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  » Infertility  »  Amenorrhea

Primary Amenorrhea

Is the absence of menses by the age of 16 (no menarche). 

Secondary Amenorrhea

Lack of menstrual periods in a woman that has had periods previously

Background

Primary amenorrhea is when the woman has never had a period in her life. This page will not discuss primary amenorrhea, which is rare. The causes of primary amenorrhea are also quite different from secondary amenorrhea.

Secondary amenorrhea is the absence of menstrual periods for 6 months in a woman who had previously been regular, or for 12 months in a woman who had irregular periods.

This problem is seen in about 1% of women of reproductive age.

The most common cause of secondary amenorrhea in reproductive age women is pregnancy and physical exam and laboratory testing for the pregnancy hormone - HCG, should always exclude this.

History

A good history can reveal the etiologic diagnosis in up to 85% of cases of amenorrhea.

A detailed menstrual history should be taken.

Any history of galactorrhea (milky discharge from the breasts) is important and indicates the need for a prolactin hormone level to rule out hyperprolactinemia.

A woman who has had hot flashes, breast atrophy and decreased libido along with her amenorrhea may have premature ovarian failure.

Certain medications such as phenothiazines (used for psychiatric disorders) and some narcotics can cause amenorrhea, usually in association with an elevated prolactin and galactorrhea.

A large amount of weight loss or gain can also lead to anovulation - as can stress or extensive exercise.

Anorexia nervosa is often accompanied by secondary amenorrhea.

Both Cushing's disease (over activity of adrenal glands) and hypothyroidism (under-functioning thyroid gland) can cause amenorrhea.

If the patient has a history of severe postpartum hemorrhage (very heavy bleeding after a delivery), she may have pituitary insufficiency from infarction (Sheehan's syndrome).

When amenorrhea follows a D&C (dilation and curettage) one should suspect intrauterine adhesions (Asherman's syndrome), particularly if the procedure was pregnancy related.

Asherman's can also occasionally be seen following other types of uterine surgery such as metroplasty, myomectomy or cesarean section.

Amenorrhea following cervical conization can be due to procedure related cervical stenosis.
Following discontinuation of oral contraception, some women will not have periods for up to several months. However, the reported incidence for amenorrhea lasting more than 6 months after the pill is stopped is 0.8%, which is essentially the same as the incidence of amenorrhea in the general population. Therefore, amenorrhea of greater than 6 months duration after oral contraceptive use is not related to the pill use.

Physical examination (what the OB/GYN doctor will look for on the exam)

Signs of androgen excess such as hirsutism (excess hair growth) and clitoromegaly (enlargement of the clitoris).

The breast exam may reveal galactorrhea.

Estrogen deficiency may be suggested on pelvic exam by a smooth vagina that lacks the normal rugae (wrinkles) and a dry endocervix with no mucous.

Workup after history and physical (what the doctor will do next)

If the history and physical exam are suggestive of a certain etiology then the initial laboratory or radiographic workup can be tailored appropriately.

For example, a 32-year-old woman who has previously had regular menses presents with 10 months of amenorrhea following curettage for heavy bleeding associated with an incomplete abortion. She has no signs or symptoms that suggest ovarian failure or thyroid disease. There is no galactorrhea and she uses no medications or street drugs. She most likely has intrauterine adhesions causing her amenorrhea. A reasonable approach to this patient would be an HCG level to rule out pregnancy, an FSH level to demonstrate the presence or absence of ovarian function, and then a hysterosalpingogram or hysteroscopy if these first 2 tests are normal. One could also do the entire diagnostic workup as recommended for patients without any etiology apparent. However, for the sake of efficiency and cost-effectiveness, the workup can sometimes be more directed.

Some patients will not demonstrate any obvious etiology for their amenorrhea on history and physical exam. These patients can be worked up in a logical manner using a stepwise approach. Diagnostic approaches may vary, however, differences between them pertain mainly to the order in which tests are performed.

There are several ways that a workup for secondary amenorrhea can be approached. One reasonable diagnostic approach is described here. If your doctor did things differently, that doesn't mean that he or she was wrong or that this approach is wrong. Every case should be treated individually.

In the approach described here, the first tests to perform after pregnancy is ruled out are a progesterone withdrawal test as well as a TSH (thyroid stimulating hormone) and prolactin level.

Thyroid function

Both hypothyroidism and hyperprolactinemia can cause primary or secondary amenorrhea. If these entities are discovered, appropriate therapy should result in resumption of regular menstrual periods.

Progestational challenge (progesterone withdrawal test)

The progestational challenge test is performed by giving oral medroxyprogesterone acetate 10 mg daily for 7-10 days or progesterone in oil 100-200 mg intramuscularly. A positive response is any bleeding more than light spotting that occurs within 2 weeks after the progestin is given. This bleeding will usually occur 2-7 days after the progestin is finished. Withdrawal bleeding will usually be seen if the patient's estradiol level is 40 pg/ml or more.

If the patient experiences bleeding after the progestin she has estrogen present but is not ovulating. If no withdrawal bleeding occurs, either the patient has very low estrogen levels or there is a problem with the outflow tract such as uterine synechiae (adhesions) or cervical stenosis (scarring).

Women with withdrawal bleeding

We will first consider the diagnostic evaluation of the woman with withdrawal bleeding and normal prolactin and TSH levels. The basic diagnosis at this point is anovulation for which there are many causes. If there is a history of recent stress, weight loss, medications or street drugs, these factors could be causing the amenorrhea.

Some experts believe that an LH and FSH level may be helpful at this point. If the LH is high (above about 10 MIU/ml) and the LH/FSH ratio is above 2:1, this supports the clinical diagnosis of polycystic ovarian disease (PCO).

However, many patients with PCO do not demonstrate this high LH/FSH ratio. Testosterone and DHEAS levels may be useful in women with PCO, especially in the presence of hirsutism or other signs of hyperandrogenism (excess male hormones).

Chronic anovulation should be managed by periodic progestin withdrawal, or oral contraceptive pills if the patient does not desire pregnancy at this time.

If she desires pregnancy, induction of ovulation with clomiphene citrate or injectable gonadotropins can be discussed.

If the anovulatory state has been longstanding, one should consider endometrial biopsy to rule out significant hyperplasia or carcinoma of the endometrium.

Women without withdrawal bleeding

We will now consider the evaluation of patients who do not have withdrawal bleeding after the progestin challenge. These patients have either a hypoestrogenic state or a compromised outflow tract.

There are 2 ways to approach the next step.

1. One way is to give estrogen to ensure endometrial proliferation, followed by a progestin to induce withdrawal. A course of 2.5 mg of Premarin for 21 days including 10 mg of Provera on days 17-21 will be adequate.

If bleeding occurs, her amenorrhea is due to hypoestrogenism.

If bleeding does not occur, then the patient most likely has outflow tract obstruction - either Asherman's syndrome or cervical stenosis.

2. The other approach is to perform an FSH level. If the level is high (above 30-40 MIU/ml), the woman has premature ovarian failure (see below) and does not need the estrogen and progestin challenge. If the FSH is normal, it is still a good idea to proceed with the course of estrogen and progestin as described above.

The next step in the women that do not bleed after the combined hormonal regimen is either hysterosalpingography or hysteroscopy . If adhe sions are found, they should be hysteroscopically lysed if the patient is desirous of pregnancy or menses.

Intrauterine adhesions are rare in the absence of a history of pelvic infection or curettage. Therefore, if the pelvic exam is normal and the history is not consistent with development of adhesions, consideration can be given to skipping the estrogen-progestin step.

FSH testing

If the patient did bleed after the combined hormonal regimen (or if that step was skipped) the next test to obtain is an FSH level. This should not be drawn for at least 2 weeks after the estrogen-progestin regimen is completed so that the level is not affected by the exogenous estrogen.

If the FSH is greater than 30-40 MIU/ml, the patient almost certainly has ovarian failure. Midcycle FSH peak levels in ovulatory cycles should not be this high. FSH levels that are in the menopausal range should be checked at least once again in about 4 weeks. An estradiol level can be checked as well for further confirmation. With ovarian failure, the estrogen level will be low (usually less than 20-30 pg/ml).

Ovarian failure (premature menopause)

Once ovarian failure is confirmed consideration should be given to 2 special etiologic situations.

If the woman is under 30, a karyotype should be performed to rule out any mosaicism involving a Y chromosome. This is important because of the high risk (about 25%) for a gonadal malignancy developing if there is any testicular tissue present. If a Y chromosome is found the gonads should be surgically excised. These tumors apparently do not appear after age 30 so that karyotypic analysis is then no longer necessary. Other chromosomal anomalies will occasionally be found. These are usually either 45X (Turner's syndrome) or some variation of Turner's mosaic.

The other special category of premature ovarian failure is that associated with autoimmune disease. These patients have autoimmune related dysfunction of other endocrine organs. The most common association is with thyroid disease, but the parathyroids and adrenals can also be affected. Therefore, it is prudent to screen for these conditions. Thyroid function tests and thyroid antibody levels should be obtained. A morning cortisol level or a corticotropin (ACTH) stimulation test assesses adrenal reserve. Serum calcium, phosphate and protein levels are ordered to evaluate possible hypoparathyroidism. A CBC with differential, sedimentation rate, anti-nuclear antibody and rheumatoid factor may be useful in further assessing any possible autoimmune dysfunction.

Laboratory evidence of autoimmune phenomenon is much more prevalent than clinically significant disease. Several studies have shown laboratory evidence of immune problems in about 15-40% of women with premature ovarian failure. Thyroid and Lupus-related antibodies are most commonly found.

It is presently unknown as to what the incidence of clinically apparent autoimmune disease will be in these patients when followed over time. Women with well documented premature ovarian failure should be placed on estrogen/progestin replacement therapy if there are no contraindications. This will provide some protection against osteoporosis and cardiovascular disease by eliminating the severely hypoestrogenic state associated with menopause.

Regardless of the etiology, there currently is no effective treatment that will be likely to result in a pregnancy (with her own eggs) for premature ovarian failure. However, some women will spontaneously ovulate on occasion and pregnancy can occur although it is unusual. Those pregnancies that do occur are almost always in women on estrogen replacement therapy. These women should be educated about this possibility.

Egg donation with in vitro fertilization (I VF) can be a very effective therapy for women with premature ovarian failure that desire pregnancy.

In general, ovarian biopsy is not indicated in patients with premature ovarian failure since no clinically useful information will be obtained.

Hypothalamic-pituitary failure

Patients who do not bleed after the progestin challenge but do after estrogen/progestin and have normal or low FSH and LH levels make up the final group of patients to be discussed. These patients have hypothalamic-pituitary failure. Some medications (e.g. phenothiazines) as well as extremes of weight loss, stress or exercise can cause this type of secondary amenorrhea. A pituitary or hypothalamic tumor would be a rare finding in these patients who were all screened with prolactin levels at the beginning of the diagnostic evaluation. However, if there is no cause apparent from the history, it would be prudent to obtain a baseline CT (or MRI) evaluation of the sellar region to rule out a space occupying lesion.

Patients with normal prolactin levels and normal imaging studies have hypothalamic amenorrhea of uncertain etiology. If the amenorrhea and lack of withdrawal bleeding persists, prolactin levels should be measured annually since a small microadenoma could be present that is escaping laboratory and radiographic detection.

Weight loss as a result of anorexia nervosa is an important diagnosis to make because of the mortality rate of 5-15%. Psychiatric counseling is indicated in most, if not all cases.

In this condition, as well as in the other hypothalamic amenorrhea situations, the patients can be significantly hypoestrogenic (a low estrogen situation similar to menopause). If the state is persistent, hormone replacement therapy should be considered for protection against osteoporosis. One approach is to get an estradiol level and if it is less than 30 pg/ml, counsel the patient that hormonal replacement therapy is indicated.

Secondary amenorrhea is a symptom that can be caused by many pathological states. The diagnostic evaluation should lead to the correct diagnosis without undue delay if the problem is attacked logically in a stepwise manner.

References

Speroff L, Glass R, Kase N: Clinical Gynecologic Endocrinology and Infertility, 5th ed. Baltimore , Williams and Wilkins, 1994.

Mishell RM, Davajan V, Lobo RA (eds): Infertility Contraception and Reproductive endocrinology, 3rd ed. Boston , Blackwell Scientific Publications, 1991.

American College of Obstetrics and Gynecologists: Amenorrhea (ACOG Technical Bulletin 128). Washington DC , ACOG, 1989.