Primary Ovarian Insufficiency

Primary ovarian insufficiency (POI) is a condition resulting from the depletion or dysfunction of the ovarian follicles, leading to cessation of ovulation and menses before age 40. Primary ovarian insufficiency is primarily idiopathic, but it can also be seen in association with chromosomal and genetic defects, including Turner syndrome (45,X karyotype) and FMR1 premutation. Patients present with signs and symptoms of menopause prior to age 40, including oligomenorrhea or amenorrhea, vaginal dryness (often leading to dyspareunia), and infertility. Key laboratory findings include elevated follicle-stimulating hormone (FSH) and low estrogen levels. Once the diagnosis of POI is made, the patient should be screened for autoimmune adrenal antibodies, and a karyotype, FMR1 premutation screen, and baseline DEXA scan should be obtained. Management includes hormone replacement therapy (HRT), addressing fertility concerns as desired, and psychological support.

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Definition and Epidemiology

Definition

Primary ovarian insufficiency is the depletion or dysfunction of ovarian follicles resulting in cessation of ovulation and menses. The disorder is accompanied by high levels of FSH prior to age 40.

Epidemiology

  • Incidence: 
    • 1:100 women by age 40 
    • 1:250 women by age 35
  • 90% of cases are idiopathic.
  • 10%–15% of women have an affected first-degree relative.
  • Associated conditions:
    • Autoimmune disorders:
      • Adrenal insufficiency/Addison’s disease
      • Hypothyroidism
      • Hypoparathyroidism
      • Rheumatoid arthritis
      • Systemic lupus erythematosus 
    • Chromosomal and genetic abnormalities:
      • Turner syndrome
      • Fragile X FMR1 premutation
    • Other conditions:
      • Myasthenia gravis
      • Dry-eye syndrome

Pathophysiology

Normal physiology of hypothalamic–pituitary–ovarian (HPO) axis

Hypothalamus:

  • Secretes gonadotropin-releasing hormone (GNRH) in pulsatile fashion
  • Affected by stress and undernutrition (eating disorders, overexercise)

Pituitary:

  • GNRH pulse stimulates pituitary to release gonadotropins:
    • FSH 
    • Luteinizing hormone (LH)
  • FSH stimulates:
    • Ovarian follicles and their oocytes to mature 
    • Developing follicles to secrete estrogen
  • LH stimulates:
    • Testosterone production (precursor to estrogen)
    • Ovulation with midcycle LH surge
  • Gonadotropins are inhibited by estrogen.

Ovary:

  • Stimulated by FSH and LH to produce sex steroids
  • Estrogen stimulates: 
    • Endometrial proliferation
    • Vaginal lubrication
    • Bone growth
  • Progesterone: 
    • Maturation of endometrium
    • Prevents endometrial hyperplasia
    • Cessation of progesterone production triggers withdrawal bleeding (menses).

Clinical importance of functioning HPO axis in younger women:

  • Fertility
  • Sexual function
  • Prevention of osteoporosis
  • ↓ Risk cardiovascular disease

Pathophysiology of POI

  • POI occurs when:
    • Number of viable remaining oocytes ↓ severely 
    • Other ovarian dysfunction → lack of regular ovulation
  • ↓ Ovulation → ↓ fertility 
  • ↓ Ovarian estrogen and progesterone:
    • No endometrial stimulation → no menses
    • Menopausal symptoms:
      • Vasomotor symptoms: hot flushes, night sweats
      • Sleep disturbance
      • Vaginal dryness and dyspareunia
      • Mood disturbances
    • ↓ Estrogen → ↓ inhibition of pituitary → FSH

Etiology

Primary ovarian insufficiency can be caused by chromosomal and genetic defects, an autoimmune process, or ovarian toxins; however, in the vast majority of cases, a clear cause is never identified.

Genetic and chromosomal causes

  • Turner syndrome: 
    • Lack of 2nd X chromosome (45,X karyotype), important for gonadal development
    • Accelerated oocyte atresia due to abnormal germ cells
    • Variable presentation due to mosaicism
  • FMR1 gene premutations:
    • Gene that causes fragile X syndrome (FXS)
    • Premutations: 55–200 CGG repeats
    • The mechanism of associated POI is unknown.
  • Other genetic disorders:
    • 46,XX gonadal dysgenesis
    • Translocations or deletions involving X chromosome
    • FSH or LH receptor mutations (e.g., Savage syndrome)
    • Galactosemia

Autoimmune causes

  • Autoimmune oophoritis:
    • Lymphocytic infiltration of theca cells → inflammation → follicular dysfunction
    • Primordial follicles are not affected.
    • Almost always associated with adrenal antibodies → adrenal insufficiency
  • Polyglandular autoimmune failure (types I and II): syndromes associated with autoantibodies to multiple endocrine and other organs

Ovarian toxins

  • Chemotherapy
  • Radiation
  • Environmental toxins

Clinical Presentation

The primary presenting complaints are usually oligomenorrhea or amenorrhea (either primary or secondary). Pregnancy always needs to be excluded first, even in patients who deny sexual intercourse.

  • Menstrual cycle abnormalities:
    • Primary amenorrhea: Patient has never had a menstrual cycle.
    • Secondary amenorrhea: 
      • No menses for 3 months with a history of previously regular cycles
      • No menses for 6 months with a history of previously irregular cycles
      • No menses for 3 of patient’s typical cycle lengths
    • Oligomenorrhea: ↓ frequency of menstruation (cycles > 35 days)
  • Signs and symptoms of estrogen deficiency:
    • Vasomotor symptoms: 
      • Hot flushes
      • Night sweats
    • Sleep disturbances
    • Vaginal dryness (atrophy) → painful intercourse (dyspareunia)
    • Mood disturbances (especially irritability)
  • Infertility
  • Symptoms of associated conditions:
    • Signs of Turner syndrome:
      • Short stature
      • Shield chest with widely spaced nipples
      • Low posterior hairline
    • Signs and symptoms of thyroid disease:
      • Enlarged thyroid
      • Changes in bowel habits (constipation/diarrhea)
    • Signs of adrenal insufficiency:
      • Hypotension
      • Vitiligo
      • Loss of pubic and axillary hair
Symptoms of menopause

Symptoms of menopause that can also be seen in POI

Image: “Symptoms of menopause” by Mikael Häggström. License: CC0

Diagnosis

Diagnostic criteria (requires all 3)

  • < 40 years of age
  • Oligomenorrhea or amenorrhea for at least 4 months 
  • ↑ FSH 
    • Requires 2 ↑ levels > 1 month apart
    • Should be drawn on cycle day 3 if menstruating

Initial laboratory and imaging evaluation

  • Hormone levels:
    • FSH
    • ↓ Estradiol
    • ↓ Anti-Müllerian hormone (AMH): ovarian reserve test
  • Exclude other causes of menstrual irregularity:
    • Pregnancy test
    • Thyroid-stimulating hormone
    • Prolactin
  • Pelvic ultrasound:
    • Assess number of follicles present.
    • Look for signs that may suggest other causes of menstrual abnormalities (e.g., polycystic-appearing ovaries, Müllerian anomalies).
Normal histo vs cell tumor of the ovary

Images demonstrating the differences between a normal ovarian biopsy on the left, with a normal number of follicles, and an ovarian biopsy from a patient with POI on the right, showing a significantly decreased number of ovarian follicles and oocytes.
Note that ovarian biopsies are typically not obtained for diagnostic purposes.

Left image: “Granulosa Cell Tumor of the Ovary” by Ed Uthman. License: CC BY 2.0
Right image: “Histological analysis” by Department of Neuroscience and Biomedical Technologies, University of Milan-Bicocca, via Cadore 48, 20052, Monza, Italy. License: CC BY 2.0, cropped by Lecturio.

Follow-up testing once POI diagnosed

  • Karyotype: look for Turner syndrome
  • FMR1 premutation screen
  • Anti-adrenal antibodies (21-hydroxylase antibodies): Look for adrenal insufficiency.
  • DEXA scan: Evaluate baseline bone density.

Management and Complications

Hormone replacement therapy

Hormone replacement therapy (HRT) is required to prevent osteoporosis and cardiovascular disease. Regimens should include both estrogen and progestins.

  • Physiologic hormone replacement mimicking natural cycle: 
    • Estradiol:
      • Given continuously
      • Transdermal lower risk than oral
    • Progestins:
      • Given cyclically (e.g., 2 weeks on, 2 weeks off)
      • Micronized progesterone (physiologic)
      • Medroxyprogesterone acetate (synthetic)
  • If patient desires contraception: combined oral contraceptive pills (OCPs)

Other management issues and potential complications

  • Fertility assistance (if desired) 
  • Counseling/emotional support
  • Screen for and treat complications:
    • Adrenal insufficiency
    • Autoimmune hypothyroidism
    • Osteoporosis
    • Cardiovascular disease

Differential Diagnosis

  • Polycystic ovarian syndrome (PCOS): syndrome of chronic anovulation that presents with irregular and infrequent menstrual cycles and signs of hyperandrogenism. Associated with metabolic syndrome, especially insulin resistance. Patients are commonly obese. Patients usually have elevated LH and androgen levels with a normal FSH. Ultrasound may demonstrate polycystic-appearing ovaries. Management is usually by prescribing OCPs and addressing fertility concerns.
  • Functional hypothalamic amenorrhea: condition of hypothalamic hypogonadism resulting from inhibition of entire HPO axis. Usually caused by stress or undernutrition (e.g., eating disorders, overexercise). Cases may present similarly to POI, though in functional hypothalamic amenorrhea, FSH is low, while in POI it is elevated. Management involves treating underlying issue, usually with psychotherapy and/or improved nutrition and exercise habits.
  • Ovarian cancer: may cause disruption to normal ovarian function, leading to amenorrhea. Sex-cord stromal tumors may secrete estrogen or androgens, disrupting ovulation. Diagnosis made with pelvic ultrasound; initial management is usually surgical. Resumption of ovulation may be possible following treatment if viable follicles remain.
  • Adrenal insufficiency/Addison’s disease: loss of adrenal function, resulting in decreased production of mineralocorticoid, glucocorticoid, and sex steroids, particularly androgens. Patients often present in shock owing to salt wasting and hypotension. Amenorrhea occurs in approximately 25% of women; these women may lack pubic and axillary hair owing to low adrenal androgen production. Management is complex, but involves steroids and managing fluid and electrolytes.
  • Hypothyroidism: thyroid hormone deficiency. Hypothyroidism may result in either oligomenorrhea or amenorrhea and may negatively impact fertility. These effects are likely due to structural similarities between thyroid-stimulating hormone, FSH, and LH, as well as to associated decreases in sex hormone–binding globulin (SHBG). Other symptoms include thinning of hair, dry skin, brittle nails, periorbital edema, constipation, and fatigue. Thyroid-stimulating hormone is increased owing to low thyroxine. Treatment is with levothyroxine. 
  • Hyperprolactinemia: condition in which elevated prolactin levels inhibit the GNRH pulse, which then decreases FSH, suppressing follicular development. In addition to menstrual abnormalities, patients may present with nipple discharge or galactorrhea. Common causes include medications that increase prolactin and pituitary adenomas. Treatment for these adenomas is with dopamine agonists, which decrease prolactin.

References

  1. Welt, C. K. (2020). Clinical manifestations and diagnosis of spontaneous primary ovarian insufficiency (premature ovarian failure). In Martin, K. A. (Ed.), UpToDate. Retrieved February 3, 2021 from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-spontaneous-primary-ovarian-insufficiency-premature-ovarian-failure 
  2. Welt, C. K. (2020). Pathogenesis and causes of spontaneous primary ovarian insufficiency (premature ovarian failure). In Martin, K. A. (Ed.), UpToDate. Retrieved February 3, 2021 from https://www.uptodate.com/contents/pathogenesis-and-causes-of-spontaneous-primary-ovarian-insufficiency-premature-ovarian-failure 
  3. Welt, C. K. (2020). Management of spontaneous primary ovarian insufficiency (premature ovarian failure). In Martin, K. A. (Ed.), UpToDate. Retrieved February 3, 2021 from https://www.uptodate.com/contents/management-of-spontaneous-primary-ovarian-insufficiency-premature-ovarian-failure
  4. Pellegrini, V.A. (2016). Ovarian insufficiency. In Lucidi, R.S. (Ed.) Medscape. Retrieved February 4, 2021 from https://emedicine.medscape.com/article/271046-overview

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