Hirsutism - excessive male-pattern hair growth

Overview of Hirsutism

Hirsutism refers to excessive male-pattern hair growth in both men and women.   However, it is particularly a problem in women, when hair grows where it is normally absent or minimal, such as on the chin, chest, face or body. Hirsutism is usually due to a hormonal imbalance, which may be adrenal, ovarian or in the hypothalmus or pituitary gland.

Hirsutism is an early manifestation of virilism (the presence of male secondary sexual characteristics in a female).   Includes, hirsutism, receding frontal hairline, masculine body build, deepening of voice, increased▲  sebaceous gland secretion/acne, clitoral enlargement.

Hirsutism is more common in certain ethnic races.   Highest percentages affected are those from Europe, and then Africa. The lowest percentages are from Asia.

Two types of hirsutism

Idiopathic hirsutism (no identifiable cause).  Refers to women with hirsutism and no other clinical abnormalities. The serum androgen concentrations in these women are more often within the normal range than are the concentrations in women with definable causes of hirsutism. A gradual increased growth of coarse body hair is typically the only symptom in women with this condition, which probably stems from a hereditary trait;

Secondary hirsutism.   A common endocrine disorder in women, defined as excessive growth of terminal (thick) hairs in a male pattern (facial and body regions), resulting from an excess of  androgen; hair follicles usually become enlarged, and the hairs themselves become larger and darker. Commonly occurs spontaneously but may also develop as a secondary disorder of various underlying diseases

What's going on? 

Hirsutism occurs with either of the following criteria:

(1) Increased androgens (E.g. Testosterone, DHEA, DHEA-S) from adrenal and/or ovarian sources induces 5-alpha-reductase enzyme activity ▲ within susceptible hair follicle.  Resulting in local production of the powerful androgen DHT ▲  , which stimulates the hair follicle for hair growth, and is the likely culprit leading to hirsutism. Normal Testosterone production rates in women average 0.2 mg /day (25% from ovaries, 25% from adrenals, 50% from peripheral pre-hormones, notably ANDROSTENEDIONE). About half the women with mild hirsutism have high androgen levels.

(2)  Hair follicles have increased sensitivity to androgen

Virilization occurs primarily from diseases of adrenals or ovaries.   However, it may also be from exogenous androgens;

-   Adrenal tumors.   Produce androgens causing virilization in association with excessive production of a wide variety of C19 androgens (E.g. DHEA, ANDROSTENEDIONE, ANDROSTENEDIOL, Testosterone, DHT).

-   Ovarian tumors.   Tend to secrete a narrower range of androgens and their presence may be occult (hidden);

-   Non-tumorous conditions.    The most common causes of hirsutism in women are mainly from ovarian origin, presenting mild to severe abnormalites of androgen production and ovarian histology. The pathogenesis of these abnormalities is still speculative, but appears to be related to increased pulsatile and tonic secretion of LUTEINIZING HORMONE (LH), over-stimulating ovaries.

Symptoms of Secondary Hirsutism

Secondary hirsutism (hirsutism with virilism) presents the following symptoms:

•  Male pattern hair growth (in women)

•  Irregular menstruation

•  Lack of ovulation (Anovulation).    Incidence considerably higher than non-hirsute women

•  Acne/ increased sebum secretion by sebaceous glands

•  Deepening of voice;

•  Balding;

•  Genital abnormalities;

Other symptoms sometimes associated with hirsutism:

•  High blood pressure

•  Enlarged ovaries

•  Enlarged adrenal glands

•  Abnormal cholesterol and glucose intolerance

Possible causes of secondary hirsutism

•  OVARIAN dysfunction

~ Polycystic ovary syndrome.   The cause of > 70% of cases of androgen excess/secondary hirsutism.   A multi-organ disease affecting 6% of reproductive age women.

~ Ovarian tumors;

~ Ovarian hyperthecosis;

~ Ovarian hyperplasia

•  PITUITARY dysfunction

~ Excess GROWTH HORMONE

•  ADRENAL dysfunction

~ Adrenal tumors

~ Congenital adrenal hyperplasia (CAH)(Defects in adrenal enzymes)

~Some forms of Cushing's syndrome (caused by excess CORTISOL)

•   Severe hyperinsulinemia

•   Hyperprolactinemia

•  Luteoma of pregnancy

 

Non-PCOS cases of hirsutism are diagnosed with rare endocrine diseases, or as a result of taking certain drugs or having INSULIN resistance (IR)

Suspected in older women and women who develop hirsutism rapidly

OVARIANtumors, hyperthecosis or hyperplasia

Androgen-secreting ovarian tumors

•  Hirsutism caused by an androgen-secreting ovarian tumor is most likely to occur later in life - and progress more rapidly than when caused by PCOS;

•  Ovarian tumors tend to secrete a narrower range of androgens than adrenal tumors;

•  Testosterone levels are usually two and a half times higher than normal.

•  Many of these tumors can be identified by vaginal ultrasonography.

Ovarian hyperthecosis (excessive hair growth anywhere on the body)

•  Presence of nests of luteinized androgen-producing theca cells in the ovarian stroma (soft tissue in ovary similar to connective-tissue or striped muscle).    As a result of differentiation of the ovarian interstitial cells into active steroid-hormone-producing luteinized stromal cells. These nests of luteinized theca cells are scattered throughout the stroma of the ovary, rather than being confined to areas around cystic follicles as in PCOS, resulting in greater production of androgens than in PCOS

•  The clinical features of hyperthecosis are similar to those of PCOS.   However, women with hyperthecosis have more hirsutism and are much more likely to be virilized.

Geist, SH, Gains, JA. Diffuse luteinization of the ovaries associated with masculinization syndrome. Am J Obstet Gynecol 1942; 43:975.

Unlike PCOS, which occurs only during the reproductive years, hyperthecosis of the ovaries can occur in postmenopausal women. Severe hirsutism and virilization in post-menopausal women are more often due to ovarian hyperthecosis than virilizing (androgen-secreting) ovarian tumors.

•  Symptoms of ovarian hyperthecosis:

Most women are obese;

Most have a long-standing history of hirsutism, usually severe.

Many have symptoms of secondary hirsutism.

Most have amenorrhea, the rest have irregular and anovulatory cycles.

Some have acanthosis nigricans - suggestive of severe insulin resistance.

A familial occurrence of hyperthecosis has been reported.

The ovariansecretion of large amounts of androgen in women with hyperthecosis means that peripheral estrogen production is increased.  As a result, the risk of endometrial hyperplasia and perhaps also endometrial carcinoma are likely to be increased, especially in postmenopausal women.

Ovarian hyperplasia (increase in # of cells).   In most cases, high Testosterone levels could be due to simple ovarian hyperplasia. Autopsies of 600 adult women revealed half with ovarian stromal hyperplasia. These women also had significantly more frequent obesity, arteriolar nephrosclerosis, endometrial overgrowths and uterine leiomyomas (uterine fibroids).

PITUITARY dysfunction (Excess GROWTH HORMONE)

Acromegaly (Increased GROWTH HORMONE)

ADRENAL dysfunction

The adrenal glands are a pair of walnut-sized organs located above your kidneys and are a prominent source of androgen. Excess adrenal androgen secretion is an occasional cause of hirsutism and virilization in women, and a well-recognized cause of virilization in infants and children. It may also contribute to the clinical findings in some patients with Cushing's syndrome;

-   Adrenal tumor.    A rare cause of androgen excess, androgen-producing tumors of the adrenals cause virilization in association with an excessive production of a wide variety of C19 androgens. A possibility when serum DHEA-S levels are 2x higher than normal; Values above 500 µg/dL suggest the presence of an adrenal tumor.

-   Congenital Adrenal Hyperplasia (CAH).    A family of inherited disorders caused by deficiencies in the adrenal enzymes used to synthesize glucocorticoids; There is a lack of CORTISOL hormones, and an increased adrenal production of glucocorticoid precursors and androgens. CAH is marked by acute hirsutism or virilization, sometimes infertility or other signs of masculinity, and possibly stunted height (compared to parents) .^2,3,5,6

Congenital Adrenal Hyperplasia (CAH)

Certain drugs (i.e iatrogenic factors)

•  Minoxidil - a drug used to widen blood vessels;

•  Danazol

•  Cyclosporine

•   Phenytoin

•  Androgenic steroids -E.g. Testosterone

•  Diazoxide

•  Glucocorticoids

•  Progestin-containing medications

•  Androgenic progestins in some oral contraceptives -E.g. Norgestrel (contained in Ovral)

Severe hyperinsulinemia

Already acknowledged as a likely factor in PCOS, high INSULIN levels (usually as a consequence of INSULIN resistance) can be a cause of an increase in androgen and probably ovarian hormone production.

Insulin Resistance (IR)

Hyperprolactinemia (higher than normal PROLACTIN level, which is < 20 ng/ml). 

Should be considered in cases with hirsutism and amenorrhea (no menstruation cycles) plus a breast discharge.

-   Clinical manifestations in women.   Galactorrhea (spontaneous milk secretion), amenorrhea, infertility and hirsutism; PROLACTIN levels usually under 150 ng/l

-   Amenorrhea (absent menstrual cycle) due to PROLACTIN's inhibition of GnRH secretion.   Leading to reduced LH/FSH secretion, also interferes with the actions of LH/FSH at the gonads.Result is a fall in estrogen and Testosterone levels; Possible causes of amenorrhea w/ hyperPROLACTINemia include:

 (1) PROLACTIN level ≤ 100 ng/mL -breast feeding, hypothyroidism, decreased PROLACTIN metabolism (as in renal failure), or medications that antagonize the dopamine D2 receptor (common psychiatric drugs)

(2) If PROLACTIN >100 100ng/mL -pituitary adenoma

-   PROLACTIN may stimulate androgen secretion from the gonads and adrenal gland.   Resulting in hirsutism.

-   PROLACTINoma (most common pituitary adenoma).   In women, they present as micro adenomas (small PROLACTIN -secreting pituitary tumor) recognized as a common cause of infertility and abnormal/absent menstrual cycles. The majority of women with PROLACTINomas have PROLACTIN levels below 150 ng/ml and a level >100 ng/mL suggests a PROLACTINoma, which can be helpful in diagnosis. If PROLACTIN levels >250 ng/ml, a PROLACTINoma is unlikely.

-   PROLACTIN release is primarily under inhibitory regulation by DOPAMINE;

-   PROLACTIN release is increased by:

•  Pronounced hypothyroidism or PCOS.   Hypothalamic peptide TRH (thyrotropin-releasing hormone) acts as PROLACTIN -releasing factor, and may cause moderate/ but more permanent elevated PROLACTIN levels .

•  Breast stimulation.   Hypothalamic peptide VIP (vasoactive intestinal polypeptide) acts as PROLACTIN -releasing factor; baby sucking on nippleincreases PROLACTIN secretion to provide breast milk.

-   Decreased PROLACTIN metabolism will cause hyperprolactinemia.   E.g. with renal failure or meds that antagonize the DOPAMINE D2 receptor (commonly used for psychiatric disorders)

 

Lab Tests for Hirsutism

The tests that provide the most useful information are:    measurements of serum Testosterone, PROLACTIN, and DHEA-S

-   DHEA-S is almost entirely derived from the adrenal gland

-   Testosterone, in hirsute women, is mostly secreted by the ovary.

Serum Testosterone (free or plasma??).   Single best test for evaluating hirsutism.

•  The upper limit of normal for serum Testosterone in women varies from 60 to 80 ng/dL

•  Values below 150 ng/dL exclude ovarian and adrenal tumors - These values also tend to exclude ovarian hyperthecosis where the serum total Testosterone is usually greater than 200 ng/dL

•  Most women with PCOS have serum Testosterone concentrations below 150 ng/dL

•  Women with idiopathic (unknown cause) hirsutism are more likely to have normal values.

Serum PROLACTIN.   Should be measured because an occasional woman with hirsutism and irregular menstrual cycles may have hyperPROLACTINemia due to hypothalamic disease or a pituitary tumor.

Serum DHEA-S - should be measured in women with rapidly progressing hirsutism and in those who are virilized, in an attempt to detect an adrenal tumor. The secretion of DHEA-S begins to fall after age 20 years; as a result, serum DHEA-S measurements must be interpreted according to age-specific normal ranges. Serum DHEA-S concentrations are normal or slightly increased in most women with androgen excess. Values above 500 µg/dL suggest the presence of an adrenal tumor.

Some studies related to hirsutism

Blood tests for androgens, progestagens, PROLACTIN in hirsute women

▼ or ▲  Significantly lower or higher

Abstract.Blood samples were obtained from 158 hirsute women for determination of dehydroepiandrosterone-sulfate (DHEA-S), Testosterone (T), Progesterone(P), 17 alpha-hydroxy-Progesterone(17OHP) and PROLACTIN (PRL).The percent frequency of elevated level of these hormones in hirsute women was: DHEA-S: 35%, T: 55%, P: 25%, 17OHP: 53% and PRL: 6%. The mean (+/-SE) levels of DHEA-S (2.36+/-0.1 microgram/ml) and T (714+/-21 pg/ml) in hirsute women were elevated, both in the pre- and postovulatory phases; while 17OHP in hirsute women was decreased in the postovulatory phase (1.59+/-0.48 ng/ml) and increased in the preovulatory phase (1.51+/-0.18 ng/ml) when they were compared with their respective controls. PRL in postovulatory hirsute women was also lower (12.0+/-1.1 ng/ml) than the control. Sixty patients were subjected to a 2-wk dexamethasone (DXM) suppression test to determine the source of androgen excess. The results of DXM suppression test suggested that the sources of androgen excess in hirsute women were: ovarian:33% / adrenal: 25% /mixed (ovarian plus adrenal): 35% / none: 7%. The results also suggested that excess progestagensin hirsute women were attributed to either ovarian (P) or adrenal (17OHP) hypersecretion. Correlation analysis between these hormones showed a significant (P less than 0.05) correlation only between P vs. 17OHP, T vs. 17P, and T vs. DHEA-S

Wu CH, Plasma androgens, progestins, and PROLACTIN in hirsutism. Eur J Obstet Gynecol Reprod Biol. 1982 Sep;13(6):377-87.

Menstruation-related studies

 

Abstract - In a study of 129 consecutively referred hirsute women, 40% had regular menstrual cycles.About one half of such individuals had elevated levels of one or more androgens(DHEAS, Testosterone or free Testosterone index), whereas a higher proportion (69%) of hirsute women with oligo-amenorrhea were abnormal. Mean androgen levels in regularly cycling hirsute women were higher than in controls, but lower than or equal to those in oligo-amenorrheic hirsutism.

Mehta A, Matwijiw I, Taylor PJ, Salamon EA, Kredentser JV, Faiman C, Should androgen levels be measured in hirsute women with normal menstrual cycles? Int J Fertil. 1992 Nov-Dec;37(6):354-7.

Endogenous Progesterone study

▼ or ▲  Significantly lower or higher

Abstract - This study was to examine indirectly the effect of endogenous Progesterone, a known competitor for 5AR, on androgen metabolism in target organs in hirsute women. Serum levels of Progesterone, Testosterone (T), ANDROSTENEDIONE (A), dihydroTestosterone (DHT) and 5 alpha-androstane 3 alpha 17 beta-diol (3 alpha-diol) and sex hormone binding globulin (SHBG) were assessed serially over a four week period in normal women, six hirsute women with regular menstrual cycles, eight hirsute women with oligomenorrhoea (and presumptive polycystic ovaries) and seven non-hirsute women with oligomenorrhoea.Serum T and A levels were significantly higher than normal in both hirsute and non-hirsute women with oligomenorrhoea, while serum SHBG was significantly lower than normal in the two groups of hirsute women. The calculated free T level was higher than normal in all three groups of patients. DHT levels were not significantly different from normal in any of the three groups of patients. The 3 alpha-diol level showed considerable overlap with normal in all groups of patients and was only significantly higher than normal in hirsute women with oligomenorrhoea (P less than 0.05). There was a small fall in DHT in the late luteal phase of the cycle of those women with a sustained rise in serum Progesteronein the second half of the cycle, but no change in serum 3 alpha-diol.

These study results suggest:

-   A rise in serum Progesterone has only a minimal effect on circulating levels of the active 5AR androgen metabolites

-   Serum 3 alpha-diol may not be as good an indicator of peripheral androgen metabolism in hirsute women as previously reported .   Although in vitro 3 alpha-diol has been shown to be a potent inhibitor of 5AR these results cast doubt on its role in this regard in vivo.

Effect of glucocorticoid treatment study

Dewis P, Newman M, Anderson DC.,, The effect of endogenous Progesteroneon serum levels of 5 alpha-reduced androgens in hirsute women, Clin Endocrinol (Oxf). 1984 Oct;21(4):383-92.

Abstract -The plasma concentrations of total Testosterone, free Testosterone index, ANDROSTENEDIONE, 17 beta-estradiol, luteinizing hormone, follicle-stimulating hormone, PROLACTIN, and urinary 17-ketosteroid and 17-ketogenic steroid excretion were measured in 48 nonhirsute and 119 hirsute patients. Hormone data were compared within and between groups according to whether the menstrual cycles were eumenorrheic, amenorrheic, or oligomenorrheic.

Also, 11 hirsute women were treated with prednisone (followed for 6 months).

It was concluded that:

(1) ANDROSTENEDIONE, Testosterone, free Testosterone index, and adrenal androgens alone or in combination play a role in the pathogenesis of:

•   Hirsutism observed in eumenorrheic women (normal cycles);

•   Amenorrhea and oligomenorrhea of both hirsute and nonhirsute women;

(2) Body weight.    Correlated with adrenal adrogens (17-ketosteroids) in non-hirsute women and with ANDROSTENEDIONE in hirsute women;

(3) Prednisone significantly suppressed.    ANDROSTENEDIONE and 17-ketosteroids (p less than 0.05), with a decline of Testosterone to 65% and luteinizing hormone to 51% of pretreatment values, with favorable clinical effects on the hirsutism, menstrual dysfunction, and infertility;

(4) Concentrations of 17 beta-ESTRADIOL - were lower in amenorrheic (no menstruation) than in eumenorrheic (normal menstruation cycles) and oligomenorrheic (infrequent menstruation) women of both groups.

Ho Yuen B, Mincey EK, Role of androgens in menstrual disorders of nonhirsute and hirsute women, and the effect of glucocorticoid therapy on androgen levels in hirsute hyperandrogenic women. AmJ Obstet Gynecol 1983 Jan 15;145(2):152-7.

PCOS-related study

Abstract.

The aim of this study was to investigate whether the absence or presence of acne or hirsutism in 248 women with PCOS was associated with different clinical, endocrine, metabolic and ultrasonographic factors - Patients were divided into three groups:

1. 96 (38.7%) without any androgenic symptoms;
2. 94 (37.9%) with only hirsutism;
3. 58 (23.4%) with only acne.

The cycle alterations (oligomenorrhea or amenorrhea) and the echographic ovarian morphology (polycystic or multifollicular ovaries) showed no significant differences between the three groups.

Hirsutism was associated with a greater incidence of obesity and insulin resistance, with an increase of 17-hydroxyprogesterone, ovarian and adrenal androgens, 3alpha-androstanediol glucuronide, INSULIN, INSULIN-like growth factor-1 and low luteinizing hormone (LH), sex hormone binding globulins (SHBGs) and INSULIN-like growth factor binding protein-1 levels.

Acne was associated only with the lowest 3alpha-androstanediol glucuronide levels -therefore, two different pathogenetic mechanisms may play a role in the onset of acne and hirsutism.

Falsetti L, Gambera A, Andrico S, Sartori E, Acne and hirsutism in polycystic ovary syndrome: clinical, endocrine-metabolic and ultrasonographic differences.(Aug 2002), Gyn. Endocrinol 16(4):275-84.

PROLACTIN-related studies

PROLACTIN in hirsute women: possible roles for androgens in suppressing basal levels, and for estrogens in enhancing TRH-induced responses

T. Joseph McKenna, Sean Cunningham, Marie Culliton, Leslie Daly, Aideen Moore, Fergal Magee and Peter P. A. Smyth

Abstract. HyperPROLACTINaemic patients occasionally demonstrate hirsutism and elevated levels of DHEA-S, a weak androgen of adrenal origin. Abnormal adrenal function is frequently observed in hirsute patients.These observations prompted speculation that PROLACTIN may modulate normal adrenal secretion and that derangements of adrenal androgen secretion may be due to abnormalities in PROLACTIN.

In this study we examined the possibility that elevated PROLACTIN levels may be involved in the pathogenesis of hyperandrogenaemia in hirsute patients. However, basal PROLACTIN levels in hirsute women, with or without menstrual disturbances, 201 ± 24.3 mU/l (mean ± SE) and 192 ± 24.3 mU/l respectively, were significantly suppressed below levels in normal women, 289 ± 12.2 mU/l.

The PROLACTIN responses to stimulation with TRH and to suppression with L-dopa were also studied in hirsute patients. The PROLACTIN response to TRH(maximum increment or integrated response) was exaggerated significantly in hirsute women with menstrual disturbances when compared to normal women, to hirsute women with normal menses or to normal men.This abnormal response may have been due to elevated estrone levels present in patients with oligomenorrhoea (infrequent) (318 ± 49.5 pmol/l compared to 191 ± 12.1 pmol/l in normal women and 161 ± 15.5 pmol/l in hirsute women with normal menses, P < 0.05). There were no abnormalities detected in the suppression of PROLACTIN in response to L-dopa in any of these groups. These findings do NOT support a role for PROLACTIN in the pathogenesis of hyperandrogenaemia in hirsute patients.

However, elevated androgen levels in women may bring about suppression of basal PROLACTIN levels to values seen in normal men. In addition elevated ESTRONE levels may exaggerate the stimulatory effect of TRH on PROLACTIN secretion. as was seen in oligomenorrhoeic hirsute women.

Treatments for Hirsutism

Treatment for hirsutism will depend on the cause.    Typically requires a combined approach of:

-   Removal of existing hair.   Electrolysis, laser, or depilatories;

-   Suppression of hyperandrogenism.    Via a combined approach of administrating oral contraceptives to suppress ovarian androgen production, continuous Progesterone, glucocorticoids, or anti-androgens;

-   Diminish the sensitivity of the hair follicles to the androgens.

-   Anti-Estrogen therapy.     ESTRADIOL stimulates production of both ER-α receptors and androgen receptors (AR's)

UNFINISHED

DISCLAIMER: The content on this website is intended for informational, and educational purposes only and not as a substitute for the medical advice, treatment or diagnosis of a licensed health professional. The author of this website is a researcher, not a health professional, and shall in no event be held liable to any party for any direct, indirect, special, incidental, punitive or other damages arising from any use of the content of this website. Any references to health benefits of specifically named products on this site are this website author's sole opinion and are not approved or supported by their manufacturers or distributors.