16 FEBRUARY 2024 ausdoc . com . au

Therapy Update

Women ’ s health

Clinical Associate Professor Amanda Vincent Monash Health ; head of early menopause studies at the Monash Centre for Health Research and Implementation , Monash University ( mchri . org . au ); and co-lead of the Early Menopause Stream at the NHMRC Centre for Research Excellence in Women ’ s Health in Reproductive Life .

Premature ovarian insufficiency and early menopause are increasingly common and cause long-term comorbidity if unrecognised or undertreated .

A recent meta-analysis indicates that premature ovarian insufficiency ( POI ) and early menopause ( EM ) are more common than originally thought , affecting 3.7 % and 12.2 % of women respectively . 1 Increasing cancer survivorship means there are more people living with POI / EM .

Aetiology

Causes of POI are shown in table 1 , although idiopathic POI is the most common diagnosis . Chromosomal , monosomic and polygenic genetic causes are associated with POI , with over 70 genes identified that may underlie the idiopathic POI diagnosis . These gene mutations are associated with abnormalities in DNA repair , meiosis , ovarian development and function , immune function and cell energy metabolism , contributing to the pathophysiology of POI / EM . 3 In addition to family history , observational data suggests early-life , reproductive , lifestyle and environmental factors influence the risk of POI / EM ( see table 2 ). 4

Clinical considerations

Individuals may present with primary

Table 1 . Causes of premature ovarian insufficiency 2

Chromosomal

• X monosomy ( Turner syndrome )

• X trisomy

X-linked :

• FMR1 mutation

• BMP15

• Deletions

• Translocations

Autosomal genes :

• GALT

• FSH / LH receptor gene

• FOX03

• NOBOX

Autoimmune thyroid disease

Addison ’ s disease

Polyglandular autoimmune syndromes

Coeliac disease

Diabetes mellitus

Connective tissue disorders ( eg , SLE , rheumatoid arthritis , Sjogren ’ s )

Mumps oophoritis

TB Malaria Shigella Varicella CMV HIV

or secondary amenorrhoea or infertility , with or without menopausal symptoms . POI and EM are associated with negative psychological , social and physical impacts , with increased risk of multimorbidity and mortality . 5-11

Australian longitudinal data show

17 hydroxylase deficiency

Galactosaemia

Ovarian or pelvic surgery

Chemotherapy , especially alkylating agents and anthracyclines

Radiotherapy : external beam or intracavity

Environmental toxins

women aged over 60 with POI have an increased risk of diabetes , stroke , CHD , asthma , COPD , osteoporosis and hypertension , compared to those with menopause aged 50-51 ( see figure 1 ). 6 This study followed 5107 women aged 61 at baseline , for six years , and compared morbidity

NEED TO KNOW

Premature ovarian insufficiency ( POI ) and early menopause ( EM ) affect 3.7 % and 12.2 % of women respectively . Genetic , early life , reproductive , lifestyle and environmental factors influence the risk .

Consider POI in individuals with ≥4 months of amenorrhoea . Diagnosis depends on an elevated FSH in the postmenopausal range ( FSH > 25 IU ) on two occasions at least 4-6 weeks apart . Low / undetectable AMH can be helpful if diagnosis is uncertain but not useful for POI prediction .

Prompt diagnosis , shared decisionmaking and providing support and information assist quality of life . New co-designed resources for women are available .

POI is associated with 2-3-fold increased risk of multimorbidity , including diabetes , dyslipidaemia , hypertension , cardiovascular disease , osteoporosis , neurocognitive dysfunction and mortality . Hormone therapy until at least the usual age of menopause decreases many of these risks .

Hormone therapy should be instituted promptly after diagnosis , unless contraindicated . Higher oestrogen doses are needed to maintain bone density ( eg , at least 2mg oral estradiol , 1.25mg oral conjugated oestrogens , 100μg transdermal oestrogen patch , 2-3mg estradiol gel or continuous use of 30μg or 35μg ethinylestradiol contraceptive pill ).

outcomes in those with menopause before age 40 ( POI ) with those with meno pause aged 50-51 . Women with POI had almost twice the odds of experiencing morbidity at age 60 and three times the odds of developing multimorbidity after six years . Women with POI were more likely to use menopausal hormone therapy , be nulliparous and less educated , smoke , have increased BMI and low levels of physical activity . The likelihood of breast cancer was not increased . 6

International observational studies have also shown increased risks of dyslipidaemia , dementia , cognitive dysfunction , mortality and Parkinson ’ s disease . 5 , 9 , 11

Comorbidity risk is higher with POI versus EM , and with POI secondary to bilateral oophorectomy versus spontaneous POI . 5 , 6 , 11

POI and EM are associated with increased risk of anxiety , depression , sexual dysfunction and impaired quality of life . 7 , 10

Figure 1 . Increased multimorbidity in women with menopause before age 40 ( POI ) compared with those with menopause aged 50-51 . The odds ratio ( OR ) of individual chronic conditions in women with POI is shown . 6

# = OR at baseline ( age 61 ) * = OR at six-year follow-up

Diagnosis

This is often delayed as the individual or health professional does not consider POI as a potential diagnosis in a young person . In contrast to the 12 months of amenorrhoea indicative of usual age menopause , a diagnosis of POI is prompted by four months or more of amenorrhoea . For confirmation of diagnosis , postmenopausal range FSH levels in the setting of low serum estradiol must be recorded on two occasions 4-6 weeks apart . 10 , 12 A low / undetectable AMH level can provide supportive information to confirm the diagnosis but is not currently useful for routine POI diagnosis or prediction . 13

POI can be a devastating diagnosis and