Hirsutism
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
secondar 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, 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 ANDROSTENEDIONE ). About half the women
with mild androgen levels.
(2)
Hair follicles have increased sensitivity to
androgen
Virilization occurs primarily from diseases of
adrenals or
ovaries 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 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
OVARIAN tumors, 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- 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
ovarian secretion 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
Testosterone levels
could be due to simple ovarian hyperplasia.
Autopsies of 600 adult women revealed
half with ovarian stromal hyperplasia uterine leiomyomas
(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 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 caused by deficiencies in the
adrenal enzymes used to synthesize glucocorticoids; lack of CORTISOL an increased adrenal production of
glucocorticoid precursors and androgens 2,3,5,6
Congenital Adrenal
Hyperplasia (CAH)
(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)
Already
acknowledged as a likely factor in PCOS, high
INSULIN
levels (usually as a consequence of
INSULIN
resistance) can be a cause androgen and probably
ovarian hormone production.
Insulin Resistance (IR)
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
(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 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
T estosterone ,
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
Plasma androgens,
progestagens , and PROLACTIN
in 158 hirsute women
% frequency Elevated
Pre-Ovulatory
Post-Ovulatory
DHEA-S
35% ▲
▲
(compared
to mean)
▲
(compared
to mean)
Testosterone
55% ▲
▲
(compared
to mean)
▲
(compared
to mean)
Progesterone (P)
25% ▲
17a-hydroxy-Progesterone(17OHP)
53% ▲
▲
(compared
to control)
▼
(compared
to control)
PROLACTIN
6% ▲
▼
(compared
to control)
▼
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
Menstrual status does not predict androgen status
in hirsute women
Menstrual Cycle
1 or more Androgen Level Elevated
Control Group
NORMAL
129 Hirsute women
Regular cycle (40%)
50% ELEVATED/ 50% NORMAL
Infrequent/ No cycle (60%)
69% ELEVATED/ ELEVATED+ / 31% NORMAL
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
Effects of
endogenous Progesterone (known
competitor for
5AR)
on Sex
Steroid Serum Levels in Hirsute vs. Non-Hirsute Women ( over 4 weeks)
Hirsute
Non-Hirsute
Regular Cycle (6)
Infrequent Cycle
/PCOS (8)
Infrequent Cycle (7)
Progesterone
▲
▲
▲
Testosterone
▲
(compared
to normal)
▲
(compared
to normal)
Testosterone (free)
▲
(compared
to normal)
▲
(compared
to normal)
▲
(compared
to normal)
ANDROSTENEDIONE
Normal
▲
(compared
to normal)
▲
(compared
to normal)
DHT
Normal
Normal
Normal
3 alpha-diol
Normal
▲
(compared
to normal)
Normal
SHBG
▼
(compared
to normal)
▼
(compared
to normal)
▼
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
Progesterone in 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 .
Effect of
glucocorticoid
therapy
(prednisone) on androgen levels in 11 hirsute
hyperandrogenic women
(over 6 months)
Hirsutism effects
Favorable effect
Menstrual dysfunction
Favorable effect
Infertility
Favorable effect
Testosterone
▼
65% of
pretreatment values
Testosterone (free)
Andro
▼
Estradiol
LH
▼
51% of
pretreatment values
FSH
PROLACTIN
Adrenal androgens
Urinary 17-ketosteroid excretion
▼
Urinary 17-ketogenic steroid excretion
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:
96 (38.7%)
without androgenic symptoms;
94 (37.9%)
with only hirsutism;
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
- 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)
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