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Investigation of the steroidal

causes of premature
adrenarche in girls

Liz Okokon
The chicken and
the egg thesis
In girls,
which comes first,
Boobs or Pubs ?
Pubertal development
 Puberty – process of sexual
development
 9-14 years in girls 10-16 years in boys
 Initiated by activation of hypothalamo-
pituitary-gonadal axis (HPG)
 Breast development first sign in girls
 Maturation of the ovaries or testes
Pubertal development 2
 Adrenarche - onset of pubic hair (PH)
development (pubarche)
 Axillary hair, adult body odour and acne
 From 9 years in girls and 10 years in boys
 Increased plasma adrenal androgen
dehydroepiandrosterone (DHEA)
 Maturation of the zona reticularis of the
adrenal cortex
Changes in mean Plasma Testosterone
with stage of life (in males)
Does Puberty
initiate
Adrenarche,
or vice versa ?
Does Adrenarche cause
Puberty?
 Under-treated CAH develop true
precocious puberty
 Pathological adrenal androgen levels may
induce HPG
 Normal Adrenarche at normal time in
 Precocious puberty

 Hypogonadism or pubertal delay

 2 maturational events occur independently


What causes Adrenarche?
 Adrenal size changes with plasma DHEAS?
 Zonal thickness – critical width?
 Steroidogenic enzymes change with age?
 Activation of 17,20-lyase &
 3-HSD activity is low in zona reticularis
 Lower 11-hydroxylase lowers cortisol
 Chronic ACTH stimulation of ZR enzymes
 Increased adrenal steroids (DHEA) result
What causes Premature
Adrenarche ?
 Pubic hair, preceding the onset of puberty
 Before 8-years in girls and 9-years in boys.
 Peripheral conversion of DHEA to T and
DHT is sufficient to stimulate AH and PH
 PH follicles possess an increased sensitivity
to adrenal androgens ?
 Changed sensitivity to ACTH stimulation ?
HPA axis & adrenal hyperactivity
Does Premature
Adrenarche
predispose girls to
develop PCOS ?
What is Polycystic ovary
syndrome ?
 Idiopathic hyperandrogenic anovulation
 Most common endocrine disorder in women
 Associated with
 hirsutism, hypertension, menstrual irregularity,
acne, dyslipidaemia, obesity and insulin
resistance
 increased risk of impaired glucose tolerance
progression to type 2 diabetes mellitus
 increased risk of cardiovascular disease
Does IR cause
PCOS or is IR a
consequence of
PCOS ?
Insulin resistance and PCOS
 PCOS are insulin resistant +/- obesity
 ↑ Insulin // ↑ Androgen concentrations
 ↓ Insulin - ↓ androgens
 ↓ Weight - ↓ Insulin & ↓ androgens
 But ↓ Androgens only, no ↓ Insulin
 But IR increases with obesity
 Insulin ↑ cortisol ↑ lipid = obesity
Aims of study
 Impact of gender, pubertal stage,
adiposity and ethnicity on normal USP
 Steroidal causes of premature
adrenarche
 Explore similarities to PCOS
 Investigate causes of adrenal
hyperactivity
 Glucocorticoid resistance
 Altered cortisol clearance
The investigation of PCOS
FAI LH FSH 17- USP Diagnosis
OHP

N or sl.  N N N  AM Simple hirsutism

  N or  N  AM, FM & DM PCOS

 N or  N or  N  AM Ovarian androgen
tumours

 N or  N or  N  DM Adrenal androgen
tumours

 N or  N or   17OHP metabs. CAH

N or  N N N FM, THF>THE Cushing’s syndrome


Androgen metabolite excretion in
girls with PA less than 10-years
2000

1800
Androgen metabolite excretion (ug/24hrs)

1600

1400

1200

1000

800

600

400

200

0
0.0 2.0 4.0 6.0 8.0 10.0
Age (years)
Cortisol metabolite excretion in girls
with PA less than 10-years
12000
Cortisol metabolite excretion (ug/24hrs)

10000

8000

6000

4000

2000

0
0.0 2.0 4.0 6.0 8.0 10.0
Age (years)
Girls with PA in study
 32 girls with Premature adrenarche recruited
 3 with PCO on U/S (@ 6.3, 8 & 17-yrs)
 Age at presentation < 6-yrs in 14
 Bone age advanced in 17/19 reported
 Low birth weight in 3/11 weight known
 F/H metabolic syndrome reported in 4
 Complete data on 22 (age 3.7 to 9.1-yrs,
mean age = 7.1 +/-1.6-yrs)
The relationship between bone age
& chronological age in girls with PA
Chronological age ■ Bone age■

12

11

10

9
AGE (years)

7 AGE

6 BA

2
IGF-1 SDS in girls with PA
6

3
IGF-1 SDS

0
4 6 8 10 12 14 16 18 20
-1

-2
Age (yrs)
Normal controls
 2 Primary schools in South East
 SFT, HT, WT, pubertal stage & ethnicity
 24-Hr Urine steroid profiles
 Compared
 % Body fat(SFT), BSA, BMISDS to
 Cortisol, androgen & DHEA excretion
Relationship between age and androgen
metabolite excretion in normal children
1200

1000

800
AM (ug/24hrs)

600

400

200

0
4 5 6 7 8 9 10 11 12
Age (years)
4

2
BMI SDS

-1

-2
4 5 6 7 8 9 10

Age (yrs)
1000

900
DHA Excretion (ug/24hrs.m-2)

800

700

600

500

400

300

200

100

0
4 5 6 7 8 9 10 11 12
Age (yrs)
1.40

1.20

1.00
FM/EM Ratio

0.80

0.60

0.40

0.20

0.00
4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 13.0 14.0

Age (yrs)
Dexamethasone suppression of
lymphocyte stimulation in girls with PA

130
% stimulation by PHA in presence of

120
110
100
90
80
DEX

70
60
50
40
30
20
10
0
0 E-10 E-9 E-8 E-7 E-6

[DEX] (M)
IC 50 ([DEX] @ 50 %
LYMPHOCYTE SUPPRESSION)

0.001
0.01
0.1
1
10
100

PA
Wild type and allelic variant in Intron 3 of
the GCR gene

Variant:
C A/G A C

Variant:
C A/G A C

Wild type:
C CAA C
PCOS: a life-long history
Many thanks to
Andoline Okokon, John Graves, Kwame and Ama Graves-Okokon, Susan and Josephine
Okokon, Dr Carol Gayle and Alan Hardy. Dr Susan Hawes, Dr Kim Khodakah (nee Johnson)
and Professor William Collins (formerly of the Department of Obstetrics and Gynaecology,
KCH.) Dr Sandra Strautnieks (KCH), Dr Richard Thompson (KCH), James Turton (UCL),
Nurse Sara Schilg (Maidstone), and all the STPEG paediatricians:
Dr. Ruth Ayling KCH Dr. Neal Martin Kent & Cant
Dr. Mike Ryalls Guildford Dr. Dorothy Garvie Lewisham
Dr. Tony Hulse Maidstone Dr. Andrew Long Farnborough
Dr. Christine Burren St. Helier Dr. Andrew Evans Greenwich
Dr Norman Taylor, Dr Charles Buchanan, Dr Hagosa Abraha, Belinda Asonganyi, Yiltan
Kani, (Dr) Walid Jervis, Dr Liz Want, Dr Caje Moniz, Dr Roy Sherwood, Dr. J. Alaghband-
Zadeh and my colleagues in Department of Clinical Biochemistry, KCH
Dedicated to the memory of my father
Dr Charles Offiong Ita Okokon
MB, BCh, BAO, DCMT, MRCP, FRCP, FWACP
R.I.P.

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