• Credits

  • Section Writer: Dr. Om J Lakhani
  • Section Editor: Dr. Om J Lakhani

• Introduction

• Q. What is the definition of Premature ovarian insufficiency (POI)?

  • Developing hypergonadotropic hypogonadism before the age of 40 years
  • ESHRE criteria for POI
  • FSH >25 mIU/ml – measured on two occasions 4 weeks apart
  • Amenorrhea for >4 months

• Q. What is the correct terminology for Premature ovarian insufficiency (POI) ?

  • Premature ovarian insufficiency (POI)

• Q. What is it's prevelance ?

  • 1%

• Q. Does ovarian activity resume in these women?

  • In 50% of cases, they do

• Q. Give the spectrum of POI?

  • Occult
  • Biochemical
  • Overt

• Q. What are occult POI and overt POI?

  • Occult POI- subtle changes were leading to infertility despite regular menstrual cycles. They have an inadequate response to exogenous or endogenous gonadotropins
  • Overt POI- Oligo/amenorrhea+ anovulation + Increased FSH

• Etiology

• Q. Which tests should be performed for etiological and complication evaluation of patients having Premature ovarian insufficiency (POI) ?

  • 1. Fragile X premutation
  • 2. karyotype
    • Turner syndrome
    • presence of Y chromosomal material
      • If Y chromosomal material is present- suggest Gonadectomy
  • 3. 21 hydroxylase antibody
    • If present- rule out Primary adrenal insufficiency
    • Additionall Anti TPO antibody is also suggested by the guidelines
  • 4. Diabetes screening is not routinely recommended
  • 5. Additional genetic testing if condition like BPES syndrome is suspected

• Women with Premature ovarian insufficiency (POI) definitley must be given MHT- because the risk is very high in these women

• Q. Enlist the etiology of POI?

  • POI with follicular atresia (Accelerated follicular atresia)
  • POI without follicular atresia (Abnormal follicular stimulation)

• Q. What are the cause of POI with Accelerated follicular atresia ?

  • 1. Genetic disorder
    • Turner syndrome
    • X chromosome deletions
    • Fragile X syndrome
    • Galactosemia
  • 2. Ovarian toxins
    • Drugs – like alkylating agents, cyclophosphamide
    • Radiation
    • Infections- Mumps, CMV
  • 3. Autoimmune disorder
    • Abnormal follicular maturation
    • FSH receptor mutation
    • Steroidogenesis defect- 17 alpha-hydroxylase, StAR
    • Gsalpha mutation
    • Aromatase mutation
    • Intraovarian modulators

• **Genetic causes **

• Q. What is the most common cause of POI?

  • Turner syndrome
  • Occurs in  1:2500 live births

• Q. Is the defect seen in Turner syndrome because of accelerated destruction of the ovaries, or is it because of abnormal development of ovaries?

  • Accelerated destruction is most likely
  • Up to 12 weeks of Intrauterine life, the number of follicles is normal

• Q. Which are the critical region in the X chromosome for ovarian development?

  • X13 to X26 (except X22)

• Q. Which gene leads to Fragile X syndrome

  • FMR1 gene

• Q. Which sequences repeated in Fragile X?

  • CGG

• Q. Which number of repeats is associated with disease

  • <40- normal
  • 40-55- gray zone
  • 55-200- called Premutation and associated with POI
  • More than200- full mutation and full phenotype, including Mental retardation, is seen

• Q. Do women with premutation have early menopause?

  • Yes

• Q. How common is Fragile X premutation ?

  • Very common
  • 1 in 259 women has it

• Q. What are the ACOG recommendations for screening for permutations?

  • It is recommended that all women with POI must be screened for premutations

• Q. What is the cause of POI is galactosemia?

  • It is because of the toxic effect of galactose

• Q. Name some other genes leading to POI?

  • FOXL2
  • STAG3
  • FIGLA

• Q. What is the role of BMP15 in follicular growth?

  • BMP15 aids in granulosa cell proliferation

• Q. How does BMP15 mutation lead to POI?

  • Mutant BMP15 suppresses the action of normal BMP15 leading to reduced follicular growth

• Q. Which syndrome presents with teletelangiectas, abnormal gait, and POI?

  • Ataxia telangiectasia

• Q. Which mutation presents with POI, chromosomal instability, and increased risk of cancer?

  • Bloom syndrome

• Q. Which mutation presents with MRI white matter changes and POI?

  • EIF2B gene

• Q. Patient has ptosis with POI, which mutation?

  • FOXL2 mutation
  • BPES syndrome (blepharophimosis/ptosis/epicanthus inversus syndrome [BPES])

• **Autoimmune etiology **

• Q. Which autoimmune polyglandular syndrome- type 1 or type 2 is associated with POI?

  • Both
  • Occurs in 40% in each case

• Q. Is there any difference in isolated autoimmune POI vs. POI associated with APS?

  • Yes
  • Isolated POI is associated with WBC in the theca cells
  • The primordial follicles per se are spared
  • There is a spillover to the primordial follicles, which causes the disease

• **Ovarian toxins **

• Q. Which drugs are associated with POI?

  • Chemotherapeutic agents are primary the cause
  • They include alkylating agents and cyclophosphamide
  • Platinum containing agents also produce the same

• Q. Does smoking cause POI?

  • It produces early menopause
  • Hence POI may also be possible

• **ABNORMAL FOLLICULAR STIMULATION (POI WITHOUT FOLLICLE ATRESIA) **

• Q. Which conditions, in general, produce POI without follicular atresia?

  • They are mainly seen in syndrome associated with abnormal estradiol synthesis
  • It is a synthesis defect

• Q. Is there any role of paracrine factors?

  • Yes
  • Various paracrine factors have been identified which inhibit ovarian estradiol release
  • One such is a polymorphism of the alpha subunit of inhibin

• Q. Which disorder of steroid synthesis present with POI?

  • StAR defect
  • 17 alpha-hydroxylase
  • Aromatase defect

• Q. Can pseudohypoparathyroidism also have POI?

  • Yes
  • This is because of LH/FSH resistance
  • Because of the Gs alpha subunit defect

• Clinical features of Premature ovarian insufficiency

• Q. Summarize the Clinical features of POI?

  • Oligomenorrhea/amenorrhea
  • Anovulation
  • Infertility
  • Raised FSH
  • Low estradiol
  • Symptoms of menopause- vaginal dryness, hot flushes

• Q. Which is the most common symptom of overt POI?

  • Menstrual irregularities
  • Oligomenorrhea/amenorrhea

• Q. A woman present with failure of return of menses after stopping OC pills, can she have POI?

  • Yes
  • Because often the OC pills mask the symptoms of POI
  • Hence the women may be having POI but did not know because of OC pills
  • Reveals itself when OC pills were stopped

• Q. Which are the symptoms of estrogen deficiency?

  • Vaginal dryness
  • Hot flushes

• Q. What about psychological health?

  • They have an effect on their emotional health also

• Q. True or false, most women with POI have normal pubertal development?

  • True
  • Except those with Turner syndrome

• Q. What to look for in physical examination?

  • Features of Turner’s
  • Ovarian enlargement suggestive of oophoritis
  • Ptosis- BPES syndrome
  • Goiter, Hyperpigmentation, vitiligo- autoimmune polyglandular syndrome

• Diagnosis of POI

• Q. What are typical biochemical features?

  • Elevated FSH
  • Low estradiol

• Q. When to measure FSH?

  • Menstruating women- day 3 of cycle
  • Women having Amenorrhea- anytime

• Q. What are typical TVS features in POI?

  • Enlarged cystic ovaries

• Q. What are the diagnostic criteria for POI?

• ESHRE criteria

  • Age <40 years
  • FSH >25 mIU/ml – measured on 2 occasions 4 weeks apart
  • Amenorrhea for >4 months

• Q. Is amenorrhea a prerequisite to the diagnosis of POI?

  • No
  • Occult POI may have a regular menstrual function
  • Diagnosis of POI does not require the presence of Amenorrhea

• Q. How is the diagnosis of occult POI made?

  • FSH is in the range of 10-15 pg/ml
  • AMH and antral follicular count on TVS can be used for the assessment of ovarian function

• Q. Can progesterone withdrawal bleeding help rule it out?

  • No
  • It is falsely reassuring
  • It is no substitute for good biochemical testing

• Q. What other tests are needed to rule out other causes?

  • HCG for pregnancy
  • Prolactin

• **Additional evaluation once the diagnosis is established **

• Q. What clues from history would you get for possible etiology?

  • Family history /personal history of autoimmune disease-  APS syndrome
  • Family history of POI- think of genetic syndromes
  • Family history of Mental retardation, POI, early menopause, parkinsonism, intention tremors- like fragile X premutation
  • History of radiation therapy, surgery, chemotherapy – ovarian damage

• Q. How common is adrenal insufficiency found in women with spontaneous POI?

  • In 3% of cases

• Q. Should adrenal antibodies be measured in all women with POI?

  • Ideally, you should
  • The test is 21 hydroxylase antibody
  • Similarly, a thyroid function test also must be done on them

• Q. Is ovarian biopsy recommended?

  • No

• Q. Should karotype be done in all women with POI ? Is there a specific age cut off for the same ?

  • Yes
  • It should be offered to all women with POI
  • Karotype abnormality are seen in 10-12 % of women with POI
  • No age cut off is determined since about 30% of women with POI having abnormal karotype were detected after the age of 30 years.

• Q. Why is important to look for Y chromosonal material in the karotype ?

  • This is because it increases the risk of gonadal neoplasia
  • If Y chromosome material is found - consider gondectomy

• Q. How to accurate assess for Y chromosomal material ?

  • By incorporating FISH or PCR along with the karotype in women with POI

• Q. Apart from katypotype what is the other method for diagnosis of Turner syndrome ?

  • Array CGH (Microarray-based Comparative Genomic Hybridization (aCGH))

• Q. What about the FMR1 gene, should it be checked in all women?

  • Yes
  • Genetic testing for FMR1 must be done in all women with POI

• Q. What about DEXA?

  • DEXA must be done in all women with POI at the time of diagnosis

• AUTOIMMUNE POI

• Q. Is an anti-ovarian antibody for diagnosis of autoimmune POI recommended ?

  • It has an unacceptably high false positive rate
  • Hence it is not generally done
  • 21-hydroxylase antibody may be done instead

• #Clinicalpearl

  • It is recommended to do 21 hydroxylase and anti adrenal antibody in all patients with POI
  • This will help diagnose autoimmune oophoritis also

• Q. What are the characteristic features of autoimmune oophritis?

  • Destruction of theca cells and not of granulosa cell
  • 21 hydroxylase antibody positive
  • Enlarged cystic ovaries on ultrasound

• Q. What is the difference in the biochemical signature of Autoimmune oophoritis vs. other POI?

  • Inhibin B is high in autoimmune. It is low in other cause of POI
  • LH is more elevated, and FSH is relatively less elevated, unlike in other causes of POI

• Q. What are the histological features?

  • Lymphocytes involving theca cells and antral follicles
  • Primordial follicles are spared

• Q. What is the test to label the patient with Autoimmune oophoritis?

  • For autoimmune oophoritis also 21 hydroxylase antibody is the test of choice
  • Anti ovarian are not validated
  • Anti – TPO are non specific

• Q. Should Thyroid function test be done in all patients with autoimmune oophoritis?

  • Yes

• Q. What is an experimental therapy for the treatment of autoimmune oophoritis?

  • Use of prednisolone in the dose of 20-40 mg for 1-6 months
  • This causes immunosuppression and may improve fertility
  • However, this is an experimental approach

• MANAGEMENT OF PREMATURE OVARIAN INSUFFICIENCY

• Q. Summarize the management aspect in POI?

  • Estrogen and progesterone replacement
  • Fertility issues
  • Bone issues
  • Risk of adrenal insufficiency

• Q. What are the consequences of estrogen deficiency in POI?

  • Vaginal dryness
  • Facial flushing
  • Diminished well being
  • Depression
  • Reduced cognition
  • Osteopenia/osteoporosis
  • Increase CV risk
  • Infertility

• Q. What is the first-line therapy for POI?

  • Estrogen replacement with progesterone (if the uterus is intact)

• Q. How long is it given?

  • Till natural age of menopause

• Q. What is the factor on which you will decide the dose of Estrogen?

  • Whether it is primary or secondary amenorrhea
  • For primary – start with a low dose to mimic normal puberty

• Q. What is the starting dose of Estrogen for these women?

  • Transdermal estrogen (Estraderm Mx)- 100 mcg daily
  • Oral 17 beta estradiol – Progynova- 2 mg
  • Congjugated equine estrogen- Premarin – 1.25 mg
  • Ethinyl estradiol- Lynoral- 10 mcg

• Q. Can Menopause hormonal therapy be given in women who are BRCA 1 or 2 positive ?

  • It can be given in those women not having a personal risk of breast cancer only after performing bilateral salphingo-ophrectomy

• Q. Which is the progesterone and the dose?

  • Medroxyprogesterone (Meprate) – 10 mg for 12 days of the cycle
  • This reduces endometrial hyperplasia and prevents endometrial cancer

• Q. Does micronized progesterone protect from Endometrial cancer ?

  • The benefits of protection from Endometrial carcinoma is maximum from OCP and less from micronized progesterone

• Q. What are the advantages of transdermal preparations ?

  • Reduces the first-pass metabolism so it allows for less dose
  • Reduces CV effects
  • Reduces procoagulant effect- less risk of thrombosis
  • Provides 17 beta-estradiol whic is more physiological
  • More steady estradiol level
  • Permits measurement of estradiol
  • Fewer GI effects on the gall bladder

• Q. Does this regime have a contraceptive effect

  • No !!
  • It is suboptimal for contraception
  • Hence an alternative contraceptive has to be used

• Q. Why are OC pills not used in place of the current Estrogen + progesterone?

  • Effect on the bone with OC pills is suboptimal

• Q. What are the risks of serious long-term effects in POI treated with HRT vis a vis postmenopause?

  • POI patients are at higher CV risk if not treated compared to postmenopausal women
  • They have low baseline CV risk and breast cancer risk  hence these side effects are not a problem. Treating them reduces CV risk than increasing it

• Q. We need androgens for these women?

  • Along with the reduction of Estrogen, they also have a decrease in ovarian androgens
  • Do we need to replace ovarian androgens to improve sexual function is debatable
  • However, currently, there is less evidence favoring the use of testosterone in these women
  • Remember, adrenals are normal, so the  issue of DHEA-S supplementation is not there
  • Those with adrenal insufficiency- DHEA may be given

• Q. How common is the presence of adrenal antibodies in these women, and what is the risk of adrenal insufficiency?

  • About 3% of them have 21 hydroxylase antibodies
  • 50% of patients with antibody-positive develop Adrenal insufficiency
  • Hence if antibodies are positive- check morning cortisol and ACTH

• Q. If antibodies are negative, is repeat testing required

  • Generally No
  • But the patient should be told about symptoms of AI

• Q. What is the best option for fertility in women with POI?

  • IVF with donor oocytes
  • Or Embryo donation

• Q. Is ovulation induction advised?

  • No

• Q. What are the chances of spontaneous ovulation?

  • <4%

• Q. Does giving Estrogen improve fertility outcomes?

  • Generally no, but some studies show favorable effect, especially with transdermal preps
  • Gonadotropin + Estrogen may be more effective. However, limited experience
  • No benefit of GnRH + Estrogen

• Q. What is the reason for poor ovulation in these women?

  • Inappopriate follicular leutinzation

• Q. Can Menopause hormonal therapy be given to women who have undergone oophorectomy for Endometriosis ?

  • Yes

• Q. Which is the best form of estrogen for women having migraine ?

  • Transdermal estorgen
  • Transdermal estrogen is also the preffered choice in women having hypertension
  • Also for patients with past history of Venous thromboembolism
  • Also for obese women !

• Q. Are Fibroids contraindication for Menopause hormonal therapy ?

  • No

• Q. Can OCP be used for pubertal induction ?

  • No
  • It is contraindicated !

• Q. Can follicular development still take place in patients with Primary ovarian insufficiency?

  • Yes
  • Intermittent follicular development can be seen in patients with POI

• Q. What is the importance of FSH in the follicular phase in women with infertility?

  • FSH 1 SD above mean in follicular phase even though the patient has regular cycles may indicate waning fertility
  • It is an early presentation of ovarian failure

• Q. What are the chances of fertility in such cases?

  • Chances of fertility are low despite having regular menstrual cycles of intermittent follicular development

• Q. What is Fragile X premutation, and what is its importance in POI?

  • Women having an increased number of CGG repeats in the FMR1 gene are at risk of POI
  • If there are 55-200 repeats, then the woman is said to have Fragile X premutation. They have the risk of POI and having a mentally retarded offspring
  • If there are more than 200 repeats – there are chances of complete Fragile X mental retardation syndrome

• Q. Why is it important to test for this mutation in women with POI?

  • If they use ART and conceive a child- there is the risk of mental retardation in the offspring
  • They are themselves at risk of developing ataxia dementia syndrome in old age
  • Other family members may be carrying a similar mutation, and hence testing may help in their genetic counseling as well

• Q. What is the need to do Karyotype in women with POI?

  • Women with POI with age <35 years maybe Mosaic Turner’s
  • Hence Karyotype must be done in such patients and screened for complications of Turner’s

• Q. What type of APS develop POI?

  • APS I and II

• Q. Should ovarian antibodies be tested in women with APS?

  • They are not required.
  • Ovarian antibodies are not specific for Autoimmune POI

• Q. What is the appearance of ovaries in Autoimmune ovarian failure?

  • They are cystic appearing or normal

• Q. Which part of the ovary is damaged first in autoimmune ovarian failure, and what is spared?

  • Theca cells are damaged first, and the granulosa cell layer is preserved

• Q. What are the chances of pregnancy with POI?

  • They are limited
  • These women may have spontaneous follicular development, but chances of pregnancy are minimal
  • Oocyte donation is the best option

• Q. Are glucocorticoids helpful in autoimmune ovarian failure?

  • They are anecdotal reports of its use

• Q. Is there any therapy which can increase the chances of spotenous ovulation ?

  • Some studies have shown that estrogen therapy can increases the chances of spotenous ovulation

    • Data for the same is mixed
    • It is generally beneficial in women with shorter duration of amenorrhea
    • Also transdermal and vaginal estorgen may be more beneficial
    • Some suggest suppressing FSH <15 may be helpful in this scenario

  • Exogenous gonadotropins have NOT found to be effective

    • Some studies have shown initial suppression with Ethinyl estradiol to FSH <15 then stimulation with HMG/rFSH has been found to improve fertility
    • GnRH agonist therpy - not effective
    • Glucocorticoid therapy - also unproven

  • Q. What is the role of oocyte donation ?

    • Oocyte donation is found to be effective in this scenario
    • this is the best option for these women

  • Q. Can a sister of the patient be a potential oocyte donor ?

    • The chances of failure are more with sister as a oocyte donor

  • Q. Are obstetric complications higher in women conceiving via an oocyte donation ?

    • Yes
    • More risk of Small for gestational age, PIH and Post partum hemorraghe

  • Q. How frequently is BMD-DEXA done in women with POI ?

    • At the time of diagnosis
    • Repeat every 5 years

#Updates

Date: Saturday, 3 April 2021

• Q. Is there any update on possibility of spontenous pregnancy in women in POI ?
  • A recent study has shown that injecting Platelet rich plasma along with recombinant FSH laparoscopically into the subcortical region of the ovary led to the resumption of menses in 11 out of 12 patients with Early menopause / [[Premature ovarian insufficiency (POI)]] ^[1]

#Updates

Date: Saturday, 4 April 2021

• Talk on Premature ovarian insufficiency (POI) by Dr. Om J Lakhani
  -

Please consider donating to "Notes in Endocrinology" to keep us going. Please visit our DONATION page to know more