Prof. Dr. Levent Şentürk

1. Fertility problems in women
with androgen excess
Levent M. SENTURK, M.D., Professor in Ob&Gyn
Istanbul University Cerrahpasa School of Medicine
Dept. of Ob&Gyn, Division of Reproductive Endocrinology, IVF Unit
December 5, 2018; 1.00 p.m. CET

2. Disclamer:
Any views or opinions expressed herein are
solely those of the author and do not
necessarily represent those of any company,
institution and/or organization with which the
presenter is employed or affiliated.

3. Increase in
Androgen
production
Receptor
hypersensitivity
Decrease in
Androgen
Turn-over
Decrease in
binding proteins
(SHBG, albumin, etc)
HYPERANDROGENISM

4. Causes of Hyperandrogenism
in Reproductive Age
PCOS
80%
Idiopathic
15%
HAIR-AN
2-4%
L-AH
1-2%
Ovarian Tm
0,7%
Adrenal Tm
0,3%

5. PCOS

6. Ovarian and adrenal vein
sampling
• Combined ovarian and adrenal vein sampling
• High serum testosterone concentrations
(testosterone >150 ng/dL /L]) and normal pelvic
ultrasonography and adrenal imaging
• In this setting, the ovary is likely to be the
source of androgen hypersecretion
• Adrenal tumors are almost always visualized on
adrenal CT, while ovarian tumors are often too
small to be seen on imaging studies
A series of seven cases has been
reported in which amenorrhea was
associated with the presence of
bilateral polycystic ovaries
Stein IF, Leventhal ML. Amenorrhea asociated with bilateral
polycystic ovaries. Am J Obstet Gynecol 1935;29:181-191
• bilateral
polycystic ovaries
and thickened
ovarian cortex
• amenorrhea
• hirsutism
• infertility

7. PCOS – sign and symptoms
%
• Hirsutism 60-90
• Oligomenorrhea 50-90
• Infertility 55-75
• PCO 50-75
• Obesity 40-60
• Amenorrhea 25-50
• Acnea 25
• DUB 30
• Regular mens. Cycle 22

8. PCOS Diagnostic Criteria
(Rotterdam, 2003)
1. Oligo-anovulation
2. Clinical hyperandrogenism and/or
hyperandrojenemia
3. Polycystic ovaries (PCO)
(2 out of 3 criteria is necessary for the Dx)
• Other androgen excess disorders should be
discarded
*Rotterdam ESHRE/ASRM-sponsored PCOS Consensus Workshop Group,
Hum Reprod & Fertil Steril 2004

9. Rotterdam, 2003
PCOS definition
NIH 1990
AE-PCOS Soc., 2006

11. Prevalence of PCOS
• Most common endocrinopathy in reproductive aged
women…
11

12. 12
PCOS-prevalence

13. Agenda
• Before pharmacologic treatment
• Pharmacologic treatment
• 1st Line
• CC / AI
• MET
• 2nd Line
• GN
• LOD
• 3th Line
• ART
14

14. Agenda
• Before pharmacologic treatment
• Pharmacologic treatment
• 1st Line
• CC / AI
• MET
• 2nd Line
• GN
• LOD
• 3th Line
• ART
15

15. 16
• Lifestyle management
• Weight loss (5 - 10%)
• Diet
• Exercise
• 5 days a week for 30’ (AHA, WHO)
• Walking, swimming, gardening
• Pharmacologic agents
• Bariatric surgery
• Behavioural control
• Realistic goals
• Frequent contact
• Autocontrol
• Psychological support (x8; Cinar N et Al, 2011)
Before pharmacological treatment

16. • RCT (n= 149), JCEM-2015
• PCOS, BMI: 27 – 42 kg/m2.
• Preconceptional (16 wks)
• OCP
• Lifestyle management (%7 weight loss + exercise)
• Combined
• Ovulation rates 46% vs. 60% vs. 67%
• LBR 12% vs. 26% vs. 24%
17
Before pharmacological treatment…

17. • Life-style management is not only recommended
for conception, but also for obstetric
complications and long-term health risks
18
Before pharmacological
treatment

18. Agenda
• Before pharmacologic treatment
• Pharmacologic treatment
• 1st Line
• CC / AI
• MET
• 2nd Line
• GN
• LOD
• 3th Line
• ART
19

19. What’s next?
• First line in OI - guidelines
20

20. Agenda
• Before pharmacologic treatment
• Pharmacologic treatment
• 1st Line
• CC / AI
• MET
• 2nd Line
• GN
• LOD
• 3th Line
• ART
• Conclusion remarks
21
Metformin
RCT (vs CC)
15
Moll, BMJ, 2006
(n: 228)
Ovulation (%) Ongoing PR (%) Miscarriage (%)
CC (6 cycles) 72 46 11
CC + MET (2 gr) 64 40 12
Legro, NEJM, 2007
(n: 626)
LBR (%) Miscarriage (%)
CC (6 cycles) 22.5 25.8
MET (2 gr) 7.2 40.0
CC + MET 26.8 30.0
MET vs. MET + CC (LBR) = OR 1.21 (0.92 to 1.59), 9 studies, 1079 women.
(Morley C et al. Cochrane, 2017)

21. What’s next?
• First line in OI - guidelines
22
Metformin
RCT (vs CC)
15
Moll, BMJ, 2006
(n: 228)
Ovulation (%) Ongoing PR (%) Miscarriage (%)
CC (6 cycles) 72 46 11
CC + MET (2 gr) 64 40 12
Legro, NEJM, 2007
(n: 626)
LBR (%) Miscarriage (%)
CC (6 cycles) 22.5 25.8
MET (2 gr) 7.2 40.0
CC + MET 26.8 30.0
MET vs. MET + CC (LBR) = OR 1.21 (0.92 to 1.59), 9 studies, 1079 women.
(Morley C et al. Cochrane, 2017)
2014…
18
Letrozol vs. CC N (RCT) OR (%95 CI)
CPR 10 1.35 (1.08 – 1.69)
LBR 6 1.79 (1.38 – 2.31)
‘The quality of this evidence is low and findings should be regarded with some caution’

22. 19
2014…
CC (n: 376) Letrozole (n: 374) P value
Ovulation (%) 76.6 88.5 < 0.001
Cumulative LBR (%) 19.1 27.5 0.007
TTP (day) 85.9 (48.8) 90.4 (44.4) 0.27

23. 20
Subgroups for CC?

24. Subgroups for CC ?
LBR N (RCT) OR (%95 CI)
BMI > 25 5 1.67 (1.31 – 2.11)
BMI < 25 2 1.54 (0.81 – 2.93)

25. 22
Subgroups for CC ?

26. § Can we predict live birth in women treated with CC?
§ n=259 PCOS
§ 50 / 100 / 150 mg CC
§ % 38 LBR (cumulative for 6 months)
§ Predictors (multivariate)
§ Age
§ FAI (100 x TT/SHBG)
§ BMI
§ Menstrual status
23
Imani B, FS, 2002
Subgroups for CC ?

27. 24
Cumulative for 6 months
AUC:0.85
FAI :5 / BMI: 35/ amenorrhea / age =25
FAI :5 / BMI: 25 / oligomenorrhea / age=22
Imani B, FS, 2002
Subgroups for CC ?

28. Arguments for CC
§ Adverse effects on endocervical glands and endometrium
(Gelety TJ, FS, 1993; Eden JA, Dehbashi S, Int J Gyn Obstet, 2003)
§ Thompson LA, FS, 1993 (histology)
§ Legro RS, NEJM, 2014 (endometrial thickness and miscarriage)
§ Increased risk of multiple pregnancy
(Franik, Cochrane-2014)
§ Legro RS, NEJM, 2014 (50 – 100 mg CC)
§ Warraich G, FS, 2015 (sextuplets with 7.5 mg AI)
25

29. Arguments for AI
§ Increased rate of congenital abnormalities (Biljan, ASRM, 2005)
§ Tulandi T, FS, 2006
§ Forman R, J Obs Gyn Can, 2007
§ Sharma S, Plos One, 2014
§ Legro RS, NEJM, 2014
§ Tatsumi R, HR, 2017
§ Side effects
§ Similar rates of side effects with CC or AI (Legro RS, NEJM, 2014)
§ Hot flashes vs. dizziness and fatigue
26

30. § Obesity, hyperandrogenemia, hyperinsulinemia…
28
Brown J and Farquhar C, Cochrane 2017
Comparison No. of RCTs No. of
patients
Outcome Results
OR (95 % CI)
CC + BRM (2.5 – 7.5 mg) vs. CC 2 174 CPR 1.0 [ 0.5 to 2.2 ]
CC + DEX (0.5 – 2 mg) vs. CC 4 424 CPR 6.2 [ 2.2 to 17.48 ]
CC + OCP (42 – 50 days) vs. CC 1 48 CPR 27.2 [ 3.1 to 235.0 ]
Tang T et al, Cochrane review 2012
CC + MET vs. CC 5 178 Ovulation 4.9 [ 2.4 to 9.7 ]
CC resistant (anovulation with 150 – 250 mg)

31. § Both CC and AI might be used.
§ If BMI >30kg/m2, consider AI (lack of FDA approval !)
§ If BMI <30kg/m2, consider CC (lower risks with ≤ 100 mg !)
§ If CC resistant, might add OCP, MET or DEXA
29
First line in OI

32. Agenda
33
• Before pharmacologic treatment
• Pharmacologic treatment
• 1st Line
• CC / AI
• MET
• 2nd Line
• GN
• LOD
• 3th Line
• ART

33. • Conventional protocol
• Increase every 5 -7 days
• 75 IU of increments
• Low dose step up
• Begin with 37.5 – 75 IU
• Wait until 7-14 days, then increase every 7 days
• 25 – 37.5 IU of increments
• Beneficial for multiple pregnancy and excessive
response without impairing pregnancy rate
(Homburg R, 1995 and 1999)
34
Second line - Gonadotropins
Conventional vs. Low dose Step up

34. PCO : NON-SURGICAL
TREATMENT OPTIONS
WT REDUCTION
CLOMIPHENE CITRATE
GONADOTROPHINS
METFORMIN
LOW-DOSE STEP-UP PROTOCOL
75 IU /g 113 IU/g 150 IU/g 187.5 IU/g
1 14 21 28 35
PcOS
LOW-DOSE STEP-UP PROTOCOL
75 IU /g 113 IU/g 150 IU/g 187.5 IU/g
1 14 21 28 35
PCOS

35. Ovulation
Atresia Atresia
FSH
Threshold
MONOFOL. Growth – WIDE, compressed window
Baird DT: J Steroid Biochem 27: 15-23, 1987
FSH Gate Theory

36. Second line - Gonadotropins
Low dose step up and Step down
33
37.5-75

37. § RCT
34
Step up (n=85) Step down (n=72)
Duration of treatment (d) 15.2 ± 7.0 9.7 ± 3.1
Multifollicular
development (%)
32 68
Excessive response (%) 2.3 11
Pregnancy per cycle (%) 19 16 (NS)
Christin-Maitre, HR, 2003.
Second line - Gonadotropins
Low dose step up and Step down

38. • n=151 WHO Grup II
• Low dose step up
• % 17.3 LBR (1 month)
• Predictors (multivariate)
• BMI
• Ovarian volume
• Menstrual regularity
39
Andersen An, HR, 2008
Second line - Gonadotropins
Prediction of least dose for response

39. 38
Weiss NS et al, Cochrane review, 2015
Comparison No. of RCTs No. of
patients
Outcome Results
OR (95 % CI)
RecFSH vs. urinary FSH
hMG (3) FSH-HP (7)
5 505 LBR 1.3 (0.8 to 2.0)
Other arguments for GN

40. § CC resistant / failure
39
Bordewijk EM et al, Cochrane review, 2017
Comparison No. of RCTs No. of
patients
Outcome Results
OR (95 % CI)
Metformin plus FSH vs. FSH
Rec FSH (4) hpFSH (1)
2-3 x 850 mg (1 – 3 m)
4 232 OPR 2.5 (1.4 to 4.5)
Weiss NS et al, Cochrane review, 2015
RecFSH vs. urinary FSH
hMG (3) FSH-HP (7)
5 505 LBR 1.3 (0.8 to 2.0)
Other arguments for GN

41. Ovarian and adrenal vein
sampling
• Combined ovarian and adrenal vein sampling
• High serum testosterone concentrations
(testosterone >150 ng/dL /L]) and normal pelvic
ultrasonography and adrenal imaging
• In this setting, the ovary is likely to be the
source of androgen hypersecretion
• Adrenal tumors are almost always visualized on
adrenal CT, while ovarian tumors are often too
small to be seen on imaging studies
A series of seven cases has been
reported in which amenorrhea was
associated with the presence of
bilateral polycystic ovaries
Stein IF, Leventhal ML. Amenorrhea asociated with bilateral
polycystic ovaries. Am J Obstet Gynecol 1935;29:181-191
• bilateral
polycystic ovaries
and thickened
ovarian cortex
• amenorrhea
• hirsutism
• infertility
WEDGE RESECTION
Laparoscopic Ovarian Drilling
(LOD)

42. Second Line - LOD
• Uni – bipolar energy
• 4–5 puncture in each ovary (40 – 50W, 4 –5sec)
• Benefits
• No prescription
• No monitorization
• Least risk of multiple pregnancy
• Disadvantages
• Requires LS
• 54 % requires consecutive medical treatment
• 10 – 20 % periadnexial adhesion
43
Bayram N, BMJ, 2004

43. • LOD
• Lack of monitorization and singleton pregnancy but needs
appropriate surgery
• Proper for lean women with hyperandrogenemia
• Gn
• Low dose step up decreases multiple pregnancy and cycle
cancellation rates but needs patience
• No need for insemination???
44
Second line in OI

44. Agenda
45
• Before pharmacologic treatment
• Pharmacologic treatment
• 1st Line
• CC / AI
• MET
• 2nd Line
• GN
• LOD
• 3th Line
• ART

45. OHSS as a measure of success !
§ The Netherlands National Registry
§ Total ~ 100,000 IVF treatment cycles
§ 6 deaths directly related to IVF
§3OHSS,
§ 3 thrombosis and sepsis after egg retrieval
§ Possibility of underreporting IVF related complications
43

46. Type of OS protocol
44
Kollmann M et al, Ultrasound Obstet Gynecol, 2016
Comparison No. of RCTs Outcome Results
RR (95 % CI)
GnRH-agonist vs. antagonist 12 OPR/LBR
OHSS
0.95 (0.8 to 1.1)
0.63 (0.5 to 0.8)
Metformin vs. no treatment 10 OPR/LBR
OHSS
1.28 (1.01 – 1.63)
0.47 (0.29 – 0.76)
Weiss NSet al, Cochrane Database Syst Rev. 2015 OR (95 % CI)
Urinary vs. recombinant-FSH
(HP-FSH in 3RCT)
10 LBR
OHSS
1.26 (0.8 – 2.0)
1.52 (0.8 – 2.8)
Tso LO et al, Cochrane Database Syst Rev. 2014 OR (95 % CI)
Metformin vs. no treatment 5 LBR
OHSS
1.39 (0.8 – 2.4)
0.29 (0.2 – 0.5)

47. § Individualization of triggering
47
Strategies to prevent OHSS
Number Strategy
I hCG
II hCG + Dopamine agonist
III GnRHa trigger + 1500 hCG
IV GnRHa trigger + freeze all
V GnRHa trigger + freeze all + daily
GnRH antagonist injection

48. Freeze all!
48
Frozen ET (n= 746) Fresh ET (n= 742) P value
Live birth (%) 49.3 42. 0 0.004
Pregnancy loss (%) 14.6 25.6 < 0.001
Early OHSS (%) 1.3 7.1 < 0.001

49. § ART
§ Safety should be warranted as the most important outcome
of measure
§ Antagonists cycles and agonist trigger, if needed.
§ Ideal dose of gonadotropin : ≈100 IU
§ Freeze all?
49
Third line in OS for PCOS

50. ESHRE / ASRM (2008) and TSRM 2015
§ 1. STEP
§ CC (AI)
§ 2. STEP
§ LOD or GN (low dose step up)
§ 3. STEP
§ ART (cautious for OHSS)
50

51. Clinical Hyperandrogenism
• Hirsutism
• Acnea
• Alopecia
• Oligoamenorrhea
• Virilization
• Abdominal obesity
• Acanthosis nigricans

53. Hirsutism

54. Definition
• Excessive facial and body hair caused by excess
androgen production
• Terminal hair growth in androgen-dependent sites
(abdomen, face, chest, inner thighs)
• 5-10% of population
• Virilism
• Adrenal hyperplasia and androgen-producing tumor
• Ovarian tumor
• Hyperthecosis
• Clitoromegaly
• Deepening of the voice
• Balding
• Changes in body habitus

55. Types of hair
Lanugo Vellus Terminal
• Covers the fetus
• Lightly pigmented
• Thin in diameter,
short in length
• Fragile in
attachment
• Downy,
unpigmented
hair
• Prepubertal
years
• Coarse,
pigmented
hair
• Adult years
Hirsutism: Vellus to terminal hair transformation and growth in
androgen-dependent sites

56. • Total endowment of hair follicles is made by 22
weeks gestation
• Total concentration of hair follicles per unit
area
• No difference between sexes
• May differ between ethnic groups and races:
White > Asian;
Mediterranean > Nordic

58. Structure and Growth
• Anagen: the growing phase: 4 months
• Catagen: rapid involution phase, transitional phase: 3-4
weeks
• Telogen: quiscent phase, resting phase: 3-4 months
• Androgens: Increase anagen phase; increase hair
diameter; increase hair follicle size, shorter anagen in scalp
hair
• Scalp hair: Longer anagen, catagen: 2-5 years, relatively
short resting phase
• Forearm: Short anagen and long telogen
• Stable nongrowing length
• The appearance of continues growth
• The degree to which individual hair follicles act asynchronously with their
neighbours

59. Stimulation of hair growth
Hair
growth
Local factors
(number and
concentration
of hair
follicles)
Circulating
androgen
concentrations
End-organ
sensitivity
(5α-reductase
activity)

60. There are two conditions characterized by
generalized hair growth that do not represent
true hirsutism
• Lanugo
• Hypertrichosis
• Drugs
• Hypothyroidism, anorexia nervosa,
malnutrition, porphyria, and dermatomyositis,
and as a paraneoplastic syndrome in some
patients

61. DHEA
DHEA-S
ANDROSTENEDION
TESTOSTERON
>90%
80%
50%
25%
10%
50%
25%
50%
ADRENAL OVARY

62. Pathophysiology of androgens in
hirsutism
• Increased serum level of androgens, especially
free-T
• Decreased level of SHBG
• Increased activity of 5α-reductase activity

63. Estrogen therapy
Combined oral contraceptives
Pregnancy
Hyperthyroidism
Cirrhosis
Obesity
Increased androgen production
Hyperinsulinemia
Corticosteroid therapy
Hypothyroidism
Acromegaly
SEX HORMONE-BINDING GLOBULIN

64. TESTOSTERONE DIHYDROTESTO
STERONE
5α-REDUCTASE
INCREASED 5α-REDUCTASE ACTIVITY IN HIRSUTISM
3α-Andronostenediol glucuronide is the peripheral
tissue metabolite of DHT
5α-REDUCTASE

65. Etiology
• Polycystic ovary syndrome
70-90%
• Congenital adrenal hyperplasia
1-15%
• Idiopathic hirsutism
• Normal serum androgen
concentrations
• No menstrual irregularity
• No identifiable cause of the
hirsutism
• Severe insulin resistance
syndromes
• Cushing’s syndrome
• Pituitary disorders
Hyperprolactinemia
Acromegaly
• Y-containing mosaics and
incomplete androgen
insensitivity
• Hyperthecosis
• Increased production of
testosterone by luteinized
thecal cells in the stroma
• Ovarian tumors
• Adrenal tumors
• Drugs

66. Congenital adrenal hyperplasia
• Classical
• Nonclassic (late-onset)
• Peripubertal hirsutism
• Sometimes menstrual irregularity or primary amenorrhea
• No manifestations of cortisol deficiency
• Prevalence: 1 to 15 percent
• 21-hydroxylase: Autosomal recessive
• 11β-hydroxylase
• 3β-hydroxysteroid dehydrogenase
• It is nearly always due to 21-hydroxylase (P450c21)
• 17-hydroxyprogesterone 
• Androstenedione 
Adrenal Androgen Biosynthesis
Cholesterol
Pregnenolone
17-Hydroxy
pregnenolone
DHEA
Androstenediol
Progesterone
17-OHP
Androstenodione
Testosterone
11-deoxy
corticosterone
11-deoxycortisole
Estrone
Estradiol
Aldosterone
Corticosterone
Cortisole
21
OH OH
SD

67. Ovarian tumors
• Sertoli-Leydig cell tumors
• Granulosa-theca cell (stromal cell) tumors
• Hilus-cell tumors
• T > 200 ng/dL.

68. Adrenal tumors
• DHEA and DHEA-S secretion
• DHEA-S>700-800 μg/dl
• Usually cortisole is also secreted
• Clinical manifestations of androgen excess and
Cushing's syndrome
• A normal serum DHEA-S value does not exclude
the diagnosis

69. Insulin
Theca cell
receptors
Insulin-like
growth factor-I
Decrease
SHBG
Increased
Androgen
Production
Severe insulin resistance syndromes

71. History
• Age of onset
• NCCAH due to 21-hydroxylase deficiency and idiopathic hirsutism-
similar age of symptom onset
• Androgen-secreting tumors or ovarian hyperthecosis
• Third decade of life or later
• Both diagnoses are most common after menopause
• Stable versus progressive hair growth
• NCCAH due to 21-hydroxylase deficiency and idiopathic hirsutism-
similar presentation.
• Androgen-secreting tumors
• Recent onset, short duration (typically less than one year), or rapidly
progressive hirsutism
• Hyperthecosis: Severe hirsutism, postmenopausal, more gradual
compared to tumors

72. Physical examination
• Ferriman-Gallwey scoring
• Poor interobserver agreement
• Evidence of virilization
• Findings include deepening of the voice, temporal and/or crown
balding, increased muscle mass, and clitoromegaly
• Clitoral enlargement is typically determined on the basis of
clitoral length or the clitoral index (length times width): length
>10 mm or an index >35 mm2 is considered above normal
• Other important findings
• Other skin findings: Acne, seborrhea, acanthosis nigricans, striae
• Body mass index
• Abdominal and pelvic exam
OBESITY
android
obesity gynecoid
obesity
Waist / Hip ratio < 0.85

74. Evaluation
• For Mediterranean, Hispanic, and Middle Eastern
women, FG score ≥ 9-10 is considered abnormal
whereas for Asian women ≥2
• Scores between 8 and 15 are usually considered to
be mild hirsutism, 16 to 25 moderate, and scores
>25 severe hirsutism
• There is only a modest correlation between the
quantity of hair growth and serum androgen levels

75. Prolactin
TSH
Total
Testo
sterone
17-
hydroxy
proge
sterone
hCG
Biochemical testing
Not routine
Dehydroepiandrosterone
sulfate (DHEA-S)
Androstenedione
Cortisol
Gonadotropin
s
3α-
glucrunode
Idiopathic hirsutism (hirsutism-normal cycle): Testosterone
Hirsutism and oligo/amenore: T, 17-OHP, hCG, PRL, TSH, FSH, LH
Androgen secreting tumor: T, DHEAS

76. 17-OHP
17-OHP
>200 ng/dL
ACTH stimulation
test
Normal
response
Abnormal
response
Adrenal hyperplasia
21-OH deficiency
variant
<200 ng/dL
Rules out CAH, 21-
OH deficiency
Rule out CAH,
21-OH deficiency

77. Testosterone
Testosterone assay
>150 ng/dL
Palpable
adnexal mass
Normal pelvic
exam
L/S or L/T
<150 ng/dL
Anovulatory
hirsutism
Selective vein
catheterization
L/S or L/T Imaging
Especially in those
interested in future
fertility

78. Assesment of Insulin secretion
• 2-hour 75 mg glucose tolerance test
• Normal: Less than 140 mg/dL
• Impaired: 140-199 mg/dL
• Noninsulin-dependent diabetes: 200 mg/dL and
higher

79. Pelvic ultrasonography
• Large cysts, solid masses, and complex cysts that
do not resolve spontaneously in two to four weeks
• Small hilus-cell tumors
• May not be seen by ultrasonography
• Sex cord stromal tumors, are often not visualized
• May not be seen by ultrasonography
• MRI, PET

80. Adrenal imaging
• Markedly elevated serum testosterone and
pelvic ultrasound is negative
• A serum DHEA-S concentration >700 mcg/dL
• Adrenal CT is the imaging test of choice

81. Fertility problems in women
with androgen excess
Levent M. SENTURK, M.D., Professor in Ob&Gyn
Istanbul University Cerrahpasa School of Medicine
Dept. of Ob&Gyn, Division of Reproductive Endocrinology, IVF Unit
December 5, 2018; 1.00 p.m. CET
Thank
you...