approach to hirsutism

*Approach to HirsutismDr. Saeid KhezerFamily doctorUniversity of Duhok Iraq / Kurdistan 2016/5/[email protected]

*Definition: Hirsutism Excessive terminal hair that appears in a male pattern (i.e., sexual hair) in women

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Photo ofAnnie Jones, a bearded lady, taken byCharles Eisenmannaround 1900. The cause of Jones' hypertrichosis is unknown.*A young women with hirsutism.

Epidemiology

overall prevalence of hirsutism is unknown.The definition of normal must also consider race & ethnicityMost Asian & Native American women have little body hair, while Mediterranean women on average have moderately heavy body hair; serum androgen concentrations are similar in the three groupsThe most important consideration, whatever the woman's background, is whether the pattern of hair growth has changed or the rate of growth has increased.

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Pathophysiology:

androgen production (by the ovaries or adrenal) Testosterone is usually of ovarian origin Dehydroepiandrosterone sulfate (DHEA-S) is of adrenal origin Androstenedione can be of either adrenal or ovarian originRarely target organ production of androgen

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Causes of hirsutismMost common :

Idiopathic hirsutismPolycystic ovarian syndrome [82%]Less common

HyperprolactinemiaDrugs Congenital adrenal hyperplasia [CAH]HyperthecosisOvarian tumors Adrenal tumors Severe insulin resistance syndrome

*Carbamazepine Fluoxetine IsotretinoinOlanzapinePregabalin Corticosteroids (systemic)Oral contraceptive

Idiopathic hirsutism

women with hirsutism and no other clinical abnormalities ( NR ovulatory function , and no identifiable cause of their hirsutism ).Ovulatory function may be verified by a luteal phase day 7 progesterone, which should be at least 5 ng/ml.Total & free serum testosterone are more often within the normal range.More in women of Mediterranean ancestry.There may becutaneouse 5 alpha reductase activity.

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Polycystic Ovary Syndrome

The most common identifiable cause of androgen excess in womenThe minimum criteria for this diagnosis are :

Menstrual irregularity, due to oligo- or anovulation

Evidence of hyperandrogenism, whether clinical (hirsutism, acne, or male pattern balding) or biochemical (elevated serum androgen concentrations)

Exclusion of other disorders such as congenital adrenal hyperplasia and androgen-secreting tumors.*

Polycystic Ovary Syndrome

the diagnosis does not require biochemical tests (except as needed to exclude other disorders) or pelvic US to evaluate ovarian structure.Usually becomes evident about the time of puberty or soon thereafter.the symptoms gradually worsen with age.

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DDX. Of PCOS :Idiopathic hirsutism HyperprolactinemiaHypothyroidism Non classical CAHOvarian tumorsAdrenal tumorsCushings syndrome

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Hyperprolactinemia

Some women with hirsutism have mild hyperprolactinemia, but whether it alone can cause hirsutism is not clear.Sometimes associated with serum DHEA-S concentrations (prolactin receptors have been identified in human adrenal cells, and prolactin can increase adrenal DHEA secretion)

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Hyperprolactinemia

Underlying problem in many of these women is probably the PCOS.DHEA-S is such a weak androgen that the hirsutism associated with hyperprolactinemia is probably due more to the ovarian hyperandrogenism characteristic of the PCOS than any effect of hyperprolactinemia.

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Congenital Adrenal Hyperplasia

Basal (8 AM) 17-OH Progest ... > 8 ng/ml is diagnostic.

2-8 ng/ml ( CAH or PCOS )

A rise at least 10 ng/ml 60 min. after IV ACTHis diagnostic for nonclassical CAH.*

Hyperthecosis

Nonmalignant ovarian disorder production of testosterone by luteinized thecal cells in the stroma.It is still unclear if hyperthecosis is a distinct disorder or is part of the spectrum of the PCO.The woman's history usually is one of gradual onset of hirsutism and other manifestations of androgen excess.

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Ovarian Tumors

Occur later in life and progress more rapidlyAndrogen-secreting tumors constitute only 5 percent of all ovarian tumorsHistologically : Sertoli-Leydig cell tumors(androblastoma, arrhenoblastoma), granulosa-theca cell(stromal cell) tumors, and hilus-cell tumors.Serum testosterone 1.5 - 2.0 ng/ml ( 3 the upper limit of Nl in women is 0.60 to 0.80 ng/ml)Many of these tumors can be identified by vaginal US.

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Adrenal Tumors

Rare cause of androgen excessMost are carcinomas that often secrete not only androgen ( mostly DHEA and DHEA-S )May lose the ability to sulfate DHEA NR serum DHEA-S value does not exclude the Dx.An unequivocally elevated serum DHEA-S ( >700 g/dl ) is suggestive of an adrenal tumors.

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Insulin ResistancePossibly acting via the theca-cell receptors for IGF-1Insulin also serum SHBG fraction of serum testosterone that is free at any serum total testosterone concentration.

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Diagnostic Approach

Documentation of the degree of androgen excessExclusion of the serious but rare causes of hirsutism such as hyperprolactinemia due to pituitary and hypothalamic tumors and ovarian and adrenal tumors

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findings that suggest one of the rare causes of hirsutism

Abrupt onset, short duration (typically < 1 year), or progressive worsening of hirsutism.Onset in the 3rd decade or later, rather than near puberty.Symptoms or signs of virilization ( frontal balding, acne, clitoromegaly, increased muscle mass, or deepening of voice). More severe hirsutism and virilization are typically seen in ovarian hyperthecosis.Moderately elevated serum androgen concentrations :

serum testosterone > 150 ng/dL, serum free testosterone > 2 ng/dL, and serum DHEA-S >700 g/dL in young.*

The important elements of the history

The age of onset of hirsutism, its nature (vellus vs. terminal), and the rate of progressionThe benign forms of hirsutism [hyperthecosis, nonclassical congenital adrenal hyperplasia (CAH), and obesity related insulin resistance] tend to begin in the pubertal yearsHirsutism that appears clearly before puberty or clearly after puberty is more often caused by an ovarian or adrenal neoplasm, or it is medication related

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History : Menstrual history

The normal menstrual pattern varies with age. In pubertal girls, the average cycle length is 34 d. In older women, it is 28 d.A normal pattern is roughly 12 cycles per year, varying in length, the longest cycle minus the shortest cycle being no more than 10 d

- Women with consistently regular cycles and symptoms of ovulation are unlikely to have severe hyperandrogenemia.- A woman who has irregular cycles should be evaluated for hyperprolactinemia.*

History

Cutaneous manifestations of hyperandrogenism

- frontal balding - acneTime course of symptoms : progressive worsening of hirsutism, a later age of onset, or rapid rate of progression suggest the possibility of ovarian or adrenal tumorWeight history : Obese women have increased androgen productionMedication history: drug Hx. ( danazol, norgestrel )

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History : Family history

- Hirsutism, acne, menstrual irregularity, infertility, early cardiovascular disease, and obesity are all potential indicators of a familial tendency towards the PCOS.- A family history of known or suspected CAH would prompt a ACTH stimulation test.*

Physical Examination

Body habitus The pattern of body fat distribution (truncal obesity, a buffalo hump, and supraclavicular fat) may suggest the presence of Cushing's syndrome.Skin The location and quantity of terminal hair should be determined objectively using the Ferriman-Gallwey score. A total score > 8 is considered to be abn.Acne, seborrhea, temporal balding, acanthosis nigricans ( suggest insulin resistance), striae, thin skin, or bruising (suggest Cushing's syndrome )

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The Ferriman-Gallwey scale for hirsutism*


The male terminal hair pattern differs from the female

pattern with temporal balding, full beard distribution, hair over the shoulders, chest, and upper abdomen.The female terminal hair pattern lacks temporal balding and

terminal facial hair other than on the upper lip and chin.Normal women have no terminal hair on the shoulders

and chest other than a few periareolar hairs. It is veryuncommon for women to have terminal hair on the upper

abdomen*


Signs of virilization In addition to acne, deepening of the voice, frontal (or crown) balding, increased muscle mass, and clitoromegaly [clitoral length >10 mm or the clitoral index ( length width ) >35 mm ] indicate the presence of moderate androgen excess.

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Galactorrhea The presence of any breast discharge (spontaneous or expressible) is suggestive of hyperprolactinemia and warrants measurement of serum prolactin even if the woman's menstrual cycles are regular.Abdominal and pelvic examination may reveal mass lesions that could indicate the presence of an androgen-secreting tumor.

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Laboratory Testing

Serum Testosterone- the best overall estimate of androgen production in hirsute women is the single best test- values < 150 ng/dL (5.2 nmol/L) exclude ovarian or adrenal tumors, also tend to exclude ovarian hyperthecosis.- most women with the PCOS have serum testosterone < 150 ng/dL & are sometimes normal; women with idiopathic hirsutism are even more likely to have normal values.*

Serum Testosterone

In all women with androgen excess ( PCOS, hyperinsulinemia, idiopathic hirsutism ) serum free testosterone concentrations are disproportionately higher than serum total testosterone concentrations.

*Androgen excess hepatic production of SHBG

Laboratory Testing: Serum ProlactinSerum Prolactin-If serum testosterone in an anovulatory woman serum TSH & prolactin to R/O anovulation associated with hyperprolactinemia moderately elevated value should be followed by imaging of the hypothalamic-pituitary region.- slightly elevated values can be found in women with PCOS.*

Serum DHEAS

- should be measured in women with rapidly progressing hirsutism and in those who are virilized.- Nl or slightly increased in most with androgen excess.- values > 700 g/dL (13.6 mol/L) in a young woman, suggest the presence of an adrenal tumor.- secretion of DHEA-S begins to fall after age 20 years serum DHEA-S must be interpreted according to age-specific normal ranges.- Low values have been reported in a few women with adrenal carcinoma, however, due to lack of sulfating activity within the tumor.*

Summary

Women with long-standing mild hirsutism, not different from family members, and regular ovulatory menstrual cycles require no laboratory testing at all.The Endocrine Society guidelines suggest testing in women with moderate to severe hirsutism, or for hirsutism associated with irregular menses, obesity, signs of virilization, or rapid progression

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SummaryWomen with mild to moderate hirsutism should have measurements of serum testosterone; serum prolactin & TSH should also be measured if menstrual cycles are irregular.Serum DHEA-S should be measured in addition to testosterone in women with progressive hirsutism, irregular menstrual cycles, and any signs of virilization

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Additional test in selected patient

Serum FSH- if there is any suspicion of declining ovarian estrogen production ( periods of amenorrhea or menopausal symptoms ).- Serum FSH should be elevated if estrogen production is reduced.- Low estrogen production can contribute to increased hair growth by reducing SHBG production, thereby raising serum free testosterone.*


Serum LH- Women with PCOS tend to have elevated serum LH concentrations and normal or low serum FSH.- high LH/FSH ratio is not required for the diagnosis, because LH secretion is pulsatile and many women with PCOS have normal serum LH concentrations-because the LH measurement was obtained at the nadir of a pulse.*


Pelvic UltrasonographyTo screen for ovarian tumors- Suspicious findings include large cysts, solid masses, and complex cysts that do not resolve spontaneously in 2-4 wks.- The sensitivity and specificity of US for the Dx. of ovarian tumors in hyperandrogenic women has not been determined.- Small hilus-cell tumors of the ovary that produce large amounts of testosterone may not be seen by US or even at the time of surgery.*

Pelvic Ultrasonography

can also be used to identify polycystic ovaries

- enlarged ovaries, consist of a ring of small peripheral follicles, typically each < 8 mm, with an increased amount of central stroma.- However, the correlation between polycystic ovaries, as detected by US & the PCOS is only fair.-women with non-ovarian causes of hirsutism, such as CAH and adrenal tumors, may have polycystic-appearing ovaries.*

Pelvic UltrasonographyIndicationsIn patients with an elevated serum androgen concentration if a tumor is suspected.It may also be indicated to exclude endometrial hyperplasia, which is common in PCOS.

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Testing for CAH- should be considered in women with an early onset of hirsutism (including those with premature adrenarche), hyperkalemia , a F Hx. of CAH, or a strong desire to know a specific etiologic diagnosis.-by measuring serum 17-hydroxyprogesterone (and cortisol) before and 60 min. after IV injection of 250 g of synthetic ACTH (cosyntropyn, ACTH amino acids 1-24) A positive test consists of a 60-minute serum 17-OHP value > 10 ng/mL (30 nmol/L).*


Testing for Cushings Syndrome- if hirsute women have symptoms and signs of cortisol excess, screening for this disorder may be indicated.- by measuring 24-hour urinary excretion of cortisol (and creatinine) or by performing an overnight DST.*


Abdominal CT or MRI- Is indicated to look for an adrenal mass if the woman has a markedly elevated serum DHEA-S concentration or other evidence of excess adrenal steroid production.-Radiologic testing is otherwise not indicated, and may be misleading, because nonfunctioning adrenal masses are common*


Laparascopy or Laparatomy- In a hirsute woman who has menstrual abnormalities, a serum testosterone > 200 ng/dL (6.9 nmol/L), and no evidence of an adrenal tumor.- Such a patient may have a small ovarian tumor (especially a hilus-cell tumor) that is too small to be detected by pelvic ultrasonography.*

Summery

Endocrine Society suggest measuring serum total testosterone and DHEA-S in all women presenting with hirsutism.We suggest an adrenal CT scan to look for an adrenal androgen-secreting tumor if the serum DHEA-S concentration is 700 mcg/dLWe suggest a transvaginal ultrasound if the serum total testosterone concentration is 150 ng/dL

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Treatment

For women with patient-important hirsutism despite cosmetic:

# measures pharmacological therapy # direct hair removal methodsThe choice between these options depends on:

(a) patient preferences(b) the extent to which the area of hirsutism that affects well- being is amenable to direct hair removal(c) access to and affordability of these*

direct hair removal methods

Cosmetic methods (shaving, plucking, waxing, bleaching) can be effective, and their use is reasonable either alone or as a supplement to drug therapy.Permanent hair reduction including electrolysis and photoepilation (laser and intense pulsed light )women with underlying hyperandrogenemia are likely to experience hair regrowth because of the continued stimulation of hair follicles by endogenous androgens. This can be prevented by pharmacologic therapy

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Topical therapy

Vaniqa (eflornithinehydrochloride) cream available for the treatment of unwanted facial hair in women.It is an inhibitor of hair growthImprovement, manifested by shorter, softer, and less visible hair, is seen in about 8 wk.must be used indefinitely to prevent regrowth

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pharmacological therapy

Oral contraceptives :the first line drug for the management of hirsutismantiandrogenis added if the clinical response is suboptimal after six months of therapyInsulin lowering agents are not considered to be an effective therapy for hirsutism (Metformin,rosiglitazone)

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Oral contraceptives

*Inhibition of LH secretion and therefore LH-dependent ovarian androgen productionIncreased hepatic synthesis of SHBG by estrogen, resulting in decreased concentrations of serum free testosteroneInhibition of adrenal androgen secretion

Oral contraceptives

*The best choice for treating hirsutism OCP that contain 30 micg of ethinylestradiol and progestin with low androgenicity (cyproterone acetateor drospirenone)The side effects:

- increased deep vein thrombosis- breast cancer

Antiandrogens

*For women who cannot or choose not to conceive OCPs or antiandrogens

- spironolactone- Cyproterone acetate- Finasteride-Flutamide

Spironolactone

*The most useful and available antiandrogen for the treatment of hirsutismIt is usually given in doses between 100 and 200 mg/dSide effects: menstrual irregularity ,mild diuretic effect and hyperkalemia

approach to hirsutism

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