Michael Green, MD, MSc
1. Systematically evaluate a woman presenting with secondary amenorrhea
2. Appreciate that women with hypoestrogenic amenorrhea are at risk for osteoporosis
3. Know that women with hyperandrogenic anovulation (PCOS and other conditions) are at
risk for endometrial hyperplasia→ cancer due to unopposed estrogen
4. Perform, appreciate the limitations of, and interpret the progestin challenge test
A 19-year-old college student presents to your office with a history of amenorrhea for
five months. Prior to this, her periods were regular (30 day cycle), with neither
dysmenorrhea nor menorrhagia. She is G0P0 and had menarche at age 12. She is
sexually active in a monogamous heterosexual relationship, using a condom for
contraception. Of note, she swims for the varsity team and has been training for a
national tournament. In addition, she admits to feeling "stressed out" over her course
work and has lost 12 pounds over the last several months.
1. What additional information would you obtain on your initial history and physical?
Please explain the importance of each finding.
See table 2 in the American Family Physician article. Importantly, one should
distinguish between primary amenorrhea (absence of menarche by age 16 with
secondary sexual characteristics or by 14 in the absence of secondary sexual
characteristics), and secondary amenorrhea (absence of menses for three months with
previously normal cycles or nine months in woman with previous oligomenorrhea).
2. What is the most likely cause of her amenorrhea?
Overwhelmingly, the most likely cause is functional hypothalamic amenorrhea due to
vigorous exercise, weight loss, and psychological stress. All of these stressors, as well as
depression and anorexia nervosa, can disrupt the normal GnRH stimulation of the
pituitary, leading to decreased gonadotropin (FSH, LH) stimulation of ovarian estrogen
production and follicular maturation. Thus, these patients have hypoestrogenic
amenorrhea. (Patients with premature ovarian failure also have hypoestrogenic
amenorrhea. See bonus question for causes and evaluation of patients with estrogenic
Because this woman’s particular form of competitive athletics is swimming, we should
recognize that a subset of swimmers have a distinct amenorrhea syndrome that is
characterized by mild hyperandrogenism and normal estradiol levels (Constantini,
1995). Investigators believe that, unlike long distance runners and dancers, swimmers
do not need to be thin because swimming is not a weight bearing activity. They
recommend that the distinction can be made based on hormonal profiles, weight, and
somatotype. Women with this syndrome would then not be at risk for osteoporosis (see
question 5). With her weight loss and additional stressors, the swimmer in this case
probably has functional hypothalamic amenorrhea.
3. Despite your strong diagnostic suspicion, what minimum initial laboratory
evaluation would you order?
HCG, TSH, FSH, and prolactin. With few exceptions, pregnancy, thyroid disease,
premature ovarian failure, and hyperprolactinemia should be excluded in all cases of
amenorrhea. It is also important to recognize that hypothyroidism can cause pituitary
gland enlargement and hyperprolactinemia (because the lactrotroph cells cross respond
to TSH) and thus should not be confused with a lactotroph adenoma.
4. Her initial laboratory screen is unrevealing. Does she have estrogenic or
hypoestrogenic amenorrhea? How would you confirm her estrogen status?
Describe the progestin withdrawal test. Will this patient have withdrawal bleeding
As above, amenorrhea due to exercise, weight loss or psychological stress is
hypoestrogenic, due to inadequate gonadotrophic stimulation of the ovaries. Her
estrogen status can be confirmed by the progestin withdrawal test. The patient takes 10
mg of medroxyprogesterone acetate (Provera) p.o. for 10 consecutive days. Any uterine
bleeding within two to seven days of stopping the progesterone is considered a "positive
test," which establishes both adequate estrogen levels (to proliferate the endometrium)
and a competent uterus and outflow tract. In this woman with hypoestrogenic
amenorrhea, we would expect no withdrawal bleeding in response to a progestin
Of note, in addition to the ones in the AFP article, there are many different algorithms
recommended in the evaluation of amenorrhea. I am not aware of any studies comparing
their diagnostic accuracy, efficiency, or cost effectiveness. I think most physicians use
them as guides in concert with clinical judgment rather than as binding protocols. Also,
other authors discourage the use of the progestin and progesterone-estrogen (see below)
challenge tests, citing the chances of false positives (bleeding in patients with low
estrogen) and false negatives (no bleeding in patients with normal estrogen) (Practice
Committee 2006). They recommend relying strictly on “clinical characteristics and
clinical judgment” to differentiate, for example, between hypothalamic amenorrhea and
5. She experiences no menstrual bleeding in response to the progesterone challenge. Is
this consistent with your leading diagnosis? What other conditions result in this
response and how would you exclude them?
Her "negative" progestin challenge test most likely confirms her low estrogen state,
which is consistent with the diagnosis of functional hypothalamic amenorrhea, strongly
suggested by her history. Other causes of hypoestrogenic amenorrhea include
infiltrative, neoplastic, or ischemic diseases of the hypothalamus or pituitary and
premature gonadal failure (elevated FSH). Given her classic history, however, pursuit
of these diagnoses may not be necessary at this point, but we should remember that
functional hypothalamic amenorrhea is a diagnosis of exclusion. If this patient did not
give such a suggestive history or had CNS symptoms or signs, you would certainly obtain
an MRI of the brain.
Additionally, instead of inadequate estrogen stimulation of the endometrium, lack of
withdrawal bleeding may indicate a nonreactive endometrium or incompetent outflow
tract. This can be differentiated by a combined estrogen/progesterone challenge, which
corrects a possible estrogen deficiency. However, this step can be safely omitted in a
woman with a normal pelvic exam and no history of pelvic infection, trauma, or surgery.
On the other hand, if a woman does have a history of, for example, a D & C, and does
not have withdrawal bleeding after a combined estrogen/progestin challenge, a
hysterosalpingogram or hysteroscopy will probably reveal an anatomic abnormality or
6. Assured that she has a "benign condition," she is not concerned with the temporary
absence of her menstrual periods and does not want to get pregnant. Would you
acquiesce or insist on initiating treatment? For the latter, what intervention would
It is true that her condition is non-progressive and likely to resolve when her stessors are
removed. However, her low estrogen state will predispose her to accelerated
osteoporosis. Hormonal therapy, then, should be strongly recommended. The optimal
dosages of estrogen and progesterone have not been established, but there is concern
that the standard postmenopausal HRT regimen (0.625 mg conjugated estrogen plus
progestin) may not provide sufficient estrogen. Most authors recommend treating these
patients with low dose oral contraceptive agents (35 micrograms ethinyl estradiol and a
progestin to protect from unopposed estrogen). Calcium supplementation is also
recommended. Women with amenorrhea who want to get pregnant should be referred to
a reproductive endocrinologist.
7. Assume that your patient did experience withdrawal bleeding in response to the
progestin challenge. How would this change your differential diagnosis? What
further evaluation would you undertake?
Unless this was a false positive (a distinct possibility since it would be unexpected with
the history), this would indicate adequate estrogen levels in the setting of amenorrhea
due to chronic anovulation. Many of these women will have polycystic ovary syndrome,
which disrupts the pulsatile secretion of GnRH. The ovaries produce estrogen under FSH
stimulation, but, in the absence of the normal LH surge, they do not ovulate and progress
to the luteal phase. Thus, they never experience the progestin withdrawal that leads to
menses. These women remain at risk for endometrial hyperplasia due to the effect of
estrogen unopposed by progestin. The differential diagnosis of this type of amenorrhea
is listed in table 4 of the AFP article under hyperandrogenic anovulation in the
normogonadotropic amenorrhea category. You would certainly consider these
diagnoses sooner in the evaluation if the patient had hirsuitism, obesity, insulin
resistance, or acne. In patients with suspected PCOS, the question always arises
whether or not to evaluate for androgen producing tumors or adrenal hyperplasia.
There is no consensus on this, but I think it is reasonable to reserve this evaluation for
women who are virilized or have extremely high testosterone levels (> 200 ng/dl). Note
that virilization denotes more than just hirsuitism and acne. A truly virilized woman may
have a male somatotype, a male escutcheon (distribution of pubic hair), a deep voice, or
1. Master-Hunter T, Heiman DL. Amenorrhea: evaluation and treatment. American Family
1. Constantini NW, Warren MP. Menstrual dysfunction in swimmers: a distinct entity. J
Clin Endocrinol Metab. 1995;80(9):2740-2744.
2. Practice Committee of the American Society for Reproductive Medicine. Current
evaluation of amenorrhea. Fertility & Sterility. 2006;86(5 Suppl):S148-155.
Michael Green completed his residency and general medicine fellowship at Beth Israel
Hospital and the Harvard Medical School. His scholarly interests include graduate
medical education curriculum development and evaluation, evidence-based practice, and
life-long self-directed learning. Dr. Green practices general internal medicine and
accepts referrals for dyslipidemia and HIV-related lipodystrophy.