Premature Ovarian Insufficiency

Michael Savvas

King’s College Hospital

Premature Ovarian Insufficiency

•Loss of ovarian function before the age of 40

•Affects 1% of women

•Affects 0.1% of women before age of 30

•May present with subfertility

POI causes

• Idiopathic

• Iatrogenic

• Auto immune

• X Chromosome abnormalities

• Familial Genetic Causes

• Viral infection

• Sickle cell disease

• HIV

Diagnosis of Menopause

Women >45 years – Clinical diagnosis

Consider using a FSH test to diagnose menopause only:

•In women aged 40 to 45 years with menopausal symptoms

•in women aged under 40 years in whom menopause is suspected

NICE 2015

Premature Ovarian insufficiency

Diagnosis in women aged under 40 years is based on:

•Menopausal symptoms, including no or infrequent periods

•Elevated FSH levels on 2 blood samples taken 4–6 weeks apart.

AMH unhelpful

POI Investigation

•Auto antibodies

Unhelpful

•Chromosomal analysis

Primary amenorrhoea

Family history

Premature Ovarian Insufficiency

•Symptoms

•Long term

Infertility

Osteoporosis

Heart disease

Dementia

Increased mortality

Symptoms

•Oligo/amenorrhoea

•Hot flushes / night sweats

•Disturbed sleep

•Tiredness

•Cognitive function

•Mood swings

•Dry thin skin

•Hair loss

•Urinary symptoms

•Sexual function

Premature Ovarian Insufficiency

Psychological symptoms

•Depression

•Low levels of self esteem and Life satisfaction

•Sexual Dysfunction

Sexual Function

•Loss of libido

•Anorgasmia

•Vaginal dryness

•Superficial dyspareunia

May be reflection of general well being

Infertility

POF

Most Distressing symptom

Loss of fertility 54%

Feeling Older 27%

Baber, Abdalla and Studd

Premature ovarian Insufficiency

May first present to the fertility specialist

Infertility

Oligo/amenorrhoea

Pregnancy after POI

• Around 5%

• But variable

• No effective intervention to enhance this

Cardiovascular Disease

•Increased risk

CVD Incidence

CVD Mortality

Most marked following surgical menopause

OSTEOPOROSIS

•Increased risk of osteoporosis and fractures

Cognitive Function

•Increased risk of cognitive impairment and dementia

Worse after surgical menopause

Premature Ovarian insufficiency

•Offer HRT or OCP until age of natural menopause

•HRT may have a beneficial effect on blood pressure when compared with a combined oral contraceptive

•HRT is not contraceptive

NICE 2015

HRT

•Alleviates menopausal symptoms

•Reduce risk of long-term sequalae

•Facilitates fertility treatment donor eggs.

HRT

•Oestrogen

•Testosterone

•Progestrone / Progestogen

To protect endometrium

OESTROGEN

PROGESTOGEN

1 14 28

Mimics the normal menstrual cycle

Aims to produce a regular cyclical bleed

Sequential HRT

Altered Sexual Function

•Consider Testosterone if oestrogen alone is not effective

NICE 2015

HRT in POI

•Testosterone

Libido

Moods

Energy

Progestogens

•PMS type symptoms

•?Increased risk of Breast Cancer

•Adverse effects on Lipids

•Regular withdrawal bleed

Micronised progesterone

•Oral /vaginal

•200mg for 12 days

•Lower risk of breast cancer

•Better metabolic profile

•Fewer progestogenic side effects

Routes of Administration

•Oral

•Transdermal patches or gels

•Subcutaneous implants

HRT in POI

•Transdermal route avoids first pass effect through liver

•No increased risk of thrombosis

Cardiovascular Disease

•Initial WHI study suggested increased risk of CVD in all ages

•Subsequent analysis confirms reduction in CVD when HRT started after 60 years

POI and Osteoporosis

HRT is first line

•100 -150 μg transdermal

•2mg oral

•30 μg EE may be less good

•Bisphosphonates best avoided

Bone densitometry every 2-3 years

HRT and cognitive function

•Improved cognition

•Reduced risk of dementia

When commenced early

POI and Breast cancer

•Reduced incidence of breast cancer

•HRT does not increase risk above that in women of same age without POI

•Oestrogen alone associated with reduced risk of breast cancer

POI and Breast cancer

•Combined HRT – Very small increase

Absolute risk is very small

But no increase in mortality

•Progesterone may be safer

Venous Thromboembolism

•Increased risk with oral but not transdermal

•Transdermal in women at increased risk

NICE 2015

HRT

•Benefits outweigh risk if started before the age of 60.

HRT Conclusion

•Can alleviate symptoms

•Long term benefits

Osteoporosis

Heart disease

Overall mortality reduced

Fertility

Age of women giving birth in UK

Fertility Cryopreservation

• Embryo Freezing

• Egg freezing

• Ovarian tissue freezing

• Ideally undertaken when the woman has normal ovarian reserve.

Predicting Premature Ovarian Failure

•Clinical

•Family history

•History of poor ovarian response to stimulation (POR)

•Ovarian reserve testing

Vitrifed donor eggs

Egg Bank Fresh

Age of donor 26 26

Age of recipient 41 41

BMI 22.6 22.5

CPR 50.2% 49.8%

Twins 32.4% 37.5%

Cobo et al Hum Rep 2010

Oocyte Freezing

•Age

•Number of eggs

8-10 eggs in women <35 years

•Increased obstetric complications

•Use of Donor sperm (47%)

Ovarian Tissue Cryopreservation

•Ovarian cortex removed laparoscopically

•Cryopreserved

•Autologous transplantation

•Large number of eggs

Donor egg treatment

Egg donors

• Shortage of altruistic anonymous donors in UK

• Known donors

• Egg Sharing

• Treatment overseas

Egg Donors

• Healthy women, between the

• Age of 18 and 35 years of age

• Should preferably have had healthy children of her own.

• No history of mental disorders.

• There should be no family history of genetic or heritable diseases.

• Infectious screen

Egg Donors

• Donors have no legal rights or obligations to children born as a result of their donated eggs.

• Can be told whether any children were born the sex and the year they were born.

Donor Anonymity

• Since 1 April 2005 are identifiable

• Only donor-conceived person can initiate contact

Egg recipient

• Can be provided with non-identifying information such as height and ethnicity

• Pen portrait

Obstetric outcomes

Donor eggs compared with own eggs

•Increased risk of first trimester bleeding and pregnancy induced hypertension

•Higher caesarean section rate

Stoop et al 2012

Fertility - Conclusion

• Infertility most distressing consequence of POI

• Elective fertility preservation prior to iatrogenic menopause or in young women at risk of POI

• Donor egg treatment remains only treatment option in POI.

Management of POI

• Women with POI require long term support

• HRT until at least age of 51

• Donor egg treatment only effective treatment