Primary Ovarian Insufficiency (POI)

Primary Ovarian Insufficiency (POI):
The Pediatric Endocrinologist’s Approach
Yardena Tenenbaum-Rakover
Pediatric Endocrine Institute
Ha’Emek Medical Center, Afula
Rappaport Faculty of Medicine, Technion, Haifa
‫בית ספר לאנדוקרינולוגיה של הרבייה‬
2015 ‫ בנובמבר‬20
‫‪Sex differentiation- Default theory‬‬
‫‪Alfred Jost‬‬
‫במחקרים שלו הוא הסיר את הגונדות לפני התמיינותן מרחם‬
‫של עוברי ארנבות ומצא שכל העוברים ללא קשר לכרומוזומים‬
‫שלהם התפתחו כנקבות עם אברי מין פנימיים וחיצוניים נקביים‬
‫‪ ‬מסקנתו הייתה שלהתפתחות הזכר יש צורך בגונדות ואילו‬
‫התפתחות הנקבה הינה ברירת מחדל של הטבע‬
‫‪ ‬הוא מצא שהאשך מפריש טסטוסטרון שחשוב להתפתחות‬
‫אברי המין הזכריים והורמון בשם ‪ MIF‬שאחראי על ניוון ה‪-‬‬
‫‪Mullerian ducts‬‬
‫)‪(Jost a 1947, Arch Anat Microsc Morph Exp‬‬
Default theory
‫בנוכחות‬
SRY
‫בהעדר‬
SRY
New theory –Ovarian development
What are the causes for referral of girls with POI ?
 Primary amenorrhea (absence of menarche by the age
of 15 years)
 Secondary amenorrhea (absence of menses for more
than 3 cycle or 6 months in women who were
previously menstruating)
 Delayed puberty (absence of any pubertal signs at the
age of 12 years in female)
 Short stature
 Others
Diagnostic evaluation of primary amenorrhea
History: Signs of puberty, growth spurt, family history,
consanguinity, stature, dismorphism, virilization, diet,
exercise, drugs, galactorrea, headaches, fatigue, visual
defects
Inheritance of Familial delayed puberty
Diagnostic evaluation of primary amenorrhea
Physical examination: height, weight, genital
examination, skin-hirsutism, acne, striae, pigmentation,
vitiligo, BP, dismorphism, Tanner pubertal stage
Etiology of Primary Amenorrhea
 Chromosomal abnormalities (50%)
 Hypothalamic hypogonadism (20%)
 Mullerian duct anomalies (15%)
 Imperforated hymen or transverse vadginal septum (5%)
 Pituitary disease (5%) [hyperprolactinemia]
____________________________________________
Etiology of Primary Amenorrhea
 Chromosomal abnormalities (50%)
 Hypothalamic hypogonadism (20%)
 Mullerian duct anomalies (15%)
 Imperforated hymen or transverse vadginal septum (5%)
 Pituitary disease (5%) [hyperprolactinemia]
____________________________________________
 PCOD
 CAH-NC type
 IBD, celiac disease, malnutrition
 Anorexia nervosa
 Intensive physical activity
 Disorder of Sex Development (DSD-46,XY) [Androgen insensitivity,
adrenal enzyme deficiency)
 Primary gonadal failure-non chromosomal
Laboratory & imaging evaluation of primary
amenorrhea
 LH, FSH, E2, testosterone, prolactin, βHCG, 17-OHP,
thyroid function
 Celiac serology, CRP, exclude systemic diseases –CBC,
chemistry
 Karyotype, FISH of X chromosome
 GnRH test, ACTH test
 Pelvic US
 MRI-abdomen, brain
 MAP test
Evaluation of primary amenorrhea
LH , FSH 
Hypogonadotropic
Hypogonadism
LH , FSH 
Hypergonadorophic
Hypogonadism
Primary gonadal failure
Hypergonadotrophic hypogonadism
Karyotype
46,XY
Disorder of androgen synthesis
or actions
46, XX/ 45,X
Primary ovarian insufficiency
(POI)
46, XY (Disorder of androgen synthesis or actions)






LHR mutations
3β-hydroxysteroid dehydrogenase deficiency (HSD3B2)
17α-hydroxylase/17,20-yase deficiency (CYP17)
17β-hydroxysteroid dehydrogenase deficiency (HSD 17B3)
5α-reductase deficiency (SRD5A2)
Androgen insensitivity (AR)
Case 1.
Result
Age
17 y
Consanguinity
Yes
Phenotype
Pelvic MRI revealed 2 gonads
Presenting symptom
Primary amenorrhea
FSH (mIU/l)
8.04
Peak FSH (mIU/l)
12.5
LH (mIU/l)
26.1
Peak LH (mIU/l)
80
E2
< 100
Testosterone (ng/ml)
< 0.1
Prolactin (ng/ml)
Diagnosis:
DSD-XY – Defect in
testosterone production
Female
3.4
US & MRI
Agenesis of uterus
and vagina
Karyotype
46,XY
Testicular biopsy
Leydig cells nodular
hyperplasia
Definition of POI
 POI is defined as cessation of menstruation prior to 40
years and diagnosis is confirmed by elevated serum FSH
levels (40IU/l)
 About 1% of the population is affected before the age of
40 years
 0.1% before the age 30 years
 0.01% before the age 20 years
Primary ovarian failure, Premature ovarian failure, Premature
ovarian insufficiency, Primary ovarian insufficiency
Etiologies of primary ovarian insufficiency
 Syndromic (PHP-type 1a , Ataxia telangectasia )
 Metabolic- Galactosemia (galactose-1-phosphatase
uridyltransferase deficiency, mitochondrail diseases)
 Immunologic (APG type 1 – AIRE (Addison,
hypoparathyroisdism, mucocotaneous candidiasis); APG
type 2; auto-immune lymphocytic oophoritis)
 Iatrogenic (radiotherapy, chemotherapycyclophosphamide, surgery)
 Viral (mumps, HIV)
 Enviormental
 Enzymatic (17α-hydroxylase/17,20-yase deficiency (CYP17);
aromatase deficiency (CYP19)
 Genetic
Genetic etiologies of primary ovarian insufficiency X- chromosome
 Chromosomal anomalies (Turners 'syndrome, 47XXX, mosaicism,
isochromosome, deletions and X/autosomal translocation)
 Fragile X mental retardation 1 (FMR1)
 Nuclear receptor subfamily (DAX1)
 Bone morphogenetic protein 15 (BMP15 )
Autosomal gene mutations:
 FOXL2
 FSH receptor , FSH-β
 LHR, LH-β
 GALT, AIRE, INHA
 Newborn ovary homeobox (NOBOX )
 Steroidogenic factor 1 (SF1)
 GDF-9
primary ovarian failure-new genes
Novel genes , which result in meiotic defects were identified recently as a cause for
primary ovarian insufficiency
Zangen et al., XX ovarian dysgenesis is caused by a PSMC3IP/HOP2 mutation that
abolishes coactivation of estrogen-driven transcription. Am J Hum Genet
2011;89:572–9.
de Vries et al., Exome sequencing reveals SYCE1 mutation associated with autosomal
recessive primary ovarian insufficiency. J Clin Endocrinol Metab, 2014;99:E2129-32.]
Caburet et al., Mutant cohesin (STAG3) in premature ovarian failure. N Engl J Med
2014;370:943–9.
Tenenbaum-rakover et al; Minichromosome maintenance complex component
8 (MCM8) gene mutations result in primary gonadal failure. ., J Med Gen, 2015
Schematic representation of chromosomal location of
possible genes associated with POI
Yingying Qin et al. Hum. Reprod. Update 2015;21:787-808
Laboratory evaluation of POI:
Does GnRH test is necessary?
Changes in FSH levels in girls with Turner syndrome
Laboratory evaluation of POI:
Does ACTH test is required?
0-5 ng/mL :‫תגובה תקינה‬
5-15 ng/mL :‫נשא‬
15 ng/mL ‫ מעל‬: NC - ‫חולה בצורה ה‬
Symptoms of Non classical 21OHD CAH
Premature pubarche
Hirsutism
Menstrual disorder
Amenorrhea
Accelerated growth
Advanced BA
Polycystic ovary syndrome
Infertility
ACTH test
17α-hydroxylase/17,20-yase deficiency
Sympt0ms of 17α- hydroxylase deficiency:
Hypertension
Amenorrhea
AMH plasma levels in POI
A. La Marca et al. Hum. Reprod. 2009;24:2264-2275
 One main advantage of AMH measurement may be its use as a cycle-independent test
Longitudinal serum levels of AMH in 85 healthy girls and adolescents as a
function of age
Casper P. Hagen et al. Hum. Reprod. 2012;27:861-866
Grey lines indicate the AMH reference range: median, 2.5th and 97.5th percentile
What are possible mechanism of POI ?
1. Initial decrease in the primordial follicle pool
Luca Persani et al. J Mol Endocrinol 2010;45:257-279
2. Accelerated
follicular atresia
3. Altered maturation of primordial follicles
© 2010 Society for Endocrinology
‫? ‪Turner syndrome –When to think about‬‬
‫‪‬‬
‫‪‬‬
‫‪‬‬
‫‪‬‬
‫‪‬‬
‫‪‬‬
‫‪‬‬
‫‪‬‬
‫בתינוקת‪ -‬לימפאדמה‬
‫קומה נמוכה‬
‫דיסמורפיזם‪ :‬צוואר קצר ומעובה‪ ,‬פטמות מרוחקות‪ ,‬קו עורפי נמוך‪ ,‬קיצור‬
‫‪ ,MC-4‬חזה רחב‪ ,‬דפורמציה ע"ש מדלונג‪ ,‬גפים קצרות‪cubitus valgus ,‬‬
‫מום לבבי‪coarctation of aorta :‬‬
‫זיהומי אוזניים חוזרים‬
‫ליקוי שמיעה‬
‫אנומליות בדרכי השתן‬
‫השימוטו תיררואידיטיס‬
Turner’s syndrome
 The prevalence of TS is about 50:100,000 live- born girls with
80% of cases being maternal origin
 20-30% of TS shown spontaneous signs of puberty
 2-5% spontaneous menses
 2%- pregnancies
Although one X chromosome is sufficient to allow
ovarian differentiation, oocytes need two active X
chromosomes (unlike most somatic cells). Therefore,
haploinsufficiency of many genes on the X chromosome
in fetuses with Turner’s syndrome results in oocyte apoptosis after 12
weeks, and oocyte depletion within the first 10 years of life.
What are the goals for treatment of POI?






Induce puberty
Menstrual bleeding
Achieve peak bone mass
Prevent osteoporosis
Prevent cardiovascular diseases
Improve cognitive achievements
 [A guidelines of the Turner syndrome study group. JCEM, 2007;
92:10-25.
 Sex hormone replacement therapy in Turner syndrome. Trolle et
al., Endocrine 2012 ,41:200-219.]
Treatment of POI
 There is international consensus to induce puberty around the age of 12 y
 Low dose of estrogen (1/10 of the adult doses) for optimal breast development
should be titrated by the development of Tanner stages, LH, FSH and BA
 Progesterone is added after 2 years of treatment or when breakthrough bleeding
commences
 The natural 17-β estradiol is the preferred compound Preparations with
conjugated conjugated estradiol should be avoided, since it contains more than
100 estrogenic compounds of different estrogenic potency which cannot be
measured reliably in any assay
 The preferable route of administration has not been determined, although
transdermal administration could offer a more physiologic delivery
 The use of oral contraceptive pills to achieve pubertal development is best
avoided, because the synthetic estrogen doses in most formulations are too high
and the typical synthetic progestin may interfere with optimal breast and uterine
development
Replacement therapy
Years
Age specific suggestions
Doses
10-11
Monitor for spontaneous puberty by Tanner
staging
12-13
If no spontaneous puberty begin low dose E2
replacement therapy
Transdermal 6.25 µg/d
Micronized E2 o.25 mg/d
13-15
Gradually increase E2 dose every 6 months over
about 2 years to adult dose (e.g.,
14.25,37,50,75,100, 200 µg/d via patch).
Adult dose: transdermal
100 µg/d, micronized 2
mg/d; Ethinyl E2 20 µg/d,
conjugated estrogen 1.25
mg/d
14-16
Begin cyclic progesterone after 2 years of
estrogen or when breakthrough bleeding
occurs
200 mg/d micronized
progesterone on days 2030
14-30
Continue full doses
30-50
Lowest E2 dose providing protection versus
osteoporosis
>50
Like other postmenopausal women
The effects of estrogen on growth
 Estrogen has a biphasic effect on growth
 By stimulating GH production, it results in an increase in growth
during puberty
 At high doses there is inhibition of growth and stimulation of
fusion of the epiphyses
Does early initiation of estrogen compromise final height in
Turner syndrome?
The height gain was greater
for the growth hormone–
estrogen group than for the
GH–alone by 2.3±1.1 cm
(Ross et al., N Engl J Med. 2011
364:1230–1242.)
Does early initiation of estrogen compromise final
height in Turner syndrome?
 Patients in whom estrogen was delayed until age 15 yr were, on the
average, 3.4 cm taller (150.4 vs. 147.0 cm) (J Clin Endocrinol Metab
85: 2439–2445, 2000)
Does estrogen therapy improve neurocognitive performance in
Turner’s syndrome ?
 An abnormal neuro-cognitive profile is well-described in females with
TS (lower IQ - poor arithmetic skills, visuospatial , visual–spatial
organization , social cognition, problem solving and motor deficits)
 It has been suggested that low dose childhood estrogen might
improve some of the neuro-cognitive deficits seen in TS
BUT:
 Many genes that are associated with cognition are located on
chromosome X
 Girls with POI from other etiologies (apart from Turner) does not have
intellectual impairment
2000
78
Does estrogen therapy improve neurocognitive performance in
Turner’s syndrome ?
A beneficial effect of estrogen replacement was found on
immediate and delayed recall. BUT verbal and nonverbal tasks were handled similarly in the estrogen
treated group of TS girls and the control group
(Ross et al., Neurology 54, 164–170, 2000)
Does deficiency of estrogen influence bone mass,
fracture risk and hormonal replacement
 Marked deficiency of estradiol is a concern in terms of not
achieving normal peak bone mass and the risk of fractures and
osteoporosis
 Volumetric BMD (vBMD) is normal in the pre-pubertal TS
 TS girls are at high risk of fracture
Does deficiency of estrogen influence bone mass, fracture risk
and hormonal replacement
 Osteopenia in late prepuberty in young women with TS, suggests a potential role
of prepubertal estrogen. Early estrogen supplementation is essential to improve
BMC accrual during growth in TS. (HO¨ GLER et al., J Clin Endocrinol Metab 89:193–199, 2004)
 Turner's patients on ERT from adolescence show vBMD values in the normal range
in young adulthood without difference from GH treated patients (Bertelloni et al.,
Volumetric bone mineral density in young women with Turner's syndrome treated with estrogens or estrogens
plus growth hormone. Horm Res. 2000;53:72-6)
 Different results depends of area of measurements, methods type
and areal vs. volume measurements
In a clinical context, estrogen therapy timed as to
achieve peak bone mass and inducing puberty without
compromising final height, is of most importance. Vitamin
D, calcium supplements, and regular exercise as well
as measures to prevent falls are pivotal
No Good quality data on:




Glucose metabolism
Body composition
Quality of life
Cardio-protective effect
There are uncertainties as to whether earlier initiation of
low dose estrogen during childhood, mimicking the normal
physiological levels, could actually have a positive effect
on glucose metabolism, physical fitness, cardio-vascular
risk and quality of life
Summary:
 Primary amenorrhea is the most common first symptom of POI
 Turner syndrome is the most common etiology of POI in childhood
 Work-up diagnosis of primary amenorrhea includes : karyotype,
gonadotropins and E2 and testosterone levels, Pelvic US
 GnRH and ACTH test may help in the work-up in some cases
 WES is suggested when genetic background is suspected
 Initiation of low dose E2 is recommended at 12 years to induce
pubertal signs
 Gradual increase in estrogen dose during 2 years and thereafter
cyclic therapy is recommended
 No consensus data exist on the influence of estrogen on final height,
BMD, fracture risk, cognitive performance , cardiovascular effects ,
prevent of osteoporosis and quality of life