1. Hirsutism & Virilization
Assoc. Prof. Gazi YILDIRIM, M.D.
Yeditepe University, Medical Faculty
Dept of Ob&Gyn

2. Objectives
To define
Hirsutism
To learn
Androgen biosynthesis
To treat

4. 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

5. 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

6. 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

7. Normal Androgen Synthesis
Pituitary 
aldosterone
Cortex:
(+) ACTH G F R 
Cortisol
Androgens
Adrenals
(+) LH
Ovaries
Theca Cells  Androstenedione & Testosterone
(+) FSH
Granulosa Cells
Estrone & Estradiol

8. Asetat Kolesterol Pregnanolon Progesteron 17 OH Pregnanolon
Sitokrom P450 scc
Pregnanolon
Progesteron
17 α OH ase
17 α OH ase
17 OH Pregnanolon
17 OH Progesteron E3
3 β OH SDH
17-20 Desmolase
17-20 Desmolase ?
AROMATAZ
DHEA
Androstenedion E1
17 β OH SDH
17 β OH SDH
17 β OH SDH
AROMATAZ
Androstenediol
Testosteron E2
5 α redüktase
DHT

9. T DHEA DHEAS Adrenal Korteks %25 %50 %50 %100 %50 %25 %50 %20 Over
Androstenedion
DHEA
DHEAS
%50
%30
%25
%50
%20
Over

10. In women Major circulating androgens (in descending order of serum concentration)
DHEA-S ( micg/dl)
DHEA (1-10 ng/ml)
Androstenedion ( ng/ml)
Testosterone (20-80 ng/dl)
DHT

11. EXCESS REPONSIVITY TO ANDROGEN
TESTOSTERONE
5-ALPHA -REDUCTASE
DIHIDROTESTOSTERONE

12. 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…

13. %19 Albumin %30 Albumin %80 Albumin %85 Albumin %80 SHBG %69 SHBG
%1 serbest
%1 serbest
%7 serbest
%2 serbest
%19 Albumin
%30 Albumin
%80 Albumin
%85 Albumin
%80 SHBG
%69 SHBG
%18 CBG
%8 SHBG T E2
Androstenedion P4

14. Men Normal Women Hirsute Women
%3 serbest
%19 Albumin
%78 SHBG
Normal
Women
Hirsute
Women
%1 serbest
%2 serbest
%19 Albumin
%19 Albumin
%80 SHBG
%79 SHBG
T ( ng/dl)
T (20-80 ng/dl)
T (20-80 ng/dl) 14

15. 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

16. 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

17. Causes of Hirsutism (3) Exogeneous medications Hormonal
Anabolic steroids
Danazol
Oral contraceptives containing androgenic progestins
Glucocorticoids
ACTH
Metyrapone

18. Causes of Hirsutism (4) Not-Hormonal
Diazoxide
Phenytoin
Psoralens
Streptomycin
Phenothiazine
Minoxidil
Severe insulin resistance syndromes
Hyperprolactinemia
SHBG defect (primary or secondary)
Menopause
Idiopathic hirsutism
Idiopathic hyperandrogenism

19. Physical Exam Hair pattern Balding Body habitus Female contours
Atrophic breast changes
Clitoromegaly
Ovarian masses
Cushingoid features
Acanthosis nigricans (associated w/ PCOS)

20. Suggested laboratory investigations in hirsute women
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

21. Lab.Evaluation of Hirsutism
Three basic hormonal evaluation 1. Total testosterone 2. DHEAS 3. AM 17-hydroxyprogesterone

22. 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

23. Total Testosterone Normal Value (0.2 –0.8 ng/ml) - (20 –80 ng/dl)

24. DHEAS ( micg/dl)
>700 micg/dl

25. 17 –hydroxyprogesterone (<0.2) ng/ml ) - (<200) ng/dl )

27. 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

28. 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

29. THERAPEUTIC OPTIONS GENERAL MEASURES : Eliminating causative factors
Optimizing weight
Manage hair
Bleaching
Cutting or shaving
Electrolysis
Laser epilation

30. 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

31. 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

32. 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

33. THERAPEUTIC OPTIONS MANAGEMENT OF EXCESS ADRENAL ANDROGEN PRODUCTION
Metabolic correction of the disorder,usually with exogenous steroids
Dexamethasone,mostly used,But LIMITED ROLE

34. THERAPEUTIC OPTIONS Management directed to the target organ and cells
Competition with Androgen receptors:
Spironolactone,
Flutamide,
Ketoconazole,
Cyproterone acetate
5-alpha reductase Inhibitors :
Finasteride

35. 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

36. 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

37. Spironolactone *Synthetic steroid *Aldosterone and androgen antagonist
*Competition with DHT for binding to receptors
*Inhibition of androgen synthesis

38. Cyproterone acetate
*A steroidic anti-androgen derivated from 17-hydroxyprogesterone
*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

39. Cyproterone Acetate Side effects Weight gain Edema Decreased libido
Headache
Vomiting
Hepatotoxicity
Fatigue
Enlarged mammary glands
Mood changes

40. Finasteride *5 -reductase inhibitor
*Inhibits conversion of testosterone to DHT
*It does not bind to androgen receptors
*There is no effect in testosterone secretion

41. Flutamide *Non-steroid, periferic androgen antagonist
*Inhibitory effect in steroid biosynthesis (adrenal)

42. 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