Ovarian failure (menopause) results when the ovary has no remaining eggs available for maturation. The fertility prognosis with ovarian failure is poor unless donor eggs are used. Consistently elevated FSH concentrations (usually greater than 25 IU/L and certainly greater than 40 IU/L) with a coincident low estradiol concentration (to rule out a FSH producing pituitary tumor) and secondary amenorrhea (lack of menstrual flow in a woman with previous menses) strongly suggest ovarian failure.

Menopause is the absence of menstruation due to the depletion of eggs capable of maturation. The average age of menopause in the USA is about 51-52 years old. Less than 1% of women have “menopause” when younger than 40 years old, so that when this occurs it is called “premature ovarian failure” or POF. There appear to be two main causes of this accelerated loss of eggs such that there is total depletion of maturation capable eggs at a very young age (POF). First, there may be a chromosomal abnormality in the X chromosome affecting the genes that regulate the rate of egg loss. Second, autoimmune disease (that produces antibodies that can attack and destroy the ovaries) is able to result in early ovarian failure.

If POF occurs prior to 30 years of age, there is a chance that the cause of ovarian failure is associated with an abnormal X chromosome that actually contains Y chromosome (male) material. It is very important to recognize when this is the case since the ovaries containing Y chromosome material have a high chance of malignant degeneration (about 25% develop highly malignant cancers such as gonadoblastomas, dysgerminomas, or yolk sac tumors). Therefore, any ovary with Y chromosome material should be removed as early as possible (many of the cancers develop at less than 20 years age) to avoid this life threatening complication. Of note is that many new Y chromosome probes are now available in certain research centers and new Y specific probes are constantly being developed. If available to the physician, special chromosomal analysis including the use of these new Y chromosome probes should be considered. It is not necessary to perform chromosomal analysis if POF developed after the age of 30 since cancer formation after this age is exceedingly rare.

It is expensive and not usually practical (at least in 2002) to distinguish which of the types of causes has resulted in a particular woman’s POF (if occurring after the age of 30). Many deletions or other genetic abnormalities in the X chromosome can result in POF. These can occasionally be found with standard or site directed chromosome analysis. The two clinical situations in which this testing appears to be most reasonable (in addition to those younger than 30) are when

• the woman with POF has a sister or daughter who might also possess the X chromosome abnormality and has not yet undergone POF. In this situation, if an abnormality in the X chromosome is identified in both the woman with POF and her sister (or daughter) then that female relative could consider childbearing at an earlier age since she may develop POF.
• the woman with POF is short in stature, usually less than 5 foot 3 inches. In a large series of patients with primary amenorrhea, it was demonstrated that all women with a major X chromosome abnormality were less than 63 inches tall (5 foot 3 inches) and up to one third of these had other major organ system abnormalities (mostly cardiovascular or renal). Therefore, if the woman with POF is short a chromosome analysis looking for major X deletions or mosaic cell lines should be considered. If identified, then autoimmune, cardiovascular and renal (kidney) evaluations are in order.

Coincident autoimmune disease appears to occur in many women with POF. More than 50% may have non-organspecific antibodies such as ANA and Rheumatoid factor. Possibly 30% will have an associated autoimmune disorder. Therefore, screening bloodwork for autoimmune disease should be considered, including

• a circulating TSH concentration and anti thyroid antibodies levels,
• an A.M. cortisol level, or the more demanding ACTH stimulation test, to assess adrenal reserve since there is a relatively high incidence of autoimmune adrenal insufficiency with autoimmune POF
• a complete blood count (CBC) and chemistry profile to look for autoimmune parathyroid disease (calcium and phosphorus concentrations) and hemolytic anemia (CBC).
• I do not currently (2002) recommend anti-ovarian antibody testing since the tests are expensive and it has been shown that up to 30% of normally ovulating women have the antiovarian antibodies.

In women with POF the likelihood of fertility is poor but not impossible. Some women will have an occasional spontaneous ovulation that might result in pregnancy. The incidence of this is not known or predictable, but there seems to be a less than 5% chance of spontaneous pregnancy.

• Pregnancy in women with POF has been associated with the use of estrogen hormone replacement medication. The mechanism underlying this association is not clear, with some postulating (based on theory rather than data) that the estrogen administered might enhance the number of FSH receptors on the follicles to make them more responsive to the circulating FSH.
• The use of corticosteroids to treat POF that has an autoimmune cause has not been uniformly successful and is not generally advised.
• The use of fertility medication has resulted in rare and unpredictable ovarian response and is usually discouraged. If the FSH concentration is less than the LH concentration and/or the estradiol concentration is greater than 40 pg/mL (the amount required for a withdrawal flow) then ovulation induction can be more reasonably considered.
• Hopefully, the ongoing research in this area will provide clinicians with more successful approaches to this difficult problem in the near future.

Uncommon forms of POF exist. The “resistant ovary syndrome” (where numerous early stage follicles can be found but do not respond to FSH) and some “steroid hormone enzyme deficiencies” (where the enzymes required for hormone production are decreased or absent) possibly present as amenorrhea after a few spontaneous menses at puberty.

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