Premature Ovarian Insufficiency, Premature Menopause

1. DR. KIRTAN VYAS

2. Gujarat Uni. First-Gold medallist
Gujarat Public Service Commission(GPSC) first
Fellow in Gynec Endoscopy(Mumbai)
Fellow in Ultrasonography(FOGSI)
Publications in various International Journals
Presented Scientific Papers and Chaired Sessions at State and National
conferences.
Faculty at State and National Conferences
Local Joint Secretary of SOGOG-Gujarat State Org of Ob Gy
 Organizing Secretary for the First Rajkot Obstetrics and Gynec
Society Annual Conference 2015 and Committee Member at State and
National conferences
Organizing secretary for the West Zone Yuva Fogsi 2016,Rajkot
At present working as an Assistant Professor at P.D. U. Medical
College and Hospital, Rajkot

3. DEFINITION
 Premature ovarian failure ( POF)
 Primary ovarian insufficiency (POI)
 Premature menopause
 Early menopause
It is either a primary ovarian defect
charectrized by absent menarche(Primary
amenorrhea) or premature depletion of
ovarian follicles/ arrested folliculogenesis
before the age of 40( Secondary
amenorrhea)*
* Santoro N, Ann Endocrinal 2003

4. MENOPAUSE & AGE
AT 40 YRS
PREMATURE MENOPAUSE
AT 45 YRS
EARLY MENOPAUSE

5. INCIDENCE
 Around 1%*
 0.1% by age 30
*Coulam et al; 1986

9. ANATOMY
In the embryo, germ cells migrate from urogenital
ridge to the primitive ovary, where they proliferate to
form 3.5 million oocytes in each ovary
But only fixed number of oocytes in each ovary at the
time of birth(1 million)
This number steadily declines throughout life as a result
of atresia and ovulation
So, fewer than 500 of original 7 million oocytes are
released in entire reproductive life span of a woman

11. POF
Idiopathic
65%
Familial
Genetic
20%
Autoimmune
10%
X
chromosome
abnormality
(Deletion,
Translocation)
5%

12. CLEAR CAUSE CAN BE DEFINED IN
ONLY LIMITED CASES*
*Woad et al;2006

13. IDIOPATHIC
• Unknown mechanism affecting the rate of
oocyte apoptosis *
• Reduced complement of oocytes in the
ovaries at birth or accelerated atresia
• However USG and ovarian biopsy have not
been useful in prognostication of future
ovulation and fertility
* Morita and Tilly et al; 1999

14. GENETIC
 In primordial follicle, oocyte is surrounded by granulosa
cells, which provide growth factors to oocyte
 Mutations in FOXL2 gene lead to defect in granulosa cells
activity and can lead to POF
 Isolated gene defects in FSH R gene also play role
Both – X
chromosomes
and autosomal
involvement*
Reduced gene dosage
and non-specific
chromosome defects
that impair meiosis
Decrease in pool
of primordial
follicles ,
increased atresia
of ovarian
follicles due to
apoptosis or
failure of ovarian
maturation
*Conway et al; 1997

15. AUTOIMMUNITY
Genetic or environmental factors
might initiate immune response
HLA antigens and cytokines
Possibility of disease specific therapy
to prevent further autoimmune
ovarian damage in POF patient with
proven autoimmune etiology

16. INDUCED OR
IATROGENIC FAILURE
 Irradiation
 Chemotherapy
 Smoking
 Increased use of gonadotrophic
stimulation
 Any surgery on ovary
 PCO Drilling
 Interestingly only hysterectomy too*
*Farquhar et al;2005

17. GALACTOSEMIA
GALT Deficiency
Intracellular accumulation of
galactose metabolites or deficient
glycosylation reaction
Decrease in number of oogonia
through apoptosis

18. CLINICAL TRIAD*
* Woad et al ; 2006
Primary Amenorrhea-Streak
ovaries
Secondary Amenorrhea
Small ovaries without
growing follicles
< 40 years
Hypergonadotropism
FSH > 40 mIU/ml
Hypoestrogenism
Estradiol < 50pg/ml

19. For most women, it is an unexpected and
distressing diagnosis with unpleasant
symptoms
Loss of fertility due to…
 Absence of follicles
 Inability of remaining follicles to respond to stimulation*
*Nelson et al ; 2009

20. There is no evidence that it is
becoming more common
But certainly it is becoming
more important due to
tendency to delay first child

21. Decreased
sexual
desire Hot
flushes
Night
sweats
Vaginal
dryness
Irritability
Poor
concentration
Irregular
or skipped
menses

24. * D.Goswami and G.S.Conway 2005
Investigations
Education and Counseling
Treatment
aaaaaaaaa
ISSUES IN THE MANAGEMENT OF WOMEN WITH POF

25. LABORATORY
INVESTIGATIONS
1. Clarify the etiology
2. Screening tests
3. To establish effect of POF
 UPT
 FSH , LH, Estradiol
 AMH, Inhibin
 Blood chemistry
 Karyotype
 Test for fragile X chromosome (FMR1 permutation)
 Bone density by dual-energy x-ray absorptiometry (DEXA) scan
 USG ovary (though not much useful)

26. AUTOIMMUNE SCREEN
 CBC -ESR
 S. Electrolytes, calcium, phosphate, protein
 S. Cortisol
 ANA, Rheumatoid factor
 Ovarian antibody
 TSH
 Anti TPO
 Serum adrenal antibodies
 Blood sugar

27.  Pregnancy
 Secondary ovarian insufficiency/failure
 Eating disorder, Exercise
 Prolactinoma
 Pituitary and hypothalamic tumors, hemorrhage
 Systemic diseases-Medications
 Hyper androgenic conditions
 PCOS
 CAH
 Androgen-producing tumors
 Ovarian hyperthecosis
 Outflow tract abnormalities
 Pseudo premature ovarian failure
 Gonadotropin-producing pituitary adenoma
 Antibodies to gonadotropins

30. As POF has cumulative negative effects over time, it is
important for clinicians to make a timely diagnosis and
begin appropriate strategies for ….
Symptoms management
Emotional Support
Risk reduction Dealing with
menopausal symptoms like
osteoporosis & loss of fertility

31.  Studies have come up with the result that HRT causes
Ca breast, MI or stroke..
 But HRT is effective in some group of women with
menopausal symptoms( for shortest possible duration
and lowest possible dose)*
 So, POF women should undergo HRT till their
physiological age of menopause - around 50
#
*Roberts et al ; 2007
#Christine-Maitre et al ;2008

32. HRT IN POF VS NATURAL
MENOPAUSE
• True example of replacement therapy Vs extension
therapy
• Started at time of diagnosis AND continued till natural
age of menopause
• No long-term ill effects (WHO study) as estrogen years
are not increased
• Low dose short-term Vs Full dose long term
• 5-10% will resume spontaneous ovulation &
menstruation

33. ESTROGENS
 Higher doses than those for post menopausal women may be needed to achieve adequate
estrogenization of the vaginal epithelium in young women and help maintain age-appropriate
bone density
 Estrogen replacement therapy does not prevent ovulation and conception in these patients
PROGESTINS
 To prevent endometrial hyperplasia
 If an expected withdrawal bleeding is missing, a pregnancy test should be performed. 5-10%
chance of spontaneous pregnancy*
ANDROGENS#
13% have levels below normal. Given for short periods in..
 Addisons disease
 Persistent fatigue
 Low libido
 Poor well being despite adequate estrogen replacement
 Oral methyl testosterone 1.25-2.5 mg/d, injectable testosterone esters 50 mg every 6 weeks IM
*Driilion and Davis; 2007
#Welf ; 2009

34. TAILOR HRT ACCORDING TO TYPE
OF POF
TYPE CLINICAL CHARACTERISTICS
I
Pre-pubertal
Lack of pubertal development & primary
amenorrhea
II
Post-pubertal
Secondary amenorrhea, before age of 40 years
III
Iatrogenic
Surgical menopause(B/L oophorectomy, post
hysterectomy), post chemo/radiotherapy/ stem
cell therapy

35. TYPE I POF - PREPUBERTAL
Estrogen will initiate & sustain maturation and
function of 2° sexual characters
Promote full height
Adolescent increase in bone density is important
determinant of later risk of osteoporosis. This can
be the only justification of starting HRT
Maintain sexual & menstrual function

36. TYPE I POF - PREPUBERTAL
Turner’s syndrome
45X0
• Start small dose
oestrogen at 12 yrs
• Change to full dose
EPT after 2 years
Swyer’s
syndrome 46XY
• Start full dose
EPT at 12years

37. Turner’s
syndrome
Low dose
unopposed
estrogens at bone
age 12
0.3mg CEE
or
0.5mg E 2 daily x
2 years
0.625mg CEE
or
1mgE 2 daily
+
5mg MPA 14 days
each cycle
Calcium
supplementation
Annual check up
COC ??

38. I EPT REGIMEN ESTROGEN PROGESTERONE
Cyclic Day 1-25 Last 10-14 days of ET
cycle
Cyclic- combined Day 1-25 Day 1-25
Continuous - cyclic Daily 10-14 days every month
Continuous - long
cycle
Daily 14 days every 3-6 months
Continuous - combined Daily Daily
II Tibolone Daily
TYPE II POF- HRT REGIMES

39. PROGESTERONE PREPARATIONS
DRUG ROUTE SEQUENTIAL
(10-14 DAYS)
CONTINUOUS
MPA Oral 5mg daily 2.5mg daily
Norethisterone Oral 1mg daily 0.3 mg daily
Norethindrone Oral 2.5mg daily 0.5mg daily
Dydrogesterone Oral 10mg daily 5mg daily
Drospirenone Oral - 2mg daily
Natural progesterone Oral 300mg daily 200mg daily
Natural progesterone Vaginal 200mg daily 100mg daily
Natural progesterone Vaginal gel 45mg daily 45mg daily
LNG-IUS Intra-uterine _ 20mcg daily

40. TIBOLONE
 19-nortestoterone derivative
 Active metabolites
 Mildly estrogenic, progestogenic & androgenic
 Amenorrhoea
 Good for VMS, libido, bones
 No change in breast density

41. TYPE III POF - IATROGENIC
 Sudden & precipitous fall of estrogens – VMS, CHD,
osteoporosis, suicidal depression
 Lack of androgens – lack of energy & libido
 Need to start HRT early while in the hospital & full/
higher dose

42. RESTORATION OF FERTILITY
 Unproven treatments to restore fertility should be
avoided
 ART
 Oocyte/ embryo donation
 Surrogacy
 Ovarian cryopreservation in Iatrogenic POF
 Adoption

43. ADJUVENTS
 Bisphosphonates
 SSRIs
 SERMs
 Soy Proteins
• Recent Advances-
Pentoxiphylline and Tocopherol (Vit E)
for 9 months with Growth Hormone

44. CONSULTATION
The mere understanding of the problem helps patients
cope better
Endocrinologist / Psychiatrist / Geneticist
International Premature Ovarian Failure Association

45. LIFESTYLE
MODIFICATION
DIET
 Elemental Calcium : 1200-1500 mg
day and Vitamin D
YOGA / MEDITATION
ACTIVITY
 Weight-bearing exercises for 30
minutes per day, at least 3 days per
week
 Outdoor sports