Primary Ovarian Insufficiency

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Reading: Committee Opinion 604

What is Primary Ovarian Insufficiency? 

  1. Definition 

    1. Depletion or dysfunction of ovarian follicles with cessation of menses before age 40 

    2. Used to be caused premature menopause or primary ovarian failure 

    3. Note: should not be confused with menopause because 5-10% of women with POI can still experience spontaneous conception and delivery 

What Causes POI? 

  1. Causes of POI 

    1. There are many, but usually caused by chromosomal abnormalities or damage from chemotherapy or radiation therapy  

    2. Common cause: chemo and radiation 

      1. Immediate loss of ovarian function after chemo/radiation is called acute ovarian failure 

      2. Highest incidence occurs after use of alkylating agents or procarbazine 

      3. Younger the patient at time of receiving chemo, the more likely some follicles will survive  

    3. Common cause: premutation of the FMR1 gene for fragile X 

      1. As a reminder, Fragile X is an X-linked dominant condition

      2. Caused by an increase in the repeats of CGG, typically >200 

      3. In fragile X, there is genetic anticipation, meaning that the number of repeats can increase as they get passed onto future generations 

      4. 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 

      5. 1% of pre mutation carriers will experience final menses before age 18 

    4. Another common cause: Turner Syndrome 

      1. Chromosomal abnormality with XO instead of XX 

      2. Certain people can also have Turner mosaicism, which can also lead to POI 

      3. When evaluating adolescents with primary amenorrhea and no associated comorbidities, about 50% will have chromosomal abnormalities 

      4. Can also lead to pubertal and growth delays 

    5. Gonadal dysgenesis 

    6. Less frequently can be caused by infection or infiltrative process 

    7. Other cause could be iatrogenic (ie. removal of the ovaries) 

    8. Can also have autoimmune component, as 4% of patients with POI will have adrenal or ovarian antibodies 


How do we diagnose primary ovarian insufficiency? 

  1. Diagnosis 

    1. Unfortunately, no consensus criteria to identify POI in adolescents, and so a delay in diagnosis is common 

    2. Some adolescents may have hot flashes or vaginal dryness, but the most common presenting symptom is POI 

    3. 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) 

  2. Work up 

    1. History and physical 

      1. Ask about menstrual history, family history of early menopause, and other factors that may place patients at risk for POI (ie. above etiologies) 

      2. Physical exam should include other signs of disorders of sexual development (ie. breast development, uterus present or absent) 

    2. Labwork 

      1. Obtain basal FSH and estradiol levels - do not obtain when patient is on OCPs or other hormonal medications 

      2. Pregnancy test 

      3. Thyroid function tests and prolactin 

    3. If gonadotropins are elevated in menopausal range (FSH 30-40 mIU/L), a repeat FSH measure is indicated in 1 month

      1. If FSH is still elevated, this is diagnosed as POI 

      2. Hypoestrogenism is when estradiol levels are <50 pg/mL 

      3. Once diagnosis is established 

        1. Karyotype 

        2. FMR1 pre mutation testing 

        3. Adrenal antibodies 

        4. Pelvic ultrasound  

        5. Meeting with genetic counselor depending on genetic findings 

    4. Other tests being studied  

      1. AMH is currently being used to assess ovarian reserve, but should not be used to determine if someone is fertile or not 

      2. Inhibin B is not recommended as there is significant variability between menstrual cycles 


Management 

  1. Note about treatment 

    1. Diagnosis can be emotionally distressing in young women 

    2. Therefore, treatment should have focus on sensitivity to both physical and emotional needs 

    3. Some patients may need referral to counseling/group therapy for support  

  2. Goal overall physically is to replace the hormones that the ovary would be producing before age of menopause 

    1. May need more than menopausal women 

    2. Pubertal development 

      1. Breast development 

        1. Initiate estrogen and increase gradually before administering progesterone until breast development is complete to prevent tubular breast formation 

      2. Consultation to REI or PAGs for further management 

    3. Ongoing hormonal treatment 

      1. Will be necessary to prevent comorbidities 

      2. Usually, transdermal, oral, or occasionally transvaginal estradiol of doses of 100 mcg daily is the therapy of choice 

        1. Remember that oral estradiol can be used, but there is a higher risk of VTE compared to transdermal estrogen 

      3. Addition of progesterone for 10-12 days each month is protective against endometrial hyperplasia 

      4. 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 

  3. Associated Comorbidities 

    1. Bone loss 

      1. We know that ovarian function loss can affect bone architecture, especially in adolescents when bone accrual is at its maximum 

      2. 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 

      3. Long term use of bisphophonates is not recommended because of uncertain adverse effects and safety profiles 

    2. Cardiovascular Disease 

      1. Those with early estrogen loss are at higher risk of CV mortality 

      2. Other than supplementing estrogen, there should be monitoring 

      3. Routine visits should also focus on other methods of prevent CV morbidity: smoking avoidance, appropriate diet and exercise 

      4. Blood pressure measurement annually and lipid levels every 5 years 

    3. Endocrine Disorders 

      1. 20% of adults with idiopathic POI will experience hypothyroidism, commonly Hashimoto’s thyroiditis 

      2. No formal recommendation, but appropriate to test for thyroid insufficiency every 1-2 years 

      3. Test for adrenal antibodies and should undergo yearly corticotropin stimulation testing as there is a 50% chance of developing adrenal insufficiency 

  4. Fertility and Contraception 

    1. For patients that desire to start families, they should be referred to REI to discuss options 

      1. Can have egg preservation if possible 

      2. Can also discuss other ways of having offspring (ie. donor eggs, gestation carrier) 

    2. Fertility can still persist as long as few follicles are present 

      1. Therefore, contraception should still be a discussion 

      2. OCPs can be prescribed, but other methods such as IUDs or barrier methods can also be used 

      3. Even if estrogen method is not chosen, estrogen should still be supplemented for the above reasons 

      4. A missed period should still warrant a pregnancy test 

Diagnosis and Workup of Primary Amenorrhea

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Today's topic will be a broad overview of the diagnosis and workup of primary amenorrhea... There’s a lot to take in, but don't worry! There will more to come on each of the topics that we touch on down the line. 

Fei has made a handy chart for thinking about primary amenorrhea below!

For further reading on primary amenorrhea, see the ASRM guideline on amenorrhea.
And remember… always check a pregnancy test.