Hirsutism

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Hirsutism

• F.Fatemi,MD
• Isfahan university of medical sciences

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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.

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Pathophysiology

• Vellus hairs are fine, unpigmented hairs that
  cover most of the body before puberty.
• Pubertal androgens promote the conversion of
  these vellus hairs to coarser terminal hairs.
• 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
• However, some terminal hair growth is
  androgen-independent (eg, scalp, eyebrows,
  lashes).

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Pathophysiology

• Dihydrotestosterone(DHT) is the androgen that
  acts on the hair follicle to produce terminal
  hair.
• This hormone is derived from both the bloodstream
  and local conversion of a precursor,
  testosterone.
• The local production of dihydrotestosterone is
  determined by 5-alpha-reductase activity in the
  skin.
• Differences in the activity of this enzyme may
  explain why women with the same plasma levels of
  testosterone can have different degrees of
  hirsutism.

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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 should be considered in a
  patient of any age presenting with
• 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.)

Adrenal hirsutism
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• 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 ß -hydroxysteroid dehydrogenase (less
  frequent)
• 11-ß -hydroxylase deficiency (least frequent).
• 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.

Non-tumoral adrenal hirsutism Adrenal
hyperplasias
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Late onset CAH (Non classic CAH)

• 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

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•  The biochemical findings are less severe in
  patients with the late-onset form of the
  disorder.
• 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.
• 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.

Diagnosis
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Adrenal Androgens

• DHEA-S excess is of adrenal origin(CAH,Cushing,Tum
  ors)
• Androstenedione can be of adrenal or ovarian
  origin
• 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
• DHEA-S gt700 mcg/dL (13.6 µmol/L) raise suspicion
  for an adrenal androgen-secreting tumor.

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• 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.

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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).
• 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, ..
• 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.

Hypercortisolism (Cushing's syndrome)
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• In most instances, Cushing syndrome is caused by
  glucocorticoid therapy.
• 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,
• 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
• A reduction of free testosterone below 8 pg/mL
  (27 pmol/L)
• reduction of DHEAS to levels below the normal
  range for adult controls (lt70 mcg per dL).

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• If the patient presents with
• Lateral hirsutism( neck and the breasts)
• SAHA
• obesity
• obvious menstrual disorders
• the presumed diagnosis is hirsutism of ovarian
  origin.
• This may also have a tumoral or non-tumoral
  etiology

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
• Oligo- or anovulation (menstrual cycles longer
  than 35 days or fewer than 10 menses a year).
• Clinical (hirsutism, acne, androgenetic
  alopecia) or biochemical evidence of
  hyperandrogenism.
• Polycystic ovaries (12 follicles in each ovary
  measuring 2-9mm in diameter and/or increased
  ovarian volume to gt10ml) on ultrasound
  examination.
• If using the Rotterdam criteria for PCOS
  diagnosis, many women with idiopathic hirsutism
  would be considered to have a subtle form of PCOS

Non-tumoral ovarian hirsutism
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Polycystic ovary syndrome

• Biochemically, one can see
• 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.

Non-tumoral ovarian hirsutism

• The characteristic endocrine abnormality is an
  elevation in levels of plasma free testosterone
  that is not suppressed by dexamethasone

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• PCOs is associated with
• infertility
• insulin resistance manifested as
• diabetes mellitus
• metabolic syndrome , including central obesity,
  hypertension, glucose abnormalities, and
  dyslipidemia)
• possibly with an increased risk of endometrial
  cancer.

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• This is similar to PCOS, but with greater
  production of androgens, especially testosterone.
  
• The patients present with signs of
• virilization,
• hirsutism
• and even androgenic alopecia.
• 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.

Ovarian Tumor
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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
• We will consider four types of dermatologic
  hirsutism.
• 1)Ovarian SAHA
• 2)Adrenal SAHA
• 3)Hyperprolactinemic SAHA
• 4)Familial hirsutim

Constitutional or dermatologic hirsutism
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• 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
• laboratory tests are absolutely normal.

Familial hirsutism
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Diagnosis

• (A) Hirsutism must be distinguished from
  hypertrichosis
• 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.)
• Hypertrichosis, in which hair is distributed in
  a generalized, nonsexual pattern, is not caused
  by excess androgen

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Diagnosis

• (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).

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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.
• _Other causes of androgen excess occur
  infrequently
• 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.
• 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.

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Evaluation

• 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
• anabolic steroids(Oral Fluoxymesterone
  ,Methyltestosterone ,Testosterone -Parenteral
  Testosterone)
• 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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Diagnosis

• History
• Age of onset
• 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.  
• Family history
• 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.
• 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.

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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
• 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
• ?-4-androstenedione
• 3a-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.
• 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.
• 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 ).
• The difference is most evident in women with
  idiopathic hirsutism, in whom serum free
  testosterone may be high but serum total
  testosterone is normal.

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Treatment
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• The therapeutic options of hirsutism can be
  divided into
• systemic
• Topical
• dermato-cosmetic therapies.
• Patients should be informed that the response to
  systemic agents is slow occurring over 3-6
  months after therapy has begun

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• (OC) agents are considered to be the first-line
  therapy for hirsutism in premenopausal women.
• Ocs commonly contain ethinyl estradiol (EE)
  progestin.
• 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.
• 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.

Oral Contraceptives
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Antiandrogens
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• Spironolactone, an aldosterone antagonist, has
  several actions.
• 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.
• In the first months of treatment, measurements of
  blood pressure and serum potassium levels every 4
  weeks are recommended.
• Spironolactone should not be prescribed to
  patients with renal insufficiency or
  hyperkalemia.
• 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.
• CA (2mg) combined with EE has been shown to be
  more effective than placebo, but not better than
  other antiandrogens.
• 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.
• 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
• 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-a-reductase
• Finasteride has been shown to lower hirsutism
  scores by 30-60 in addition to reducing the
  average hair diameter.
• In comparative studies, finasteride demonstrated
  efficacy similar to that of other antiandrogens
  with fewer adverse effects.
• Other trials suggested that spironolactone and
  flutamide were more effective than finasteride.
• 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.
• Thiazolidinediones (rosiglitazone and
  pioglitazone) sensitize end organs to insulin
  through their action on the peroxisome-proliferato
  r-activated receptor-?.
• 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.

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Gonadotropin-Releasing Hormone (GnRH) Agonists

• 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
• 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.

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Glucocorticoids

• Glucocorticoids can be prescribed to women who
• 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.

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Topical Treatment

• Eflornithine hydrochloride cream 13.9 (Vaniqa,
  Skin Mediea) has been approved by the US FDA for
  the reduction of unwanted facial hair in women.
• Noticeable results take about 6-8 weeks.
• Adverse effects include itching and skin dryness.

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• Direct Hair Removal Methods
• These modalities can be divided into temporary
  methods of hair removal and permanent methods of
  hair reduction.
• Temporary methods of hair removal include
  plucking, waxing, shaving and chemical depilatory
  agents.
• Permanent methods of hair reduction include
  photoepilation (using laser and intense pulse
  light IPL) and electrolysis.
• 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,
  NdYAG, or ruby
• Paradoxical hypertrichosis is a possible, but
  rare, adverse effect of photoepilation,
  particularly in dark-skinned individuals

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