Dr Sunita Chandra ,Lucknow, presented these to a gathering of more than 150 eminent gynecologists

1. Dr. Sunita Chandra

3. PREMATURE
OVARIAN
INSUFFICIENCY
(POI)
16th December 2020

4. Synonymous/Interchangeable
• Premature ovarian failure (POF) - Earlier
• Premature ovarian insufficiency (POI) - Now
• Premature menopause
TERMINOLOGY

5. DEFINITION of POI
5
F1000Res. 2017;6:2069.
• Premature ovarian insufficiency is cessation of menstruation
in women under the age of 40.
• Elevated serum follicle-stimulating hormone (FSH) levels
(>25 IU/L) on two separate occasions at least one month
apart, with concomitant low estradiol (E2) levels (<50 pg/mL)
and Amenorrhea for at least 4 months in women younger
than 40 years of age are collectively required to establish a
diagnosis of POI.
(Webber L, Davies M, et al.: ESHRE Guideline: Hum Reprod. 2016)

6. INCIDENCE
6
F1000Res. 2017;6:2069.
(Vujovic S et al. EMAS position statement, 2010)
YEARS INCIDENCE
20 1: 10 000
30 1: 1000
35 1:250
40 1:100

7. MECHANISM of POI
• A number of mechanisms impact on the pace and
magnitude of progressive ovarian follicular atresia.
• Early ovarian senescence may reflect an inherently small
pool of ovarian reserve or quantity of primordial
follicles that a woman is endowed with at the time of
gametogenesis.
• Alternatively, POI may be the result of an accelerated
destruction of oocyte complement because of a complex
spectrum of disorders with genetic, autoimmune, or toxic
underpinnings.

8. ACCELERATED FOLLICULAR ATRESIA
Genetic Defects
Turner’s Syndrome
Fragile X premutations
X chromosome deletions and translocations
Galactosemia
Ovarian toxins
Chemotherapeutic drugs (especially alkylating
agents)
Radiation
Mumps or cytomegalovirus infection
Autoimmune injury
Isolated or part of polyglandular autoimmune
syndromes
ABNORMAL FOLLICULAR STIMULATION
Intraovarian modulators
BMP15, polymorphisms of inhibin alpha subunit
Steroidogenic enzyme defects
CYP17 deficiency, StAR mutation
Aromatase gene mutation
Gonadotropin receptor function
FSH receptor mutations
Gs alpha subunit gene mutation
AETIOLOGY

9. Aetiology Frequency (%)

10. GONADOTROXIC RISKS OF CHEMOTHERAPEUTIC AGENTS
High risk Medium risk Low risk or no risk
Cyclophosphamide Ciplatin Methotrexate
Busulfan Adriamycin 5-Flurouracil
Melphalan Paclitaxel (needs more
studies)
Actinomycin D
Procarbazine Bleomycin
Nitrogen mustard Vincristine
Chlorambucil

11. Aetiology of premature ovarian failure cases managed
at the west London Menopause and PMS 387 Centre,
londan, UK ( Maclaran and Panay, 2011)

12. CLINICAL PRESENTATION OF PREMATURE
OVARIAN INSUFFICIENCY
• Menstrual abnormalities
• Missed cycles leading to amenorrhea
• Sudden onset of secondary amenorrhea
• Primary amenorrhea
• Subfertility/infertility
• Menopausal symptoms
(hot flashes, vaginal dryness, and sleep disturbances)
• Changes in skin pigmentation
• Vitiligo (autoimmune)
• Hyperpigmentation-adrenal insufficiency (autoimmune)
• Hair loss/alopecia (autoimmune)
• Goiter (autoimmune)
• Fatigue
• Anxiety/Depression

13. Proprietary and confidential — for internal use
Sequelae in
POI
Reduced
fertility
Reduced
BMD;
 fracture
risk
 CVD risk
Poor QOL
Genito-
urinary
symptoms
All-cause
mortality
6 ‘M’ Sequelae In
POI
Maternity
Mechanical
Cardio-
Metabolic
Mood
Micturition
Mortality
Treatment – Combined Sequential (E+P) MHT till Age of Natural Menopause

14. SEQUELAE IN POI
High mortality
rates
Reduced fertility
Reduced BMD;
Increased fracture
risk
Increased
cardiovascular risk
Poor QOL
Genito-urinary
symptoms
14ESHRE Management of women with premature ovarian insufficiency. Dec 2015

15. DIAGNOSISHISTORY / EXAMINATION
Medical and Family history
Chronology of events, personal exposures and family history.
Detailed menstrual history
Medical conditions, medications prescribed, or previous gonadotoxic exposures
Documentation of any endocrinopathies (such as type 1 diabetes mellitus and
hypothyroidism associated with Hashimoto’s thyroiditis).
Maternal age at menopause
Family history of POI in first- or second-degree relatives
Recurrent pregnancy loss
History of any known autoimmune or genetic disorders in family members
Symptom of fatigue and weight fluctuations.
Physical examination - stigmata of any underlying disorder (skin depigmentation or
hyperpigmentation, a goiter) evidence of hypoestrogenism.

16. Diagnostic criteria for primary ovarian
insufficiency
 Age ˂ 40 years
 Cycle irregularity ≥ 4 months
Amenorrhea
Oligomenorrhea
Polymenorrhea
Menometroohgia
Dysfunctional uterine bleeding
 FSH in the menopause range
On 2 occasions
≥ 1 month apart
INVESTIGATIONS FOR DIAGNOSIS
1. Cycle irregularly for at least 4
months + Oligo/amenorrhea:
2. An elevated FSH level > 25
IU/l on 2 occasions > 4 weeks
apart.

17. DIAGNOSTIC CONSIDERATIONS IN EVALUATION
OF PRIMARY OVARIAN INSUFFICIENCY
Laboratory tests Rationale
• Human Chorionic gonadotropins • Exclude pregnancy
• Follicle-stimulating hormone
• Estradiol
• Assess hypothalamic-pituitary-ovarian
axis
• Anti-mullerian hormone • Assess ovarian reserve
• Karyotype, fragile X mental
retardation 1 (FMR1) premutation
• Evaluate for genetic etiology
• Thyroid-stimulating hormone
• Thyroid peroxidase antibody
• 21-hydroxylase antibody
• Evaluate for thyroid function
• Quantify risk for thyroid and adrenal
dysfunction
Radiologic tests Rationale
• Transvaginal ultrasound • Evaluate antral follicle count to assess
• ovarian reserve
• Dual-energy x-ray absorptiometry
scan
• Assess bone density

18. INVESTIGATIONS FOR CAUSES
1. Chromosomal analysis should be performed in all.
{Gonadectomy should be recommended for all women with
detectable Y chromosomal material}.
• Fragile-X premutation testing is indicated. The implications of
the fragile-X premutation should be discussed before the test
is performed. Permission from the patient to perform the test
• Autosomal genetic testing is not indicated, unless there is
evidence suggesting a specific mutation (e.g. BPES).

19. FRAGILE-X TESTING IS INDICATED IN ALL
WOMEN WITH POI
{. establish the causation of POI . it has major implications for herself and her family}.
1. Family members ±carriers: developing POI and a risk of having (grand)children with fragile-X
syndrome.
2. Patient: risk of fragile-X-associated tremor/ataxia syndrome (FXTAS), a late onset neurological
problem

20. SCREENING FOR 21OH-AB
(OR ALTERNATIVELY ADRENOCORTICAL
ANTIBODIES (ACA)
{if +ve: an endocrinologist for testing of adrenal function and to rule out Addison’s
disease}.

21. 3. SCREENING FOR THYROID (TPO-AB)
ANTIBODIES.
{if positive: TSH should be measured /y}.
If 21OH-Ab/ACA and TPO-Ab are negative: No indication for re-testing later in life,
unless signs or symptoms of these endocrine diseases develop

22. ROUTINE SCREENING FOR DIABETES
INSUFFICIENT EVIDENCE
Infection screening
No indication
Unexplained or idiopathic POI.
In a significant number of women with POI

23. DIAGNOSIS
• Biochemical evidence of hypergonadotropic hypogonadism.
• AMH may be particularly beneficial early in the phase of menstrual
irregularity since the timing of analysis is independent of timing in a
menstrual cycle, whereas FSH levels can fluctuate throughout the
cycle and give a false sense of reassurance.
• Pelvic ultrasound, transvaginal approach, confirm ovarian
compromise.
• Evidence of a thin endometrial echo (<4 mm), small ovarian volumes,
low antral follicle counts (<5) consistent with a picture of POI.
• Radiological imaging is not essential to establish the diagnosis.

24. WHY TO MANAGE PREMATURE OVARIAN
INSUFFICIENCY
• Menopausal Symptoms
• Cardiovascular Health
• Infections
• Bone Health
• Emotional Health
• Infertility
• Cognition

25. MENOPAUSAL SYMPTOMS
• Adequate systemic estrogen replacement critical for
symptom control, local estrogen may be required for
focal symptoms - dyspareunia or genito-urinary
symptoms.
• Testosterone supplementation as an adjunct to
systemic estrogen therapy - decreased libido, long-
term efficacy and safety uncertain.

26. CARDIOVASCULAR HEALTH
• Women with untreated POI have a decreased life expectancy, largely
due to cardiovascular morbidity and stroke.
• Compared with age-matched controls, women with POI had reduced
vascular endothelial function, which is an early precursor to
atherosclerosis.
• Estrogen has beneficial effects on cholesterol metabolism lessening
atherosclerotic plaque formation and prevents coronary constriction,
early initiation of HT following onset of menopause has been
suggested as a cardio-protective strategy.
(Webber L, Davies M, et al.: ESHRE Guideline: Hum Reprod. 2016)
(Rocca WA, et al.: Menopause. 2012)

27. BONE HEALTH
• Deprivation of estrogen consequent to POI is a known fracture risk in
later life, risk can be mitigated with use of HT.
(Popat VB et al.: Clin Endocrinol Metab. 2009)
• Assessment of BMD may be useful and should be considered for women
with POI, after the initial assessment, repeat BMD assessments can be
deferred for those choosing to continue HT until the population’s average
age of menopause (51 years) or until the recommended age of 65 for all
women.
• Serial monitoring of bone mass (within 2 to 5 years of initiating HT) is
warranted
• Lifestyle modifications - weight-bearing exercises, optimization of dietary
calcium intake and vitamin D status, avoidance of cigarette use all
contribute to help preserve bone health.
• Declining BMD despite adequate HT dosing requires consideration of
secondary causes of bone loss, dictate consideration for use of non-
hormonal anti-resorptive agents for fracture risk reduction.
(Webber L, Davies M, et al.: ESHRE Guideline: Hum Reprod. 2016)

28. COGNITION
• Premature deprivation of estrogen, as following bilateral
oophorectomy undertaken in pre-menopausal women, has
been associated with neurocognitive decline.
• Earlier the age of surgical POI,more rapid the cognitive
decline.
• Surgical POI data offers a logical benchmark to guide use of
HT by women with POI until the age of natural menopause as
a strategy to minimize including osteoporosis, premature
cardiovascular disease and neurocognitive well-being.
(Rocca WA et al: Mol Cell Endocrinol, 2014)

29. EMOTIONAL HEALTH
• Compromised fertility
• Premature aging,
• Reduced self-esteem, increased
• Social anxiety and shyness, and
• Symptoms of depression
Early psychological counseling should be advocated, and
made easily accessible, multi-disciplinary team should be
arranged to provide continued observation of her coping
strategies and to address unmet needs.

30. INFERTILITY
• Up to 25% of women with POI may spontaneously ovulate, and
5% to 10% will conceive and deliver after being diagnosed with
POI.
• No interventions that can reliably improve residual ovarian reserve
parameters or any treatment other than use of donor eggs which
can improve conception rates in women with POI.
• Contraceptive strategies should be recommended in those
women who wish to avoid pregnancy.
• Women with POI who are identified with chromosomal aberrations
(such as balanced translocations or Turner mosaicism) or single-
gene disorders such as FMR1 premutation carrier state should
undergo preconception counseling.
• Use of in vitro fertilization (IVF) with preconception genetic
diagnosis can minimize transgenerational transmission of
identifiable genetic mutations in families.
(Van Kasteren YM, et al, Hum Reprod Update. 1999)

31. HORMONE TREATMENT IN THE
MANAGEMENT OF PREMATURE
OVARIAN INSUFFICIENCY
The goal of HT in POI population is to mimic
endogenous levels of sex hormones, which
equates to a serum E2 level of about 100 pg/mL,
and once initiated, HT should be continued until the
age of natural menopause (average age of 51
years).
(Sullivan SD, et al,: Fertil Steril;2016.)

32. HORMONE TREATMENT IN THE
MANAGEMENT OF PREMATURE
OVARIAN INSUFFICIENCY
• Post-pubertal premature ovarian insufficiency
• Pre-pubertal premature ovarian insufficiency

33. POST-PUBERTAL PREMATURE
OVARIAN INSUFFICIENCY
• This population often requires higher doses of systemic estrogen
than is commonly used for managing symptoms in older menopausal
women.
• In deciding on the choice of HT, consideration should be given to dose,
route, and regimen; while estrogen alone is optimal for managing
symptoms in women who have undergone hysterectomy, the addition of
progestin must be incorporated to estrogen therapy in those with an
intact uterus.
• The typical starting formulation for women with POI includes
transdermal estradiol in a daily dose of 100 μg, oral estradiol in a
dose of 1 to 2 mg/day, or conjugated estrogen at a dose of 0.625 to
1.25 mg daily.

34. Cont..
• Patients advised to maintain a symptom chart, hormone dose
should be adjusted to achieve a level of optimal symptom
control.
• In all women with a uterus, progesterone should be added
to the estrogen regimen to minimize the untoward risk of
endometrial hyperplasia or endometrial cancer.
• Both natural progesterone and synthetic progestins are
available in a wide array of formulations (oral tablets, vaginal
creams/tablets, intramuscular injection, intrauterine devices)
and regimens (continuous and cyclic).

35. Cont..
• Common formulations that are used for endometrial protection in HT users
include medroxyprogesterone acetate 10 mg daily for 12 days each
month and oral or vaginal micronized progesterone 100 mg daily or
200 mg daily for 10 to 12 days per month.
• Strongest evidence of endometrial protection is for oral cyclic
medroxyprogesterone acetate.
• The efficacy of oral micronized progestin or progestin-containing
intrauterine contraceptive devices to effectively induce endometrial
decidualization has not been systematically evaluated as a component of
HT for women with POI.
• Future trials should specifically explore their value for women with POI.

36. PRE-PUBERTAL PREMATURE
OVARIAN INSUFFICIENCY
• In keeping with pubertal physiology wherein a gradual
escalation in circulating estrogens predates menarche by a few
years, for a patient in whom POI strikes prior to puberty, the
goal of HT is to achieve exposure to increasing estrogen
levels in a progressive fashion over months, starting with
very low doses of 17-β estradiol.
• Typical regimens include 6.25 μg/day of 17-β estradiol
transdermally or micronized oral estradiol 0.25 mg/day.

37. Cont..
• 17-β estradiol is gradually increased every 3 to 6 months over the
course of 2 years until an adult dose is reached or spontaneous
menses ensues, which point cyclic progesterone regimen is added
to ensure endometrial protection. Oral micronized progesterone
100 to 200 mg/day for 12 to 14 days is the most common regimen
used.
• Use of a hormone contraceptive formulation as HT strategy is to be
avoided, can result in tubular breast formation.
(Webber L, Davies M, et al.: ESHRE Guideline: Hum Reprod. 2016)

38. ESTROGEN SUBSTITUTION THERAPY IN ADOLESCENCE
(ADAPTED FROM (Bondy and Turner Syndrome Study Group, 2007)

40. What are the risks of HRT?
• Women with POI should be informed that HRT has not been found to
increase the risk of breast cancer before the age of natural menopause
• Progestogen should be given in combination with estrogen therapy to
protect the endometrium in women with an intact uterus.
What are the options for HRT?
• 17-bestradiol is preferred to ethinyl estradiol or conjugated equine
estrogens for estrogen replacement.
• Women should be informed that whilst there may be advantages to
micronized natural progesterone, the strongest evidence of endometrial
protection is for oral cyclical combined treatment
• Patient preference for route and method of administration of each
component of HRT must be considered when prescribing, as should
contraceptive needs.

41. Monitoring HRT
• Once established on therapy, women with POI using HRT should
have a clinical review annually, paying particular attention to
compliance
• No routine monitoring tests are required but may be prompted by
specific symptoms or concerns.
Treatment with androgens
• Women should be informed that androgen treatment is only
supported by limited data, and that long-term health effects are
not clear yet
• If androgen therapy is commenced, treatment effect should be
evaluated after 3–6 months and should possibly be limited to 24
months

42. HRT IN POI WOMEN WITH SPECIAL ISSUES
Women with Turner Syndrome
• Girls and women with POI due to Turner Syndrome should be offered HRT
throughout the normal reproductive lifespan.
Women with POI and a BRCA gene mutation or after breast cancer
• HRT is generally contra-indicated in breast cancer survivors.
• HRT is a treatment option for women carrying BRCA1/2 mutations but without
personal history of breast cancer after prophylactic bilateral salpingo-
oophorectomy
Women with POI and endometriosis
• For women with endometriosis who required oophorectomy, combined
estrogen/progestogen therapy can be effective for the treatment of vasomotor
symptoms and may reduce the risk of disease reactivation
Women with POI and migraine
• Migraine should not be seen as a contraindication to HRT use by women with
POI

43. Sequelae of POI
Indication for
presecription
of HRT
Supporting recommendation
Vasomotor symptoms Yes Hormone replacement therapy for the treatment of vasomotor
symptoms in women with POI
Genitor-urinary symptoms Yes Both systemic & local estrogen are effective in treatment of
genitor-urinary symptoms
Life expectancy ? Life expectancy appears to be reduced due to cardiovascular
mortality: HRT may be of indirect benefit
Bone health Yes Estrogen replacement is recommended to maintain bone health
and prevent osteoporosis; it is plausible that it will reduce the risk
of fracture
Cardiovascular health Yes Despite lack of longitudinal outcome data, hormone replacement
therapy with early initiation is stongly recommended in POI to
control future risk of cardiovascular disease; it should be continued
at least until the estimated normal age of menopause
Quality of life ? Quality of life appears to be reduced; HRT may be of indirect
benefit
Sexual fuction Yes Adequate estrogen replacement is regarded as a starting point for
normalising sexual function, local estrogen may be required to
treat dyspareunia.
Neurological function ? Estrogen replacement to reduce the possible risk of congnitive
impairment should be considered in women with POI.

44. Proprietary and confidential — for internal use
44References
HOW DO YOU APPROACH?
Must Start the
Therapy as
• No RISK of Ca-BREAST
• Reduce the CVD Risk,
Osteoporosis,
Alzheimer's, Premature
Death
• Symptoms – Moderate
to Severe
• High strength of
estrogens required
• Continue Treatment
till age of natural
menopause (50 years)
POI

45. Proprietary and confidential — for internal use
45References
Only Available Combined MHT in India
17ß-Estradiol Hemihydrate + Dydrogesterone
= “FEMOSTON”
1 mg E2 + 10 mg Dydro
Peri-menopause
POI
Sequential MHT (sMHT)
Continuous combined MHT (ccMHT)
POI – Need at least 1mg E2 (2mg is Ideal
Duration of Rx – Till Natural Age of Menopause
Post-Menopause 1 mg E2 + 5 mg Dydro

46. TAKE HOME HIGHLIGHTS
Vast majority of cases remain idiopathic.
POI is a state of estrogen deprivation that holds both short-term and life-long
implications for health and for psychosocial well-being.
Timely initiation of HT and a multi-disciplinary approach must be recognized as
cornerstones to effectively manage this complex entity to ensure that physical,
psychological, and emotional challenges that result from POI diagnosis are met.

48. ACKNOWLEDGMENT
• Saioa Torrealday et al,: F1000 Faculty Rev; F1000 Research
2017.
• Webber L, Davies M, et al,: ESHRE Guideline: Hum Reprod.
2016.
• Sullivan SD, et al,: Fertil Steril;2016.
• Rocca WA et al,: Mol Cell Endocrinol, 2014.
• Rocca WA, et al,: Menopause. 2012.
• Popat VB et al,: Clin Endocrinol Metab. 2009.
• Vujovic S et al. EMAS position statement, 2010.
• Van Kasteren YM, et al, Hum Reprod. Update. 1999.