PREMATURE OVARIAN INSUFFICIENCY

DR. SIMRAN THAKKAR

DRNB TRAINEE/REGISTRAR
ENDOCRINOLOGY
 Cases
 Definition
 Etiology
 Investigations
 Management
 Pubertal Induction
CASE 1

 15-year-old female presented with growth failure and poor development of secondary sexual
characteristics
 Neonatal period was uneventful
 Normal developmental milestones
 Growth failure since the age of 6 years onward
 Height -126 cm
 Multiple pigmented nevi over face, Low hairline, Nystagmus in primary gaze and Cubitus
valgus
CASE 1

 T3 1.49 ng/ml (N 0.8–2.0)

 T4 8.21 μg/dl (N 4.8–12.7)
 TSH 3.05 μIU/ml (N 0.27–4.2)
 TPO antibody <5.0 IU/ml (N <34)
 0800h cortisol 559 nmol/L (N 171–536)
 LH 32.8 mIU/ml (N 1.7–8.6)
 FSH 117 mIU/ml (N 1.5–12.4)
 E2 5 pg/ml (N 12.5–166, follicular phase)
 30 cell karyotype 46Xi(X) (q10) (isochromosome)
CASE 2

 25-year-old female presented with complaints with amenorrhea, hot flashes since 9 months
 Menarche - 13 years
 Initially menses were regular, developed oligomenorrhea at the age of 21 years
 No history of behavioral/cognitive/ intellectual impairment
 Family history of early onset menopause in patients mother and aunt
 Family history of autism and mental retardation in patients brother and maternal cousin
CASE 2
CASE 2

 Thyroid function tests normal

 Thyroid peroxidase antibodies negative
 Prolactin normal
 FSH 68 mIU/L ; estradiol – 18 pg/ml
 Karyotyping 46 XX
 FMR premutation analysis Positive : Electropherogram of the proband showing
detection of peak at 134/151 CGG repeats.
DEFINITION

 Premature ovarian insufficiency is a clinical syndrome defined by loss of ovarian

activity before the age of 40. (2 standard deviation below the average age at menopause)

 A decline in ovarian function, loss of oocytes and folliculogenesis, and elevated

gonadotropin levels

 Compromised fertility and marked reduction of ovarian hormone production

DEFINITION

 Premature ovarian insufficiency (POI) is defined as Oligo/Amenorrhoea(for 4

months) with raised FSH (>25 IU) on two occasions 4 weeks apart and low
estradiol before the age of 40 years. (European Society of Human Reproduction and Embryology
2015)

 A combination of oligomenorrhoea / amenorrhoea of more than 4 months’ duration

associated with elevated gonadotropins (FSH >40 iu/l) on at least two occasions
measured 4-6 weeks apart in women under the age of 40. (British menopause society
consensus 2024 )
`Early menopause` refers to an onset of the menopause between the age of 40 to 45
years of age
 Arises from a
 Premature decrease in the number of ovarian follicles,
 Acceleration of follicle destruction, or
 Poor follicular response to gonadotropins.
INCIDENCE

The estimated incidence rate ratio varies with age:

 1:100 cases by the age of 40 years (1%)
 1:250 cases at the age of 35 years
 1:1000 cases by 30 years (0.1%)
 1:10,000 cases during the age of 18–25 years
NORMAL OVARIAN RESERVE
ETIOLOGY OF POI - GENETICS

 First-degree relatives of approximately 10–30% of idiopathic POI cases also have

this condition, strongly supporting the association of POI etiology with genetics

 Chromosomal abnormalities, genetic polymorphisms, and single-gene mutations

have been recognized as causes of POI

 X-chromosome abnormalities comprise of duplications, deletions, and

translocation of the X chromosome
GENETICS

 Turner syndrome -total or partial deletion of one X-chromosome

 Presence of CGG repeats (in the range of approximately 55–199

repeats) in the fragile-X mental retardation (FMR1) gene
FMR1 GENE

 Normal 5-44- no increased risk of having child with fragile X syndrome

 44-54 Intermediate zone (gray zone)
 55 to 200- primary ovarian failure
 >200 tremor ataxia syndrome; autistic spectrum disorder; ADHD; parkinsonism
RECOMMENDATION

Chromosomal analysis should be performed in all women with non- iatrogenic

Premature Ovarian Insufficiency

Fragile-X premutation testing is indicated in all POI women

GENETICS OF POI
• Bone morphogenetic protein 15
 Oocyte-specific transcription factors :
(BMP15)
 newborn ovary homeobox (NOBOX)
 factor in germline alpha (FIGLA) • Growth differentiation factor 9 (GDF-9),
 Transcription factors affecting
folliculogenesis • Mutations of the FSH receptor
 Forkhead box L2 (FOXL2)
 WT1 (Wilms tumor 1),
• Cytochrome P450, family 19, subfamily
A, polypeptide 1 (CYP19A1)
 NR5A1 (nuclear receptor subfamily 5
group A member1) : gonadal
differentiation and controls
• lutropin- choriogonadotropic
steroidogenesis by regulating hormone receptor (LHR)
steroidogenic acute regulatory protein
(StAR) • Inhibin alpha subunit (INHA) genes
RECOMMENDATION

Autosomal genetic testing/whole genome sequencing is not at

present indicated in women with POI
AUTOIMMUNE CAUSES
 4–30% of the cases
 Lymphocytic oophoritis and the presence of anti-ovary antibodies
 Autoimmune diseases associated with POI :
 Hypothyroidism(~20%)
 Autoimmune adrenal insufficiency (60-80%)
 Autoimmune polyglandular syndrome ½ (10-15%)
 Hypoparathyroidism
 Type 1 diabetes mellitus
 Hypophysitis
RECOMMENDATION

Screening for 21OH-Ab should be considered in women with POI of unknown cause or if an
immune disorder is suspected.

POI patients with a positive 21OH-Ab Testing of adrenal function and to rule out Addison’s disease.

Screening for thyroid (TPO-Ab) antibodies should be performed in women with POI of unknown
cause or if an immune disorder is suspected.

In patients with a positive TPO-Ab test, thyroid stimulating hormone (TSH) should be measured
every year

Insufficient data to screen for DM

NON-ENDOCRINE AUTOIMMUNE DISEASES

 Systemic lupus erythematosus (SLE)

 Sjogren's syndrome  Alopecia areata
 Rheumatoid arthritis  Coeliac disease
 Immune thrombocytopenic purpura  Inflammatory bowel diseases
 Autoimmune haemolytic anemia  Primary biliary cirrhosis
 Pernicious anemia  Glomerulonephritis
 Vitiligo  Multiple sclerosis
 Myasthenia gravis
OTHER CAUSES

 Pelvic Tuberculosis -3%

 Smoking can generate POI through polycyclic hydrocarbons in smoke
 Iatrogenic : Chemotherapy(cyclophosphamide, busulfan, cisplatin, etc) (~40%;
alkylating agents)
 Radiotherapy
 Rarely, metabolic causes of POI include galactosemia, myotonic dystrophy, and
hydroxylase deficiency.
RECOMMENDATION

There is no indication for infection screening in women with POI

CLINICAL MANIFESTATIONS

 Primary or secondary
amenorrhea  Frequent mood swings, irritability,
 Hot flashes poor concentration
 Insomnia  Night sweats
 Vaginal dryness/Dyspareunia  Dry eyes
 Decreased sexual desire
CLINICAL FEATURES

 Turner syndrome : short stature, webbed neck, short fourth and fifth
metacarpal bones, shield-like chest, wide carrying angle elbow, low
set ears, and low hairline

 Patchy loss of skin pigmentation, premature graying of hair, spot

baldness, candidiasis, and nail dystrophy
CLINICAL FEATURES

 Hyperpigmentation, orthostatic hypotension, salt craving, anorexia,

abdominal pain, and loss of hair in the axillary and pubic areas.

 Bulging eyes, goitre, and increased or decreased heart rate

FAMILY HISTORY

 A thorough family history should be obtained, including age at

menopause as well as any known cases of POI among family
members.

 Cognitive impairment or autism in male family members should be

noted, because these conditions arouse concern for premutation of
the fragile X gene as a cause of amenorrhea.
HOW TO INVESTIGATE

Pregnancy test

Prolactin

Thyroid function test

FSH and serum estradiol levels

(2 values 1 month apart)
TO ESTABLISH THE ETIOLOGY

 Karyotyping and genetic analysis for FMR premutation

 Testing for thyroid peroxidase antibodies
 Adrenal 21-hydroxylase antibodies
 Fasting blood glucose or glycosylated haemoglobin levels
 Ovarian antibody testing is not indicated owing to low sensitivity
and specificity
OVARIAN RESERVE

 Anti-Müllerian hormone(AMH) -marker of low ovarian reserve

 Not routinely recommended for diagnosis of POI
 Detection of AMH corresponds to 15 or more follicles in the ovaries
 Ultrasonography : Antral follicle count
WHY TREATMENT IS REQUIRED

 Reduction in systemic estrogen before the age of natural

menopause is associated with the development of
 osteoporosis,
 cardiovascular disease, and
 possibly accelerated neurodegenerative aging.

 Risk of cardiovascular disease events was approximately 50%

greater among women who had menopause before 40 years of age
than among those who had menopause at 50 or 51 years of age.
 POI AND BONE HEALTH

 Measurement of BMD at initial diagnosis of POI should be considered for

all women

 If a diagnosis of osteoporosis is made and estrogen replacement or other

therapy initiated, BMD measurement should be repeated within 5 years.
POI AND CARDIOVASCULAR SCREENING

 Blood pressure, weight and smoking status should be monitored

annually

 In women with Turner Syndrome, Blood pressure, smoking, weight, lipid

profile, fasting plasma glucose, HbA1c at the time of diagnosis and then
annually
HORMONE REPLACEMENT THERAPY

 Continuous estrogen replacement is required to avoid symptoms of estrogen

deficiency.
 Women using the combined oral contraceptive pill for estrogen replacement will
be symptomatic during the pill-free (or inactive pill) week.
HORMONE REPLACEMENT THERAPY

 Unopposed estrogen therapy is associated with an increased risk of endometrial

hyperplasia after 1 to 3 years of treatment at all doses in postmenopausal women.

 Therefore, estrogen replacement in postmenopausal women with an intact uterus

should always be supplemented with a progestogen to prevent endometrial
hyperplasia and increased risk of malignant neoplasia
TREATMENT

 HRT use is not recommended in women with a history of breast and ovarian
cancer, in breast-feeding mothers (as it can cause neonatal jaundice and neonatal
breast enlargement), and in patients that have reached the age of 50 years
Society Estrogen Progesterone (Sequential) Progesterone(Continuous)
American College of -17-B-E2, Medroxyprogesterone Medroxyprogesterone
Obstetrics and Gynecology administered orally, 1 acetate 10 mg daily acetate, administered
to 2 mg daily; for 12 days per orally, 2.5 to 5 mg
Transdermal estradiol month; Micronized daily, Micronized
delivered at a dose of progesterone, progesterone,
100 μg per day; administered orally administered orally,
Conjugated equine 200 mg daily for 12 100 mg daily
estrogens, days per month
administered orally,
0.625 to 1.25 mg
daily
International 17-B-E2, administered Medroxyprogesterone Medroxyprogesterone
Menopause Society orally, 2 mg daily; acetate, administered acetate, administered
Conjugated equine orally 10 mg daily for orally, 2.5 to 5 mg
estrogens, 12 days per month; daily Micronized
administered orally, Micronized progesterone,
1.25 mg daily; progesterone, administered orally,
Estradiol, administered orally 100 mg daily
administered 200 mg daily for 12
transdermally, 75 to days per month
100 μg daily;
Ethinyl estradiol,
administered orally,
Society Estrogen Progesterone

European Society of Human 17-B-E2, administered orally, Micronized progesterone

Reproduction and Embryology 2 mg daily; Conjugated administered orally, 100 to
equine estrogens, 200 mg daily for 12 to 14
administered orally, 1.25 mg days per month;
daily; Estradiol, administered Dydrogesterone,
transdermally, 75 to 100 μg administered orally, 5 to 10
daily; mg daily for 12 to 14 days per
Ethinyl estradiol, month
administered orally, 10 μg per
day
BIOEQUIVALENCE

Name of the preparation Route of Administration Dose

Estraderm Mx Transdermal 100 mcg
Progynova- 17 beta estradiol Oral 2 mg
Premarin- Conjugated equine estrogen Oral 1.25 mg
Lynoral-Ethinyl Estradiol Oral 10 mcg
 PROGESTERONE

 Cyclic micronised progesterone in a dose 200 mg/day for 12 days/month

 Cyclic medroxyprogesterone acetate in a dose 10 mg/day for 12 days/month
 Continuous medroxyprogesterone acetate in a dose 2.5 mg/day
 Micronised progesterone and dydrogesterone- more selective effect on
progesterone receptors ; less interaction with androgenic and mineralcorticoid
receptors compared with other progestogens.
 The levonorgestrel intrauterine device (LNG IUD) - 4-year license for use in this
context.
TRANSDERMAL VS ORAL

 Advantages of transdermal Conjugated equine estrogens are

preparations : associated with higher incidence of
1. Reduces first pass metabolism hypertension and thrombosis.

2. Reduces CV effects
3. Reduces procoagulant effect
4. Provides 17 beta estradiol- more
physiological
5. Fewer GI side effects
POI AND FERTILITY

 Intermittent ovulation has been reported to occur in 50 to 75% of women with the
disorder, with return of menses in 25 to 50% and pregnancy in 5 to 10%.
 Oocyte Donation is the best option available if the women desire pregnancy.
PUBERTY INDUCTION

 Puberty should be induced or progressed with 17β-estradiol, starting with low dose at
the age of 12 with a gradual increase over 2 to 3 years.
 Evidence for the optimum mode of administration (oral or transdermal) is inconclusive.
Transdermal estradiol results in more physiological estrogen levels and is therefore
preferred.
 Begin cyclical progestogens after at least 2 years of estrogen or when breakthrough
bleeding occurs.
 OCP is contraindicated for puberty induction
PUBERTY INDUCTION
 SUMMARY- KEY POINTS
 POI is a pathological condition that should not be considered as hastening of
menopause
 Approach to health maintenance is distinct from postmenopausal women
 Sequelae of POI include vasomotor symptoms, urogenital atrophy, osteoporosis,
cardiovascular disease, increased all-cause mortality
 Karyotyping/screening for FMR premutation, anti-TPO, 21-hydroxylase antibodies
should be done in all patients
 Hormone therapy forms the mainstay of therapy
 HT should be stopped at the age of 50-51 years