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Case 2

Secondary Amenorrhea
A 28-year-old woman presents to her physician’s office with amenorrhea of 6 months’ duration.
Her medical history includes a spontaneous vaginal delivery 1 year ago. This delivery was
complicated by prolonged labor, fever, and postpartum bleeding, which necessitated a dilation and
curettage (D&C) and a blood transfusion. The patient nursed her infant for 4 months and stopped
because of lack of milk. She had two spontaneous light bleeds 6 weeks apart before becoming
amenorrheic. She states that she always had irregular cycles and actually took 1 year to become
pregnant. She has lost 50 lb. since her pregnancy.

What is the differential diagnosis of secondary amenorrhea in this patient?
Do the events before or after the pregnancy help to narrow the diagnosis?
This is a clinical picture of secondary amenorrhea with many possibilities included in the differential
diagnosis. With the history alone, the patient could be pregnant or the amenorrhea could be secondary to
hypothalamic, pituitary, ovarian, or endometrial dysfunction. Hypothalamic amenorrhea may occur due to
stress or the significant weight loss this patient has incurred since her delivery. The postpartum bleeding
and hypotension may have lead to Sheehan syndrome (pituitary necrosis due to hypotension), which can
often present as inability of the mother to breastfeed and is associated with hypoactive adrenal, thyroid,
and ovarian function. It is not clear if this patient had the bleeding and hypotension immediately after the
delivery, which is associated with the development of Sheehan syndrome, or at a later date. Pituitary
causes also include a pituitary adenoma. Ovarian causes include polycystic ovary syndrome, since this
patient reports irregular menses prior to establishing a pregnancy. Premature ovarian failure would be

unlikely but possible. Scarring in the uterine cavity, Asherman syndrome, can result from D&C in an
infected and postpartum uterine cavity, leading to lack of menstrual bleeding.

Physical examination shows no significant abnormalities. Breast examination is normal without
any galactorrhea. Pelvic examination shows a normal-sized, firm uterus with no apparent adnexal
masses. The result of a urine pregnancy test is negative.

What is the next step?
The next step would be to obtain blood tests to determine what is going on hormonally: folliclestimulating hormone (FSH), estradiol, TSH, prolactin, and human chorionic gonadotropin (hCG).
Although a negative urine pregnancy test suggests no pregnancy, a serum pregnancy test is more sensitive
and in this case should be obtained.

The results of the blood tests are as follows: FSH = 5.4 mIU/mL, estradiol = 42 pg/ml, TSH and
prolactin normal, and hCG less than 5.

What do these results indicate?
Why are the normal values of the pituitary target glands important?
The FSH value reported is in the normal range, and the estrogen level is in the low-normal range. These
values are consistent with either hypothalamic amenorrhea or eugonadotropic amenorrhea.

Hypergonadotropic causes are excluded by the normal FSH (i.e., premature ovarian failure). Normal
values for TSH and prolactin exclude thyroid disease and a prolactin-secreting microadenoma, which
leads to amenorrhea by suppression of FSH and luteinizing hormone (LH). Normal TSH and prolactin
make the diagnosis of Sheehan syndrome unlikely since pituitary function is intact (also the fact the
patient was able to breastfeed for a short time makes that diagnosis less likely as well). At this point the
patient could still have Asherman syndrome, polycystic ovary syndrome (PCOS), or hypothalamic

What is the next step to determine the correct diagnosis?
The next step is to exclude intrauterine adhesions from the differential since this is relatively easy to do.
Options include radiologic tests and functional tests. Radiologic tests to evaluate the uterine cavity for the
presence of intracavitary adhesions include hysterosalpingogram (HSG) and sonohysterogram. HSG
involves injecting radio-opaque dye through the cervical os into the uterine cavity and fallopian tubes
while performing radiography to capture the image on film. Any filling defects in the uterine cavity will be
highlighted by the dye. A sonohysterogram involves placing a catheter in the uterine cavity through which
sterile saline is injected while observing with ultrasound. Adhesions in the uterine cavity will be
highlighted by the saline. Another way to determine if there are adhesions in the uterus is to give estrogen
and progesterone to induce menstrual flow. If there is no bleeding, then adhesions or an outflow tract
obstruction is suggested.
Once an outflow tract abnormality is excluded, then hypothalamic amenorrhea must be
distinguished from PCOS for a number of reasons. If this patient has hypothalamic amenorrhea, then her

bones are at risk of developing osteopenia or osteoporosis due to the hypoestrogenic state. If the patient
has PCOS, then she is at risk of developing diabetes and insulin resistance.

HSG reveals a normal uterine cavity with no filling defects.

How can you distinguish between hypothalamic amenorrhea and PCOS?
PCOS and hypothalamic amenorrhea can have an FSH in the normal range. Usually the FSH is in the low
range (i.e., less than 3 mIU/mL) with hypothalamic amenorrhea, but not always. This can make it difficult
to distinguish between the two situations. In this case, since the patient had irregular menses prior to
getting pregnant, the same reason may cause her to have amenorrhea now, or it may be a new reason. The
easiest way to sort this out is to see if she has PCOS. That would involve looking for hyperandrogenic
symptoms or biochemical evidence of hyperandrogenemia and/or polycystic ovaries on ultrasound. Her
exam was unremarkable. Serum testosterone and free testosterone are both in the normal range, and her
ultrasound reveals normal ovaries that are not polycystic in appearance. Since PCOS is effectively
eliminated as a possibility, then the patient most likely has hypothalamic amenorrhea. Reasons for this are
weight loss and possibly stress. Her BMI should be assessed and she should be given dietary and
emotional counseling. If these are not successful in causing resumption of menses, then hormone
replacement with estrogen and progesterone should be initiated to prevent bone loss. It is important to
recognize that the current cause of her amenorrhea may not be the same as the cause of her irregular
menses prior to pregnancy.