PCOS and HIRSUTISM
G. I. Serour,
FRCOG, FRCS, FACOG, FSOGC, FJSOG, FIFFS, FISOG,FEBCOG, (Hon.)
Professor of Obstetrics and Gynaecology,
Director, International Islamic Center for Population Studies and
Research, Al-Azhar University
Clinical Director, The Egyptian IVF-ET Center,
Maadi, Cairo, Egypt
FIGO Past President
EBCOG/TSOG Joint Congress,
Antalya, Turkey
17th – 21st May 2017
7/31/2017
1
Conflict of interest
I declare I have no
conflict of interest in this
presentation.
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Items Addressed
Androgens production in women.
Hyperandrogenism in PCOS.
Hirsutism.
Evaluation of Hirsutism.
Management of Hirsutism.
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PCOS
PCOS is a heterogeneous
syndrome, not a disease. Patients
with PCOS have a set of
phenotypic characteristics but lack
a single defining element or “gold
standard” on which the diagnosis
could be anchored.
4
PCOS Phenotypes
Phenotype
OA
HA
PCOM
A
Yes
Yes
Yes
B
Yes
Yes
NO
C
No
Yes
Yes
D
Yes
No
Yes
Dewailly D, et al 2006 J Clin Endocrinol Metab 91(10): 3922-7.
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Some authors questioned whether
it is appropriate to apply the
definition of PCOS in the absence
of overt hyperandrogenism and
called for a need for a rethink of
diagnostic criteria for PCOS
Dewailly D 2016
Best practice and Research clinical Obst&Gynec.
37,5-11, 2016
6
Androgen Production in women
Androgens are produced
primarily from dietary
cholesterol that circulates in
the form of low-density
Lipoproteins (LDL) in the
plasma.
Gwynne JT, Strauss JF. The role of lipoproteins in steroidogenesis and
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cholesterol
metabolism in steroidogenic glands. Endocr Rev. 1982:3:299-329.
Testosterone
In the circulation testosterone is
present as the free or conjugated
testosterone. The free portion of
testosterone is biologically active
and is very small in amount.
-Depleski D, Rosenfield RL: Role of hormones in pilosebaceous unit development [review]. Endocr Rev
2000; 21:363-392.
-Azziz R, Carmina E, Sawaya ME: Idiopathic hirsutism [review]. Endocr Rev 2000; 21:347-362.
8
Conjugated Testosterone
Almost 98-99% of plasma
testosterone is bound to steroid
hormone-binding globulin (SHBG), to
cortisol-binding globulin or
nonspecifically to albumin and other
proteins and is biologically inactive.
-Depleski D, Rosenfield RL: Role of hormones in pilosebaceous unit development
[review]. Endocr Rev 2000; 21:363-392.
-Azziz R, Carmina E, Sawaya ME: Idiopathic hirsutism [review]. Endocr Rev 2000;
21:347-362.
9
Sources of Androgen in women
Ovaries & Adrenals
In women, androgens are secreted in
almost equal quantities by the ovaries
*
35-40% and adrenal glands 40% and
the enzymes involved in the
steroidgenesis pathway are similar**.
* Carmina E (2006). Ovarian and adrenal hyperandrogenism Ann NY Acad Soc. 2006:
1092:130-7.
**Miller WL, Aushus RJ. (2011). The molecular biology, biochemistry and physiology of
human
steriodogenesis and its disorders. End. Rev 2011; 32:81-151.
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Liver/ Skin/ Adipose Tissue
Peripheral conversion of
androgenic prohormones to
testosterone occurs in the liver,
genital skin, hair follicles, and
adipose tissue.
-Depleski D, Rosenfield RL: Role of hormones in pilosebaceous unit development
[review]. Endocr Rev 2000; 21:363-392.
-Azziz R, Carmina E, Sawaya ME: Idiopathic hirsutism [review]. Endocr Rev 2000;
21:347-362.
- Papadopoulos V et al . Steroid biosynthesis in adipose tissue steroids. 2015; 103:89-104
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Androgenic Prohormones and Hormones
In women, the major circulating androgens or proandrogens in a descending order of serum concentration
are:
1- Dehydroepiandrosterone sulphate
(DHEAS),
2- Dehydroepiandrosterone (DHEA),
3- Androstenedione (AT),
4- Testosterone (T) /
/has strong affinity to AR
5- Dihydrotestosterone (DHT)/
12
Androstenedione (AT), derived from
the ovaries and adrenals, is the most
important precursor of T while
DHEAS and DHEA, derived almost
exclusively from the adrenals, account
for only 5% and 13% of circulating T
among women of reproductive age
respectively.
Longcape C. Adrenal and Gonadol androgen secretion in normal females.
Clin. EndocrinolMetab. (1986):15 (2) 213-228.
13
Estrogen/ Androgens/ SHBG
Estrogens increase and androgens
decrease the production of SHBG
in the liver. In hyperandrogenic
condition, the SHBG is decreased
thus allowing higher levels of free
testosterone.
14
Insulin/ SHBG
Insulin decreases the production of
SHBG. In condition of insulin
resistance and compensatory
hyperinsulinemia, the production
of SHBG is decreased and this
leads to higher levels of free
testosterone.
15
In the hair follicles,
testosterone is converted to its
biologically active form,
dihydrotestosterone, by the
enzyme. 5α- reductase.
-Depleski D, Rosenfield RL: Role of hormones in pilosebaceous unit development
[review]. Endocr Rev 2000; 21:363-392.
-Azziz R, Carmina E, Sawaya ME: Idiopathic hirsutism [review]. Endocr Rev 2000;
21:347-362.
16
Hyperandrogenism in PCOS
Studies with ovarian theca cells taken
from women with PCOS have
demonstrated increased androgen
production due to increased CYP17A1
and HSD3B2 enzyme activities that
produce androgens from cholesterol.
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Yong EL et al 1992
Clin. Endocrinol:37:51-58
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In women the most common
cause of hyperandrogenism is
PCOS. Ovarian theca cells
increased androgen production in
response to chronically elevated
LH and high insulin levels are the
causes of this hyperandrogenism.
18
Hyperinsulinemia promotes androgen
biosynthesis via insulin receptor and to a
lesser extent, the insulin-like growth factor-1
(IGF.1) receptor on theca cells and increases
levels of circulating free testosterone by
suppressing hepatic production of steroid
hormone binding globulin SHBG.
-
-
Landy M , Huang A, Azziz R. Degree of hyperinsulinemia, independent of androgen
levels, is an important determinant of the severity of hirsutism in PCOs. Fertil and
Steril, 2009; 92 (2): 643-7.
Ovalle F, Azziz R. Insulin resistance, PCOs and type 2 diabetes mellitus. Fertil&Steril
2002; 77 (6): 1095-105.
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Hyperandroginsim - Hirsutism
While androgen excess will contribute
to the ovulatory and menstrual
dysfunction of PCOS patients the most
recognizable sign of
hyperandrogenaemia includes
hirsutism, acne and androgenic
alopecia or female pattern hair loss.
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Normal Pattern of Hair distribution
Vellus Hair
Adults have two types
of hair, vellus and
terminal. Vellus hair is
soft, fine, generally
colorless, and usually
short.
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Vellus Hair
Vellus hair covers
the face, chest, and
back and gives the
impression of
“hairless” skin.
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Terminal Hair
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Terminal hair
is long, coarse,
dark, and
sometimes
curly.
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Terminal hair grows
on the scalp, pubic,
and armpit areas in
both men and women.
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Excessive hair that is due
to genetic and ethnic
variation rather than
hormonal causes is
typically located on the
arms, hands, legs, and feet.
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If excessive hair growth is
present only on the lower
legs and forearms, it is not
considered hirsutism and
will not respond to
hormonal therapy.
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If hair follicles are hormonesensitive, androgens may
cause some vellus hairs to
change to terminal hairs and
cause the terminal hairs to
grow faster and thicker.
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Clinical Diagnosis of Hirsutism in PCOS
Hirsutism due to hormonal causes is
the excessive growth of coarse dark
hair on the face, chest, abdomen, back
upper arms or upper legs of women*
and PCOS is the most common
etiology of hirsutism**.
*American society of Reproductive Medicines (ASRM) 2016. Hirsutism and PCOS. A
guide for patients, 2016.
r
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**Spritzer
PM et al. 2016. Curr. Pharm 2016; 22 (36):5603-5613.
The prevalence of hirsutism
in PCOS ranges from 70 to
80%, vs. 4% to 11% in
women in the general
population.
Spritzer PM et al. 2016. Hirsutims in PCOS. Pathophysiology and Management.
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Evaluation of Hirsutism
Hirsutism is usually evaluated by scoring
facial and body terminal hair growth
using the modified Ferriman-Gallwey
method. However, the hirsutism score
correlates poorly with serum androgens.
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Haung A et al 2006, Fertil & Steril: 86 S12-S
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Biochemical Assessment
 Total and free testosterone (High normal)
 Serum LH elevated.
 LH/FSH higher than 3.
 Dehydro-epiandrosterone Sulphate
(DHEAS) (marginal elevation).
 Prolactin level (mildly elevated in 30%
PCOS.
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Ultrasound Evaluation
Ultrasound evaluation of the
ovaries, adrenals or both may be
useful for screening if symptoms
or biochemical levels suggest the
presence of neoplasm.
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Differential Diagnosis of hyperandrogenic Patient
• Idiopathic hirsutism.
• Hyper-androgenic insulin-resistant acanthuses nigrican (HAIRAN)
syndrome.
• 21-hydroxylase-deficient non-classic congenital adrenal
hyperplasia.
• Classic congenital adrenal hyperplasia.
• Androgen-secreting neoplasm.
• Side effects of medication.
• Cushing disease.
• Hypothyroidism.
• Hyper-prolactinaemia.
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- Azziz R et al 2004 J. Clin EndrocrinolaMetab:89(2) 453-62
- Lergo RS et al 2013. J Clin. Endocrinol Metab:98(12)4565-92.
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Management of Hirsutism in PCOS
Hirsutism is a sign, not a disease
of itself and PCOS is the most
common etiology and found in
72% to 82% of patients with
hyperandrogenism.
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Azziz R et al 2004 J. Clin EndrocrinolaMetab:89(2) 453-62
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The patient needs to be assessed
and evaluated. Treatment should
be patient centered whether for
hirsutism only or hirsutism and
anovulation, anovulatory
bleeding, desire to get pregnant or
metabolic comorbidities.
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Initiation of treatment
should be based on the
patient’s perception of
hirsutism rather than the
quantitative characteristics
of hirsutism.
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Martin KA et al 2008 J. Clin Endocrinol Metab. 93(4) 1105-20.
37
Furthermore monitoring of T
and other androgens during
treatment is generally
unnecessary as the hirsutism
score correlates poorly with
serum androgens.
Legro RS et al 2010 J Clin Endocrinol Metab. 95(12) 5305-13.
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Modification of life style smoking
Smoking cessation is strongly
recommended for hirsute patients as
many of the undesirable side effects of
the medications prescribed to treat
hirsutism are exacerbated when
patients indulge in smoking.
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Escobar-Morreale HF et al 2012
Hum. Reprod. Update. 18(2): 146-70.
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Weight Loss
A systematic review of six small RCTs
observed that lifestyle modification was
beneficial in the reduction of serum
androgens and increased SHBG, along
with some improvement in hirsutism as
achieved by the mFG Score.
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Moran LJ et al 2011, Cochrane Database Syst Review (7) CD007506.
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Medication
The management of hirsutism due to
PCOS involves primarily either androgen
suppression, with a hormonal
combination contraceptive or androgen
blockade as with androgen receptor
blocker or a 5α reductase inhibitor or a
combination of the above.
Yong EL 2016 Best Practice and Research Clinical Obstet and Gynecol 37:1-4.
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Androgen Suppression
Hormonal Combination contraceptives HCCs
- Progestins in HCCs cause suppression of LH levels
and inhibition of LH-mediated ovarian androgen
synthesis*
- Ethinylestrodial in HCCs leads to significant
increase in SHBG, thereby contributing to a
reduction of free T **.
- HCCs decrease the synthesis and release of
androgens by the adrenal.***
*Archer DF et al 2009 Contraception 80 (3): 245-53.
** Vrbikova J et al 2005, Hum. Reprod Update. 11(3): 277-91.
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*** Madden JD et al 1978 Am. J Obstet Gynecol. 132(4): 380-4.
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- 60-100% of women with hirsutism
demonstrate improvement on oral HCCs *.
- 21 day active 7 day placebo provides better
ovarian suppression compared to
continuous regimen**
* Burkman JR RT 1995, Am. J M Med 98(1A) S 130-5.
** Legro RS et al 2008, J. Clinical Endocrinol Metab 93 (2): 420-9.
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HCCs with Antiandrogenic Progestins
- Cyproterone acetate (CPA).
- Chlormadinone acetate (CMA).
- Drospirenone (DRSP).
- Dienogest (DNG).
Comparative studies of HCCs containing progestin
with antiandrogenic properties are limited.
Lizneva D et al 2016, Best Practice and Research Clinical Obstet and gynecol 37:98-118.
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Antiandrogens Monotherapy
Androgen Receptor Blockers
-
Spironolactone.
Flutamide.
Cyproterone acetate.\
5 α reductase inhibitor.
Antiandrogens have not been used with any
regularity in women, all are teratogenic and their
use is generally discouraged.
Lizneva
D et al 2016, Best Practice and Research Clinical Obstet and gynecol 37:98-118.
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Combined Treatment of Antiandrogens with HCCs
Four RCTs demonstrated that
antiandrogens in combination
with HCCs were more
effective than monotherapy
with HCCs.
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Swiglo BA et al 2008 J Clin Endocrinol Metab. 93 (4): 1153-60.
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Why antiandrogen+HCCs?
- Efficacy is generally higher when using a
combination of HCCs and antiandrogens
than with either HCCs or antiandrogen
monotherapy,
- HCCs minimize the risk of teratogenicity.
It is advisable to begin therapy with a
combination of HCCs and antiandrogens.
Lizneva
D et al 2016, Best Practice and Research Clinical Obstet and gynecol 37:98-118.
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GnRHa and Insulin Sensitizers
Several studies have demonstrated
the superior efficiency of HCCs
monotherapy compared to
GnRHa* and insulin sensitizers **
* Heiner JS et al 1995 J Clin Endocrinology Metab. 80(12) 3412-8.
** Costello M et al 2007 Cochrane Database Syst Review (1) CD 005552.
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Metformin
If HCCs are contraindicated,
mainly in the presence of insulinresistance related comorbidities, a
second-line option for reducing
androgen secretion may be
metformin associated with lifestyle
changes.
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Combined Treatment of Antiandrogen with Metformin
In a small RCT, flutamide
in combination with
metformin appeared to be
superior to monotherapy.
Koulouri O et al 2008 Clin Endocrinol (Oxf) 68 (5): 800-5.
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Cosmotic Approaches
Cosmotic treatment hirsutism
should be combined with medical
treatment and is widely used and
categorized as short and long
term approaches.
Yong EL 2016 Best Practice and Research Clinical Obstet and Gynecol 37:1-4.
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Short Term Methods
- Shaving.
- Chemical depilation.
- Plucking (threading).
- Waxing.
- Bleaching.
- Eflornithine hydrochloride.
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Depilation/Epilation
- Depilation is the removal of the hair shaft
from skin’s surface as shaving and
chemical depilation.
- Epilation is the extraction of hair above
the bulb (eg plucking, waxing). It provides
the most long lasting action on hair
regrowth with hair absent for 6-8 weeks.
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Ramos-e-Silva M et al 2001 Clin Dermatol 19 (4) 437-44.
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Eflornithine Hydrochloride Cream
Topical application of 13.9% eflornithine
hydrochloride for facial hirsutism inhibits the
enzyme ornithine decarboxylase which is required
for the growth and differentiation of cells in the
hair follicle, it requires daily use and hirsutism
relapses after 8 weeks of cessation of treatment,
and not approved for large surface area.
Wolf Jr JE et al., 2007 Int J Dermatol 46(1): 94-8.
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Long Term Approaches
- Electrolysis.
- Laser therapy.
- Intense pulse light (IPL).
Martin KA 2008 An Endocrine Society Clinical Practice Guideline
J. Clin Endocrinol Metab 93(4): 1105-20.
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Conclusion
Treatment of hirsutism takes
time and absolute cure is
rarely possible and relapse
may follow cessation of
medical treatment.
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The majority of experts
recommend lifelong
treatment with maximum
suppression for
approximately 2 years.
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Depending on the
progression of hirsutism
antiandrogens may be
reduced or stopped while
continuing oral HCCs.
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Monitoring and treatment
for metabolic
complications or
associated infertility with
PCOS are necessary.
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In all cases, strong
clinical support is
crucial to ensure
treatment adherence
and success.
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Furthermore, overexpression
of DENND1A variant 2 in the
theca cells of women with
PCOS resulted in a PCOS
phenotype with increased
androgen production.
Indran IR et al 2016. Best Practice and Research,
Clinical Obstet & Gynecol, 37:12-14, 2016
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