Premature Ovarian Failure

PREMATURE OVARIAN FAILURE

DR. KIRTAN VYAS

Gujarat Uni. First-Gold medallistGujarat Public Service Commission(GPSC) firstFellow 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 ConferencesLocal 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 conferencesOrganizing secretary for the West Zone Yuva Fogsi 2016,RajkotAt present working as an Assistant Professor at P.D. U. Medical College and Hospital, Rajkot

Dr. Kirtan VyasM.S.(Ob/Gy)

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

MENOPAUSE & AGE

AT 40 YRS

PREMATURE MENOPAUSE

AT 45 YRS

EARLY MENOPAUSE

INCIDENCEAround 1%*0.1% by age 30 *Coulam et al; 1986

ANATOMYIn 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

POF

Idiopathic65%

Familial Genetic

20%

Autoimmune10%

X chromosome abnormality

(Deletion, Translocation)

5%

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

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

GENETIC In primordial follicle, oocyte is surrounded by granulosa cells,

which provide growth factors to oocyteMutations in FOXL2 gene lead to defect in granulosa cells activity

and can lead to POFIsolated 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

AUTOIMMUNITYGenetic 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

INDUCED OR IATROGENIC FAILUREIrradiationChemotherapySmokingIncreased use of gonadotrophic stimulationAny surgery on ovaryPCO Drilling Interestingly only hysterectomy too* *Farquhar et al;2005

GALACTOSEMIA

GALT Deficiency

Intracellular accumulation of galactose metabolites or deficient glycosylation reaction

Decrease in number of oogonia through apoptosis

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

For most women, it is an unexpected and distressing diagnosis with unpleasant symptoms

Loss of fertility due to…

Absence of folliclesInability of remaining follicles to respond to stimulation*

*Nelson et al ; 2009

There is no evidence that it is becoming more common

But certainly it is becoming more important due to tendency to delay first child

Decreased sexual desire Hot

flushes

Night sweats

Vaginal drynessIrritability

Poor concentration

Irregular or skipped

menses

* D.Goswami and G.S.Conway 2005

Investigations

Education and Counseling

Treatment

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ISSUES IN THE MANAGEMENT OF WOMEN WITH POF

LABORATORYINVESTIGATIONS

1. Clarify the etiology2. 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)

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

PregnancySecondary ovarian insufficiency/failure

Eating disorder, Exercise Prolactinoma Pituitary and hypothalamic tumors, hemorrhage

Systemic diseases-MedicationsHyper androgenic conditions

PCOS CAH Androgen-producing tumors Ovarian hyperthecosis

Outflow tract abnormalitiesPseudo premature ovarian failure

Gonadotropin-producing pituitary adenoma Antibodies to gonadotropins

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

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

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

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 patientsPROGESTINS 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

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

TYPE I POF - PREPUBERTALEstrogen 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

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

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 supplementationAnnual check up

COC ??

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

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

TIBOLONE

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

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

RESTORATION OF FERTILITY

Unproven treatments to restore fertility should be avoided

ART Oocyte/ embryo donation Surrogacy Ovarian cryopreservation in Iatrogenic POF

Adoption

ADJUVENTSBisphosphonatesSSRIsSERMsSoy Proteins

• Recent Advances- Pentoxiphylline and Tocopherol (Vit E) for 9 months with Growth Hormone

CONSULTATION The mere understanding of the problem helps patients

cope betterEndocrinologist / Psychiatrist / Geneticist

International Premature Ovarian Failure Association

LIFESTYLE MODIFICATIONDIETElemental Calcium : 1200-1500 mg

day and Vitamin D

YOGA / MEDITATION

ACTIVITYWeight-bearing exercises for 30

minutes per day, at least 3 days per week

Outdoor sports

THANK YOU