 [2731]: 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 thatinterfere 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


749a


59b


39


18


2


6


Glintborg et al., 2004 [28]


340


134


86b


115


2


1


2


Unluhizarci et al., 2004 [29]


168


96


29b


27


12


3


1


Carmina et al., 2006 [30]


950


685c


150


72


41


2


0


Escobar-Morreale et al., 2008 [31]


270


171


61b


24


6


0


8


Total no. (%)


2601 (100)


1835 (71)


385 (15)


277 (10)


79 (3)


8 (0.3)


17 (0.7)


Jan 31, 2017 | Posted by in GYNECOLOGY | Comments Off on Hirsutism: managing the basics

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