What is the Best Management Strategy for a 20-year- old Woman With Premature Ovarian Failure? Reporter: R1 魏君卉 Supervisor: VS 蔡永杰 Clin Endocrinol. 2012;77(2): © 2012 Blackwell Publishing

Introduction POF * or ovarian insufficiency [1] is a devastating diagnosis. Doctor shopping: – Effect on rate of conception, long-term health,and psychological well-being Prevalence: <30 y/o, 0.1% ; <40 y/o, 1% * Spontaneous premature ovarian failure

S/S: menstrual disturbance or amenorrhoea Menopausal symptoms: – hot flushes and night sweats, – vaginal dryness, – low libido, low energy levels, – sleep disturbance, lack of concentration, – stiffness, skin/hair changes and mood swings intermittent, reflecting the fluctuations in spontaneous ovarian function, and caused by oestrogen withdrawal.

Investigation Confirmation of Diagnosis: – 1) 6-month period of amenorrhoea or oligomenorrhoea – 2) follicle-stimulating hormone (FSH) > 30 IU/l x2 times, taken at least 4 weeks apart. ** FSH is not an ideal diagnostic tool, because: 1)rises only in the later stages of follicle depletion, 2)marked cycle-to-cycle variability 3)poor at predicting reproductive status

**Better marker - anti-Mullerian hormone (AMH): 1)closely follows the reduction in follicle number 2)falls to very low levels prior to menopause  In assessment of amenorrhoea : -> exclude PCOS # -> antral follicle count -> understand the diagnosis AMH + transvagianl ultrasound # PCOS : polycystic ovarian syndrome

There is no obvious cause of POF, and even if causation is established, the management – including fertility options – remains unchanged. Aetilolgy Gene 5% Offer Karyotype : <25 y/o with POF or Turner’s syndrome FMR 1 ( Fragile X) premature testing * Risk of hereditary Antoimmue 30% little value in assessing antiovarian antibodies Family history pules anti-thyroid Ab: 24% of women with POF * FMR 1 ( Fragile X) premature testing : 4~5% of women with POF ; 14% of women with POF with family history

Associated Medical Conditions Thyroid dysfunction: – TFT test* and antibody testing – TFT : repeated every 2–5 years ;even annually if Ab (+) Adrenal insufficiency: – developing Addison's disease – the danger of cortisol deficiency in pregnancy Low bone mineral density (BMD): – DXA of the lumbar spine and hip Vitamin D deficiency * TFT : thyroid function tests

Psychological Support Premature ovarian failure is a very difficult diagnosis to accept. Effect on her sexuality, femininity and self-image – sexual dysfunction and much higher depression rates – Maybe Infertility Usual support network of family can’t work ! Fertility counsellor: egg donation and adoption

Long-term Health Effects Published data on health risks derive largely from cohort studies of women with surgical menopause (bilateral oophorectomy) -> oestrogen deficiency is less extreme than surgical menopause of women with POF -> The health effects may not be as great increased fracture risk due to lower bone density increased cardiovascular disease decreased breast cancer risk

lower bone density increased fracture risk HRT* : oestradiol-based HRT prevent adverse effects of oestrogen deficiency. Form: transdermal patch**, gel, oral pills Add progestogen : for women with ut. Mass -> oestradiol –base HRT + 14 days progesterone Or-> COCP***: synthetic oestrogen with progestogen in a cyclical formulation testosterone replacement : controversial, only has role of women with lack of libido or energy *HRT: Hormone replacement therapy ** bypassing first-pass metabolism, matching the normal premenopausal state, suitable for the women with migraine or with risk factors for venous thromboembolism ***COCP : combined oral contraceptive pill

Other Treatments Selective serotonin reuptake inhibitors: – venlafaxine and clonidine – treat hot flushes in older women – do not relieve other symptoms or provide bone protection. Complementary Therapy: – widely used, but no convincing evidence for their efficacy Lifestyle Factor: – Calcium: 1200mg/day ; GI upset and renal stone – Vit. D: sunscreen

Fertility spontaneous pregnancy rate: 5% – if don’t want be pregnant, contraception is necessary – Good prognosis: short duration of amenorrhoea autoimmune aetiology ovarian activity seen on ultrasound scan very low AMH

But, there is no intervention has been found to improve conception rates: ovarian stimulation FSH suppression the use of steroids in autoimmune Treatment: – IVF with donor oocytes (the younger, the better) – high-dose HRT: for endometrium thickened – Avoid related donor : maybe poor response to ovarian stimulation due to family history

Egg donation: not allowed : Germany carefully regulated: UK & Canada UK, where donors are unpaid and their anonymity is not guaranteed.

Long-term Follow-up Monitoring: – The role of FSH,serum oestradiol and ethinyloestradiol (in OCPs) or oestrone are poor. Duration of Hormone Replacement Therapy: – Till the age of natural menopause (51 years) – long-term use of HRT in physiological doses does not increase the risk of breast cancer or cause other problems

Take home message 1.POF is a devastating disease which has influence on bone density, CVD risk, social role and conception. 2.HRT has benefit for women with POF, and the dose should be titrated with symptoms control and bone density. 3.Life-long survey is needed, including BMD and the function of endocrine.

Thanks for your attention~