The prevalence of premature ovarian insufficiency (POI) is approximately 1%. It is a clinical syndrome defined by loss of ovarian activity before age 40 and characterised by menstrual disturbance (oligoamenorrhea), raised gonadotrophins and low oestradiol.
and Infertility Specialist, West Perth
Women with POI may present with the typical symptoms of oestrogen deficiency, such as vasomotor symptoms, however the clinical presentation may vary. Some may not experience any symptoms, and this is less likely in those with primary amenorrhea.
To illustrate, here are two cases. A 28-year-old couple present with primary couple infertility. She has irregular cycles 21-60 days. Pelvic ultrasound shows an antral follicle count of 3, AMH is 0.6 pmol/L and a Day 2 FSH of 24IU/L. Within three months was amenorrheic and developed hot flushes.
A 17-year-old girl presents for investigation of primary amenorrhea. She is a twin and her sister had menarche aged 14. She has secondary sexual characteristics and short stature. Blood tests revealed FHS 55 IU/L, LH 16 IU/L and oestradiol <25 pmol/L. Transabdominal ultrasound revealed 1mL size ovaries along with a juvenile uterine size. Karyotype revealed 45XO – Turners syndrome.
Both women have POI.
The causes of POI are wide ranging: 10-12% of women with POI have chromosomal abnormalities (majority being X chromosome abnormalities). It is important to check for presence of Y chromosome due to the risk of gonadal neoplasia. Fragile X syndrome is an X-linked condition caused by a mutation of the FMR1 gene leading to mental retardation predominantly in men.
Women carrying the mutation have a 13-26% increased risk of developing POI. Testing for Fragile X premutation in women with POI is important as this diagnosis has implications for her and her family. Premutation carriers have an increased risk of developing cerebellar gait ataxia and intention tremor. Routine screening for autosomal genetic mutations is not recommended unless there is evidence suggesting specific mutation (e.g. Blepharophimosis-ptosis-epicanthus-inversus-syndrome – BPES).
Autoimmune disorders are more frequent in those with POI than the general population, and POI is more frequent in populations with autoimmune disorders. Identification of those with subclinical or latent Addison’s disease with adrenocortical antibodies and those with autoimmune hypothyroidism by screening for thyroid antibodies is important.
Mumps oophoritis has been considered a cause of POI in 3-7% of cases. Infection screening in women with POI is not indicated. Medical interventions (e.g. chemotherapy radiotherapy or surgical procedures such as bilateral ovarian cystectomy for endometriomas) can lead to POI. This risk with these interventions should be discussed as part of the consenting process. In a significant number of cases the cause is not identified.
There are no ideal diagnostic biomarkers to confirm diagnosis. It is confirmed by a period of four to six months where there is amenorrhea or oligomenorrhea and two serial measures of FSH above 25 IU/L on two occasions over four weeks apart. AMH is not sufficiently discriminative for a diagnosis of POI. There is no indication to include ultrasound. As ovarian function may fluctuate with POI, follicular activity may be seen, and this doesn’t differentiate POI from other diagnoses.
Menopause Hormone Therapy (MHT) is the mainstay of treatment in POI. In addition to the management of symptoms associated with hypoestrogenism (e.g. hot flushes) there are multiple reasons to consider introducing MHT (see Table 1).
Many women worry about the long-term effects of MHT. Women with POI should be informed that there is no increased risk of breast cancer if MHT is introduced before the age of natural menopause. Progestogen should always be given in combination with oestrogen therapy to protect the endometrium in women with an intact uterus or where progestogens are indicated such as endometriosis.
17B-estradiol is preferred to ethinyl oestradiol or conjugated equine oestrogen for oestrogen replacement. The strongest evidence for endometrial protection is with oral progestogen given cyclically. Patient preference for route of administration of MHT (transdermal vs oral) must be considered, as is the need for contraception.
Untreated POI is associated with reduced life expectancy, largely due to cardiovascular disease. Women with POI should be advised to reduce cardiovascular risk factors by not smoking, regularly exercising and maintaining a healthy weight. Bone health should also be monitored throughout life.
Key messages
- Premature ovarian insufficiency affects 1% of women
- There are multiple causes, but no cause may be identified
- Menopause hormone therapy is the mainstay of treatment.
– References available on request
Author competing interests – nil