Primary Ovarian Insufficiency
/Reading: Committee Opinion 604
What is Primary Ovarian Insufficiency?
Definition
Depletion or dysfunction of ovarian follicles with cessation of menses before age 40
Used to be caused premature menopause or primary ovarian failure
Note: should not be confused with menopause because 5-10% of women with POI can still experience spontaneous conception and delivery
What Causes POI?
Causes of POI
There are many, but usually caused by chromosomal abnormalities or damage from chemotherapy or radiation therapy
Common cause: chemo and radiation
Immediate loss of ovarian function after chemo/radiation is called acute ovarian failure
Highest incidence occurs after use of alkylating agents or procarbazine
Younger the patient at time of receiving chemo, the more likely some follicles will survive
Common cause: premutation of the FMR1 gene for fragile X
As a reminder, Fragile X is an X-linked dominant condition
Caused by an increase in the repeats of CGG, typically >200
In fragile X, there is genetic anticipation, meaning that the number of repeats can increase as they get passed onto future generations
A pre-mutation is when there is between 55-200 repeats, and those with Fragile X or a pre-mutation have a 20% chance of developing POI in their lifetime
1% of pre mutation carriers will experience final menses before age 18
Another common cause: Turner Syndrome
Chromosomal abnormality with XO instead of XX
Certain people can also have Turner mosaicism, which can also lead to POI
When evaluating adolescents with primary amenorrhea and no associated comorbidities, about 50% will have chromosomal abnormalities
Can also lead to pubertal and growth delays
Gonadal dysgenesis
Less frequently can be caused by infection or infiltrative process
Other cause could be iatrogenic (ie. removal of the ovaries)
Can also have autoimmune component, as 4% of patients with POI will have adrenal or ovarian antibodies
How do we diagnose primary ovarian insufficiency?
Diagnosis
Unfortunately, no consensus criteria to identify POI in adolescents, and so a delay in diagnosis is common
Some adolescents may have hot flashes or vaginal dryness, but the most common presenting symptom is POI
So in someone who is presenting with amenorrhea or menstrual irregularity for 3 or more months, important to evaluate for all etiologies (ie. pregnancy, PCOS, hypothalamic amenorrhea, thyroid abnormalities, hyperprolactinemia, and POI)
Work up
History and physical
Ask about menstrual history, family history of early menopause, and other factors that may place patients at risk for POI (ie. above etiologies)
Physical exam should include other signs of disorders of sexual development (ie. breast development, uterus present or absent)
Labwork
Obtain basal FSH and estradiol levels - do not obtain when patient is on OCPs or other hormonal medications
Pregnancy test
Thyroid function tests and prolactin
If gonadotropins are elevated in menopausal range (FSH 30-40 mIU/L), a repeat FSH measure is indicated in 1 month
If FSH is still elevated, this is diagnosed as POI
Hypoestrogenism is when estradiol levels are <50 pg/mL
Once diagnosis is established
Karyotype
FMR1 pre mutation testing
Adrenal antibodies
Pelvic ultrasound
Meeting with genetic counselor depending on genetic findings
Other tests being studied
AMH is currently being used to assess ovarian reserve, but should not be used to determine if someone is fertile or not
Inhibin B is not recommended as there is significant variability between menstrual cycles
Management
Note about treatment
Diagnosis can be emotionally distressing in young women
Therefore, treatment should have focus on sensitivity to both physical and emotional needs
Some patients may need referral to counseling/group therapy for support
Goal overall physically is to replace the hormones that the ovary would be producing before age of menopause
May need more than menopausal women
Pubertal development
Breast development
Initiate estrogen and increase gradually before administering progesterone until breast development is complete to prevent tubular breast formation
Consultation to REI or PAGs for further management
Ongoing hormonal treatment
Will be necessary to prevent comorbidities
Usually, transdermal, oral, or occasionally transvaginal estradiol of doses of 100 mcg daily is the therapy of choice
Remember that oral estradiol can be used, but there is a higher risk of VTE compared to transdermal estrogen
Addition of progesterone for 10-12 days each month is protective against endometrial hyperplasia
The instinct may be to reach for OCPs, but OCPs have a much higher dosage of estrogen than is needed, and so is not first line treatment
Associated Comorbidities
Bone loss
We know that ovarian function loss can affect bone architecture, especially in adolescents when bone accrual is at its maximum
There is no consensus regarding DEXA scan or monitoring bone density annually; some do, but the the implications of low bone mineral density result in this population is unclear given low risk of fracture
Long term use of bisphophonates is not recommended because of uncertain adverse effects and safety profiles
Cardiovascular Disease
Those with early estrogen loss are at higher risk of CV mortality
Other than supplementing estrogen, there should be monitoring
Routine visits should also focus on other methods of prevent CV morbidity: smoking avoidance, appropriate diet and exercise
Blood pressure measurement annually and lipid levels every 5 years
Endocrine Disorders
20% of adults with idiopathic POI will experience hypothyroidism, commonly Hashimoto’s thyroiditis
No formal recommendation, but appropriate to test for thyroid insufficiency every 1-2 years
Test for adrenal antibodies and should undergo yearly corticotropin stimulation testing as there is a 50% chance of developing adrenal insufficiency
Fertility and Contraception
For patients that desire to start families, they should be referred to REI to discuss options
Can have egg preservation if possible
Can also discuss other ways of having offspring (ie. donor eggs, gestation carrier)
Fertility can still persist as long as few follicles are present
Therefore, contraception should still be a discussion
OCPs can be prescribed, but other methods such as IUDs or barrier methods can also be used
Even if estrogen method is not chosen, estrogen should still be supplemented for the above reasons
A missed period should still warrant a pregnancy test