LH (IU/L)

Hypogonadotropic
Hypogonadism & Amenorrhea
Pr N. Pitteloud
Service d’endocrinologie
CHUV, Lausanne
Clinical case
•
37yr old woman referred for infertility.
•
She presented with 12 months of amenorrhea after discontinuing the
birth control pill.
Anovulatory infertility: Causes
Hypothalamic amenorrhea 36%
GnRH
Pituitary disease
17%
PCOS
33%
POF
12%
LH
InhibIn B
FSH
+
Estradiol
Progesteron
e
Thyroid diseases
Reindollar et al 1986
3%
Clinical case
•
37yr old woman referred for infertility with 12 months of amenorrhea
after discontinuing the birth control pill
Present history
- No headache, no galactorrhea, no visual disturbances
- no acne, no hirsutism
- Jogging 2x week 3 km, no psychological stress, no eating disorder
- Thin, stable weight
- No anosmia, no cleft, no hearing loss…
History of pubertal development
- Primary amenorrhea
- Tanner 3-4 breast development
- Oral contraceptives started at age 17
- 2 h of gymnastic a day
- BMI 19 at 17 yr old
Cas clinique
Physical examination (age 37)
•
•
•
•
Normal corpulence, Height 163 cm, weight 54 kg, BMI 21
Breast development Tanner V, pubic hair Tanner V
No galactorrhea
No acne, Ferriman-Gallway score 7, no frontal alopecia
Infertilité anovulatoire: Evaluations
Laboratory
- hCG negatif
- FSH 2.3 IU/L, LH 2.1 IU/l, estradiol 0.15 pmol/l, T 0.5 nmol/l
- Other pituitary function normal including normal prolactin
Transvaginal US
- Endometrium 3 mm
Brain MRI
- Normal
Anovulatory infertility: Evaluations
Anovulatory
infertility
Rule out
pregnancy hCG
FSH & LH 
POF
LH> FSH, T
PCOS
LH&FSH N/
E2
HH
PRL 
Hyperprolactinemia
TSH abnl
17 OH prog
Thyroid
disease
LOAH
Primary amenorrhea
N=74
HH (tumor, CHH)
FHA
CDP
Sedlmeyer I L , Palmert M R JCEM 2002
What is the differential diagnosis in this patient?
Congenital hypogonadotropic hypogonadism?
Functional hypothalamic amenorrhea?
Congenital hypogonadotropic hypogoandism
Fetus
Néonatal
Enfancy
Puberty
GnRH deficiency
• Multiple genes involved
• Defects in specification & migration CDP
of GnRH neurons and/or secretion/action
CHH
“Classic”
Adult
ADULT
HA
IHH
IHH
“Reversal”
Primary amenorrhea
Absence of breast development
Absence of secondary
characteristics
Primary amenorrhea
Infertility
Ostoporosis
Function of Genes Involved in human
GnRH deficiency
Sykiotis et al, 2010
Clinical spectrum of CHH
35
30
Breast development prior to tx in 120 patients with CHH
25
20
Série1
15
10
5
0
S1
severe
Absence of pubertal
development
S2
S3
S4
S5
mild
Spontaneous thelarche
Primary amenorrhea
Hormonal spectrum of CHH female patients
A
B
9
8
8
7
7
6
6
5
5
4
4
3
3
2
2
1
1
0
C1
C2
C3
Controls
C4
IHH 1 IHH 2 IHH 3 IHH 4
Patients
0
C1
C2
C3
Controls
C4
IHH 1 IHH 2 IHH 3 IHH 4
Patients
J Young , D Vincent, A Bachelot, M L Kottler ,I Plotton,
P Chanson, S Brailly, , C Dode, M Pugeat, P Touraine, D Dewailly
Does this patient has a partial form of congenital
hypogonadotropic hypogonadism?
Primary amenorrhea
Tanner III‐IV before treatment
Isolated HH
Persistant amenorrhea with HH
Possible
Functional Hypothalamic
Amenorrhea
•
•
•
Functional GnRH deficiency
Stress,  energy availability
Amenorrhea with
Hypoestrogenism
Low/nl gonadotropins
No neuroanatomic lesion
•
1/3 of 20 amenorrhea
NORMAL
FETUS
INFANT
CHILD
PUBERTY
ADULT
Etiology of FHA in a Cohort of 93 Women
Exercise + wt.
Loss (13%)
Competitive
Sport (6%)
Weight loss (40%)
Stress (29%)
Stress +
wt. loss
(12%)
Falsetti et al, JCEM 2002
Hormonal spectrum in patients with FHA
18
16
18
LH IU/L
16
14
14
12
12
10
10
8
8
6
6
4
4
2
2
0
0
 AHF (n=55)
 NL (n=60)
FSH IU/L
Caronia et al, NEJM 2011
Patterns of GnRH Secretion in HA
LH (IU/L)
Apulsatile
 Frequency
30
30
20
20
10
10
0
0
Developmental Arrest
LH (IU/L)
 Amplitude
30
30
20
20
10
10
0
0
0
2
4
6
8 10 12 14 16 18
Time (hours)
0
2
4
6
8 10 12 14 16 18
Time (hours)
Santoro, Martin, Hall 1998
Sleep
FHA, BMI, and age of menarche
35
25
% of Subjects
20
15
??
10
5
HA
Controls
30
% of Subjects
HA (n=55)
Controls
(n=60)
25
20
15
10
5
0
0
14
16
18
20
22
24
BMI (kg/m2)
26
28
30
10
11
12
13
14
15 16
17
Age at Menarche (yrs)
Caronia et al, NEJM 2011
Relationship between weight, physical activity
in a young ballet dancer
Poids
(kg)
60
50
40
Menarche
Menses
Activité
physique
Fracture
10 11
12
16 yr ans
1
2
3
4
5
6
17 yr
7
8
9
10
11
12
1
2
3
4
18 yr
Warren 1987
Does this patient has FHA?
Pubertal period
Primary amenorrhea
Tanner III‐IV prior to treatment
2h of gymnastic a day
BMI 19
Adult age
Persistent hypothalamic amenorrhea
No more risk factor: weight stable, moderate exercice, no psychologic stress
Reversibility in 90% of patients after correcting risk factors
K. Martin et al JCEM 2005 possible
Patterns of LH secretion
Does not distinguish CHH from FHA
LH (IU/L)
Healthy Control
25
20
15
10
5
0
NIGHTTIME
NIGHTTIME
LH (IU/L)
Our patient
25
20 LH 2.3.0 IU/L, FSH 2.6 IU/L
E2 0.15
15
10
5
0
8:00
12:00
16:00
Apulsatile
20:00
0:00
Clock Time (hrs)
4:00
8:00
Familial history
01
03
02
04
CDP
HH
05
Loss‐of‐function mutations in FGFR1 Partial CHH or FHA?
01
FGFR1
03
FGFR1
WT 02
L342S WT
04
05
WT L342S
Delayed Puberty
HH
Variable susceptibility to inhibition of the HPG axis by stressors among women.
Genetic component?
Hypothesis
Mutations in genes involved in congenital GnRH deficiency confer
susceptibility to the functional changes in GnRH secretion that
characterize HA
10% of HA carry Mutations in Genes Involved with
Congenital GnRH Deficiency
* Cole et al JCEM 2008
** De Roux et al NEJM 1997
Caronia LM et al. N Engl J Med 2011
If HA has a genetic basis partially in common
with CHH what are the factors that ultimately
generate these divergent clinical phenotypes?
Oligogenicity in congenital GnRH deficiency
A
10
FGFR1
5.7
KAL1
4.8
TAC3R
4
3.7
GNRHR
SPRY4
2.8
PROKR2
2
1.7
IL17RD
HS6ST1
1.4
1.4
FGF8
DUSP6
1.1
0.9
0.9
0.9
0.9
0.6
0.3
KISS1R
NELF
FLRT3
PROK2
FGF17
GNRH1
TAC3
0
386 CHH, 155 Controls
monoallelic
biallelic
oligogenic
2
4
6
8
% of patients carrying a mutation
10
12
B
# of alleles with rare
protein-altering variants
IHH Patients
(n=350)
Controls (n=155)
≥2: different genes
7% (n=23) ***
0% (n=0)
* p < 0.05 (compared to controls)
*** p < 0.001 (compared to controls)
Miraoui et al. Am J Hum Genet 2013
Human GnRH Deficiency: a model for geneenvironment interaction
Environment
Epigenetics
Mutations loads
CHH
Mild CHH /
Reversals
Functional
Hypothalamic
Amenorrhea
Clinical case
•
•
•
•
•
•
Patient pregnant (GnRH pump)
Restared on OCP
Each summer the patient discontinued the pill for 3 M
18 M after the birth of her daughter, the patient consulted for
one episode of menses 6 weeks after discontinuing OCP
Stop OCP
Menstrual cycles resumed (28-32 days)
Partial CHH with reversibility vs
FHA with reversibility ?
Thank you
Acknowledgments
My lab
Yisrael Sidis
Andrew Dwyer
Cheng Xu
Sara Santini
Ginny Hughes
Daniele Cassatelli
REU
Lisa Caronia
Cecilia Martin
William Crowley
Collaborations
Catherine Dode
Marc Jean-Pierre
Jacques Young
Anna Claudia Latronica
Ursula Kaiser
Luc Pellerin
Urs Albrecht
Pierre Bouloux
Richard Quinton
Moosa Mohammadi
Pei Tsai
Hannes Bulow
Funding NIH, FNS, EU Cost
Amenorrhée hypothalamique:
Indications à IRM cérébral

Aménorrhée primaire hypogonadotropique
 Elévation persistente de la prolactinémie
 Maux de tête ou autres symptômes neurologiques
 Association d’hypogonadisme avec d’autres dysfonctions hypothalamiques ou
hypophysaires
Traitement de la patiente avec une
Pompe à GnRH
q 90 '
200
q 60'
q 90 '
q 90' q 4 h
q 60'
q 90' q 4 h
150
CHH
Normals (n=112)
100
50
E2 (pg/mL)
LH (IU/L)
400
200
100
0
30
P4 (ng/mL)
FSH (IU/L)
0
300
20
10
0
20
10
0
‐14
‐7
0
7
14
‐14
Days (Adjusted to Ovulation)
‐7
0
7
14
The clinical spectrum
Aménorrhée secondaire
oligomenorrea
4%
1
AP
2
APS
3
O
Primary amenorrhea
94%
J Young , in preparation 2013.
n=104
Etudes comparant RPS et HHC: une
littérature pédiatrique
Activation de l’axe gonadotrope
à la puberté
FSH
LH
Cas 1: Reversibilité de l’hypogonadotropisme
hypogonadisme
• CO interrompue
• Cycles menstruels entre 29-34 jours
• Progestérone à 6 ng/l en phase lutéale
Demonstration of reversible Kallmann Syndrome
(Raivio et. al., N Engl J Med 2007)
Case # 3
LH (IU/L)
Diagnostic
20
T=2.5 nmol/L
LH (IU/L)
LH (IU/L)
# 14
LH (IU/L)
# 12
20
20
LH (IU/L)
# 11
20
20
LH (IU/L)
#8
T=9.5 nmol/L
10
0
#7
Re-evaluation
20
2
4
6
8
10
12
T=3.6 nmol/L
0
2
4
6
8
10
12
T=13.9 nmol/L
10
T=2.3 nmol/L
T=21.3 nmol/L
10
T=1.2 nmol/L
T=17.5 nmol/L
T=0.8 nmol/L
T=20.6 nmol/L
T=3.6 nmol/L
T=16 nmol/L
10
10
10
Time (hr)
Time (hr)
GnRH au travers les cycles de vie:
Normal et Déficience en GnRH
ADULT
CDP
HA
IHH
CHH
“Classique”
Fetus Néontatal
CHH
“Reversibilité”
Enfance
Puberté
Adulte
Cas 1
• Patiente de 37 ans en BSH consulte pour une
infertilité avec aménorrhée depuis 12 mois suite à
l’arrêt des CO
100
20
50
E2 (pg/mL)
0
00
20
300
200
10
100
0
0
‐20
Menses
‐10
‐5
0
5
10
Follicular development
Changes in endo
Proliferative
Secretory
P4 (ng/mL)
LH (IU/L)
40
FSH (IU/L)
150
L’endomètre reflète l’environnement
hormonal stéroidien
menstruel
-E-P
proliferatif
+E-P
secretoire + E + P
Baseline Ultrasound Examination
Transvaginal scan of the uterus on day 3 of menses
Women with PCOS frequently have irregular menses and may need a
withdrawal bleed before treatment
Rule out a follicular cyst, dose A serum E2 level.
Follicular cyst
Cas 1
• Diagnostic d’hypogonadisme hypogonadotrope
• Traitement de pompe à GnRH
• Ovulation et patiente enceinte
Quel type HH? Flash back sur la puberté
GnRH/LH Secretion across the Menstrual Cycle
Mid-Cycle Surge
Early/Mid/Late
Follicular Phase
LFP
MFP
Early/Mid/Late
Luteal Phase
200
ELP
0
40
40
0
0
40
EFP
40
LH
0
40
FSH
0
MLP
E2
LLP
0
P4
40
0
MENSES
Review: JE Hall 1998
Primaire Secondaire
Hypothalamus 27%
36%
GnRH
Hypophyse
2%
15%
PCOS
7%
30%
Ovaire 43%
12%
Uterus 19%
7%
LH
InhibIn B
FSH
+
Estradiol
Progesterone
Infertilité anovulatoire: Evaluation
Ecarter une grossess (hCG) !!
Documenter l’anovulation
‐ Midluteal progesterone level < 6 ng/mL
‐ No Temperature rise
27%
Bilan de base : hCG, FSH day 3, TSH, prolactine^
US of the ovaries.
Semen Analysis
Document Tubal patency
‐ HSG
The clinical spectrum :
breast development
35
30
%
25
20
n=104
Série1
15
10
5
0
S1
J Young , in preparation 2013.
S2
S3
S4
S5

Download Report