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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.

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hyperandrogenism beata banaszewska

HyperandrogenismBeata Banaszewska

Department of Infertility and

Reproductive Endocrinology

androgens are c 19 steroids produced in
Androgens are C-19 steroids produced in:
  • Ovary
  • Adrenal gland

Androgens are metabolised in:

  • Skin
  • Adipose tissue
  • Liver
  • Placenta
slide3
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

1% Free

2% Free

19% Albumin

19% Albumin

80% SHBG

79% SHBG

Normal women Hirsute women

Testosteron is transported:
the main androgens
The main androgens
  • Dehydroepiandrosterone (DHEA)-a weak carbon-5 androgen secreted principally by the andrenal gland
  • Androstendione (A) - a weak carbon-4 androgen secreted in equal amounts by the adrenal glands and ovaries
  • Testosterone (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 a-reductase
origin of circulating androgens
Origin of circulating androgens

ADRENAL

CORTEX

25%

50%

90%

99%

50%

Testosterone Androstendione DHA DHAS

25%

50%

10%

OVARY

causes of hyperandrogenism
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
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
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

slide10

Polycystic ovary syndrome (PCOS)

  • 5-10% of women in reproductive age
  • Hyperandrogenism
  • Amenorrhoea
  • Anovulation
  • Infertility
  • Obesity
the clinical consequences of chronic anovulation in pcos women
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
Sign and symptoms of PCOS patients

Observation Average incidence

Infertility 75%

Hirsutism 56%

Amenorrhea 47%

Obesity 33%

Regular menses 16%

Virilisation 17%

endocrine abnormalities in pcos
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
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 Polycystic Ovary on ultrasound
  • The ovaries have pericentic cysts of 5 to 10 mm - usually at least 10 in one sonographic plane
  • Increased ovarian stroma
  • Only 75-80% wonem with the clinical diagnosis of PCOS had polycystic ovary
  • Prevalence of the polycystic ovaries in 16 to 23% of „normal” women
  • In 50% women with hyperprolactinemia
  • 24% of women with hypothalamic amenorrhoea
  • 100% of women with CAH
constitutional hirsutism
Constitutional hirsutism
  • Women with greater activity of 5 a-reductasein in the skin
  • Normal ovulation
  • Regular menstrual cycle
  • Normal hormone concentrations
slide17

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 hyperinsulinemia
  • Decrease in SHBG and IGFBP-1 production
  • Excessive androgen production
slide18

Types of insulin resistance

Type B

Type A

Insulina

Autoantibodies

to insulin receptors

Genetic defect

of insulin receptor

(Kahn syndrome)

a

a

Type C

b

b

tyrozine kinase

Defect of tyrozine

kinase

wchich comes first the hyperinsulinemia or the hyperandrogenism
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
slide20

Defects of tyrosine

kinase

Autoantibodies to

insulin receptor

Genetic defects

of insulin receptor

Insulin resistance

Hyperinsulinemia

Ovarian insulin

receptors

Ovarian IGF-I

receptors

IGFBP-1

SHBG

LH/FSH

IGF1

Free

Testosterone

Ovarian stymulation

Hyperthecosis

PCOS

Hyperandrogenizm

slide21

GnRH pulse frenuency

LH/FSH ratio

THECA CELL

LH receptor

cholesterol

Pregnenolone Progesterone

17a hydroksyprogesterone

Androstenedione

Testosterone

17a-hydroksylase

Steps

involving

P450c17a

17, 20 -lyase

b

17b-reductase

a

Insulin

IGF receptor

ovarian defect in the pathogenesis of pcos
Ovarian defect in the pathogenesis of PCOS
  • Dysregulation of cytochrome P450c17a that results in :
    • increased activity of 17a-hydroksylase
    • disordered 17,20-lyase activity
    • excessive ovarian androgen production
  • There is hypothesis that hyperinsulinemia stimalates ovarian cytochrome P450c17a
  • Defect in 3b-hydroksysteroid dehydrogenase or aromatase activity
two clinical categories of functional ovarian hyperandrogenism

Hyperandrogenism Hyperandrogenism

with insulin resistance without insulin resistance

Testosterone Elevated Elevated

Fasting insulin Elevated Normal or minimally

elevated

LH Minimally elevated Markedly elevated

LH response Normal Exaggerated

to GnRH

DHAS Low-normal Normal or elevated

Ovarian pathology Stromal hyperthecosisPolycystic ovaries

Two Clinical categories of Functional Ovarian Hyperandrogenism
differentation of hyperandrogenism
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 OVARY

thecosis often>1.5

ng/ml

Idiopatic Regular Normal Normal Normal Normal SKIN

hirsutism

Adrenal Irregular Elevated Often Usually Elevated ADRENAL

hyperpla- Normal Normal >4ng/ml

sia at 8pm in

follicular

phase

congenital adrenal hyperplasia cah
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 wasting
  • 11-hydroksylase deficiency

Late onset adrenal hyperplasia sometimes occurs in women in reproductive age.

differentation of ovarian and adrenal hyperandrgenism
Differentation of ovarian and adrenal hyperandrgenism
  • DHAS
  • 17-OH Progesterone
  • 17-KS
  • Test with dexamethasone
treatment of infertile pcos women
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
OGTT in PCOS

Chang et al 1983, JCEM, 57:356

hyperinsulinemia treatment
Hyperinsulinemia treatment
  • Metformin
  • Troglitasone
  • Weight loss
slide30

Metformin

  • Biguanide used in NIDDM
  • Inhibits hepatic glucose production
  • Suppresses intestinal glucose absorption
  • Increases insulin sensitivity in peripheral tissues
  • Regulates lipid metabolism
slide31

Metformin in PCOS therapy

  • Improvement in insulin sensitivity, hyperinsulinemia and androgen levels
        • Velazquez 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 WHR
        • Velazquez et al. 1994, Metabolism, 43, 647-54
  • Improvement of menstrual regularity
        • Morin-Papunen et al..1998, Fertil Steril, 69, 691-6, Velazquez et al. 1997, Obstet Gynecol, 90, 392-9
  • No beneficial effects in some studies
        • Acbay 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
slide32

Effect of metformin therapy on insulin

35

Insulin before treatment

Insulin after treatment

30

25

*

20

Insulin(mU/ml)

15

10

5

mean +/_ SEM

0

* statistically different, p<0,001

slide33

Effect of metformin therapy on testosterone

1,4

Testosterone before treatment

Testosterone after treatment

1,2

1

*

0,8

Testosterone (ng/mL)

0,6

0,4

0,2

mean +/_ SEM

0

* statistically different, p<0,001

slide34

Effect of metformin therapy on SHBG

60

SHBG before treatment

SHBG after treatment

50

40

*

SHBG (nmol/L)

30

20

10

mean +/_ SEM

0

* statistically different, p<0,05

slide35

Effect of metformin therapy on FTI

25

FTI before treatment

FTI after treatment

20

15

*

FTI

10

5

mean +/_ SEM

0

* statistically different, p<0.001

slide36

Effect of metformin therapy on LH, FSH and LH/FSH ratio

Before treatment

15

15

15

After treatment

10

10

10

LH/FSH

FSH (mIU/mL)

LH (mIU/mL)

5

5

5

0

0

0

LH FSH LH/FSH

mean +/_ SEM

slide37

Effect of metformin therapy on body mass index

BMI before treatment

40

BMI after treatment

*

30

BMI (kg/m2)

20

10

mean +/_ SEM

0

* statistically different, p<0.005

slide38

Effect of metformin therapy on lenght of menstrual cycle

80

Lenght of cycle

before treatment

Lenght of cycle after

treatment

60

*

Lenght of menstrual cycle (days)

40

20

mean +/_ SEM

0

* statistically different , p<0,001

slide39

Effect of metformin therapy on WHR

1,2

WHR before treatment

WHR after treatment

1

*

0,8

0,6

WHR

0,4

0,2

mean +/_ SEM

0

* statistically different, p<0.001

troglitasone
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
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
Results of gonadotropin therapy in PCOS women

Ovulation 90%

Pregnancy rate 70%

Pregnancies/ovulatory cycle 25-30%

Multiple pregnancies 10%

Abortion rate 25-30%

slide43

Women with PCOS have a higher incidence

of ovarian hyperstimulation syndrome after

ovulation stymulation

treatment of hirsutism
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 5a-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
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
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
Gynandroblastoma
  • Tumors have both granulosa cells and androblastoma components
  • Masculinisation
  • Estrogen production produce endometrial hyperplasia and irregular uterine bleeding
  • Surgical treatment
iatrogenic androgen levels
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
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
Increased risk of diabetes mellitus in PCOS women

PCOS

Age 40-49 lat 50-61 lat

WHR 0.81 +/- 0.06 0.84+/- 0.09

Diabetes (%) 11.1 20.0

Controls

Age 40-49 lat 50-61 lat

WHR 0.78 +/- 0.06 0.79+/- 0.09

Diabetes (%) 3.5 1.3

Dahlgren, Acta Obstet Gynecol Scand,1992,71,599

abnormalities in lipid profile in pcos women
Abnormalities in lipid profile in PCOS women
  • Increased total cholesterol
  • Increased triglycerides
  • Increased LDL
  • Deacrised HDL

Talbott et al.,1998,J Clin Epidemiol,51,41

Conway et al.,1992,Clin Endocrinol,37,119

von Eckardstein,1996,Gynecol Endocrinol,10,311

abnormalities in lipid profile in pcos women1
Abnormalities in lipid profile in PCOS women

Abnormal lipids pattern is independent

of body weight

Wild et al.,1992, Am J Obstet Gynecol,166,1191

Graf et al., 1990, Clin Endocrinol,33.119

slide53

PAI-1

Glucose intolerance

NIDDM

Insulin resistance and

Hyperinsulinemia

Advers lipid profile

Obesity

Cardiovascular disease