Transcript Hirsutism & Virilization

Hirsutism & Virilization
Assoc. Prof. Gazi YILDIRIM, M.D.
Yeditepe University, Medical Faculty
Dept of Ob&Gyn
Objectives
• To define
– Hirsutism
• To learn
– Androgen biosynthesis
• To treat
– Hirsutism
HIRSUTISM
APPEARANCE OF EXCESSIVE COARSE
(TERMINAL)HAIR IN A PATTERN NOT NORMAL
IN THE FEMALE
• Definition highlights the abnormal distribution
of excess hair growth ,such as facial ,chest,or
upper abdominal hair
HYPERTRICHOSIS
GROWTH OF HAIR IN EXCESS OF THE NORMAL
WHILE LIMITED TO A NORMAL PATTERN OF
DISTRIBUTION
• It is frequently associated with the use of
medication such as antiepileptics
VIRILIZATION
REFERS TO CONCURRENT PRESENTATION OF
HIRSUTISM WITH A BROAD RANGE OF SIGNS
SUGGESTIVE OF ANDROGEN EXCESS,SUCH AS
• ACNE,
• FRONTOTEMPORAL BALDING,
• DEPPENING OF THE VOICE ,
• A DECREASE IN BREAT SIZE
• CLITORAL HYPERTROPHY
Normal Androgen Synthesis
Pituitary
Cortex:
G
Adrenals
F
R


aldosterone
Cortisol
Androgens
Ovaries
Theca Cells  Androstenedione & Testosterone
Granulosa Cells
Estrone & Estradiol
Asetat
Kolesterol
Sitokrom P450 scc
Progesteron
Pregnanolon
17 OH Pregnanolon
17-20 Desmolase
17 α OH ase
3 β OH SDH
17 α OH ase
17 OH Progesteron
17-20 Desmolase
Androstenedion
DHEA
17 β OH SDH
Androstenediol
E3
17 β OH SDH
Testosteron
5 α redüktase
DHT
?
E1
17 β OH SDH
E2
Adrenal Korteks
%25
T
%25
%50
%50
%50
Androstenedion
DHEA
%50
%20
Over
%100
%30
DHEAS
In women Major circulating androgens
(in descending order of serum concentration)
•
•
•
•
•
DHEA-S (100-350 micg/dl)
DHEA (1-10 ng/ml)
Androstenedion (0.5-2.0 ng/ml)
Testosterone (20-80 ng/dl)
DHT
EXCESS REPONSIVITY TO ANDROGEN
TESTOSTERONE
5-ALPHA -REDUCTASE
DIHIDROTESTOSTERONE
DHT
• Major nuclear androgen
• Produced only in the periphery
• Circulating level is low and do not reflect the 5
alpha reductase activity
• 3alpa androstenediol glucuronide (3alpha-AG) is the
peripheral metabolite of DHT and can be used
as a marker of peripheral androgen metabolism.
• Low clinical utility…
%1 serbest
%19 Albumin
%1 serbest
%7 serbest
%2 serbest
%30 Albumin
%80 Albumin
%85 Albumin
%80 SHBG
%69 SHBG
%8 SHBG
T
E2
Androstenedion
%18 CBG
P4
Men
%3 serbest
%19 Albumin
Normal
Women
%1 serbest
%78 SHBG
%19 Albumin
%80 SHBG
T (200-800 ng/dl)
T (20-80 ng/dl)
Hirsute
Women
%2 serbest
%19 Albumin
%79 SHBG
T (20-80 ng/dl)
Causes of Hirsutism (1)
Adrenal
Congenital adrenal hyperplasia
21-hydroxylase deficiency
11 -hydroxylase deficiency
3 -hydroxysteroid dehydrogenase deficiency
Cushing’s syndrome
Androgen-secreting adrenal tumors
Causes of Hirsutism (2)
Ovarian
 Androgen-secreting ovarian neoplasms
 Sertoli-leydig cell tumors
 Granulosa-theca cell tumors
 Hillus-cell tumors
 Pregnancy-related
 Luteoma
 Hyperreactive leuteinalis
 Hyperthecosis
 Polycystic ovary syndrome
Causes of Hirsutism (3)
Exogeneous medications
 Hormonal
 Anabolic steroids
 Danazol
 Oral contraceptives containing androgenic progestins
 Glucocorticoids
 ACTH
 Metyrapone
Causes of Hirsutism (4)
 Not-Hormonal
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
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



Diazoxide
Phenytoin
Psoralens
Streptomycin
Phenothiazine
Minoxidil
Severe insulin resistance syndromes
Hyperprolactinemia
SHBG defect (primary or secondary)
Menopause
Idiopathic hirsutism
Idiopathic hyperandrogenism
Physical Exam
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•
•
•
•
•
•
•
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Hair pattern
Balding
Body habitus
Female contours
Atrophic breast changes
Clitoromegaly
Ovarian masses
Cushingoid features
Acanthosis nigricans (associated w/ PCOS)
Suggested laboratory investigations in hirsute women
Laboratory
investigation
Indication
Ultrasonography
Identification of the adrenal/ovarian tumor
to demonstrate PCO
FSH-LH-Estradiol
Evaluation of gonadal axis
Testosterone
Demonstration of androgen excess (mostly
indicate ovarian source)
DHEAS
Demonstration of androgen excess (mostly
indicate adrenal source)
17-OH P
When NCAH considered
ACTH test
Hormonal diagnosis of NCAH
Unluhizarci K, Yilmaz S, Kelestimur F.
Women’s Health, 2005
Lab.Evaluation of Hirsutism
Three basic hormonal evaluation
1. Total testosterone
2. DHEAS
3. AM 17-hydroxyprogesterone
Diagnosis & Evaluatoin
•  T, androstenedione, DHEAS
– adrenal source
– Abdominal CT & medical tests r/o CAH or Cushings
• DEAHS normal or minimally elevated
– Ovarian source
– Pelvice U/S r/o tumor
• Elevated LH-FSH ratio
– Ratio>3 suggests PCOS
• Rapid Onset Virilization w/ T>200ng/dL
– May indicate ovarian neoplasm
Total Testosterone
Normal Value (0.2 –0.8 ng/ml) - (20 –80 ng/dl)
>150-200 ng/dl
DHEAS (100-350 micg/dl)
>700 micg/dl
17 –hydroxyprogesterone
<200 ng/dl
200-800 ng/dl
<1000 ng/dl
>1000 ng/dl
(<0.2) ng/ml ) - (<200) ng/dl )
>800 ng/dl
Treatment
1-General principles
-Detection and treatment of the underlying disease
-Multidisciplinary interventions
-Obesity treatment
2-Drug therapy
-Adrenal suppression
-Ovarian suppression
-Anti-androgen therapy
-Therapy for insulin resistance
3-Cosmetic therapy
4-Education and psychotherapy
5-Combination therapy methods
 The management of hirsutism depends on;
1-Underlying cause,
2-Contraceptive needs,
3-Patient’s preference
 At least 6-9 months of treatment is
necessary for clinical response
THERAPEUTIC OPTIONS
GENERAL MEASURES :
• Eliminating causative factors
• Optimizing weight
• Manage hair
Bleaching
Cutting or shaving
Electrolysis
Laser epilation
THERAPEUTIC OPTIONS
Management of excess ovarian androgen production :
Standard therapy is :combined E+P,most commonly OCs
• It reduces ovarian androgen production
• It increases SHBG
• It induces competition at the cellular level for binding
to the androgen receptor
THERAPEUTIC OPTIONS
Choice of OC
• EE + Norgestimarte approved in USA
• Cyproterone acetate used as progesterone
component in Ocs
OVARIAN SUPPRESSION BY LONG ACTING GnRH
ANALOGUE
• Can be used for functional ovarian androgen
overproduction and even for malignant condition
• But to be used for long with back-up
THERAPEUTIC OPTIONS
• Long acting GnRH analogues used
• But there is doubt that this therapy will be
beneficial over Ocs
• INSULIN SENSITIZING AGENTS:
For PCO with acanthosis nigicans
Commonly used agent is : Metformin and
Troglitazone,Pioglitazone,Rosiglitazone
THERAPEUTIC OPTIONS
• MANAGEMENT OF EXCESS ADRENAL
ANDROGEN PRODUCTION
• Metabolic correction of the disorder,usually
with exogenous steroids
• Dexamethasone,mostly used,But LIMITED
ROLE
THERAPEUTIC OPTIONS
Management directed to the target organ and
cells
• Competition with Androgen receptors:
– Spironolactone,
– Flutamide,
– Ketoconazole,
– Cyproterone acetate
• 5-alpha reductase Inhibitors :
– Finasteride
Mechanisms of anti-androgen treatment
1) Gonadotropin suppression
2) Stimulation of SHBG synthesis
3) Inhibition of 5- reductase enzyme
4) Binding to androgen receptor
5) Effects to steroid biosynthesis
Mechanisms of actions of the commonly used anti-androgens
Androgen
receptor
blockade
Clearence
of
androgens
Effect on
LH
secretion
Glucocorticoid
activity
5-a
reductase
activity
Progestogen
like activity
Cyproterone
acetate
+
+
+
+
-
+
Spironolactone
+
+
-
-
-
+
Drospirenone
+
+
+
-
-
-
Flutamide
+
-
-
-
-
-
Finasteride
-
-
-
-
+
-
Spironolactone
*Synthetic steroid
*Aldosterone and androgen antagonist
*Competition with DHT for binding to receptors
*Inhibition of androgen synthesis
Cyproterone acetate
*A steroidic anti-androgen derivated from 17hydroxyprogesterone
*Inhibitory effect to testosterone and
dihydrotestosterone by binding to intracellular
receptors
*Decreased ovarian testosterone production due
to inhibition of LH secretion
*There is a low glucocorticoid effect
Cyproterone Acetate
Side effects
Weight gain
Edema
Decreased libido
Headache
Vomiting
Hepatotoxicity
Fatigue
Enlarged mammary glands
Mood changes
Finasteride
*5 -reductase inhibitor
*Inhibits conversion of testosterone to DHT
*It does not bind to androgen receptors
*There is no effect in testosterone secretion
Flutamide
*Non-steroid, periferic androgen antagonist
*Inhibitory effect in steroid biosynthesis (adrenal)
Eflornithine hydrochloride 13.9%
• Eflornithine 13.9% cream is a topical treatment that does not remove
the hairs, but acts to reduce the rate of growth and appears to be
effective for unwanted facial hair on the mustache and chin area.
• It can be used in combination with other treatments to give the
patient the best chance for successful hair removal.
• Eflornithine acts as an inhibitor of L-ornithine decarboxylase
which may be important in controlling hair growth and
proliferation