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Hyperandrogenism
Beata Banaszewska
Department of Infertility and
Reproductive Endocrinology
Androgens are C-19 steroids produced in:
Ovary Adrenal gland
Androgens are metabolised in: Skin Adipose tissue Liver Placenta
The production rate of testosterone in the normal female is 0.2 to 0.3 mg/day
Normal total testosterone concentration in serum is below 0.8ng/ml
Testosteron is transported:
Normal women Hirsute women
80% SHBG 79% SHBG
19% Albumin 19% Albumin
1% Free 2% Free
The main androgens Dehydroepiandrosterone (DHEA)-a weak carbon-5
androgen secreted principally by the andrenal glandAndrostendione (A) - a weak carbon-4 androgen secreted
in equal amounts by the adrenal glands and ovariesTestosterone (T)- a potent carbon-4 androgen secreted by
the adrenal glands and ovaries and produced in adipose tissue from the conversion of androstendione
Dihydrotestosterone (DHT)-even more potent than testosterone.The conversion from testosterone is the result of action of 5 reductase
Origin of circulating androgens
Testosterone Androstendione DHA DHAS
25%
25%
99%90%50%
50%
50% 10%
OVARY
ADRENAL CORTEX
Causes of hyperandrogenism:PCOS 75%
Idiopatic hirsutism 15%
Adrenal hyperplasia 3%
Cushing’s disease 1%
Hyperprolactinemia 1%
Tumor of the ovary 1%
Tumor of the adrenal 0,1%
After medications 1%
Hyperandrogenism- clinical symptoms:
Irregularity of menstrual cycle Hirsutism Acne Clitorimegaly Alopecia Deepending of the voice The changes in the body shapes Increased muscular mass Infertility
Hirsutism It is cutaneus manifestation of
hyperandrogenism Women have male-pattern hair growth In areas :
– upper lip – chin– sideburn area – upper neck – chest– upper arm– lower abdomen– intergluteal region– perineum– thigh
Hirsutism rating scale by Ferriman Gallwey>8 points - hirsutism
Polycystic ovary syndrome (PCOS)
5-10% of women in reproductive ageHyperandrogenismAmenorrhoea Anovulation InfertilityObesity
The clinical consequences of chronic anovulation in PCOS women
Infertility Oligomenorrhea and amenorrhea Hirsutism and acne An increased risk of endometrial cancer An increased risk of cardiovascular disease An increased risk of diabetes mellitus in
patients with hyperinsulinemia
Sign and symptoms of PCOS patients
Observation Average incidenceInfertility 75%
Hirsutism 56%
Amenorrhea 47%
Obesity 33%
Regular menses 16%
Virilisation 17%
Endocrine abnormalities in PCOS
testosterone or normal LH/FSH ratio Normal Estrogens SHBG or normal Insulin or normal Prolactin or normal DHS
Characteristic of the polycystic ovary
The surface area is doubled The number of growing and atretic
follicles is doubled (Each ovary may contain 20-100 cystic follicles)
The thickness of the tunica is increased by 50%
There are 4 times more ovarian hilus cells nests
The Polycystic Ovary on ultrasound
The ovaries have pericentic cysts of 5 to 10 mm - usually at least 10 in one sonographic plane
Increased ovarian stromaOnly 75-80% wonem with the clinical diagnosis of PCOS had
polycystic ovaryPrevalence of the polycystic ovaries in 16 to 23% of „normal”
womenIn 50% women with hyperprolactinemia24% of women with hypothalamic amenorrhoea100% of women with CAH
Constitutional hirsutism
Women with greater activity of 5 reductasein in the skin
Normal ovulationRegular menstrual cycleNormal hormone concentrations
Polycystic ovary syndrome (PCOS) -patogenesis
Insulin resistance:-postreceptor defect in tyrosine kinase
activity , dysfunction of GLUT-4-defect of insulin receptor-anti-receptor antibodies
Compensatory hyperinsulinemiaDecrease in SHBG and IGFBP-1
productionExcessive androgen production
Insulina
Types of insulin resistanceTypes of insulin resistance
Type BType A
Type C
Autoantibodies to insulin receptorsGenetic defect
of insulin receptor(Kahn syndrome)
Defect of tyrozine kinase
tyrozine kinase
Wchich comes first, the hyperinsulinemia or the hyperandrogenism ?
There are 6 reasons that hyperinsulinemia causes hyperandrogenism The administration of insulin to women with PCOS increases circulating
androgen levels The administration of glucose to women with PCOS increases the circulating
levels of both insulin and androgen Weight loss decreases the levels of both insulin and andrgens In vitro , insulin stimulates thecal cell androgren productions The experimental reduction of insulin levels in PCOS women reduces
androgen levels After normalisation of androgen with GnRH agonist treatment, the
hyperinsulin response toglucose tolerance testing remains abnormal in obese women with polycystic ovaries
IGFBP-1
IGF1
HyperinsulinemiaHyperinsulinemia
Ovarian stymulationOvarian stymulation
HyperandrogenizmHyperandrogenizm
Insulin resistanceInsulin resistance
Genetic defects of insulin receptor
Autoantibodies to insulin receptor
Ovarian insulin receptors LH/FSH
Ovarian IGF-I receptors
PCOSPCOS Hyperthecosis
SHBG
FreeTestosterone
Defects of tyrosine kinase
cholesterol
Pregnenolone Progesterone
17hydroksyprogesterone
Androstenedione
Testosterone
THECA CELL
GnRH pulse frenuency
LH/FSH ratio
LH receptor
InsulinIGF receptor
17hydroksylase
17-lyase
17-reductase
StepsinvolvingP450c17
Ovarian defect in the pathogenesis of PCOS
Dysregulation of cytochrome P450c17 that results in :– increased activity of 17hydroksylase
– disordered 17,20-lyase activity
– excessive ovarian androgen production
There is hypothesis that hyperinsulinemia stimalates ovarian cytochrome P450c17
Defect in 3-hydroksysteroid dehydrogenase or aromatase activity
Two Clinical categories of Functional Ovarian Hyperandrogenism
Hyperandrogenism Hyperandrogenism with insulin resistance without insulin resistance
Testosterone Elevated ElevatedFasting insulin Elevated Normal or minimally
elevatedLH Minimally elevated Markedly elevated
LH response Normal Exaggerated to GnRH
DHAS Low-normal Normal or elevated
Ovarian pathology Stromal hyperthecosis Polycystic ovaries
Differentation of hyperandrogenism
Diagnosis Menstrual Total DHAS LH 17OHProg Sourse of Pattern Testoste- Androgens
rone
PCOS Irregular Elevated Elevated Elevated Normal OVARY
Hyper- Amenorrhea Elevated Normal Normal Normal OVARYthecosis often>1.5
ng/ml
Idiopatic Regular Normal Normal Normal Normal SKINhirsutism
Adrenal Irregular Elevated Often Usually Elevated ADRENALhyperpla- Normal Normal >4ng/mlsia at 8pm in
follicular phase
Congenital adrenal hyperplasia (CAH)
Enzyme deficiency: 21 hydroksylase deficiency (85% of cases of
CAH) -without sait wasting– cortisol– 17OHprog, DHAS– 17-KS, prednantiol, pregnandiol
21 hydroksylase deficiency -with sait wasting11-hydroksylase deficiency
Late onset adrenal hyperplasia sometimes occurs in women in reproductive age.
Differentation of ovarian and adrenal hyperandrgenism
DHAS
17-OH Progesterone
17-KS
Test with dexamethasone
Treatment of infertile PCOS women
Induction of ovulation – Clomiphene citrate– gonadotropins
Treatment of hyperinsulinemia– weight loss– metformin, troglitasone
Surgical treatment– ovarian wedge resection by laparotomy– ovarian wedge resection by laparoscopy– ovarian cauterisation by laparoscopy
OGTT in PCOS
Chang et al 1983, JCEM, 57:356
Hyperinsulinemia treatment
Metformin
Troglitasone
Weight loss
Metformin
Biguanide used in NIDDMInhibits hepatic glucose production Suppresses intestinal glucose absorptionIncreases insulin sensitivity in
peripheral tissuesRegulates lipid metabolism
Metformin in PCOS therapyImprovement in insulin sensitivity,
hyperinsulinemia and androgen levelsVelazquez et al. 1994, Metabolism, 43, 647-54;Velazquez et al. 1997, Metabolism, 46, 454-7; Nestler et Jakubowicz, N Engl J Med., 335, 617-23
Significant decrease in BMI and WHRVelazquez et al. 1994, Metabolism, 43, 647-54
Improvement of menstrual regularityMorin-Papunen et al..1998, Fertil Steril, 69, 691-6, Velazquez et al. 1997, Obstet Gynecol, 90, 392-9
No beneficial effects in some studiesAcbay et al,1996 Fertil Steril, 65, 949-9; Ehrmann et al., 1997, JCMB, 82, 524-30
No data on effects on clinical parameters : hirsutism and acne
Effect of metformin therapy on insulin
* statistically different, p<0,001
0
5
10
15
20
25
30
35
Insu
lin
(U
/ml)
Insulin before treatment
Insulin after treatment
*
mean +/_ SEM
0
0,2
0,4
0,6
0,8
1
1,2
1,4
Tes
tost
eron
e (n
g/m
L)
Testosterone before treatment
Testosterone after treatment
*
Effect of metformin therapy on testosterone
* statistically different, p<0,001
mean +/_ SEM
* statistically different, p<0,05
Effect of metformin therapy on SHBG
0
10
20
30
40
50
60
SH
BG
(n
mol
/L)
SHBG before treatment
SHBG after treatment
*
mean +/_ SEM
Effect of metformin therapy on FTI
* statistically different, p<0.001
mean +/_ SEM0
5
10
15
20
25
FT
I
FTI before treatment
FTI after treatment
*
Effect of metformin therapy on LH, FSH and LH/FSH ratio
0
5
10
15
LH
(m
IU/m
L)
0
5
10
15
FS
H (
mIU
/mL
)
0
5
10
15
LH
/FS
H
Before treatment
After treatment
LH FSH LH/FSH
mean +/_ SEM
Effect of metformin therapy on body mass index
* statistically different, p<0.005
mean +/_ SEM
0
10
20
30
40
BM
I (kg
/m2)
BMI before treatment
BMI after treatment
*
0
20
40
60
80
Len
ght
of m
enst
rual
cyc
le (
day
s) Lenght of cyclebefore treatmentLenght of cycle aftertreatment
Effect of metformin therapy on lenght of menstrual cycle
mean +/_ SEM
* statistically different , p<0,001
*
Effect of metformin therapy on WHR
* statistically different, p<0.001
mean +/_ SEM0
0,2
0,4
0,6
0,8
1
1,2
WH
R
WHR before treatment
WHR after treatment
*
Troglitasone Mechanism of action is not completely
anderstood Enhance insulin action without insulin
secetion It is a selective ligand for peroxisome
proliferation-activated receptor in adipose tissue
hepatotoxity ?
Results of clomiphene therapy in PCOS patients
Ovulation 80%Pregnancy rate 75%Pregnancies/ovulatory cycle 25-35%Multiple pregnancies 8%Abortion rate 30-40%
Results of gonadotropin therapy in PCOS women
Ovulation 90%Pregnancy rate 70%Pregnancies/ovulatory cycle 25-30%Multiple pregnancies 10%Abortion rate 25-30%
Women with PCOS have a higher incidence
of ovarian hyperstimulation syndrome after
ovulation stymulation
Treatment of hirsutism Cyproterone acetate (It bloks androgen
action by competitive binding to androgen receptor) 50-100mg/day on days 5-14 of the cycle nad ethinyl estradiol 30-35ug/day on cycle days 5-25 or combination of CPA (2mg/day) and EE (35ug/day) on cycle days 5-25
Spironolactone (aldosteron antagonist) 50-200mg/day between days 4 and 22 of cycle ; 50-75mg/day-mild to moderate hirsutism; 100-200mg/day severe hirsutism
Flutamide (used in prostate cancer ,It inhibits the binding of 5-DHT to androgen receptor ;250mg twice a day - it was used continuosly
Cimetidine (Imidazole is an antagonist of H2 receptor) 300mg four to five times daily for3-12 months
Androgen-producing ovarian neoplasm
Sertoli-Leydig cell tumors (Androblastoma, Arrhenoblastoma)
Hilus cell tumors Lipoid cell tumor Granulosa-theca cell tumors on ocassion Gynandoblastoma in wchich both granulosa
and leydig cell elements coexist
<1% of all ovarian tumors
Androblastoma Sertoli-Leydig cell tumors The ovarian neoplasms secrete testosterone Less than 0.4% The tumors occur in women between the
ages of 20 and 40 The most often unilateral Rapid onset of hirsutism and virilisation Surgical treatment
Gynandroblastoma Tumors have both granulosa cells and
androblastoma components Masculinisation Estrogen production produce
endometrial hyperplasia and irregular uterine bleeding
Surgical treatment
Iatrogenic androgen levels
Danazol• It is administered in endometriosis• Spome women develop hirsutism, acne
and deepening of the voice
Oral contraceptives• Progestins compartment• Ralely women develop acne and even
hirsutism
Hyperandrogenism and menopause
The high circulating LH levels activates ovarian stroma and hilus cells steroidogenesis
The menopausal ovary is a major source of testosterone, secretes moderate amounts of androstendione
The pattern of androgen secretion is changed:
Before menopause After menopause
A>>T T>A
Increased risk of diabetes mellitus in PCOS women
PCOSAge 40-49 lat 50-61 latWHR 0.81 +/- 0.06 0.84+/- 0.09Diabetes (%) 11.1 20.0
Controls
Age 40-49 lat 50-61 latWHR 0.78 +/- 0.06 0.79+/- 0.09Diabetes (%) 3.5 1.3
Dahlgren, Acta Obstet Gynecol Scand,1992,71,599
Abnormalities in lipid profile in PCOS women
Increased total cholesterolIncreased triglyceridesIncreased LDLDeacrised HDL
Talbott et al.,1998,J Clin Epidemiol,51,41Conway et al.,1992,Clin Endocrinol,37,119von Eckardstein,1996,Gynecol Endocrinol,10,311
Abnormalities in lipid profile in PCOS women
Abnormal lipids pattern is independent
of body weight
Wild et al.,1992, Am J Obstet Gynecol,166,1191Graf et al., 1990, Clin Endocrinol,33.119
Insulin resistance and Hyperinsulinemia
Advers lipid profile
Glucose intoleranceNIDDM
Cardiovascular disease
PAI-1
Obesity