HIRSUTISMHIRSUTISM

F.Fatemi,MDIsfahan university of medical sciences

DefinitionDefinition 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.

PathophysiologyPathophysiologyVellus 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).

PathophysiologyPathophysiology

• 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.

classificationclassificationFor clinical and therapeutic purposes, hirsutism

can be classified into eight categories:1)Hirsutism of pituitary origin2)Hirsutism of adrenal origin3)Hirsutism of ovarian origin:4)Constitutional hirsutism5))Hepatic hirsutism6)Hirsutism due to ectopic hormone production7)Iatrogenic hirsutism8) Hirsutism due to peripheral failure in

converting androgens into estrogens:

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.)

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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 β -hydroxysteroid dehydrogenase (less frequent)◦ 11-β -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.

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Late onset CAH (Non classic CAH)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

 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.

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◦ DHEA-S excess is of adrenal origin(CAH,Cushing,Tumors)◦ 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 >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 available2) Genetic counseling may be necessary.

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.H

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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. 

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 (<70 mcg per dL).

If the patient presents with :Lateral hirsutism( neck and the breasts)SAHAobesity obvious menstrual disorders the presumed diagnosis is hirsutism of ovarian

origin.

This may also have a tumoral or non-tumoral

etiology

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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 >10ml) 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

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Polycystic ovary syndromePolycystic 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.

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

PCOs is associated with :

infertility

insulin resistance manifested as: diabetes mellitusmetabolic syndrome , including central obesity,

hypertension, glucose abnormalities, and dyslipidemia)

possibly with an increased risk of endometrial cancer.

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.

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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

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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.

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DiagnosisDiagnosis

(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

(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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EtiologyEtiology 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.

EvaluationEvaluationThe 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 OCsDanasole, valporeic acid

2)An Endogenous source( i.e. adrenal cortex or ovaries)

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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sHistoryAge 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.

Lab investigationLab 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

Bolognia recommends measuring:total and free testosterone,DHEA-SProlactinSHBGΔ-4-androstenedione 3α-androstanediol glucuronide (metabolite of DHT)

Depending on the results of these Tests, the laboratory evaluation can be expanded

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.

Treatment Treatment

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

(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.

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AntiandrogensAntiandrogens

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.

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.

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.

Finasteride: is a potent inhibitor of the type 2 isoenzyme of 5-α-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.

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-proliferator-activated receptor-γ.

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 Gonadotropin-Releasing Hormone (GnRH) Agonists 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.

Glucocorticoids 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.

Topical Treatment 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.

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, Nd:YAG, or ruby

Paradoxical hypertrichosis is a possible, but rare, adverse effect of photoepilation, particularly in dark-skinned individuals