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Secondary amenorrhea: Diagnostic approach and treatment considerations

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Secondary amenorrhea:
Diagnostic approach and
treatment considerations
By Katherine Pereira, DNP, FNP-BC, FAAN, FAANP and Ann J. Brown, MD, MHS

Abstract: Disruptions in the menstrual cycle he menstrual cycle is an important indicator of

are a common complaint in primary care and
women’s health. Irregular or absent menstrual
T health, and disruptions are a common complaint
seen by both primary care and women’s healthcare
providers. This article discusses secondary amenorrhea (or lack
periods should trigger an evaluation to of menstruation) in a woman who previously had menstrual
periods and provides a systematic approach to its diagnostic
identify the root cause. This article discusses evaluation, with guidance about when to refer to a specialist.
secondary amenorrhea and provides a
■ Causes of secondary amenorrhea
systematic approach to its diagnostic
Amenorrhea is classified as either primary or secondary.
evaluation, with referral considerations. Primary amenorrhea is the lack of menstruation by age 16
in the setting of normal development of secondary sexual
characteristics. Secondary amenorrhea is the absence of
menstruation for 3 consecutive months after menarche or
in a woman who has had a normal menstrual cycle.1 In
Keywords: amenorrhea, Asherman syndrome, Cushing syndrome, endocrinology, functional hypothalamic amenorrhea, gynecology,
menstrual cycle, polycystic ovary syndrome, secondary amenorrhea, women’s health

34 The Nurse Practitioner • Vol. 42, No. 9 www.tnpj.com

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 Secondary amenorrhea: Diagnostic approach and treatment considerations

women of childbearing age, the most common causes of

absent menstrual periods are pregnancy and lactation.2 Medications associated with amenorrhea2-5,27,35-38
In deciphering the causes of pathologic amenorrhea, it
Medication Comments
is helpful to consider the key structures required for normal
menstruation and the part they may play in the problem. Cimetidine Increase serum prolactin
Metoclopramide concentrations through
These include the hypothalamus, pituitary gland, ovaries, Methyldopa dopamine receptor
and uterus. Reserpine antagonist activity
Risperidone
Molindone
Hypothalamus
Olanzapine
The hypothalamus is responsible for producing a “Morse Clomipramine
code” of gonadotropin-releasing hormone (GnRH) pulses, Desipramine
the pattern of which is critical for appropriate signaling to Phenothiazines
the pituitary to secrete luteinizing hormone (LH) and fol- Danazol Reduce both LH and FSH
licle-stimulating hormone (FSH). Changes in GnRH signal- GnRH agonists secretion
(goserelin, leuprolide)
ing from the hypothalamus to the pituitary can disrupt this
Corticosteroids Prolonged therapy can induce
communication and cause low gonadotropin (LH and FSH)
Cushing syndrome and
secretion and secondary amenorrhea. suppression of hypothalamic-
A common condition that results from disruption in this pituitary-ovarian axis
process is functional hypothalamic amenorrhea (FHA), which Valproic acid May increase ovarian
accounts for approximately 35% of all pathologic secondary testosterone production and
amenorrhea.3 FHA is caused by stress from events such as induce insulin resistance

severe restrictive dieting, poor nutritional status, extreme psy-
chological stress, or excessive exercise.3 Recently, genetic muta-
tions have been associated with FHA, which may explain the
variation in susceptibility to this condition in some women.3
Amenorrhea is typically prolonged, lasting at least 6 months.4
Because women with FHA are in a hypoestrogenic state,
there are concerns about bone health. This is referred to as
the “female athlete triad,” which includes menstrual dys-
function (amenorrhea most commonly seen), energy avail-
ability (ranging from optimal to low energy, with or with-
out disordered eating or inadequate calories), and decreased
bone density.4 Return to normal weight and energy balance
is required to restore menstrual cycles back to normal, with
referral to a mental health and/or nutrition specialist to
assist with this process.5
Less commonly, infiltrative diseases of the hypothala-
mus, such as lymphoma, sarcoidosis, or Langerhans cell
histiocytosis, can interfere with hypothalamic function.
Here, too, the altered GnRH secretion results in amenorrhea.
These women usually present with additional symptoms of
headache or neurologic changes.6
Pituitary gland
The pituitary gland responds to GnRH signaling to produce
LH and FSH (also in a pulsatile fashion). There are several
conditions that affect the pituitary gland and interfere with
appropriate gonadotropin production. A common condition
is hyperprolactinemia, and modest elevations in prolactin
levels can be caused by medications (see Medications associ-
ated with amenorrhea).
Chronic opioid use Suppresses release of GnRH
in hypothalamus and may
increase prolactin secretion
Verapamil Causes elevation of prolactin
through inhibition of central
dopamine production
A detailed medication history is important to identify
the connection between medication changes and onset of
change in the menstrual pattern. Nipple stimulation (suck-
ling) or chest wall injury can also mildly elevate prolactin
levels (typically no more than 10 ng/dL above normal), but
even a small change in prolactin may be sufficient to change
the menstrual pattern.7 Elevated prolactin levels should also
prompt a check of thyroid function because hypothyroidism
can cause hyperprolactinemia.8
Modest elevations in prolactin can also be caused by a
lesion in or near the pituitary gland that compresses the
pituitary stalk. An intact stalk is necessary for transmitting
inhibitory signals to the prolactin-secreting cells to prevent
secretion. When normal “tonic” inhibition is lifted by stalk
compression, the pituitary gland produces more prolactin.
A common cause of stalk compression is a pituitary adeno-
ma. Any structural lesion in or near the pituitary gland can
cause a modest elevation in prolactin. When prolactin levels
are elevated (2 to 10 times normal), this usually indicates a
prolactin-lactotroph-secreting pituitary adenoma.9
Pituitary infarction can cause amenorrhea, and Sheehan
syndrome is a result of pituitary infarction following post-
partum hemorrhage or severe hypotension. Gland infarction
results in partial or total loss of hormone secretion, which

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 Secondary amenorrhea: Diagnostic approach and treatment considerations
can cause various endocrine deficiencies, such as hypogo-
nadotropic hypogonadism (loss of LH and FSH secretion);
secondary hypothyroidism (loss of thyroid-stimulating
hormone [TSH] secretion); and secondary adrenal insuf-
ficiency (loss of adrenocorticotropic hormone secretion).
One cause of amenorrhea is Asherman
syndrome, which is fibrosis of the
endometrium.
It is thought that vasospasm of the pituitary arteries
occurs during severe hypotension, leading to hypoperfusion
of the gland. The initial presentation can be indicated by
the inability to lactate in postpartum women, with subse-
quent development of amenorrhea immediately postpartum
10
or in the year following traumatic delivery.
As with the hypothalamus, infiltrative processes can
occur in the pituitary gland. Amenorrhea occurs when the
process disrupts pituitary function and results in decreased
gonadotropin secretion. Hemochromatosis and lympho-
cytic hypophysitis are examples of infiltrative processes that
affect the pituitary gland.3
Ovaries
When menopause or spontaneous loss of ovarian function
occurs prior to age 40, it is called spontaneous primary ovarian or amenorrhea can be common.14 Because many women
insufficiency (POI), formerly referred to as premature ovarian
failure. Spontaneous POI is characterized by permanent cessa-
tion of ovulation and menstruation. It can be idiopathic, a
result of prior surgery or chemotherapy, or a result of an auto- Another common presentation of PCOS is amenorrhea and
immune process.11 FSH will be elevated (greater than 30 to
40 IU/L) with low estradiol levels (usually below 30 pg/mL).
Recommendations of the Endocrine Society on
diagnosing Cushing syndrome39
• 24-h urine testing for free cortisol (at least two sepa-
rate collections)
• Overnight dexamethasone suppression test*: Patient
is given 1 mg tablet of dexamethasone at 11 p.m., with
a serum cortisol drawn between 8 a.m. and 9 a.m. the
following morning. A value of >1.8 mcg/dL is support-
ive of hypercortisolism.
• Late-night salivary cortisol (at least two separate
collections) is collected at 11 p.m. A value of >145 ng/
dL suggests hypercortisolism.
*Estrogen can cause a false-positive rate of 50% for the overnight dexa-
methasone test. Therefore, this test is not recommended for women taking
estrogen or should be discontinued for 6 weeks prior to testing.
36 The Nurse Practitioner • Vol. 42, No. 9
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
There may also be symptoms of declining estrogen levels, in-
cluding hot flushes, night sweats, and vaginal dryness.12
There can be a history of erratic or progressively less
frequent menstrual cycles for years prior to permanent ces-
sation of menstruation. Other causes of spontaneous POI
include Turner syndrome (lack of a
second X chromosome), fragile X syn-
drome, radiation to the pelvis, and a
history of mumps or cytomegalovirus.13
The diagnosis of spontaneous POI can
be particularly devastating for young
women who have not had children, and
further reproductive and mental health
counseling for these women is warranted.
Polycystic ovary syndrome (PCOS) is characterized by
chronic, irregular, and infrequent menstrual cycles (defined
as occurring fewer than eight times a year or with a cycle
length less than 21 or more than 35 days); it also includes
signs of hyperandrogenism (hirsutism, acne, and/or male
pattern hair loss) and is a common cause of amenorrhea.
PCOS has a wide array of clinical presentations and men-
strual histories, varying from primary amenorrhea to a
history of regular menstrual periods that progress to oligo-
menorrhea and/or amenorrhea.
PCOS is the most common endocrine disorder in wom-
en of reproductive age, occurring in 7% to 10% of all young
women.14 Weight gain and/or worsening symptoms of hy-
perandrogenism accompanied by onset of oligomenorrhea
may start oral contraceptives or other hormonal contracep-
tion in late adolescence or early adulthood, the symptoms
of hyperandrogenism and oligomenorrhea may be masked.
new-onset hyperandrogenism that develop after stopping
hormonal contraception.14
Along with menstrual abnormalities, women with PCOS
who are overweight or obese are often insulin resistant. They
have an increased risk for prediabetes, type 2 diabetes mel-
litus (T2DM), metabolic syndrome, fatty liver disease, and
obstructive sleep apnea.15
Uterus
A less common cause of amenorrhea is Asherman syn-
drome, which is fibrosis of the endometrium and resulting
lack of regeneration that leads to amenorrhea. This can
occur after instrumentation of the uterine cavity, such as
uterine curettage, myomectomy, cervical biopsy, or polyp-
ectomy or insertion of an intrauterine device (IUD). More
recently, therapeutic endometrial ablation has been used to
induce fibrosis of the endometrium, resulting in desired
long-term amenorrhea and contraception.16
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 Secondary amenorrhea: Diagnostic approach and treatment considerations
Women with endometrial tuberculosis can develop Ash-
erman syndrome.17 Women who have uterine instrumenta-
tion at the time of delivery are at higher risk of developing
Asherman syndrome.18 Relatively low estrogen levels at the
time of delivery make the endometrium more susceptible
to trauma, with a decreased ability to regenerate.18
■ Other causes of amenorrhea
Cushing syndrome. Cushing syndrome is a result of either
endogenous cortisol oversecretion or exogenous exposure
to high doses of glucocorticoids (iatrogenic). Noniatro-
genic cortisol excess is rare, with an incidence of 3/1,000,000
annually.19 Cortisol excess can cause the menstrual period
to become irregular or absent, and this is thought to be
related to low GnRH secretion that occurs in response to
high cortisol levels.20
Other symptoms of Cushing syndrome include unex-
plained weight gain, purple striae, diabetes mellitus, hyper-
tension, facial plethora, development of a dorsocervical fat
pad (“buffalo hump”), proximal myopathy, kidney stones,
hypokalemia, depression, hirsutism, acne, and unexplained
osteoporosis (see Recommendations of the Endocrine Society
on diagnosing Cushing syndrome).
Thyroid disorders. Hypothyroidism and hyperthyroidism
can cause changes in the menstrual cycle, including amenor-
rhea, oligomenorrhea, heavy menstrual bleeding, and
frequent menstrual bleeding. Severity of hypo- or hyperthy-
roidism appears to be important, as more severe abnor-
malities in thyroid function are associated with a higher
incidence of menstrual irregularity.21,22
Nonclassic congenital adrenal hyperplasia (CAH). A he-
reditary defect in cortisol synthesis, CAH (an enzyme defi-
ciency) causes a blockage in the pathway leading to cortisol
synthesis and results in an accumulation of precursors to
cortisol. Some of these precursors are androgens, and ele-
vated levels of adrenal androgens cause symptoms of hyper-
androgenism and amenorrhea. Although uncommon, it is
important to consider this diagnosis in women with second-
ary amenorrhea and screen women at high risk for this
enzyme deficiency.23
Populations at higher risk include women with signifi-
cant histories of consanguinity, including Eastern European
(Ashkenazi) Jews and women of Mediterranean, Indian, and
Middle Eastern descent. Lab screening consists of a 17 hy-
droxyprogesterone level drawn in the morning.24 This syn-
drome is important to identify, as women with this disorder
need to receive genetic counseling prior to becoming pregnant.
■ Getting a proper history
An important first step in evaluating a patient with amenor-
rhea is a careful menstrual and reproductive history. There
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Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
Important components of a patient’s history5,14
• Age at menarche
• Details regarding puberty and development of second-
ary sexual characteristics
• Menstrual intervals (number of days between men-
strual periods)
• Menstrual length (number of days of menstrual bleeding)
• Character of menstrual flow (light, heavy, or “spotting”)
• Number of pregnancies, terminations, miscarriages,
live births
• History of infertility and any treatment
• Medical and surgical history
– Personal or family history of autoimmune disorders
– Family history of spontaneous POI or intellectual
disability
– History of gynecologic surgery or procedures
• Medication history
• Use of hormonal contraception
• Weight history
• Exercise history
• History of stress (psychological stress, severe illness,
or injury)
• Symptoms of hyperandrogenism (hirsutism, acne,
male pattern hair loss)
are several elements that should be included in the history
(see Important components of a patient’s history).
It is important to establish primary versus secondary
amenorrhea. The age of menarche should be determined
along with verifying that the first menstrual period occurred
spontaneously without the assistance of medications, such as
oral contraceptives or progesterone. If the patient had a late
menarche (one that occurred after age 16), it is valuable to
determine if she received any medical evaluation for this and
to review when secondary sexual characteristics developed.
A thorough menstrual history should follow, including
determination of menstrual intervals and length of men-
strual periods. A normal menstrual interval is between 28
and 35 days.25 Many women may have more lengthy or
frequent menstrual intervals that they consider to be “nor-
mal.” Review the menstrual intervals since menarche, and
note when any changes may have occurred along with any
other changes in medical history, social history, medications,
or weight that may have coincided with a change in the
menstrual pattern. Some women may consider “spotting”
to be a normal menstrual cycle, so ascertaining typical men-
strual flow is also important.
Many events and medications can alter the menstrual
cycle, making it difficult to determine a woman’s native
menstrual cycles. Pregnancy and lactation will cause amen-
orrhea, but be sure to determine if menstrual cycles re-
turned to the previous pattern after pregnancy or cessation
The Nurse Practitioner • September 2017 37
 Secondary amenorrhea: Diagnostic approach and treatment considerations
of lactation. Use of oral contraceptives, medroxyprogester-
one injections, hormonal contraception such as an etono-
gestrel implant, or progesterone-containing IUDs will result
in either amenorrhea or a bleeding pattern induced by es-
trogen withdrawal and progesterone. Medications used to
treat infertility can also alter the menstrual cycle. Women
who have undergone chemotherapy and/or radiation for
cancer treatment can develop amenorrhea.
Chronic opioid use is increasingly recognized as a cause
of disrupted cycling.26,27 Opioids interfere with the normal
pulsatile secretion of GnRH from the hypothalamus. Al-
though this is described more extensively in males, some
evidence indicates that opioid use in women leads to reduced
LH and FSH and ovarian estrogen production. In contrast
to PCOS where LH, FSH, and estradiol are typically in the
normal range, lab testing in patients with opioid-induced
amenorrhea would be expected to show hypogonadotropic
hypogonadism with low LH, FSH, and estradiol.28
Important components of the reproductive history in-
clude: pregnancies, lactation intervals, pregnancy losses or
Women who are involved in competitive
sports are three times more likely to
develop amenorrhea.
pregnancy terminations, history or treatment of infertility
and outcome of treatment, and history of uterine instrumen-
tation, such as dilatation and curettage. Informal evidence
of anovulation (long lengths of time with unprotected inter-
course and no resulting pregnancy) may also prompt other
questions regarding infertility.
Social and weight history are also significant components.
The provider should question patients about any behaviors
consistent with eating disorders or excessive focus on weight Initial lab evaluation for amenorrhea should include a preg-
and exercise. This would include history of severe caloric
restriction, binge/purge behaviors, laxative or diuretic use, common causes of amenorrhea. If the FSH is elevated (as in
extreme and prolonged exercise regimens, or evidence of
obsession with weight/exercise. It may be helpful to frame
these nonjudgmentally in questions about “an unhealthy
relationship with food.”
Another subtle clue of induced vomiting or excessive
laxative use is unexplained hypokalemia in an otherwise
healthy young woman. A history of intense athletic training
should also be obtained. Women who are involved in com-
petitive sports are three times more likely to develop amen-
orrhea, especially those who are long-distance runners.29
Weight history should include history of weight gain
and loss, especially in relationship to any change in the men- elevated with no clear cause for this (lactation, nipple
38 The Nurse Practitioner • Vol. 42, No. 9
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
strual cycle, and whether or not weight gain was intended
or unintentional. Review of previous weight trends (if pres-
ent) in the medical record may also be helpful. An assessment
of psychological or physical/health stressors in the patient’s
life should be included in the social history.5
Psychological stressors may include domestic violence
and/or a history of sexual or psychological trauma. Health
stressors could include severe or life-threatening illness or
injuries, noting the relationship of these events to any
change in the menstrual cycle or amenorrhea.
■ Physical exam
The physical exam should include height, weight, and body
mass index. If the patient is more than 15% below the
ideal body weight, an eating disorder or malnutrition
should be considered.3 The Tanner scale helps confirm
normal sexual development and the presence of the phys-
iologic effects of estrogen. Female genitalia should be in-
spected carefully for an enlarged clitoris (sign of viriliza-
tion). The thyroid gland should be inspected and palpated
for enlargement. An eye exam should
include inspection for any exophthal-
mos or lid lag that could signal thyroid
disorders.
Visual fields should be assessed, as
changes in peripheral vision could in-
dicate the presence of a pituitary tumor,
creating pressure on the optic chiasm.
Careful skin inspection should be performed to assess for
facial plethora, purple striae, and bruising (all signs of cor-
tisol excess). Hirsutism, acne lesions or scarring from previ-
ous acne lesions (on the face but also on the upper back and
chest), and hair thinning in the temporal and/or vertex scalp
are all signs of hyperandrogenism.14
■ Lab evaluation
nancy test, TSH, FSH, and prolactin to rule out the more
menopause or spontaneous POI) or abnormally low (as in
hypothalamic amenorrhea), obtaining an estradiol level can
be helpful to further confirm a hypoestrogenic state. If clin-
ical signs of hyperandrogenism are present, testosterone
(both free and total) and dehydroepiandrosterone sulfate can
be measured to determine the degree of hyperandrogenism.14
Androgen values that are greater than two times the
upper limit of normal may indicate an androgen-secreting
tumor and should prompt referral to an endocrinologist. If
the prolactin level is elevated, another measurement to con-
firm elevation is prudent; if the prolactin level remains
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 Secondary amenorrhea: Diagnostic approach and treatment considerations

Diagnostic considerations for amenorrhea evaluation1,40 Normal lab values*

Prolactin 3.34–26.76 ng/dL
• Initial testing should include beta-human chorionic gonadotropin, TSH 0.450–4.5 uIU/mL
prolactin, TSH, FSH FSH 4.7–21.5 mIU/mL
LH Follicular phase 1.9–12.5 mIU/mL
• TSH abnormalities → further workup for thyroid disease with free T4 Mid-cycle peak 8.7–76.3 mIU/mL
Luteal phase 0.5–16.9 mIU/mL
Prolactin elevated → Recheck
• Prolactin still high, get pituitary MRI Estradiol 30–400 pg/mL
• Positive MRI → refer to endocrinology Total testosterone 10–70 ng/dL
Free testosterone 0.7–3.6 pg/dL
• Prolactin still high, MRI negative—consider
DHEA-sulfate <395 pg/mL
medications and other causes of high 17-OH progesterone <200 ng/dL
prolactin (see text)
* Institutional lab norms may vary

Prolactin normal → FSH, LH, estradiol, PCT

Low FSH, LH, and
estradiol no bleeding
in response to PCT:
Consider hypothalamic
dysfunction (FHA,
Sheehan syndrome,
see text)
Elevated FSH and low
estradiol, no bleeding
in response to PCT:
Consider menopause
if FSH is elevated
>40 mlU/mL
Normal FSH, LH, and Normal FSH, LH,
estradiol but bleeding estradiol;
in response to PCT: no bleeding response
Consider PCOS to PCT

Refer to endocrinology
for further evaluation
If POI suspected, repeat Total and free testos- Consider Asherman
FSH, LH, estradiol at terone, DHEA-sulfate, syndrome if history
least 1 month later to 17-OH progesterone in of uterine instrumen-
confirm certain populations tation; check pelvic
ultrasound

Refer to endocrinology Refer to endocrinology

or women’s health for or women’s health for
further evaluation further evaluation

Testosterone/DHEA- Normal testosterone/ Normal-to-mild eleva-

sulfate elevated 2X
upper limit of normal
or >200ng/dL: Consider
androgen secreting
tumor
DHEA-sulfate, dark
straie, easy bruising,
facial plethora, supra-
clavicular fullness,
hypertension, T2DM
tion of testosterone/
DHEA-sulfate: Consider
PCOS if irregular
menstrual cycle and
clinical evidence
hyperandrogenism

Computed tomography Workup for Cushing Consider metabolic

of adrenal glands
Pelvic ultrasound
Refer to endocrinology
for further evaluation
syndrome workup: A1C, lipids,
Consider referral to gamma glutamyl
endocrinology transpeptidase test,
aspartate amino-
transferase, alanine
aminotransferase

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 Secondary amenorrhea: Diagnostic approach and treatment considerations

stimulation, or medications), magnetic resonance imaging
(MRI) of the pituitary gland should be done to assess for a
pituitary adenoma. Lab screening for late-onset CAH con-
sists of a morning 17 hydroxyprogesterone level.24
Pelvic ultrasound can be performed to assess for chang-
es in the endometrial lining, including thickening of the
lining (indicating lack of adequate endometrial shedding)
or absence of lining, as seen in FHA or Asherman syndrome.
Ultrasound can be used to support the diagnosis of PCOS,
Initial lab evaluation for amenorrhea should
include a pregnancy test, TSH, FSH, and prolactin
to rule out common causes of amenorrhea.
but because polycystic ovaries are frequently noted as a
nonspecific finding, specific measurements of ovary sizes
and follicle location, size, and number are required.30
In recent years, anti-Müllerian hormone (AMH) has
been identified as a way to measure ovarian ovulatory capac-
ity and has become an additional diagnostic tool in the
evaluation of amenorrhea. AMH is produced in the ovarian
granulosa cells by the antral and preantral follicles and is
involved in the regulation of follicular growth, along with
suppression of follicular sensitivity to FSH.
AMH levels do not fluctuate substantially during phas-
es of the menstrual cycle.31 Studies have shown that AMH
is two to four times higher in women with PCOS compared
with healthy ovulatory controls. Women with POI have very
low AMH levels, whereas women with FHA have AMH
levels similar to controls.32 Therefore, an elevated AMH is
supportive of a PCOS diagnosis and can help to distinguish
it from POI (low AMH) and hypothalamic amenorrhea
(normal AMH).
To identify metabolic problems associated with PCOS,
lab evaluation should include a screen for T2DM (such as
an oral glucose tolerance test, fasting glucose, or hemoglobin is made from peanut oil and should not be prescribed to
A1C), a fasting lipid panel to assess for hyperlipidemia, and women with peanut allergies.28
a hepatic function panel to evaluate for fatty liver disease.
■ Diagnostic approach
Oral contraceptive therapy and other hormonal contracep-
tion can make lab evaluation of amenorrhea difficult. Com-
bined oral contraceptives containing estrogen and a progestin therapy in a number of ways. Because amenorrhea may not
will suppress FSH, LH, and androgen levels. Estradiol will
also be low, since the estrogen used in oral contraceptives
(ethinyl estradiol) is not measured in the estradiol assay,
making interpretation of these lab tests in women taking oral
contraceptives unhelpful.33
Likewise, AMH can be reduced up to 50% in women
who are taking oral contraceptives and is not a useful diag-
nostic tool in this circumstance.32 Accurate measurement of
gonadotropins and androgens is done when a woman is not
taking oral contraceptives or has discontinued oral contra-
ceptives for 3 months.33 It is best to fully determine the cause
of amenorrhea prior to initiating any hormonal treatment.
Interpreting androgen levels in women, especially tes-
tosterone, can be difficult due to the lack of accuracy in
testosterone assays along with the vari-
ation in assays used to measure testos-
terone.15 These assays are most accurate
at the higher levels of testosterone seen
in most men. Because normal testoster-
one levels in women can vary from 10
ng/dL to 70 ng/dL, these relatively low
measurements may not be accurate.15
It is important to correlate hyperandrogenism with the
physical exam. If the patient has significant hirsutism, per-
sistent adult acne, or male pattern scalp hair loss, this is
strong positive evidence for clinical hyperandrogenism and
supports suspicion for PCOS or other androgen excess
disorders.14
Another useful diagnostic maneuver is the administra-
tion of a progesterone challenge test (PCT). This can be
done with a 7- to 10-day course of medroxyprogesterone or
micronized progesterone. If a woman is secreting adequate
levels of estradiol (such as in PCOS) and exposing the uter-
ine lining to estrogen effects, a course of progesterone will
initiate a withdrawal of menstruation.33
If estradiol levels are low (such as in spontaneous POI,
menopause, Sheehan syndrome, or hypothalamic amenor-
rhea), a woman will not respond to progesterone with vaginal
bleeding. Likewise, a woman with Asherman syndrome will
not respond to a PCT because the uterine lining cannot regen-
erate. Typically, a woman will respond to progesterone within
2 to 7 days of the last dose of progesterone, indicating func-
tional endometrium and estrogen production.34 Progesterone
■ The role of NPs
Amenorrhea is an important clinical sign that should initi-
ate an evaluation of cause. The NP can play an important
role in the care of women with amenorrhea and can impact
be identified by the patient as a problem, simply asking
about it, identifying it as an issue to be investigated, and
diagnosing the cause are three significant contributions.
Caring for women with amenorrhea may involve many
providers, including an obstetrician/gynecologist, mental

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 Secondary amenorrhea: Diagnostic approach and treatment considerations
health professional, primary care provider, nutritionist, and
endocrinologist. Coordinating care is another important
role of the NP. Referral to an endocrinologist can be helpful
if there is a question about the cause, if there is evidence of
a hormone-secreting tumor (for instance, testosterone lev-
els over 200 ng/dL, elevated prolactin), or if the referring
provider needs help tailoring a treatment plan.
Amenorrhea is a common complaint in women and
presents with a variety of accompanied symptoms. Some
causes of amenorrhea can pose significant risk for long-term
metabolic, reproductive, and bone health problems. In ad-
dition, women should be educated that amenorrhea consti-
tutes a red flag for other possible health concerns.
A careful history and appropriate diagnostic workup are
important to determine etiology and an appropriate treat-
ment plan for women with this complaint. NPs can play an
important role in the long-term care of women with PCOS
by providing advice, education, and support along with
medical care and referral when needed.
REFERENCES
1. U.S. National Library of Medicine. Medline Plus. 2016. www.nlm.nih.gov/
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Katherine Pereira is an associate professor at Duke University School of Nurs-
ing, Durham, N.C., and a family NP at Duke University Medical Center, Divi-
sion of Endocrinology, Metabolism and Nutrition, Durham, N.C.
Ann J. Brown is an associate professor of medicine and vice dean for faculty at
Duke University School of Medicine, Durham, N.C.
The authors have disclosed that they have no financial relationships related to
this article.
DOI-10.1097/01.NPR.0000520832.14406.76
The Nurse Practitioner • September 2017 41