Transcript hirsutism

HIRSUTISM
F.Fatemi,MD
Isfahan university of medical sciences
Definition
 The term refers to women with excess growth of terminal hair in a
male pattern.
 Affecting approximately 10% of women
 In these women, the hairiness implies the presence of abnormal
androgen action, which may represent a serious or, more likely, a
nonserious medical problem.
 Hirsutism can produce mental trauma& emotional anguish.
The major objectives in the management of hirsutism are:
•to rule out a serious underlying medical condition
• to devise a plan of treatment.
Pathophysiology
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Vellus hairs are fine, unpigmented hairs that cover most of
the body before puberty.
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Pubertal androgens promote the conversion of these
vellus hairs to coarser terminal hairs.
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The extent of conversion from vellus to terminal hair
depends on:
◦ The level and duration of exposure to androgens
◦ The local 5-alpha-reductase activity
◦ The intrinsic sensitivity of the hair follicle to androgen
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However, some terminal hair growth is androgenindependent (eg, scalp, eyebrows, lashes).
Pathophysiology
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Dihydrotestosterone(DHT) is the androgen that acts on the hair
follicle to produce terminal hair.
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This hormone is derived from both the bloodstream and local
conversion of a precursor, testosterone.
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The local production of dihydrotestosterone is determined by 5alpha-reductase activity in the skin.
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Differences in the activity of this enzyme may explain why women
with the same plasma levels of testosterone can have different
degrees of hirsutism.
classification
For clinical and therapeutic purposes, hirsutism can be
classified into eight categories:
 1)Hirsutism of pituitary origin
 2)Hirsutism of adrenal origin
 3)Hirsutism of ovarian origin:
 4)Constitutional hirsutism
 5))Hepatic hirsutism
 6)Hirsutism due to ectopic hormone production
 7)Iatrogenic hirsutism
 8) Hirsutism due to peripheral failure in converting androgens
into estrogens:
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Adrenal hirsutism
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Adrenal hirsutism should be considered in a patient of any
age presenting with:
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Obvious central hirsutism
androgenetic alopecia (SAHA)
Signs of virilization
Thin body habitus
◦ Adrenal Hirsutism classified as :
◦ 1)Non tumoral AH
◦ 2)Tumoral AH ( adrenal tumor may be responsible for above
symptoms together with the other characteristic signs of Cushing's
syndrome.)
Non-tumoral adrenal hirsutism
Adrenal hyperplasias
◦ CAH is actually a family of defects in 1 of 5 enzymes that are
responsible for the biosynthesis of cortisol.
◦ However, only 3 of these defects can produce hirsutism :
◦ 21-hydroxylase (most frequent)
◦ 3 β -hydroxysteroid dehydrogenase (less frequent)
◦ 11-β -hydroxylase deficiency (least frequent).
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21-hydroxylase deficiency is responsible for 95% of cases
◦ This leads to a build-up of the intermediate product before the deficient
enzyme in the pathway. As these intermediate products are not
recognized by the pituitary, the feed-back mechanism is not initiated,
which results in very high levels of ACTH.
Late onset CAH (Non classic CAH)
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Is due to partial enzyme deficiencies (e.g. of 21-hydroxylase), which are
manifested only when demand for steroids increases at puberty or
thereafter.
they have no manifestations of cortisol deficiency
Virilization is again a clinical feature; Other signs: precocious pubarche ,
SAHA,..
however, 40% of patients only have hirsutism.
The prevalence of late-onset congenital adrenal hyperplasia among hirsute
women is 1-15% in different studies .(Ashkenazi Jewish women)
It is nearly always due to 21-hydroxylase deficiency, which leads to increased
production of both :
17-hydroxyprogesterone & androstenedione & DHEA
Diagnosis
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The biochemical findings are less severe in patients with the
late-onset form of the disorder.
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Basal serum 17-hydroxyprogesterone concentrations (during
the follicular phase of the menstrual cycle) may be only
slightly high, especially late in the day, but :
A 7-9 morning value greater than 200 ng/dL (6 nmol/L) in
women or greater than 82 ng/dL(2/5nmol/L) in children
strongly suggests the diagnosis.
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The diagnosis may be confirmed by a high dose (250 mcg)
ACTH stimulation test. The response to ACTH is
exaggerated, and most patients have values exceeding 1500
ng/dL (43 nmol/L) 60 minutes after ACTH stimulation.
◦ DHEA-S excess is of adrenal origin(CAH,Cushing,Tumors)
◦ Androstenedione can be of adrenal or ovarian origin
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Adrenal Androgens
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Serum DHEA exhibit a circadian rhythm that reflects the secretion of ACTH,
while serum DHEA-S do not exhibit a circadian rhythm because the plasma
half-life of DHEA -S is much longer.
so, DHEA-S reflects a better marker of androgen production.
DHEA& DHEA-S have little intrinsic androgenic activity.
Small amounts are converted to androstenedione and then to test (and to
estrogen) in both the adrenal glands and peripheral tissues.( hair
follicles& external genitalia & Adipose tissue)
In women, approximately 50% of plasma testosterone is derived in equal
proportions from ovarian and adrenal secretion. The remaining 50%
derives from conversion of androstenedione & DHEA in peripheral tissues,
including adipose tissue
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DHEA-S >700 mcg/dL (13.6 µmol/L) raise suspicion for an adrenal
androgen-secreting tumor.
◦ Hyperandrogenism in CAH can cause infertility, but
dexamethasone therapy in this setting may
induce ovulation.
◦ Two important reasons for the diagnosis of CAH
are :
1)specific therapy is available
2) Genetic counseling may be necessary.
Hypercortisolism (Cushing's syndrome)
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Cushing's syndrome may be associated with high plasma ACTH levels
(pituitary hyperproduction and 'ectopic ACTH syndrome') or with a nearly
complete lack there of (adrenal primary nodular hyperplasia, adrenal
adenoma or carcinoma).
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All patients have an increase in plasma cortisol, which is the cause of the
major clinical features (e.g.central obesity with 'moon facies' and 'buffalo
hump', hypertension, glucose intolerance, ..
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If there is significant production of androgens, which is not the norm for
adrenal adenomas, there will be a virilization syndrome with hirsutism in
addition to the typical manifestations of Cushing's syndrome.
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In most instances, Cushing syndrome is caused by glucocorticoid
therapy.
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Because pure glucocorticoids have no androgenic activity, the treatment
rarely produces hirsutism.
Instead, glucocorticoid therapy is one of the causes of hypertrichosis
, resulting in vellus hair growth, especially on the face.
Thus, hirsutism in a patient with the clinical stigmata of Cushing syndrome
suggests that the syndrome has an endogenous origin,
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Cushing syndrome, as a cause of hirsutism, is diagnosed based on the
presence of dexamethasone that fails to suppress both androgens and
cortisol.
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Normal adrenal suppression is indicated by:
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A reduction of free testosterone below 8 pg/mL (27
pmol/L)
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reduction of DHEAS to levels below the normal range
for adult controls (<70 mcg per dL).
hirsutism
Ovarian
If the patient presents with :
 Lateral hirsutism( neck and the breasts)
 SAHA
 obesity
 obvious menstrual disorders
the presumed diagnosis is hirsutism of ovarian origin.
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This may also have a tumoral or non-tumoral etiology
Non-tumoral ovarian hirsutism
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According to the Rotterdam criteria for diagnosis of
PCOS, the diagnosis could be achieved if 2 of the following 3
criteria are present:
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Oligo- or anovulation (menstrual cycles longer than 35
days or fewer than 10 menses a year).
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Clinical (hirsutism, acne, androgenetic alopecia) or
biochemical evidence of hyperandrogenism.
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Polycystic ovaries (≥12 follicles in each ovary measuring 29mm in diameter and/or increased ovarian volume to
>10ml) on ultrasound examination.
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If using the Rotterdam criteria for PCOS diagnosis, many women with
idiopathic hirsutism would be considered to have a subtle form of PCOS
Polycystic ovary syndrome
Non-tumoral ovarian hirsutism
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Biochemically, one can see :
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A decrease in follicle stimulating hormone (FSH)
An increase in luteinizing hormone(LH)
An increase in estrone and testosterone.
Occasionally the serum prolactin levels are also increased.
◦ As many as 50% of patients also show abnormal adrenal androgen
secretion.
◦ • The characteristic endocrine abnormality is an elevation
in levels of plasma free testosterone that is not suppressed
by dexamethasone;
PCOs is associated with :
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infertility
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insulin resistance manifested as:
 diabetes mellitus
 metabolic syndrome , including central obesity, hypertension, glucose
abnormalities, and dyslipidemia)
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possibly with an increased risk of endometrial cancer.
Tumor
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This is similar to PCOS, but with greater production of androgens, especially
testosterone.
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The patients present with signs of :
virilization,
hirsutism
and even androgenic alopecia.
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Ovarian
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Serum levels of LH and FSH are normal, but estrone levels are greatly
elevated.
If hirsutism is mild relative to the degree of virilization in an older (especially
postmenopausal woman) one should think about the possibility of an
ovarian tumor.
Constitutional or dermatologic hirsutism
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Although SAHA may occur in patients with PCOS and other disorders
of androgen excess, isolated SAHA can be distinguished by a lack
of :
◦ substantial hormonal abnormalities
◦ anovulatory menstrual cycles
◦ ultrasonographic evidence of polycystic ovaries
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We will consider four types of dermatologic hirsutism.
1)Ovarian SAHA
2)Adrenal SAHA
3)Hyperprolactinemic SAHA
4)Familial hirsutim
This is generally facial,
presenting as a
prolongation of the
preauricular
 hair implantation
line .
 It is not accompanied
by other alterations of
the SAHA syndrome
Familial
hirsutism
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laboratory tests are
absolutely normal.
Diagnosis
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(A) Hirsutism must be distinguished from hypertrichosis
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HT: generalized excessive hair growth that occurs as the
result of :
◦ Heredity
◦ metabolic disorders (eg, hyperthyroidism, anorexia nervosa, porphyria)
◦ some medications (eg, phenytoin, diazoxide, minoxidil, glucocorticoids,
cyclosporine, hexachlorobenzene, streptomycin, penicillamine, heavy
metals, sodium tetradecyl sulfate, acetazolamide, interferon.)
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Hypertrichosis, in which hair is distributed in a generalized,
nonsexual pattern, is not caused by excess androgen
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Diagnosis
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(B)The most widely accepted method of quantitation uses
the Ferriman and Gallwey scale.
However, use care because this method has significant
interobserver variability.
In this approach, hair growth is judged in each of 9-12
androgen-sensitive areas.
◦ A woman with a score of 8 or higher is considered to have hirsutism.
◦ Normal scores have also been established for Turkey (up to 11) and
Thailand (up to 3 on the modified Ferriman and Gallwey scale).
Etiology
Approximately half of women with mild hirsutism (FGS 8-15 of toial of 36)
have the idiopathic condition, whereas in the remainder of these women
and in most of those with more marked hirsutism, androgen levels are
elevated.
 Hyperandrogenism is caused by :
_Most often the polycystic ovary syndrome
_ About 8 % of women with hirsutism have mild, often asymptomatic,
idiopathic hyperandrogenism. This condition may be due to abnormal
peripheral metabolism of prohormones.
_ Androgenic medications also may cause hirsutism.
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_Other causes of androgen excess occur infrequently:
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Nonclassic CAH is present in only 1.5 to 2.5% of women with HA.
◦ Androgen-secreting tumors are present in about 0.2 % of women with HA. more than
half of such tumors are malignant.
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Cushing's syndrome, hyperprolactinemia, acromegaly, and thyroid dysfunction must be
considered as causes of androgen excess, but these conditions usually present because of
symptoms other than hirsutism.
Evaluation
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The first step in evaluating a woman with hirsutism is to
determine the source of the responsible androgens.
Excess androgens can be from :
1)An exogenous source :
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anabolic steroids:(Oral : Fluoxymesterone ,Methyltestosterone ,Testosterone Parenteral : Testosterone)
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Androgenic OCs
Danasole, valporeic acid
2)An Endogenous source( i.e. adrenal cortex or ovaries)
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It should be noted that, as a general rule, 'whenever there
is hirsutism which appears abruptly and which evolves
quickly, one must first suspect that there is an ovarian,
adrenal or pituitary tumor'.
In addition,when the hirsutism is mainly localized on the
areola and the lateral surfaces of the face and neck, the
androgens usually have an ovarian origin, whereas if the
location is central, with a distribution from the pubic
triangle to the upper abdominal area and from the
presternal region to the neck and the chin, the origin is
usually adrenal.
When there is only hair on the lateral aspect of the face
and on the back, the hirsutism is usually iatrogenic.
With time, however, the distribution can evolve to produce
both central and lateral involvement.
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History
Age of onset
Diagnosis
◦ Idiopathic hirsutism and the other less-serious causes of hirsutism usually
begin at puberty.
◦ Conversely, hirsutism that occurs in middle-aged or older women should
suggest an adrenal or ovarian tumor.
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Family history:
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A patient with a family history of hirsutism is consistent with congenital
adrenal hyperplasia (CAH); however, idiopathic hirsutism and polycystic
ovary syndrome (PCOS) can also be familial.
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A thorough abdominal and pelvic examination is important in patients with
hirsutism because more than half of androgen-secreting adrenal and ovarian
tumors are palpable.
Lab investigation
According to the Endocrine Society Clinical Practice
Guidelines, testing for androgen is recommended in:
 women with moderate-to-severe hirsutism
 hirsutism of any degree when it is associated with any of
the following:
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sudden onset
rapid progression
menstrual irregularity
Infertility
central obesity
Clitoromegaly
acanthosis nigricans
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Bolognia recommends measuring:
total and free testosterone,
DHEA-S
Prolactin
SHBG
Δ-4-androstenedione
3α-androstanediol glucuronide (metabolite of DHT)
Depending on the results of these Tests, the
laboratory evaluation can be expanded
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Testosterone — total or free test, is the single best test for
evaluating hirsute women.
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Total test are more widely available, and better standardized than
free test & are sufficient to exclude andrgen-secreting tumors;
specifically, values below 150 ng/dL (5.2 nmol/L) exclude ovarian or
adrenal tumors.
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Free test are disproportionately higher than total test, because of a
reduction in the SHBG. (The reduction is due to reduced hepatic
production of this protein due to androgen excess and, in women with PCOS, to
hyperinsulinemia ).
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The difference is most evident in women with idiopathic hirsutism, in
whom serum free testosterone may be high but serum total
testosterone is normal.
Treatment
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The therapeutic options of hirsutism can be divided into:
◦ systemic
◦ Topical
◦ dermato-cosmetic therapies.
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Patients should be informed that the response to systemic
agents is slow; occurring over 3-6 months after therapy has
begun
Contraceptives
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The most androgenic progestins : norgestrel and levonorgestrel.
The least androgenic progestins are norgestimate & desogestrel.
Other progestins, such as cyproterone acetate and drospirenone, work as
androgen receptor antagonists.
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Oral
(OC) agents are considered to be the first-line therapy for hirsutism in
premenopausal women.
Ocs commonly contain ethinyl estradiol (EE) + progestin.
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The recommended OC includes a combination of EE with either 2mg of
cyproterone acetate (Diane-35) or 3mg drospirenone (Yasmin).
OCs should not be prescribed to women with a history of venous
thrombosis.
Antiandrogens
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Spironolactone, an aldosterone antagonist, has several actions.
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A recent Cochrane review of trials comparing spironolactone 100mg/d
with placebo showed a significant subjective improvement in hair growth.
The Ferriman-Gallwey score, however, did not validate these findings.
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In the first months of treatment, measurements of blood pressure and serum
potassium levels every 4 weeks are recommended.
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Spironolactone should not be prescribed to patients with renal insufficiency
or hyperkalemia.
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As spironolactone usually causes feminization of the male fetus as well as
menstrual alterations, it is best to add OCPs.
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Cyproterone acetate is a progestin with antiandrogenic activity.
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CA (2mg) combined with EE has been shown to be more effective than
placebo, but not better than other antiandrogens.
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A small randomized controlled study showed that CA when combined
with EE at a dosage of 0.01mg/d for the first week, 0.02mg/d for the
second week, 0.01mg/d for the third week, followed by a pause of 7
days, and 12.5mg CA/d added during the first 10 days of every
month for 12 months seems to be the most effective treatment to reduce
the hirsutism score when compared with flutamide 250mg/d,
finasteride 5mg/d, and ketoconazole 300mg/d.
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The recommended dose is :
12.5-100mg/d added to the first 10 days of each calendar pack of oral
contraceptives.
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Flutamide is a pure nonsteroidal antiandrogen that acts as
an androgen receptor blocker.
Studies have shown that flutamide 250-500mg/d is more
effective than finasteride.
RCTs assessing the efficacy of different antiandrogens for the
treatment of hirsutism reported that:
flutamide reduced the hirsutism score by 5
Spironolactone reduced the score by 1.3
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Due to its propensity for severe hepatotoxicity, which is
occasionally fatal, flutamide should not be used as first-line
therapy for hirsutism.
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Finasteride: is a potent inhibitor of the type 2 isoenzyme of 5-αreductase
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Finasteride has been shown to lower hirsutism scores by 30%-60% in
addition to reducing the average hair diameter.
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In comparative studies, finasteride demonstrated efficacy similar to that of
other antiandrogens with fewer adverse effects.
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Other trials suggested that spironolactone and flutamide were more effective
than finasteride.
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In women with hirsutism, finasteride is used in doses of 2.5-7.5mg/d.
Doses of 2.5mg and 5mg seem to be equally effective.
As with the other antiandrogens, the use of finasteride requires a
reliable method of contraception in order to avoid a pregnancy given
the potential risk of feminization of the male fetus.
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Insulin-Sensitizing Drugs
Metformin lowers hepatic glucose production and
decreases insulin levels.
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Thiazolidinediones (rosiglitazone and pioglitazone) sensitize
end organs to insulin through their action on the
peroxisome-proliferator-activated receptor-γ.
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Meta-analyses of RCTs of insulin sensitizers for the
treatment of hirsutism concluded that insulin sensitizers
provide limited or no improvement for women with hirsutism.
Gonadotropin-Releasing Hormone
(GnRH) Agonists
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GnRH agonists suppress luteinizing hormone, and to a lesser degree follicle
stimulating hormone secretion, leading to a decline in ovarian androgen
production.
GnRHagonist therapy seems to have no therapeutic advantage over OC and
antiandrogens.
As GnRH agonist therapy is:
◦ expensive
◦ requires injections
◦ and estrogen needs to be added to the therapy
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its use should be reserved for severe forms of hyperandrogenemia, such
as patients with ovarian hyperthecosis who have a suboptimal response to
OCs and antiandrogens.
Glucocorticoids
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Glucocorticoids can be prescribed to women who:
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Have hirsutism that is due to nonclassic CAH
Have a suboptimal response to OCs and/or antiandrogens
Exhibit poor tolerance to OCs
Are seeking ovulation induction.
Topical Treatment
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Eflornithine hydrochloride cream 13.9%
(Vaniqa®, Skin Mediea) has been approved by
the US FDA for the reduction of unwanted
facial hair in women.
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Noticeable results take about 6-8 weeks.
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Adverse effects include itching and skin dryness.
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Direct Hair Removal Methods
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These modalities can be divided into temporary methods of hair removal
and permanent methods of hair reduction.
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Temporary methods of hair removal include plucking, waxing, shaving and
chemical depilatory agents.
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Permanent methods of hair reduction include photoepilation (using laser
and intense pulse light [IPL]) and electrolysis.
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Photoepilation seems to be superior to the conventional methods, such
as shaving, waxing and electrolysis.
A Cochrane review of photoepilation of unwanted hair growth showed
that alexandrite and diode lasers are more effective, whereas little evidence
was obtained for the effect from IPL, Nd:YAG, or ruby
Paradoxical hypertrichosis is a possible, but rare, adverse effect of
photoepilation, particularly in dark-skinned individuals
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