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ologies and clinical features, J Clin Endocrinol Metab 101:2300–2312, 2016.
Udelsman R, Akerstrom G, Biagini C, et al: The surgical management of asymptom-
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opausal women with primary hyperparathyroidism, J Clin Endocrinol Metab
94:2306–2312, 2009.
HYPERPROLACTINEMIA
Method of
Ming Li, MD, PhD; and Lawrence Chan, MD
CURRENT DIAGNOSIS
• Hyperprolactinemia is diagnosed by biochemical tests based on
two-site immunoassay, which can be confounded by extreme
hyperprolactinemia (hook effect) and biologically inactive
macroprolactinemia.
• Hyperprolactinemia can be caused by physiological, pharma-
cological, or pathological conditions; careful clinical, laboratory,
and radiology evaluations are required to identify its
V Endocrine and Metabolic Disorders
underlying cause.
• The most common causes of hyperprolactinemia include medi-
cations, prolactinoma, and other pituitary and hypothalamic/
pituitary stalk diseases.
• Clinical features of hyperprolactinemia include galactorrhea,
menstrual abnormalities (in women), impotence (in men),
infertility, and osteoporosis.
• Patients with prolactinoma may also have local compression
symptoms including headache, visual disturbance, and
hypopituitarism.
• Pituitary magnetic resonance imaging (MRI) is the imaging
method of choice for diagnosing prolactinoma and other sellar/
parasellar lesions.
CURRENT THERAPY
318
• For secondary hyperprolactinemia, treatment should be
directed at correcting underlying causes.
• Treatment goals for prolactinoma are relief of symptoms and
the long-term effects of hyperprolactinemia, and of tumor mass
effects.
• The dopamine agonists cabergoline (Dostinex) and bromocrip-
tine (Parlodel) are effective in normalizing the prolactin level
and shrinking the tumor in patients with prolactinoma.
• Surgery and radiotherapy of prolactinoma are reserved for
patients resistant to or intolerant of medical therapy.
• Temozolomide (Temodar)1 monotherapy is the first-line che-
motherapy for aggressive or malignant prolactinomas after
failing standard treatments.
1
Not FDA approved for this indication.
Biochemistry and Physiology of Prolactin
Prolactin is a polypeptide hormone produced by pituitary lacto-
troph cells. It is also produced locally in a variety of extrapituitary
tissues such as mammary glands, decidua, gonads, brain, liver, fat,
pancreas, and the immune system, along with its receptors. Prolac-
tin is highly pleiotropic in terms of its functions. Many of its actions
collectively support puerperal lactation. Prolactin displays consid-
erable sequence homology to growth hormone (GH) and placental
lactogen. The prolactin and GH receptors both belong to the class I
cytokine/hematopoietic receptor superfamily. Prolactin is responsi-
ble for maturation of the mammary glands during pregnancy, but it
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requires GH instead. It appears not to be an essential hormone for
non-childbearing individuals. Rare patients deficient for either pro-
lactin or its receptor are largely healthy despite difficulty with fer-
tility and lactation.
Prolactin circulates mainly as a 23-kDa 199-aa polypeptide. Sev-
eral of its cleavage products exist in blood, which may have func-
tions unrelated to lactation; for example, one 16-kDa cleavage
product of prolactin displays antiangiogenic and prothrombotic
properties, and has been implicated in the development of pre-
eclampsia and peripartum cardiomyopathy. Several forms of prolac-
tin aggregate, known as macroprolactins, also exist in circulation at
lower levels. They are formed either by covalent bonding of prolac-
tin monomers or by their nucleating around autoimmune IgG. These
macroprolactins are not biologically active in vivo and have a pro-
longed half-life. At times they can build up in the circulation to a level
high enough to cause diagnostic difficulties.
Among the major pituitary hormones, prolactin is unique for its
predominantly negative mode of regulation by the hypothalamus.
It does not have a known hypothalamus-derived releasing hor-
mone. Instead, lactotrophs are under tonic inhibition by dopamine
secreted from hypothalamic neurons. Increase in prolactin output
is mostly mediated by withdrawing dopaminergic control in
response to environmental cues, such as physical activity, stress,
and nipple stimuli (Figure 1). Under experimental and pathological
conditions, several factors, including thyrotropin-releasing hor-
mone (TRH), vasoactive intestinal peptide (VIP), oxytocin, and
vasopressin, have been shown to increase prolactin secretion, but
these peptides appear to play only minor and insignificant roles
for the physiological regulation of prolactin.
Estrogen is the main driver of prolactin secretion during preg-
nancy. Stimulated by persistently elevated estrogen, lactotrophs
grow in number and size. By term the pituitary gland can reach 2
to 3 times its normal size, and prolactin levels increase some 20-
fold. Along with placental hormones such as estrogen, progester-
one, and placental lactogen, prolactin drives the maturation of
the mammary glands. Lactation starts after parturition, when estro-
gen withdraws from the circulation. Frequent infant suckling main-
tains physiological hyperprolactinemia, which is important for
sustained milk production. In addition, hyperprolactinemia during
this critical period provides a natural though unreliable way of con-
traception. This is achieved by suppression of the hypothalamus–
pituitary–gonad axis. Hyperprolactinemic hypogonadism and
parathyroid hormone related peptide (PTHrP) secreted from mam-
mary epithelial cells help mobilize skeletal calcium store in support
of milk production. Through its receptors in liver, intestine, fat, and
pancreas prolactin also adjusts maternal nutrient metabolism for
optimal milk output. In the brain, prolactin modifies parental
behavior toward closer infant attendance (see Figure 1).
Pathophysiology of Hyperprolactinemia
Physiological hyperprolactinemia as occurs during pregnancy and
nursing is essential for child raising through the actions of prolactin
in target organs discussed above. Similar changes in these organs
under the influence of persistent pathological hyperprolactinemia
in the absence of pregnancy and lactation, however, are inappro-
priate and could lead to a variety of undesired long-term
consequences.
Mammary Glands
One common symptom of persistent hyperprolactinemia is galac-
torrhea, that is, milk production not associated with childbirth or
breast-feeding. As puerperal lactation normally ends within
6 months after delivery or weaning, any milk production beyond
this point is also considered galactorrhea. Since maturation of
mammary glands is completed during pregnancy, galactorrhea
typically happens in women between 20 to 35 years of age with
previous childbirths. It also occurs in nulligravid women, postmen-
opausal women, and men, although less frequently.
Prolactin is a known mitogen for mammary epithelial cells, and
concern has been raised regarding its potential role in the
 Environmental stimuli

Mammary glands
Hypothalamus
DA

GnRH Pituitary lactotrophs Nutrient/Calcium Lactation

PRL PRL metabolism

Estrogen

Gonads Placenta Brain

Figure 1 Physiology of prolactin and its regulation. At baseline, prolactin production and secretion are under tonic inhibition by dopamine released from
hypothalamic neurons. The hypothalamus controls prolactin production by altering output of dopamine after integrating environmental stimuli and
changes in hormonal homeostasis. Prolactin increases hypothalamic dopamine output, providing a negative feedback regulatory loop. Estrogen
stimulates prolactin synthesis and secretion during pregnancy. Prolactin supports puerperal lactation via its action on the mammary glands, nutrient/
calcium metabolism, and brain. Unlike most other anterior pituitary hormones, feedback regulation of prolactin secretion does not occur via factors
produced by a peripheral endocrine target organ. Prolactin also suppresses hypothalamic-pituitary-gonadal axis by inhibiting GnRH release.
Abbreviations: DA ¼ dopamine; GnRH ¼ gonadotropin releasing hormone; PRL ¼ prolactin.

pathogenesis of breast cancer. In a large prospective study by the
Women’s Health Initiative (WHI), there was evidence of a signifi-
cant increase in breast cancer incidence in postmenopausal women
with high normal prolactin levels, which is within the highest quar-
tile of the normal range compared with those in the lowest quartile.
On the other hand, increased breast cancer risk has not been
observed in patients with overt hyperprolactinemia. In fact, early
parity and lactation history are strong protective factors against
adrenal androgens in hyperprolactinemia may contribute to the
suppression of GnRH release in the hypothalamus and secondary
hypogonadism.
Skeletal System
Premenopausal women with hyperprolactinemia have lower bone
density and approximately a 4.5 times higher risk for osteoporotic
fractures. Hypogonadism associated with hyperprolactinemia is

breast cancer. Further research is required to resolve these seem-
ingly discrepant observations.
Female Reproductive System
Persistent hyperprolactinemia significantly diminishes the pulsatile
release of gonadotropin-releasing hormone (GnRH). As GnRH
neurons do not themselves express prolactin receptors, prolactin
exerts its effects on their afferent neurons instead by suppression
of secretion of kisspeptin, a potent secretagogue for GnRH. Prolac-
tin receptors are also found in the gonads, and prolactin has been
reported to inhibit folliculogenesis and estrogen production in the
ovary directly. However, this likely has only a limited contribution
to infertility and hypogonadism associated with hyperprolactine-
mia, for the hypothalamus-pituitary-gonad axis can be reactivated
by administration of GnRH or kisspeptin, with return of ovulation
and fertility in subjects with hyperprolactinemia.
Male Reproductive System
As in women, hyperprolactinemia causes secondary hypogonad-
ism and infertility in men by suppression of GnRH pulses and a
decrease in luteinizing hormone (LH) and follicle-stimulating hor-
mone (FSH) levels. Patients often have low or low normal testos-
terone levels, as well as abnormal sperm counts and morphology
in semen analysis. Patients usually seek medical attention for
diminished libido and impotence. The central nervous system
(CNS) actions of prolactin are likely partly responsible for these
symptoms, as restoration of testosterone level alone is often inad-
equate for symptom relief, which occurs only when prolactin levels
also return to normal.
Adrenal Glands
Prolactin stimulates the synthesis of androgen in the zona reticu-
laris of the adrenal cortex. Mild elevations in serum levels of adre-
nal androgens, for example dehydroepiandrosterone (DHEA) and
dehydroepiandrosterone sulfate (DHEA-S), are seen in approxi-
mately 50% of women with hyperprolactinemia. Symptoms of
clinical hyperandrogenism such as hirsutism and acne are rare in
these patients. When present, they are almost always associated
with a concurrent increase in testosterone level. Elevation of
Hyperprolactinemia
the main cause of bone loss, whereas restoration of sex hormones
with either hormonal replacement or correction of hyperprolacti-
nemia improves bone density. Bone density is preserved in women
with hyperprolactinemia who continue to have regular menses.
Nonetheless, not all studies showed a clear correlation between
the degree of bone loss and duration of amenorrhea or levels of
sex hormones suggesting involvement of additional processes.
For example, the levels of parathyroid hormone–related protein
(PTHrP) were found to be significantly higher in patients with
hyperprolactinemia, and correlated well with bone density mea-
surements. Correction of hyperprolactinemia by dopamine ago- 319
nists was shown to normalize PTHrP levels.
Etiology of Hyperprolactinemia
Any conditions that affect production or clearance of prolactin can
lead to hyperprolactinemia (Table 1). Physiological hyperprolacti-
nemia is transient and adaptive, whereas persistent hyperprolacti-
nemia from pharmacological and pathological causes is often
symptomatic with undesired long-term consequences. Pituitary
adenomas over producing prolactin (prolactinomas) are the most
important cause of pathological hyperprolactinemia. In addition
to the elevated prolactin levels, prolactinomas also produce path-
ological local mass effects. Secondary hyperprolactinemia is most
commonly related to disruption of dopaminergic control of lacto-
trophs, secondary to the use of dopamine antagonists or hypotha-
lamic and pituitary stalk lesions.
Epidemiology and Natural History of Prolactinoma
Prolactinoma is the most common type of pituitary adenoma, con-
tributing to approximately 40–50% of pituitary tumor cases. Pro-
lactinomas are categorized according to size into
microprolactinomas (under 1 cm) and macroprolactinomas (larger
than 1 cm). Clinically these two conditions behave very differently
and can be considered as separate entities. In general, macroprolac-
tinomas tend to grow progressively and are often locally invasive;
they are also generally more resistant to treatment and have a
higher risk of recurrence. On the other hand, microprolactinomas
rarely progress in size ( 7% of cases) and have a good chance (
15% of cases) of going into remission on their own.

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 predominantly affect women of childbearing age, with a female-
TABLE 1 Causes of Hyperprolactinemia to-male ratio of approximately 20:1. Macroprolactinoma, on the
PHYSIOLOGICAL other hand, shows no sex predilection. Neoplastic transformation
of lactotroph involves accumulation of genetic and epigenetic
Pregnancy events. The best-understood candidate genes involved include the
Lactation and breast stimulation pituitary tumor transforming gene (PTTG) and the heparin-
binding secretory transforming gene (HST). PTTG expression is
Neonatal period positively regulated by estrogen.
Physical activity Most prolactinomas occur sporadically. The vast majority of
prolactinomas are benign, although they can be locally invasive.
Stress Malignant prolactinomas, as defined by the presence of extrapitui-
Sexual intercourse tary metastases, are extremely rare. Familial cases, such as those
associated with multiple endocrine neoplasia I (MEN-I) and famil-
PHARMACOLOGICAL ial isolated pituitary adenoma (FIPA), typically occur at a younger
Dopamine antagonists—antipsychotics and antiemetics age and are more often macroprolactinomas that are locally
invasive.
Tricyclic antidepressants
Selective serotonin reuptake inhibitors (SSRI) Clinical Manifestations
Clinical manifestations of prolactinomas fall under two categories:
Antihistamines (H2) systemic effects of hyperprolactinemia, and local compression
Verapamil (Calan) symptoms.
Protease inhibitors Symptoms of Hyperprolactinemia
Dopamine synthesis inhibitors Persistent hyperprolactinemia inappropriately recapitulates symp-
toms associated with normal pregnancy and nursing. In extreme
V Endocrine and Metabolic Disorders

PATHOLOGICAL cases, hyperprolactinemia has been associated with delusions of

PITUITARY DISEASES pregnancy in susceptible individuals, for example some women
on psychotropic medications.
Prolactinoma Menstrual abnormalities and infertility are the most common
Plurihormonal adenomas symptoms associated with hyperprolactinemia in women of child-
bearing age. These symptoms may be masked by use of oral con-
Lymphocytic hypophysitis traceptive pills, which often delays diagnosis. The mildest cases
Empty sella syndrome include women presenting with infertility caused by shortened
luteal phase despite preserved regular menses. As the degree of
Macroadenoma with or without suprasellar extension hypogonadism worsens, patients experience menstrual irregulari-
Idiopathic hyperprolactinemia ties ranging from anovulatory cycles to oligomenorrhea and
amenorrhea. Patients with amenorrhea may also experience psy-
HYPOTHALAMIC/PITUITARY STALK DISEASES chological stresses and other menopausal symptoms like vaginal
Tumors: meningioma, craniopharyngioma, germinoma, metastasis, etc. dryness and dyspareunia. Of note, high prolactin levels may some-
times mask vasomotor symptoms of menopausal and perimeno-
Granulomas pausal women with prolactinoma, who may develop hot flashes
Infiltrative diseases once they are successfully treated with dopamine agonists.
320 Galactorrhea occurs in up to 80% of cases of hyperprolactine-
Irradiation mia. This will need to be differentiated from nipple discharges of
Trauma other causes, especially those from breast neoplasms. Further eval-
uation with breast imaging and cytology is indicated when the dis-
NEUROGENIC: chest wall lesions, spinal cord lesions, herpes zoster, charge is unilateral, bloody, or associated with a breast mass.
and epileptic seizure Galactorrhea is by definition milk-like in appearance, and when
PARANEOPLASTIC SYNDROME in doubt, Sudan Black B staining showing fat globules is confirma-
tory. Although considered a classic sign and symptom for hyper-
SYSTEMIC DISEASES prolactinemia, galactorrhea per se is a poor predictor for
End-stage renal disease hyperprolactinemia in the absence of additional symptoms, for it
can be seen in about 10% of healthy women of childbearing
Cirrhosis age. If amenorrhea is present at the same time, the patient should
Adrenal insufficiency be assumed to harbor a prolactinoma unless proven otherwise. The
degree of galactorrhea is quite variable, from barely expressible to
Pseudocyesis bothersome bra stain and copious free flow, and does not necessar-
ily reflect the severity of hyperprolactinemia. In fact, the majority of
Adapted from Bronstein, 2016; Melmed et al., 2017.
patients with galactorrhea and normal menses have normal prolac-
tin levels. On the other hand, in some patients with extremely high
The prevalence of prolactinoma has been estimated to be 500 levels of prolactin, galactorrhea could be masked by severe
cases per million and incidence about 27 cases per million per year hypogonadism.
based on survey of asymptomatic populations. In autopsy series, Men with hyperprolactinemia mainly present with impotence and
however, lactotroph neoplasms staining positive for prolactin are diminished libido, which is not always corrected with testosterone
much more common, being found in approximately 5% of the sub- replacement. As noted in the section on pathophysiology, these
jects. They are predominantly microadenomas. Only a small frac- symptoms are not all caused by hypogonadism but may involve
tion of these small lactotroph neoplasms develop overt the central effects of prolactin. Other symptoms and signs of hypo-
hyperprolactinemia by escaping tonic dopaminergic suppression gonadism, such as loss of body hair and muscle bulk, are less com-
from the hypothalamus, presumably via down-regulation of mon. Infertility could also occur with decrease in sperm count and
dopamine D2 receptor-mediated signaling pathway and/or bypass- morphology, although hyperprolactinemia is only present in
ing the portal system for blood supply. Microprolactinomas approximately 5% of male patients seeking treatment for infertility.

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 For both male and female patients, persistent hypogonadism
from hyperprolactinemia leads to osteoporosis and increased risk
of fracture. This could be effectively treated with either sex hor-
mone replacement or dopamine agonists.
Mass Effects of Prolactinomas
Headache is the most common neurological symptom caused by
pituitary tumors. It can occur even with microadenomas presum-
ably caused by dural stretch. More severe headache results from
larger tumors, especially those with extrasellar invasion, and occa-
sionally from apoplexy.
Visual disturbance typically only happens with macroadenomas
with suprasellar extension impinging on the optic chiasm leading to
loss of visual acuity and visual field defects. The typical pattern of
visual field defect is bitemporal hemianopsia, which usually starts
from the upper field and progresses downward as the tumor
impinges upward from below. Ophthalmoparesis typically hap-
pens in the setting of apoplexy and only rarely results from para-
sellar invasion of the cavernous sinus and impingement of
cranial nerves III, IV, or VI.
By compressing the rest of the pituitary gland, including the
stalk, prolactinoma can cause deficiencies of other anterior pitui-
tary hormones including GH, thyroid-stimulating hormone
(TSH), and adrenocorticotropic hormone (ACTH), in addition
to hypogonadism from the hyperprolactinemia. The degree of
the risk is proportional to tumor size.
CSF rhinorrhea occurs when a macroprolactinoma invades inferi-
orly into the sphenoid sinus. Other rare compressive symptoms from
giant prolactinomas include epilepsy (temporal lobe involvement),
exophthalmos, and hydrocephalus. Life- and vision-threatening
emergencies could arise from apoplexy and CNS infection.
Laboratory Evaluation
Prolactin Assay and Pitfalls
Hyperprolactinemia is diagnosed by individual measurements of
serum prolactin levels. Patients should be well rested, as physical
activity stimulates prolactin secretion, but fasting is not needed.
Dynamic tests such as TRH stimulation do not appear to add to
diagnostic value and are not recommended. The level of prolactin
may provide valuable diagnostic clues. Secondary hyperprolactine-
mia rarely exceeds 150 ng/mL. On the other hand, a prolactin level
of greater than 100 ng/mL is highly suggestive, and severe hyper-
prolactinemia of greater than 500 ng/mL is virtually diagnostic
for prolactinoma. On rare occasions, secondary hyperprolactine-
mia can produce prolactin levels in the prolactinoma range. For
example, risperidone (Risperdal)-induced hyperprolactinemia
could be as high as 250 to 500 ng/mL, and patients with end-stage
renal disease who are on antipsychotics or antiemetics can have
prolactin levels greater than 1000 ng/mL. The size of the prolacti-
noma shows a rough correlation with the serum prolactin level.
Patients with microprolactinomas usually have prolactin levels in
the range of 50 to 300 ng/mL, whereas those with macroprolacti-
nomas have levels of 200 to 5000 ng/mL.
Most clinical laboratories measure prolactin using a two-site
immunoassay. A capture antibody first affixes prolactin in the sam-
ple to a solid matrix. Subsequently a second signal antibody is
attached to the now immobilized prolactin. The signal antibody
is engineered to carry either a radioisotope or a chemiluminescent
enzyme to provide a readout. The assay is accurate within its
designed linear range, which is typically under 10,000 ng/mL.
Beyond this level both capture and signal antibodies could be sat-
urated preventing the signal antibody to attach. As a result, signal
outputs will be falsely diminished. This phenomenon, known as the
hook effect, produces a falsely low reading that could lead to the
misdiagnosis of a macroprolactinoma as a nonfunctioning pitui-
tary tumor. This artifact can be circumvented by repeating the
assay with a 100-fold diluted sample. Many laboratories also
opt for an additional washout step to eliminate excess prolactin
before adding the signal antibody, preempting the artifact.
Macroprolactinemia is another potential diagnostic pitfall
masquerading as true hyperprolactinemia. Macroprolactins are
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biologically inactive prolactin aggregates that could accumulate
in blood to a high level. Macroprolactinemia does not cause any
morbidities but could contribute to analytical difficulties as the
antibodies used in prolactin assays cross-react with macroprolac-
tins. Most laboratories rely on polyethylene glycol (PEG) precipi-
tation to determine the proportion of macroprolactins and
the true concentration of monomeric prolactin. Up to 25% of
monomeric prolactin can be also precipitated by PEG, potentially
masking true hyperprolactinemia. Therefore patients with macro-
prolactinemia may still need to be further evaluated if clinical
suspicion is high for true hyperprolactinemia.
Other Supporting Laboratory Tests
After confirming hyperprolactinemia, a simple chemistry panel
may reveal or suggest the underlying cause such as chronic kidney
disease and cirrhosis. A pregnancy test (beta human chorionic
gonadotropin [βhCG] level) is essential for women of childbearing
age, and hypothyroidism needs to be ruled out with a TSH assay.
Both pregnancy and hypothyroidism may have presenting symp-
toms of sellar mass and hyperprolactinemia and therefore be mis-
taken for prolactinoma.
For established prolactinoma cases it is important to also assess
other pituitary axes. Up to 20% of GH-secreting tumors cosecrete
prolactin, and IGF-1 level is an essential screening test for these
cases. If hypogonadism is suspected, levels of LH, FSH, and sex
hormones (testosterone or estrogen) should be obtained. Screening
for central hypothyroidism and secondary adrenal insufficiency
should be done with TSH, free thyroxine (T4), and morning corti-
sol levels, respectively, for patients with pituitary tumors larger
than 6 mm.
Neuroimaging
Hyperprolactinemia
Pituitary imaging should be considered for all patients with unex-
plained significant hyperprolactinemia, especially if there are signs
or symptoms of local compression. MRI with and without gadolin-
ium contrast with dedicated pituitary protocol is the test of choice.
Compared with other modalities MRI provides superior soft tissue
contrast revealing the tumor’s inner structure and its relationship
to surrounding tissues, including cavernous sinus, pituitary stalk,
and optic chiasm. Computed tomography (CT) scan still has a role
for patients with metal implants or other contraindications for
MRI, and is especially useful for revealing bony erosions and tissue
calcification; its use is limited by suboptimal soft tissue contrast 321
and exposure to ionizing radiation.
Visual Field Testing
A formal visual field test with a perimeter is recommended when
suprasellar extension of a pituitary adenoma brings it close to
the optic chiasm. Improvement or worsening in visual field often
precedes imaging evidence of tumor shrinkage or expansion during
treatment. Therefore visual field testing is an excellent monitoring
tool for patients under treatment for macroadenoma and visual
impairment.
Diagnosis
Prolactin testing is usually prompted by suggestive signs and symp-
toms of hyperprolactinemia such as menstrual abnormalities, infer-
tility, and galactorrhea. A careful history, including medication
use, physical examination, and routine laboratory evaluation
(see preceding sections), is invaluable for uncovering secondary
causes. Pituitary imaging should be performed when no other
underlying causes are found especially if the levels of prolactin
are higher than 100 ng/mL. A diagnostic algorithm shown in
Figure 2 provides a framework for a structured and cost-effective
workup of hyperprolactinemia.
Differential Diagnosis
An exhaustive list of etiologies has been provided in Table 1. A few
entities deserve additional comments.
Drug-induced hyperprolactinemia is common and at times may
produce serum prolactin levels matching those in patients with
 If asymptomatic
⫹
Physiological βhCG(⫹) Hyperprolactinemia PEG precipitation Macroprolactinemia
⫺

PRL⬍100 ng/mL PRL⬎100 ng/mL

βhCG(⫺) βhCG(⫺)

⬍1cm Microprolactinoma

Evaluation/Correction ⫺
MRI
of secondary causes

⫹ ⫺ ⬎1cm PRL⬎150 ng/mL Macroprolactinoma

Secondary Idiopathic ⫹
PRL⬍150 ng/mL Hook effect
⫺

Pseudoprolactinoma

Figure 2 Diagnostic algorithm for hyperprolactinemia. If hyperprolactinemia occurs in the absence of relevant clinical symptoms and signs, one should
rule out macroprolactinemia by PEG precipitation. When hyperprolactinemia is confirmed, pregnancy should be ruled out with a βhCG test. In the absence
of pregnancy, if the PRL level is higher than 100 ng/dl, the pretest probability for a prolactinoma is high enough to justify a pituitary MRI scan, even if
potential secondary causes exist. Regardless of prolactin levels, secondary causes should be carefully evaluated with medication history, physical
V Endocrine and Metabolic Disorders

examination, and laboratory tests such as thyroid function tests and chemistry panel, and appropriately treated. If hyperprolactinemia remains
unexplained or persists despite correction of other contributing factors, a pituitary MRI is in order. Patients with negative sellar findings have
idiopathic hyperprolactinemia. Patients with sellar mass may have either prolactinoma or pseudoprolactinoma. The latter is suggested by a discordant
prolactin level less than 150 ng/mL for a large sellar, or a parasellar mass greater than 1 cm, after hook effect has been ruled out. Abbreviations:
βhCG ¼ β human chorionic gonadotropin; MRI ¼ magnetic resonance imaging; PEG ¼ polyethylene glycol; PRL ¼ prolactin.

prolactinoma (see prior section on laboratory evaluation). A more
typical range of prolactin level is 25 to 100 ng/mL for drug-induced
hyperprolactinemia. It is not always possible to correlate in time
the initiation of the culprit drug with the onset of symptoms, or rise
of prolactin levels. The way to confirm medication-related hyper-
prolactinemia is to discontinue the putative offending agent(s) for
three days before repeating a prolactin assay. Some medications
may require a longer period of abstinence, and in such cases the
level of prolactin can be retested later if the second value is reduced
but still elevated. Before discontinuing psychotropic medications,
one should consult with the prescribing psychiatrist to prevent
322 worsening of the patient’s mental symptoms.
Pseudoprolactinoma refers to a nonfunctioning sellar or supra-
sellar mass associated with hyperprolactinemia caused by stalk dis-
ruption. The prolactin level is seldom above 150 ng/mL. However,
before making such a diagnosis, one must exclude hook effect with
a 100-fold diluted sample. Prolactin levels are typically normalized
within several days after initiation of dopamine agonists, as
lactotrophs are still sensitive to dopamine, but local compressive
symptoms do not improve. In contrast, patients with true macro-
prolactinoma experience more gradual decrease in prolactin levels
after they are put on dopamine agonists, but they could expect
improvement in compressive symptoms within 12 hours to days,
and imaging evidence of tumor shrinkage in weeks.
Polycystic ovary syndrome (PCOS) and hyperprolactinemia are
among the most common causes of menstrual irregularities and
infertility, and affect women of similar ages. PCOS has also been
associated with hyperprolactinemia. However, multiple studies
have shown that the prevalence of hyperprolactinemia in women
with PCOS is not significantly higher than that of matched popula-
tions. Although mild elevations of DHEA-S or DHEA are common
in patients with hyperprolactinemia, hirsutism is rare, and when
present is always associated with an increase in testosterone level,
likely reflecting possible coexisting PCOS. Therefore the presence
of hyperprolactinemia in patients with PCOS or hirsutism warrants
additional evaluation.
Management of Secondary Hyperprolactinemia
Treatment of secondary hyperprolactinemia should focus on cor-
recting the underlying conditions, for example treating
hypothyroidism, and resection of nonfunctioning pituitary tumors.
For drug-induced hyperprolactinemia, the responsible medications
should be removed or replaced with alternatives. Newer antipsy-
chotics such as aripiprazole (Abilify) may be used in place of older
agents such as risperidone (Risperdal) because they have better met-
abolic/hormonal profiles. For irreversible conditions such as end-
stage renal disease, hyperprolactinemia can be effectively controlled
with dopamine agonists. Ectopic prolactin secretion, which occurs
in paraneoplastic syndrome, is a rare exception where dopamine
agonists are ineffective, because extrapituitary production
of prolactin is driven by alternative promoters, which do not
respond to dopamine. Asymptomatic patients with modest hyper-
prolactinemia may not need treatment, however, and sex hormone
replacement may be adequate for correcting hypogonadism if fertil-
ity is not desired.
Management of Prolactinoma
The goals for managing prolactinomas are twofold: treating symp-
tomatic hyperprolactinemia, and relief of tumor mass effects. Treat-
ment thus needs to be tailored to the patient’s unique clinical picture
and the desired outcome. Mass effects are not a concern for micro-
prolactinomas, whereas for patients with giant prolactinomas
(defined as >4 cm or >2 cm of suprasellar extension) and extreme
hyperprolactinemia, normalization of prolactin levels is less likely,
and treatment should focus on reversal or minimization of mass
effects. The following are appropriate options in specific settings.
Observation
Active surveillance is appropriate for patients with microprolacti-
noma who are asymptomatic or not troubled by galactorrhea,
especially if fertility is not a concern. As long as regular menses
are preserved, they seem to be spared from any long-term conse-
quences from hyperprolactinemia. Bone mineral density appears
to be preserved in these patients. It is noteworthy that a significant
fraction of patients may have tumor resolution during surveillance
without treatment. Tumor expansion is a rare event, and serial
measurements of serum prolactin level are effective for monitoring
interval tumor growth. Pituitary imaging is indicated when there is
significant increase in prolactin level or emergence of local com-
pression symptoms.

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Hormonal Replacement
For patients with microprolactinoma bothered only by symptoms
related to hypogonadism including menstrual abnormalities, sex-
ual dysfunction, and osteoporosis, but who no longer desire fertil-
ity, hormonal replacement is a valid alternative to dopamine
agonists, especially when the latter are not tolerated or are contra-
indicated. This can be achieved with oral contraceptive pills in pre-
menopausal women, or testosterone in men. This approach
compares favorably to dopamine agonists in terms of cost and side
effects. Patients may experience slight increases in prolactin level,
but tumor progression has not been associated with use of oral con-
traceptive pills for up to 2 years. It would be prudent to use lower
doses of estradiol ( 30 μg/day) and closely monitor patients for
prolactin level and tumor growth.
Dopamine Agonists
Medical treatment with dopamine agonists has replaced surgery as
the first-line treatment for prolactinomas, with excellent efficacy in
achieving treatment goals and minimal risk. The therapeutic effects
of dopamine agonists are mediated by dopamine D2 receptors in
tumor cells, which inhibit prolactin synthesis and secretion, slow
cell proliferation, and reduce tumor vascularity. Normalization of
prolactin levels and reduction of tumor size can be expected in the
majority of patients. A small fraction of prolactinomas is resistant
to dopamine agonists, as defined by failure in normalizing prolactin
level, reduction in tumor size by 50%, or restoration of gonadal
function with standard doses. In general, microprolactinomas are
more sensitive to dopamine agonists than macroprolactinomas
are, and men are more likely to be drug resistant than are women.
Rapid responders experience significant improvement of visual
symptoms within 24–72 hours; some of them may develop compli-
cations resulting from the rapid receding of macroprolactinomas
(uncorking), e.g., pituitary apoplexy, optic chiasm herniation,
and/or CSF leak. For most patients, however, progressive reduction
of tumor size occurs over the course of months to years, though some
patients may never experience tumor shrinkage despite normaliza-
tion of prolactin levels at the highest tolerated doses.
Patients with microprolactinoma may discontinue treatment
upon menopause because their treatment goal has been fulfilled.
Patients with macroprolactinoma, on the other hand, may require
life-long treatment to prevent tumor regrowth. A meta-analysis
showed that a small fraction of patients may enter long-term remis-
sion after discontinuing dopamine agonists (21% for microprolac-
tinomas and 16% for macroprolactinomas). The odds are
significantly improved if patients have been treated for at least
2 years and tumor size reduced by 50%. The 2011 Endocrine
Society practice guidelines suggest that tapering or discontinuing
dopamine agonists may be attempted in patients who have been
treated for at least 2 years and experienced complete biochemical
and radiographic resolution. The risk for recurrence after drug dis-
continuation is related to the size of adenoma at the time of the
diagnosis. For tumors larger than 2 cm, especially giant prolactino-
mas, tapering the dopamine agonists to a lower maintenance dose
for life-long treatment after achieving maximal tumor reduction
would be a better strategy for these patients. Tapering or with-
drawal of dopamine agonists should be followed by close surveil-
lance of prolactin levels and pituitary MRI when prolactin level
increases, especially during the first year.
TABLE 2 Use of Dopamine Agonists in Hyperprolactinemia
DOSING
ROUTE FREQUENCY
Bromocriptine PO Twice a day
intravaginal1
Cabergoline PO Once to twice a week
1
Not FDA approved for this indication.
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Three dopamine agonists are currently used for treating hyper-
prolactinemia, including bromocriptine (Parlodel), cabergoline
(Dostinex), and quinagolide (available only in Europe). Bromo-
criptine was the first dopamine agonist available, and it has the best
established safety record. It is still the only dopamine agonist
approved by the Food and Drug Administration (FDA) to be used
in pregnancy, when indicated. Cabergoline is a more specific ago-
nist of the D2 dopamine receptor, and is superior in many respects
to bromocriptine, for example, because of dosing convenience, tol-
erability, and treatment efficacy. Many patients not controlled with
bromocriptine may achieve normal prolactin levels after switching
to cabergoline, which has become the drug of choice for cases not
involving pregnancy. The safety data for cabergoline are not as
extensive as those for bromocriptine. Common side effects for this
class of drugs include nausea, orthostatic hypotension, fatigue,
mental fogginess, and, less frequently, nasal stuffiness, Raynaud
phenomenon, constipation, depression, and psychosis. Nausea is
more common in patients taking bromocriptine; for these patients
the intravaginal route1 can be tried. Patients receiving higher doses
of cabergoline are at risk of developing cardiac valvulopathy. This
has so far been a concern for patients with Parkinson’s disease, who
may require much higher doses. However, the life-long exposure to
high cumulative doses in patients with resistant prolactinoma is
considerable, and regular echocardiogram surveillance is recom-
mended for patients taking doses higher than 2 mg/week. Dosing
regimens for bromocriptine and cabergoline are listed in Table 2.
In general, patients should be started on the lowest doses and
titrated upward monthly based on the serum prolactin level until
treatment goals are reached.
Surgery
With the availability of the second-generation dopamine agonists,
Hyperprolactinemia
surgery is mostly reserved for the following situations: (1) patients
intolerant of, or resistant to, dopamine agonists; (2) women with
macroprolactinoma who are planning for conception, to forestall
tumor expansion during pregnancy; (3) pituitary apoplexy threat-
ening neurological and visual functions if not managed urgently.
Transsphenoidal tumor resection is the standard surgical
approach. Perioperative mortality and morbidity are low in the
hands of experienced pituitary surgeons in high-volume centers.
Major surgical complications include visual loss, CNS infection,
stroke, and oculomotor palsy. Craniotomy is occasionally needed
323
for masses with extrasellar extensions that may be inaccessible by
the transsphenoidal route, with higher risk for complications. Post-
operatively patients need to be monitored for signs of diabetes insi-
pidus and secondary adrenal insufficiency, which may be transient
or permanent.
Radiotherapy
Radiotherapy is inadequate as a primary treatment for prolacti-
noma, as its efficacy is poor and latency long. It is also associated
with long-term complications including permanent hypopituita-
rism, cerebrovascular accidents, and secondary intracranial malig-
nancies. Currently it is reserved mostly for patients with aggressive
1
Not FDA approved for this indication.
USUAL DOSE
STARTING DOSE RANGE
1.25 mg after dinner or before bed for 1 week, then twice a day 2.5–10 mg/day
0.25 mg twice a week or 0.5 mg once a week 0.5–2 mg/week

V Endocrine and Metabolic Disorders
324
and malignant prolactinomas failing medical/surgical treatment.
Stereotactic radiosurgery is preferred over conventional fraction-
ated radiotherapy for more convenient dosing, better efficacy,
and lower rate of complications. However, radiosurgery should
not be attempted for tumors in close proximity to the visual appa-
ratus (less than 5 mm of clearance), as it is associated with an unac-
ceptably high rate of vision loss.
Management of Prolactinoma During Pregnancy
Mild hyperprolactinemia is part of normal pregnancy, and there
are concerns for the safe use of dopamine agonists in pregnant
women. There is convincing evidence that as long as bromocrip-
tine is withdrawn within a week after confirmation of pregnancy,
obstetric outcome is not altered. Less robust data to date suggest
that continuing bromocriptine treatment till term is also safe.
Despite its longer half-life, as long as cabergoline is discontinued
in early pregnancy, it also has not been found to be associated
with adverse outcomes. Until there is incontrovertible evidence
for the absolute safety of these dopamine agonists, however, it
is prudent to discontinue these drugs as soon as pregnancy is con-
firmed. Given its shorter half-life and established safety record,
bromocriptine is the preferred agent for fertility induction in
women with hyperprolactinemia, although cabergoline would
also be acceptable if bromocriptine is not tolerated. The major
indication to treat prolactinomas medically during pregnancy is
the concern for tumor expansion. Such risk is negligible for micro-
prolactinomas. For patients with macroprolactinoma, however,
symptomatic tumor expansion during pregnancy can occur in
up to about 30% of cases. This risk can be significantly reduced
if the patient has been treated with a dopamine agonist for at least
a year with evidence of tumor shrinkage, or has undergone
pituitary surgery or radiotherapy prior to pregnancy. Until these
conditions are met, women of childbearing age with macroprolac-
tinomas should be advised to take nonhormonal contraceptive
measures. For patients who fail to achieve tumor shrinkage with
dopamine agonists or cannot tolerate them, prophylactic surgery
prior to pregnancy may be considered, after careful discussion
with the patient on surgical risks and the possibility of permanent
hypopituitarism, which further impairs fertility. The Endocrine
Society practice guidelines recommend against measurement of
serum prolactin levels during pregnancy. Instead the patient
should be followed clinically for any signs or symptoms of tumor
expansion. MRI without gadolinium and visual field testing
should be done when clinical suspicion arises. If tumor expansion
is confirmed, the patient should be reinitiated on bromocriptine.
Debulking surgery is reserved for patients failing or not tolerating
medical treatment. Lactation usually does not cause tumor
progression, and patients are encouraged to breastfeed their
infants with close surveillance. They should not take either
bromocriptine or cabergoline, however, as both are secreted in
the milk.
Management of Resistant and Malignant Prolactinoma
Several other treatment options are available for patients who fail
the highest tolerated doses of dopamine agonists, surgery, and
radiation. A small fraction of these patients have malignant prolac-
tinoma, which is defined by extrapituitary metastasis; histopatho-
logically, malignant prolactinomas can appear very similar to
aggressive prolactinomas. An alkylating agent, temozolomide
(Temodar)1, has been successfully used in the treatment of aggres-
sive pituitary adenoma and pituitary carcinoma. Monotherapy
with temozolomide has been established as the first-line chemo-
therapy for these conditions, following documented tumor growth
despite standard therapies. Selective estrogen receptor modulators
(SERMs), including raloxifene (Evista)1 and tamoxifen (Nolva-
dex)1, have been found to be useful adjuncts that can reduce pro-
lactin level and inhibit tumor growth.
1
Not FDA approved for this indication.
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HYPERTHYROIDISM
Method of
William J. Hueston, MD
CURRENT DIAGNOSIS
• Hyperthyroidism or thyrotoxicosis is most often caused by
Graves’ disease, toxic nodular goiter (Plummer’s disease), or
acute thyroiditis.
• Common symptoms in hyperthyroidism are tachycardia, ele-
vated systolic blood pressure, tremor, and anxiety. Patients with
Graves’ disease also might exhibit exophthalmos. In contrast,
elderly patients can present with apathetic hyperthyroidism,
which can be confused with hypothyroidism.
• Hyperthyroidism should be suspected in all patients who pre-
sent with atrial fibrillation, palpitations, panic disorder, or
unexplained tremors.
• Thyroid storm is an acute, life-threatening condition usually
occurring in patients with undiagnosed or untreated hyper-
thyroidism placed under physiologic stress.
• An elevated free T4, usually with a low thyroid-stimulating
hormone is the hallmark of hyperthyroidism, and anti–thyroid-
stimulating hormone antibodies can help identify Graves’
disease.