Ovarian Insufficiency

1. What every clinician should know

Are you confident of diagnosis?

Ovarian insufficiency develops in women who most likely underwent normal puberty and had experienced regular periods before developing ovarian insufficiency. Women with this condition tend to stop having periods or skip periods for a few months.

Ovarian insufficiency indicates cessation of ovarian function prior to age 40. Women often present with characteristics of early menopause such as heat intolerance, flushes, night sweats, irritability, anxiety, palpitations, depression, sleep disturbance, decreased libido, hair coarseness, vaginal dryness, and fatigue. Although women with ovarian insufficiency greatly vary in their symptoms, about 75% of them present with some signs of estrogen deficiency on careful questioning.

Premature ovarian failure is accompanied by loss of oocytes, lack of folliculogenesis, loss of ovarian estrogen production, and infertility. Women who have experienced four months without regular menses and have had two FSH levels in menopausal range (thirty days apart) meet diagnostic criteria for ovarian insufficiency. Random serum AMH levels less than the lowest sensitivity of the assay, generally 0.1 ng/ml, are consistent with a perimenopause/menopause transition. An AMH <0.1 ng/ml accompanied by an elevated FSH >20 IU/ml is consistent with a perimenopause/menopause transition (Figure 1).

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Figure 1.

Distribution of AMH values within single-year age groups (27, 32, 35 and 40 year olds) demonstrates with advancing age increasingly skewed distributions of AMH values.

Who is at the risk of developing the disease?

Any women of reproductive age are at risk of experiencing ovarian insufficiency; however, women with a family history of ovarian insufficiency as well as women exposed to chemotherapy, radiation, smoking, environmental pollutants, and toxic agents have higher chances of ovarian insufficiency. Increasing age certainly contributes to diminished ovarian reserve, leading to ovarian insufficiency. Women with chromosomal abnormalities such as Turner’s syndrome and fragile X carriers (FMR1 carrier) are more prone to decreased ovarian reserve. Pelvic surgeries, especially those involving ovaries and/or fallopian tubes, appear to predispose women to some extent of decreased ovarian reserve, but further studies are needed. Tubal ligation is not found to decrease change in the ovarian reserve.

2. Diagnosis and differential diagnosis

  • Pregnancy

  • Iatrogenic causes (taking GnRH analogs, antiestrogens like tamoxifen, smoking, surgery, radiation, chemotherapy)

  • Hypothalamic pituitary diseases (microadenomas and macroadenomas of the pituitary, hyperprolactinemia, Kallman syndrome)

  • Hypothalamic amenorrhea (psychological or physiological stress, weight loss, fasting, systemic diseases (e.g., SLE), excessive exercise)

  • Polycystic ovaries

  • Enzymatic defects of steroidogenesis (e.g., 21-hydroxylase deficiency)

  • Endocrine disorders such as hypothyroidism, hyperthyroidism, hyperparathyroidism, Cushing’s syndrome

  • Asherman’s syndrome

  • Obstruction of uterine outflow tract

  • Gonadal dysgenesis (e.g., mosaic Turner’s syndrome, Swyer’s syndrome)

  • Autoimmune disease (e.g., celiac disease, adrenal failure, Hashimoto’s thyroiditis, hyperparathyroidism)

What is the cause of the disease?

Pathogenesis of ovarian insufficiency can be divided in two subcategories: accelerated follicle depletion and decreased steroid production.

Accelerated follicle depletion

Genetic factors

X-chromosome disorders

  • Fragile X syndrome carrier (FMR 1 carrier)

  • Turner syndrome

  • Other chromosome deletions/translocations/mosaicism

  • Gonadal dysgenesis

Somatic chromosomal defects

  • Galactosemia

  • Bone morphogenic protein 15 (BMP-15) mutation

  • Other rare chromosomal defects such as mutation in FOXL2 gene, mutation of NR5A1 (steroidogenic factor 1), FSH receptor mutation, etc.

Autoimmune factors

Research has shown that women with adrenal insufficiency also had ovarian insufficiency. Many women with type I and type II syndromes of polyglandular autoimmune failure are associated with autoantibodies to multiple endocrine and other organs.

Environmental factors

Cigarettes, phenylcyclidine (PCP), and dioxin exposure.

Toxic factors

Chemotherapy and radiation, and viruses such as mumps and CMV.

Physical and psychological stressors

Autoimmune diseases, excessive exercise, etc.

Decreased steroid production

Genetic disorders are main contributions in decreased steroid production. Three major mechanisms though which this is done are:

Defects in intraovarian modulators

Numerous substances have been identified as paracrine modulators of ovarian responsiveness and any abnormalities in production of these modulators have can significantly affect cellular response to gonadotrophins

Steroidogenic Enzyme Defects

Genetic defects in the enzymes involved in androstenedione and estradiol biosynthesis are commonly identified. Some of the reported enzyme defect mutations are Steroidogenic acute regulatory enzyme (StAR); and mutations in aromatase gene.

FSH and LH Receptor Mutations

Including the Gs alpha subunit gene mutation.

3. Management

Treatment options

Therapy for women with premature ovarian failure often starts with transdermal E2-17 beta 100 micrograms (Estrace, Alora, etc.), which results in estrogen levels compatible with a normal menstrual cycle. Oral estrogens in the forms of conjugated estrogen 0.625 mg to 1.25 mg (Premarin) or E2-17 beta 1-2 mg (Estrace) are good medical alternatives. When it comes to progesterone administration, stabilizing the endometrium is the main goal. This is often accomplished with micronized progesterone 100-200 mg (Microgest) or medroxyprogesterone acetate 5-10 mg (Provera), which can be given for 14 days every 30-60 days.

It is understood that the administration of progesterone less frequently than every three months may not protect against endometrial hyperplasia. Therefore, transvaginal ultrasound designed to determine thickness of the endometrium after withdrawal bleeding should be considered in cases where progesterone is administered less than once a month.

There is no medication regimen that has proven to be superior over another regimen. Oral contraceptives tend to provide higher levels of estrogen than required for women with ovarian insufficiency; however, this form of hormonal replacement may be easiest and is an emotionally acceptable form of hormone replacement in women younger than 40.

Hormone therapy alleviates symptoms of hot flushes, night sweats, dyspareunia, and accelerated bone loss. Nevertheless, there are no studies that document safety of estrogen use in women with premature ovarian failure. Also, the amount of estrogen used to manage menopausal symptoms in younger women is usually greater than the amount used in menopausal women. Hormone replacement therapy is strongly recommended as therapy for patients with premature ovarian failure, even though data from randomized controlled trials are lacking.

Due to significant hormone insufficiency, women with premature ovarian failure are at high risk of developing osteoporosis and therefore their dietary supplement should include 1200-1500 mg of calcium with addition of vitamin D (600 IU daily). Supplemental treatment with bisphosphonates (i.e., Alendronate, Etidronate, or selective estrogen receptor modulators [SERMs] such as raloxifene or tamoxifen) are options particularly for those who are unwilling to take estrogen replacement therapy and are at high risk of developing osteoporosis.

Treatment for ovarian insufficiency is also inextricably linked to healthy lifestyle habits. Therefore, patients should avoid smoking, alcohol, and drugs, as well as incorporate exercise, especially weight-bearing exercise, in their lifestyle.

There are numerous ongoing trials of the use of SERMs with ovarian insufficiency, and current recommendations state that SERMs have significant effects on bone health; however, they do not have any effects on other parts of early menopause. Women experiencing ovarian insufficiency are often going though great psychological distress. These women should be encouraged to identify sources of emotional support within their families, friends, or support groups.

4. Complications

Systemic implications and complications

There are no long-term studies to access the impact of ovarian insufficiency on mortality, but there are numerous studies concerning the impact of ovarian insufficiency on quality of life. Snowdon et al. summarized that women with premature ovarian failure before age 40 have an increase in significant morbidities. Young women exposed to hypoestrogenic state are at higher risk of not achieving and maintaining adequate bone density. These women are at significantly higher risk for osteoporosis and fractures later in life, such as vertebral and hip fractures. Due to low estrogen levels, many women with a hypoestrogen state are at higher risk for multiple cardiovascular diseases and adverse events such as stroke, premature myocardial infarction due to arteriosclerosis, etc. Premature ovarian failure often coexists with other endocrine and nonendocrine diseases, and careful examination of these coexisting conditions in necessary. Premature ovarian failure has significant psychological effects on women, with increased rates of depression. Atrophy of genitourinary tract (vagina and urethra).

5. Prognosis and outcome

Optimal therapeutic approach to the disease

Women with ovarian insufficiency usually visit a few physicians and undergo numerous tests before being diagnosed with this condition. The key in treatment is adequate diagnosis and follow-up care with a team composed of a reproductive endocrinologist, and support personnel such as a psychologist or a psychiatrist, nutritionist, and physical therapist or fitness trainers. Ovarian insufficiency occurs in approximately 1% of women.

The estimated incidence is:

  • by age 20: 1:10,000

  • by age 30: 1:1000

  • by age 35: 1:250

  • by age 40: 1:100

Patient management

Prompt diagnosis, counseling, and appropriate treatment can markedly improve a woman’s quality of life. Besides baseline hormone levels (FSH, AMH, TSH, cortisol), calcium, phosphate, CBC, ANA, FMR-1 testing, and karyotype to rule out genetic causes, patients should be scheduled for a DEXA scan to assess current bone density. Women with ovarian insufficiency tend to have more anxiety, depression, and psychological distress than do healthy women of their age. Thus, psychological evaluation plus support services (nutritionist, fitness instructor, physical therapist) in addition to appropriate medical therapy should be provided as discussed earlier.

Unusual clinical scenarios to consider

There are numerous cases of pregnancies reported in women with transient ovarian failure. In 10% of women, premature ovarian failure will spontaneously resolve for varying periods of time and the patients may conceive. Attempting to induce ovulation using clomid, letrozole, or gonadotropins is ineffective and a waste of resources.

6. What is the evidence for specific management and treatment recommendations

Nelson, LM. “Clinical practice. Primary ovarian insufficiency.”. N Engl J Med. vol. 360. 2009. pp. 606-14.

Ledger, W. “Clinical utility of measurement of anti-Mullerian hormone in reproductive endocrinology”. J Clin Endocrinol Metab. vol. 95. 2010. pp. 5144-54.

Seifer, DB, Baker, VL, Leader, B. “Age-specific serum anti-Mullerian hormone values for 17,120 women presenting to fertility centers within the United States”. Fertil Steril. vol. 95. 2011. pp. 747-50.

Bidet, M, Bachelot, A, Touraine, P. “Premature ovarian failure: predictability of intermittent ovarian function and response to ovulation induction agents”. Curr Opin Obstet Gynecol. vol. 20. 2008. pp. 416-20.

Goswami, D, Conway, GS. “Premature ovarian failure”. Hum Reprod Update. vol. 11. 2005. pp. 391-410.

Persani, L, Rossetti, R, Cacciatore, C. “Genes involved in human premature ovarian failure”. J Mol Endocrinol. vol. 45. 2010. pp. 257-79.

Coulam, CB, Adamson, SC, Annegers, JF. “Incidence of premature ovarian failure”. Obstet Gynecol. vol. 67. 1986. pp. 604

Speroff, L, Fritz, M. “Clinical gynecologic endocrinology and infertility.”. 2011.

Kelekci, S, Yilmaz, B, Yasar, L, Savan, K, Sonmez, S, Kart, C. “Ovarian reserve and ovarian stromal blood supply after tubal ligation by the pomeroy technique: comparison with controls”. Gynecol Endocrinol. vol. 20. 2005. pp. 279-83.

Gleicher, N, Weghofer, A, Barad, DH. “A pilot study of premature ovarian senescence. I. Correlation of triple CGG repeats on the FMR1 gene to ovarian reserve parameters FSH and anti-Müllerian hormone”. Fertil Steril. vol. 91. 2009. pp. 1700-6.

Rebar, RW. “Premature ovarian failure”. Obstet Gynecol. vol. 113. 2009. pp. 1355-63.

Nelson, SM, Anderson, RA, Broekmans, FJ, Raine-Fenning, N, Fleming, R, La Marca, A. “Anti-Mullerian hormone: clairvoyance or crystal clear?”. Hum Reprod. 2012 Jan 11..

Snowdon, DA, Kane, RL, Beeson, WL. “Is early natural menopause a biologic marker of health and aging?.”. Am J Public Health. vol. 79. 1989. pp. 709-714.

Visser, JA, Schipper, I, Laven, JS, Themmen, AP. “Anti-Mullerian hormone: an ovarian reserve marker in primary ovarian insufficiency”. Nat Rev Endocrinol .

Seifer, DB. “Strategic planning is long overdue and could mitigate long-term complications which result from delayed diagnosis of primary ovarian insufficiency”. Fertil Steril. vol. 95. 2011. pp. 1898