PCOS ve hiperandrojenemi-Ankara-2013

(1)

PCOS ve hiperandrojenemi-Ankara-2013

Fahrettin Kelestimur, Erciyes Üniversitesi, Kayseri, Türkiye

(2)

Adrenal

100%

DHEAS

Testosterone 25%

Androstenedione DHEA

90%

Ovary

50%

25% 10%

50%

Source of androgens in women

Pucci and Petraglia. Gynecol Endocrinol 1997.

50%

(3)

Cholesterol

Mineralocorticoids Glucocorticoids Sex Hormones

StAR

Protein SCC

Pregnenolone 17-hydroxylase 17-OH Pregnenolone 17,20 Lyase Dehydroepi- androsterone

Dehydroepiandrosterone Sulfate 17-HSD

Androstenediol 3-HSD

Progesterone

21-Hydroxylase Deoxycorticosterone

Corticosterone

1 1- Hydroxylase

18-Hydroxylase

18-OH Corticosterone

18-OH Dehydrogenase Aldosterone

3-HSD

3-HSD 3-HSD

17-hydroxylase

17-OH Prog 17,20 Lyase

Androstenedione

17-HSD

Testosterone

Aromatase Aromatase

Estrone Estradiol

21-Hydroxylase

11-Deoxycortisol

Cortisol

Present in adrenal &

gonadal tissues

Adrenal ACTH

Gonadal

LH/FSH

17-HSD

Which androgens should be measured ?

(4)

Clinical manifestations of hyperandrogenemia

1-Acne 2-Balding 3-Hirsutism 4-Seborrhea 5-Clitoromegaly 6-Mammary atrophy 7-Deepening of the voice 8-Increase in muscle mass 9-Loss of female body contour

10-Temporal recession of the hairline 11-Menstrual irregularity or amenorrhea

(5)

Causes of hyperandrogenism

Freuqent causes

1- PCOS

2- Idiopathic hirsutism

3- Non-classical adrenal hyperplasia 4- Idiopathic hyperandrogenemia

Rare causes

1- Adrenal/ovarian tumours 2- Cushing‘s syndrome

3- Acromegaly

4- Hyperprolactinemia

5- Hyperandrogenism, insulin resistance, acanthosis nigricans (HAIRAN) 6- Hyperthecosis

7- Glucocorticoid resistance syndrome (Chrousos syndrome) 8- Drugs

Unluhizarcı, Kaltsas, Kelestimur. European Journal of Clinical Investigation, 2011

(6)

Exp Clin Endocrinol Diabetes 112: 504-509, 2004

number %

PCOS 96 57.1

Idiopathic hirsutism 27 16

NCAH 12 7.1

Adrenal Ca 3 1.8

Cushing’s syndrome 1 0.6 Idiopathic

hyperandrogenemia 29 17.4

(7)

Escobar-Morreale, Carmina, Dewailly, Gambineri, Kelestimur, Moghetti, Pugeat, Qiao, Wijeyaratne, Witchel, Norman. Epidemiology, diagnosis and management of hirsutism.

A consensus statement by the AE-PCOS Society. Human Reproduction Update, 2012

(8)

n %

Classic PCOS 538 56.6

Ovulatory PCOS 147 15.5

Idiopathic hyperandrogenemia 150 15.8

Idiopathic hirsutism 72 7.6

NCAH 41 4.3

Tumors 2 0.2

(9)

Routine screening for Cushing‘s syndrome is not required in patients presenting with hirsutism

Karaca,Açmaz,Tanrıverdi,Ünlühızarcı,Şahin, Keleştimur

The etiology of hirsutism was

PCOS in 79%, idiopathic hirsutism in 13%,

idiopathic hyperandrogenemia in 6%, and NCAH in 2%

Routine screening for Cushing‘s syndrome in patients with a referral diagnosis of hirsutism is not required

European Journal of Endocrinology, 168:379-384, 2013

(10)

The Investigation of Insulin Resistance in Patients with

Idiopathic Hirsutism

Ünlühizarci K, Karababa Y, Bayram F, Keleştimur F

J Clin Endocrinol Metab 89: 2741–2744, 2004

The presence of insulin resistance was investigated by using basal insulin levels, the oral glucose tolerance test, the iv insulin

tolerance test, and the homeostasis model assessment (HOMA) score in both groups. Six (18.7%) patients had impaired glucose tolerance (IGT). Overall, patients with IH had significantly

(P<0.05) higher basal insulin levels (10.51.1 mU/liter vs. 5.7 0.9 mU/liter) and HOMA scores (2.0 0.2 vs. 1.1 0.2) and lower

plasma glucose disappearance rate values (5.20.2 vs. 6.00.3) than control subjects. However, patients with IGT were notably more obese than the patients with a normal glucose tolerance test.

(11)

(12)

Medical History in Hyperandrogenic Women

• Drug use

(particularly with androgenic effets)

• The onset of hirsutism

(age of the disease)

• Progression of hirsutism

• Menstrual cycles

(13)

Physical Examination

*Obesity

*Acanthosis nigricans

*Signs of virilization

*Symptoms/signs of Cushing’s disease

*Symptoms/signs of Acromegaly

*Galactorrhea

(14)

Investigation of hyperandrogenemia 1-Total testosterone

2-Free testosterone 3-Dihydrotestosterone 4-Free Androgen index (FAI) 5-Calculated free testosterone

6-Calculated bioavailable testosterone 7-11-deoxycortisol

8-17-hydroxyprogesterone 9-Androstenedione

10-Dehydroepiandrosterone sulfate (DHEAS) 11-Sex hormone binding globulin (SHBG)

12-prolactin 13-LH 14-FSH 15-Estradiol 16-progesterone

(15)

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

Suggested laboratory investigations in hirsute women

Unluhizarci K, Yilmaz S, Kelestimur F. Women’s Health, 2005

(16)

Some useful rules ?

1. If androstenedione is predominantly elevated androgen,hirsutism usually is of ovarian

origin, particularly if LH is elevated also, 2. If DHEAS is the predominantly elevated

androgen, hyperandrogenism usually is adrenal origin,

3. If hirsutism is accompanied by disturbances of the menstrual cycle, hyperandrogenism

usually is of ovarian or mixed origin,

4. If testosterone does no surpass 6 nmol/l, an androgen producing tumour is unlikely

(17)

MA (1)

31-year-old woman presented with hirsutism

The age of menarche: 13-year-old Regular menstrual cycles

Alopecia: (+) Acne: (+)

The age of begining of hirsutism: 17–year-old FG score: 13

USG: polycystic ovarian changes

(18)

(19)

ACTH stimulation test

Time 0' 30' 60' 17-OHP 4.7 65.4 >100 (ng/ml)

MA (3)

Genotyping: V281L/V281L Genotyping: V281L/V281L

Diagnosis: NCAH

(20)

PCOS

hyperandrogenemia acne

hirsutism

menstrual disorder infertility

polycystic ovaries NCAH

(21)

LC (1)

*A 31-year-old woman was admitted to the hospital because of hirsutism, oligomenorrhea and

infertility.

*The age of begining of hirsutism: 16 yr

*Physical examination was unremerkable except acanthosis nigricans

*BMI:34 kg/m² *FG score:14

*USG: bilateral polycystic ovarian changes

*Total testosterone: 113 ng/dl

*OGTT: impaired glucose tolerance

(22)

LC (2)

*Oligomenorrhea and infertility.

*Hyperandrogenism

*Hyperandrogenemia

*Acanthosis nigricans

*Obesity

*Impaired glucose tolerance

*Bilateral polycystic ovarian changes

Diagnosis: PCOS

(23)

Androgen Ovary Adrenal Peripheral conversion

DHEAS <5 >95 0

Androstenedione (A) 60 35 5 (from DHEAS)

Testosterone (T) 60 5 35 (from A)

Dihydrotestosterone (DHT) 0 0 100 (from A and T)

3-Androstanediol glucuronide 0 0 100 (from DHT)

Sources of serum androgens in women with PCOS

*Values are percent of total production at different sites

(24)

The most common cause of hyperandrogenemia is PCOS

Signs and symptoms suggestive of PCOS

*Onset of hirsutism; 15-25 years

*Slow progression of hirsutism

*Absence of virilization

*Menstrual abnormalities (very rare)

*Obesity

(25)

*

A 45-year-old woman was admitted to the hospital because of

poorly controlled diabetes mellitus and facial hirsutism for 6 months.

*Medical history revealed that she was suffering from malaisa, fatigue, alopecia, easy bruising for one year and she had

amenorrhea for 3 years.

* Physical examination showed hypertension, facial hirsutism, and purple stria on the abdomen.

Lİ (1)

(26)

(27)

*MRI of pituitary:

microadenoma, 5 mm in size

Lİ (3)

(28)

(29)

Cushing’s syndrome PCOS

the signs of hypercortisolism predominates

protein catabolism

proximal muscle wasting thin skin

hyperandrogenism predominates

thick stria (^narrow

pale or pink) good muscle mass (Anabolic effect of androgen)

stria

(Atrophic purple)

(30)

• Some of the specific causes of

hyperandrogenemia may be diagnosed/excluded by physical examination and with some basic

laboratory evaluations.

• Those diseases constitutes less than 5% of the

women with hirsutism/hyperandrogenemia.

(31)

Escobar-Morreale, Carmina, Dewailly,Gambineri, Kelestimur, Moghetti, Pugeat, Qiao, Wijeyaratne, Witchel, Norman. Epidemiology, diagnosis and management of hirsutism.

A consensus statement by the AE-PCOS Society. Human Reproduction Update, 2011

(32)



45 year-old postmenopausal woman

 history of HT and DM for 5 years

 rapidly progressing hirsutism for 4 years

 deepening of her voice.

PE: androgenic alopecia,

male pattern hirsutism (FGS: 26)

clitoromegaly

(33)

DHEAS

(1950-5070 ng/ml)

A4

(0.1-3.1 ng/ml) Total T

(11-80 ng/dl)

Free T

(0.29-3.18 pg/ml)

Basal 969 3.16 1169 34.38

HDDST

Decrease 606 1.3

59%

934 21%

26.6 23%

Postop 1.02 44 1.3

CT and MRI: Normal

T/V USG: a mass lesion 22x14 mm on the left ovary

Pathology:

steroid cell tumor

, stained positively with inhibin

Transvaginal USG can reveal the ovarian tumors which cannot be identified on CT or MRI

(34)

Steroid cell tumor

 Ovarian neoplasm composed entirely of cells

resembling steroid hormone secreting cells, that is lutein cells, leydig cells and adrenocortical cells

with abundant IC lipids

 0.1-0.2% of all ovarian tumors

60% of all steroid cell 25-45% malign

50% hyperandrogenemic Any age, mean:32 yrs Hilar-cell

Non-hilar cell

Stromal luteoma Leydig cell Steroid cell NOS

(35)

Serum androgen levels in patients with hirsutism due to tumors



T>200 ng/dl



DHEAS>7000 ng/dl



T elevation+normal DHEAS ovarian



DHEAS >7000 ng/dl+normal T adrenal

tumor

(36)

Non-tumoral Tumoral

Onset Pubertal Outside peripubertal Progression Gradual Rapid

Family history Common Usually negative Virilization Rare Common

Degree Mild-severe Severe

Androgens Mild-severe Usually significant

Differential characteristics of patients with

hirsutism due to tumoral and non-tumoral causes

(37)

Unluhizarci K, Kaltsas G, Kelestimur F.

Non polycystic ovary syndrome related endocrine disorders associated with hirsutism.

European Journal of Clinical Investigation, 2011

(38)

Escobar-Morreale, Carmina, Dewailly,Gambineri, Kelestimur, Moghetti, Pugeat, Qiao, Wijeyaratne, Witchel, Norman. Epidemiology, diagnosis and management of hirsutism.

A consensus statement by the AE-PCOS Society. Human Reproduction Update, 2011

(39)

(40)

57 year-old postmenopausal woman Main complaint obesity

History of HT and DM for 2 years PE: BMI: 42 kg/m2

mild hirsutism FGS:10

Moon-face

(41)

DHEAS (1950-

5070 ng/ml)

Androste nedione

(0.1- 3.08 ng/ml)

Total

testosterone (11-80

ng/dl)

free

testosterone (0.29-3.18

pg/ml)

Basal 3003 4.92 305 9.07

HDDST 1860 2.21 94 3.62

(42)

(43)

(44)

ACTH pg/ml

F µg/dl

DHEAS

(1950-5070 ng/ml)

Total

testosterone

(11-80 ng/dl)

Basal 106 29 1407 123

LDDST 50 18 3118 53

Postop 13 2 73

Pituitary MRI: An adenoma 5 mm in size

Pituitary adenoma was removed succesfully.

Hyperandrogenemia resolved completely.

*Symptoms of androgen secreting tumor may be mild.

*The association of Cushing’s syndrome does not always mean an adrenal source of HA

*The type of androgen elevated is an important clue for the source of androgen excess

(45)

Preoperative hormones

Postoperative hormones

DHEAS ng/ml (1950-

5070) 3003 1407

Total testosterone

ng/dl (11-80) 305 73

free testosterone

pg/ml(0.29-3.18) 9.07

2.8

(46)

Endocrine Society Clinical Practice Guideline

Testing for androgens is suggested in women with

 Moderate or severe hirsutism (FGS>15)

 hirsutism of any degree when it is associated with -menstrual irregularity or infertility

-central obesity

-acanthosis nigricans

Martin et al 2008 JCEM

hirsutism of any degree sudden onset, rapidly progressive

-rapid progression -clitoromegaly

(47)

(48)

Testosterone >200 ng/dl DHEAS >7000 ng/ml

Neoplasm

(49)

Rare (specific) causes of hyperandrogenemia

• Cushing’s syndrome

• Acromegaly

• Hypo/Hyperthyroidism

• Hyperprolactinemia

• Some drugs

(50)

Cushing’s Syndrome-Hirsutism

• Hirsutism alone is an unusual sign of Cushing’s syndrome.

• In most of the patients, vellus type body hair is increased.

• The presence of Cushingoid signs and symptoms in addition to hirsutism should alert the physician for adrenal tumors.

(51)

• Ovarian source should be suspected when adrenal imaging is negative

• Catheterization may help localization if

imaging studies are negative or inconclusive

(52)

Mechanisms related to the associations among GH excess, acromegaly, and

hyperandrogenemia

1-Insulin resistance and hyperinsulinemia 2-Decreased SHBG

a-hyperinsulinemia   SHBG production b-GH  SHBG

Hyperinsulinemia   SHBG

 IGF-I

3-Direct ovarian effect of GH 4-IGF-I

6-Hypothalamic-pituitary dysfunction

(53)

• Pure androgen secreting tumors are very rare.

• Most of the adrenal carcinomas secrete androgens and cortisol concomitantly

leading to Cushing/subclinical Cushing’s syndrome

Cordera F et al. Surgery 134: 874-880, 2003

(54)

Adrenal Cancer on Adrenal CT

• Inhomogenous, irregular margins,

• Irregular contrast enhancement

• Local invasion, liver metastasis

• HU: <10 sens 71%, spec 98% for a benign lesion

*Attenuation >10 HU in unenhanced CT

*Enhancement washout <50%

*Delayed attenuation of >35 HU

*(10-15 min delayed enhanced CT)

Suspicious malignancy

Ilias Endoc Rel Cancer 2007

(55)

The Frequency of CYP 21 Gene Mutations in Turkish Women with

Hyperandrogenism

F. Kelestimur, H. Everest, M. Dundar, F. Tanriverdi, C. White, S. F. Witchel

(56)

• OBJECTIVE: The congenital adrenal hyperplasias (CAH) are a group of autosomal recessive disorders due to decreased activity of the

enzymes responsible for cortisol biosynthesis. Since CYP21 gene mutations in non-classical CAH (NC-CAH) due to 21-hydroxylase

deficiency among Turkish women have not been well characterized, we performed CYP21 genotype analyses to determine the frequency of specific mutations in our population.

• DESIGN: Clinical study in women with hyperandrogenism at

Endocrinology Department of a University Hospital. The CYP21 genotype analysis was performed at the Children's Hospital of Pittsburgh.

• PATIENTS AND METHODS: The study population included 32 Turkish women with hyperandrogenism and hirsutism, 5 patients with NC-CAH due to 21-hydroxylase deficiency and their 3 first degree relatives.

The following steroids were measured: cortisol, prolactin, DHEAS, free testosterone, testosterone, LH, FSH, estradiol, 17-OHP, 11-

deoxycortisol, and androstenedione. The ACTH stimulation test was performed in the follicular phase of the menstrual cycle. CYP21

mutations were detected by CYP21 specific PCR followed by allele specific restriction fragment length polymorphism (RFLP) or single strand conformational polymorphism analyses.

(57)

• RESULTS: Among hirsute Turkish women with

hyperandrogenemia 21.9% was heterozygous carriers of CYP21 mutations; all had basal and stimulated 17-OHP values within the normal range. Alleles detected were as follows: Q318X, V281L, del/gene conversion, and R356W. Thus, 21.9% of women were heterozygous CYP21 carriers.

• CONCLUSION: The frequency of CYP21 heterozygosity is high among Turkish women with hirsutism and hyperandrogenism.

Women with hyperandrogenism who are heterozygous CYP21 mutation carriers have normal basal and stimulated 17-OHP levels. In other words, normal basal and ACTH-stimulated 17- OHP responses do not exclude heterozygosity for CYP21

mutations. The molecular differences between symptomatic carriers, e.g., our patients and asymptomatic CYP21 mutations carriers, e.g., mothers of children with classical CAH, remain to be elucidated.

(58)

(59)

Causes of hirsutism

Adrenal Iatrogenic Idiopathic Ovarian

PCOS

Hyperthecosis Ovarian tm

Cushing’s S.

CAH

Adrenal tm

Testosterone Danazol

GCC

Pregnancy-rel

Luteoma

Hyperreaction luteinalis

(60)

Relative Prevalence of Clinical Hyperandrogenism

PCOS 72.1%

Idiopathic hyperandr 15.8%

Idiopathic hirsutism 7.6%

NCAH 4.3%

Carmina et al 2006

950 women

Azziz et al 2004

873 women

PCOS 82%

Idiopathic hyperandr 6.8%

Idiopathic hirsutism 4.7%

CAH and NCAH 2.2%

Kaltsas et al 2003 1000 women

Androgen secr tumours 0.2%

Androgen secr tumours 0.8%

(61)

Clinical features of virilization

• Clitoromegaly: clitoral index >35 mm

²

entire length>1 cm

transverse diameter>0.7 cm

• Deepening of voice

• Increased muscle mass and libido

• Breast atrophy

Yildiz BO Best Prac Res Clin Endocr Met 2006

(62)

author androgen sensitivity specifity

B d’Alva et al 2008

T>170 ng/dl T>125 ng/ml

45%

60%

100%

94%

fT>11.2 pg/ml fT>6.8 pg/ml

47%

82%

100%

97%

17-OHP>1.95 ng/ml 11-DOC>7 ng/ml

67%

89%

86%

100%

Kaltsas et al 2003

T>210 ng/dl 41% 100%

T>86 ng/dl 100% 53%

Age<40

T>86 ng/dl 47% 53%

Age>40

T>86 ng/dl 53% 95%

(63)

Androgens in tumoral hyperandrogenemia

B d’Alva et al EJE 2008 Kaltsas et al JCEM 2003 Non-tumoral

HA n=95

Tumoral HA 38 adrenal tm

PCOS n=211

Tumoral HA 12 adrenal

5 ovarian

A4 93% 90% 96% 79%

DHEAS 39% 82% 47% 69%

T 43% 76% 47% 100%

Free T 42% 94%

17-OHP 11% 67%

3

androgens elevated

22% 56% 20% 71%

2

androgens elevated

38% 31% 69% 94%

(64)

Dynamic tests

Non-tumoral hyperandrogenemia

GnRH FSH, LH -

- -

-

decreases androgens in ovarian hyperthecosis

ovarian and adrenal andr secr tm

No effect

Abraham et al 1981 Obstet Gynecol Melis et al JCEM 1987

Kennedy JCEM 1987

Derksen et al NEJM 1994

Pascale et al Clin Endocrinol 1994 Stephens et al Hum Reprod 2002

+

Tumoral hyperandrogenemia

GnRHa

hCG dexamethasone

(65)

The value of LDDST in the differential diagnosis of HA

Patients PCOS 211

Ovarian tm 5

Adrenal tm 12

Presenting

age 24 (14-40) 45 (18-62) 41 (21-70)

Presenting symptoms

(Prev. %)

Hirsutism 95%

Menstr irreg 65%

Acne 29%

Alopecia 10%

Clitoromegaly 8%

3 pts with postmenop.

bleeding,

2 patients like PCOS

2 patients with

virilization

3 patients like PCOS

Kaltsas et al JCEM 2003

(66)

Differential Value of LDDST

40% reduction in androgen levels sens. 100%

spec. 73%

LDDST may help to differentiate the etiology of hirsutism particularly in premenopausal

hyperandrogenemic women.

Kaltsas et al JCEM 2003

(67)

Imaging Studies

 Transvaginal and pelvic USG

 Pelvic MRI

 Adrenal USG

 Adrenal CT

 Adrenal MRI

(68)

4 year-old girl puberty precox

4 cm sertoli cell tm Abundant vascularization

59 year-old asymptomatic woman

6 cm sertoli cell tm Moderate vascularization

Demidov VN Ultrasound Obstet Gynecol 2008

(69)

RAV LAV

ROV LOV

adrenal veins 70%

ovarian veins Parous women 71%

Nulliparous women 58%

Left veins 80%

Right veins 46%

The overall 27%

success rate 29%

45%

Kaltsas et al 2003 Clin Endocrinol Wentz etal Am J Obstet Gynecol 1976 Sorensen et al Card Interv Rad 1986

Sampling for differentiation of hyperandrogenemia

(70)

imaging catheter Final diagnosis Moltz et

al, 1984 N=7 tm

-negative -Ovarian source lat: 6 no lat:1

-3 lipid cell -2 leydig cell

-2 sertoli-leydig cell Bricaire

et al, 1991 N= 6 tm 10 other

-5 negative -Adrenal mass

-Ovarian source lat: 5 -Adrenal source: 1 -No gradient: 10

-5 ovarian tm

-1 adrenal adenom -6 PCOS,4 hilus cell hyperplasia

Kaltsas et al, 2003 N=8 tm 30 PCOS

-3 adrenal mass -Bulky ovaries + adrenal mass

-4 ovarian mass

-8 PCOS

-adrenal: 2/ unsucces. 1 -unsuccesful

-Ovarian source: 2 -unsuccesful

-Ovarian source lat: 1

-Ovarian lat:3 no lat:3 -unsuccesful 2

-3 adrenal adenom -1 bilateral leydig

-2 sertoli-leydig c.

-1 granulosa cell

-1 hilus cell stromal hyp

-PCOS pathological dx

(71)

Gradient in androgen levels

• R/L >1.44 correct identification of 90% of right tm

• <1.44 correct identification of 86% of left or bilateral tm

• Sampling identifies right-sided ovarian lesions better.

Levens et al Clin Endocrinol 2009

(72)

Catheterization should be reserved for cases with:

 suspicion of tumor

 Imaging modalities unable to localize a tumor

Catheterization should be carried out in

specialized units in skilled hands

(73)

Ovarian androgen-secreting tumors

1. Sex cord stromal tumors

 Granulosa-theca cell Granulosa cell

Thecoma (typical/luteinized) Sclerosing stromal cell

 Steroid cell -stromal luteoma -Leydig cell

-Steroid cell (NOS)

 Sertoli cell

2. Germ-cell (teratoma) 3. Gonadoblastoma

4. Primary ovarian epithelial tumors-Brenner tm/mucinous tm

5. Metastasis (Krugenberg Tm)

(74)

Androgenic adult granulosa cell tumor

 Hirsutism, amenorrhea, abdominal mass

 Solid/cystic/mixed lesion on USG

 Local and lymphatic extension

 Low mitotic index

 Inhibin A and B

 Prognosis is good

Castro et al Int J Gynecol Pathol 2000 Kabaca et al Int J Gynecol Cancer 2006 Petraglia et al JCEM 1998

(75)

Leydig-cell tumors

 Seen in older ages mean age: 58

 Hirsutism is present in 3/4 of tumors

 Abdominal pain, distension

 Usually small tumors r=2.4 cm

 Reinke crystals (+)

 Prognosis is good, always benign

(76)

Sertoli-leydig cell tumor

• Reproductive age (78%)

• May secrete androgens or estrogen, 50%

hormonally inactive

• Secondary amenorrhea, 2/3 of cases hirsutism and virilization

• Small and difficult to detect

• Recurrence 95% within 5 years

• Poor prognosis with high stage tumor

(77)

Krugenberg Tumor

• Ovarian metastasis derived from abdominal and retroperitoneal organs

• 2/3 diagnosed synchronously with primary tumor

• 2/3 bilateral

• Abnormal vaginal bleeding and amenorrhea 20%

• Virilization, hirsutism rare

• Poor prognosis

• Median survival 7-14 months

Hornung et al W J Sur Oncol 2008

(78)

Adrenal androgen secreting tumors

• Rare

• 40-70% malignant

• Tumors secrete DHEA, DHEAS, A4 and T

• Stimulated with hCG, not with ACTH

• Not suppressed with dexamethasone

Cordera et al Surgery 2003 Moreno et al Surgery 2004 Derksen et al NEJM 1994

Del Gaudio et al Cancer 1993

(79)

Adrenocortical Carcinoma

• Incidence: 1-2/million population

• Peak in 4-5th decades

• Female/male: 1.5

• Rapidly progressing Cushing’s syndrome±

virilization

• Lack evidence of systemic disease

Fassnacht et al Best Prac Res Clin Endocrinol Met 2009

(80)

Adrenal Cancer on Adrenal CT

• Inhomogenous, irregular margins,

• Irregular contrast enhancement

• Local invasion, liver metastasis

• HU: <10 sens 71%, spec 98% for a benign lesion

Attenuation >10 HU in unenhanced CT

Enhancement washout <50%

Delayed attenuation of >35 HU (10-15 min delayed enhanced CT)

Suspicious malignancy

Ilias Endoc Rel Cancer 2007

(81)

Adrenal Cancer on MRI

• T1-weighted: Isointense to liver

• T2-weighted: increased intensity

• Distinct Gd enhancement and slow washout

• Sens: 81-89%

• Spec: 92-99%

Honigschnabl et al European J Radiology 2002

(82)

Scintigraphy

•

¹³¹

I-iodomethyl-norcholesterol

• FDG-PET

•

¹¹

C-metomidate for PET

•

¹²³

I-iodometomidate for SPECT

(Metomidate: binds adrenal 11-beta

hydroxylase and aldosterone synthase)

Han et al Int J Clin Prac 2007 Hennings et al JCEM 2006 Hahner et al al JCEM 2008

(83)

Gross et al EJSO 2009

(84)

Criteria for malignancy of an adrenal tumor Weiss score

• High nuclear grade

• Mitosis>5/50 hpf

• Atypical mitotic figures

• Eosinophilic tumor cell cytoplasm(>75% of tm cells)

• Diffuse architecture (>33% of tm)

• Necrosis

• Venous invasion

• Sinusoidal invasion

• Capsular invasion

0-2: benign, 3: undetermined, 4-9: malignant

Weiss et al Am J Surg Pathol 1989

(85)

Staging for Adrenocortical Carcinoma

T1<5 cm , T2>5 cm, T3: Tm infiltration in surrounding tissue T4: Tm invasion in adjacent organs

STAGE UICC/WHO 2004 ENSAT 2008

I T1N0M0 T1N0M0

II T2N0M0 T2N0M0

III T1-2 N1M0

T3N0M0

T1-2N1M0 T3-4N0-1M0

IV

T1-4N0-1 M1 T3N1M0

T4N0-1M0

T1-4N0-1M0

DeLellis et al Pathol Gen Tum End Org 2004 Fassnacht et al Cancer 2009

(86)

Weiss Score and Outcome

Pure androgen secreting

adrenal tumors

outcome Death

N=7 Alive n=14 Weiss

score N Of dis unrel With dis

Without dis

<3 6 0 1 0 5

3 5 0 1 0 4

>3 10 5 0 3 2

Moreno et al Surgery 2004

(87)

Immunohistochemical markers

• Ki67 index: 1.5-4% cut-off between adenoma and ACC >7% associated with significantly shortened disease-

free survival

• Melan A

• D11

• Inhibin-alpha

• SF-1

• Chromogranin-A, cytokeratins, S-100 negative

• LOH at 17p13, ıgf-2 overexp, cyclin E, MMP-2, telomerase, topoisomerase IIalpha, N-cadherin

(88)

Treatment

• Surgical resection

• Laparoscopy for tm<6 cm benign

tm<10 cm adrenal cancer

• Radiotherapy

• Mitotane

• Streptozocin/EDP

• IGF-1 receptor antibodies, thyrosine kinase

inhibitors, other antiangiogenic compounds

(89)

Prognosis

Adrenal carcinoma overall 5 year-survival 16-44%

47%

10 year-survival 41%

Poor prognostic criteria

 Stage of the tumor

 Diameter>12 cm

 Mitotic activity

 Ki-67 index

 Mutated TP53

Wooten et al Cancer 1993

Wajchenberg et al Cancer 2000 Fassnacht et al 2009

(90)

Summary

• Rapid onset of hirsutism, presence of virilization are important clues for tumoral hyperandrogenemia

• T>200 ng/dl, DHEAS>7000 ng/dl suggest presence of tumor

• Ovarian source should be suspected when adrenal imaging is negative

• Catheterization may help localization if imaging studies are negative or inconclusive.

(91)

Hyperthecosis

 Presence of nests of luteinized theca cells in the ovarian stroma

 Nests are scattered throughout the stroma

 Symptoms similar to PCOS

 Greater degree of hyperandrogenemia T=150-200 ng/dl

Interstitial cells Luteinized stromal cells (Steroidogenically active)

(92)

Sertoli cell tumor

• Young patients

• Secrete estrogen

• Prognosis is good

(93)

Sertoli-leydig cell tumor

• Slight changes in androgen in ACTH stim

• Partial suppression of T after dxm

• Stim of T and A4 with hCG

• No response of decreased Gntrp to LHRH stim

• Suppression of T with LHRHa (tx)

• Increase in inhibin and AFP

(94)

Hirsutism is defined as excessive growth of terminal hair in the androgen-sensitive skin regions

in women and affects 5-15% of the whole female

population of fertile age

(95)

Hirsutism results from an increase in circulating androgen concentrations, an increase in the sensitivity of the

pilosebaceous unit to normal androgen

concentrations or a combination of these

factors

(96)

(97)

(98)

(99)

(100)

The Investigation of Insulin Resistance in Patients with

Idiopathic Hirsutism

Ünlühizarci K, Karababa Y, Bayram F, Keleştimur F

The presence of insulin resistance was investigated by using basal insulin levels, the oral glucose tolerance test, the iv insulin

tolerance test, and the homeostasis model assessment (HOMA) score in both groups. Six (18.7%) patients had impaired glucose tolerance (IGT). Overall, patients with IH had significantly

(P<0.05) higher basal insulin levels (10.51.1 mU/liter vs. 5.7 0.9 mU/liter) and HOMA scores (2.0 0.2 vs. 1.1 0.2) and lower

plasma glucose disappearance rate values (5.20.2 vs. 6.00.3) than control subjects. However, patients with IGT were notably more obese than the patients with a normal glucose tolerance test.

(101)

(102)

(103)

(104)

(105)

(106)

(107)

Comparison of finasteride and flutamide in the treatment of idiopathic hirsutism. Falsetti at al. Fertil Steril 1999; 72:41-43

(108)

Additive Effects of Insulin-Sensitizing and Anti-Androgen Treatment in Young, Nonobese Women with Hyperinsulinism, Hyperandrogenism, Dyslipidemia,and Anovulation.

Ibanez et al. JCEM 2002; 87:2870-7.

(109)

The most important purpose of

investigation is to identify those women

with androgen secreting tumors, as they

require different therapy

(110)

A detailed investigation of etiologies of hirsutism in a Turkish population

Ünlühızarcı K, Gökçe C, Bayram F, Keleştimur F.

Experimental and Clinical Endocrinology & Diabetes, 2004.

“Although PCOS is the most common (57%) cause of hirsutism, it is notable that nearly one fifth of

hirsute women have no appearent cause of hyperandrogenism”

Athens,2006

(111)

(112)

ASN:androgen secreting neoplasms

Azziz R et al, JCEM, 2004. Athens,2006

(113)

In women presenting with hyperandrogenism, lack of

testosterone suppression during the LDDST is associated with 100% sensitivity and 88% specificity in distinguishing patients with ovarian and adrenal androgen-secreting

tumors from patients with nontumorous hyperandrogenism

Kaltsas GA et al. The value of the low-dose dexamethasone suppression test in the differential diagnosis of hyperandrogenism in women. JCEM, 2003

(114)

Clitoromegaly is refers to clitoral index >35 mm²

Clitoral index is the product of the sagittal and transverse diameters of the glans of the clitoris

(115)

 A 28-year-old woman presented with a 4-month history of amenorrhea, hirsutism, acne and one month history of diabetes mellitus.

 On her physical examination, extensive acne,

hirsutism, (F.Gallwey score:21) and purple striae on the abdomen have been detected.

 Her blood chemistry was normal except

hypokalemia (K:2.5 mmol/l) and hperglycemia

 Diabetes Mellitus was regulated with 50 U/d insulin

AK (1)

(116)

(117)

^AK(4)

(118)

Basal Postoperative

FSH (1.2-12.5 mIU/ml) 0.02 0.01

LH (2.5-10.2 mIU/ml) 0.1 0.01

Estradiol (11-165 pg/ml) 481.9 128

Cortisol (9-26 g/dl) 118.7 24.6

17-OHP (0.1-0.8 ng/ml) 22.2 1.3

11-DOC (<8 ng/ml) 11.8 0.9

SHBG (20-140 nmol/L) 19.5 14

DHEAS (100-3300 ng/ml) 29841 3149

Androstenedione (0.4-2.7 ng/ml) 40 2.4

T.Testosterone (7-65 ng/dl) 943 170

F.Testosterone (0.3-3.1 ng/dl) 24.4 2.6

Basal and postoperative (at two weeks) hormone levels

AK (5)

(119)

DHEAS is a valuable marker of adrenal androgen activity and a good marker of

adrenal androgen production

Testosterone is the primary marker of ovarian androgen production

DHT is the primary marker of peripheral androgen production

3α-androstanediol glucuronide is a marker

of peripheral androgen action

(120)

(121)

Cholesterol

StAR

Protein SCC

Progesterone

Corticosterone

18-Hydroxylase

3-HSD

3-HSD 3-HSD

17-hydroxylase

17-OH Progesterone

17,20 Lyase

Androstenedione

17-HSD

Testosterone

Estrone Estradiol

21-Hydroxylase 11-Deoxycortisol

Cortisol

gonadal tissues

Figure 1. Adrenal and gonadal stereidogenesis. Solid line= major pathway. Dotted line = major pathway in ovaries and minor pathway in adrenals. StAR = steroidogenic autoregulatory protein. SCC =cholesterol side chain cleavage enzyme .

3-HSD = 3 - hydroxysteroid dehydrogenase activity / ⁵ - ⁴ isomerase, 17-HSD =17  -hydroxysteroid dehydrogenase.

Gonadal

LH/FSH

17-HSD

(122)

Bioavailable testosterone:

free testosterone + albumin-bound testosterone

Free Androgen Index (FAI):

100Xtotal testosterone/SHBG

(123)

Basal LDDS T

POSTO P

Cortisol

(µg/dl) 19.11 11.1 7.26 17-OHP

(ng/ml) 5.6 1.46

11-DOC

(ng/ml) 11.6 1.31

DHEAS

(ng/ml) 16707 14368 271 A4 (ng/ml) 37 35 0.76

Free T

(pg/dl) 22.05 35.94 0.74

Adrenocortical adenoma

(124)

Basal Postoperative

Cortisol (9-26 µg/dl) 19.11 7.26

17-OHP (0.1-0.8 ng/ml) 5.6 1.46

11-DOC (<8 ng/ml) 11.6 1.31

SHBG (20-140 nmol/L) 8 32

DHEAS (100-3300 ng/ml) 16707 271

Androstenedione(0.4-2.7 ng/ml) 37 0.76

tTestosterone (7-65 ng/dl) 698 6

fTestosterone (0.3-3.1 ng/dl) 22.05 0.74

Basal and postoperative (18th month) hormone levels

(125)

‘Pure androgen-producing tumors are extremely rare. Approximately 50% are benign, and surgical resection provides excellent treatment if the

tumors are not metastatic at the time of diagnosis’

Cordera et al. Surgery 2003;134:874-880

(126)

The most important issue in the differential diagnosis of

hyperandrogenemia is the exclusion of ovarian/adrenal tumors

(127)

Rapidly Progressive Hirsutism/Acne and/or

the presence of Virilization (temporal recession of the scalp hair and male pattern balding, male type musculature, deepening of the voice and

clitoromegaly) and/or

Very high level of androgens

suggest a sinister cause-adrenal or ovarian tumor-

(128)

Cholesterol

StAR

Protein SCC

Progesterone

Corticosterone

18-Hydroxylase

3-HSD

3-HSD 3-HSD

17-hydroxylase

17-OH Prog 17,20 Lyase

Androstenedione

17-HSD

Testosterone

Estrone Estradiol

21-Hydroxylase

11-Deoxycortisol

Cortisol

gonadal tissues

Gonadal

LH/FSH

17-HSD

Which androgens should be measured ?

(129)

Cholesterol

StAR

Protein SCC

Pregnenolone 17-hydroxylase 17-OH Pregnenolone 17,20 Lyase

DHEA

DHEAS

17-HSD Androstenediol 3-HSD

Progesterone

Corticosterone

18-Hydroxylase

3-HSD

3-HSD 3-HSD

17-hydroxylase

17-OH Progesterone

17,20 Lyase

Androstenedione

17-HSD

Testosterone

Estrone Estradiol

21-Hydroxylase 11-Deoxycortisol

Cortisol

gonadal tissues

Gonadal

LH/FSH

17-HSD

Which androgens should be measured ?

(130)

(131)

Free androgen index (FAI):

100 x total testosterone/SHBG

Which androgens should be measured ?

(132)

19-year-old woman presented with hirsutism

The age of menarche: 13-year-old Menstrual cycles: regular

Alopesia: (-) Acne: (-)

The age of begining of hirsutism: 14–year-old

FG score: 18

USG: bilateral normal ovaries

FD (1)

(133)

(134)

FD (3)

Cortisol response to dex. sup. test: 1.2 (µg/dl) 17-OH P response to ACTH st. test: 5.3 (ng/ml) 2-hour blood glucose level after OGTT: 109 (mg/dl) Biochemical investigation including lipid profile: normal

Diagnosis: Idiopathic hirsutism

(135)

The Investigation of Insulin Resistance in Patients with Idiopathic Hirsutism Ünlühizarci K, Karababa Y, Bayram F, Keleştimur F

(136)

ACTH pg/ml

F µg/dl

DHEAS (1950-5070

ng/ml)

A4 (0.1-3.08

ng/ml)

Total T (11-80 ng/dl)

free T (0.29-3.18

pg/ml)

Basal 5 118 16129 40 943 32

HDDST 104 16111 41 25

postop 24 3149 2.4 270 2.6

Adrenocortical

carcinoma

(137)

ASN:androgen secreting neoplasms

Azziz R et al, JCEM, 2004.

(138)