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- To understand the release and control of prolactin
secretion and its actions both physiologically and
pathologically.
- To appreciate the workup and treatment in a case of
hyperprolactinemia and its treatment.
- To understand the anatomy, differentiation, and
development of the breast and the actions of various
endocrine factors resulting in lactation.
- To recognize the potential CNS abnormalities which may
result in hyperprolactinemia
Definitions
Prolactin: A product of the
anterior pituitary 199 amino acids with glycosylated and
nonglycosylated forms. It possesses a myriad of effects with the
most noticeable being lactation. Its secretion is inhibited by
prolactin-inhibiting factor.
Prolactin Inhibiting Factor (PIF): Inhibits the release
of prolactin and is purported to be dopamine which is secreted
by the tuber infundibular neurons.
Lactation: The production of milk through the actions
of prolactin on breast tissue to create polyamines, casein,
lactose and phospholipids.
Galactorrhea: The secretion of milky fluid from the
breast at times other than pregnancy.
Micro/macroadenoma of the pituitary secreting prolactin:
Small tumors usually located in the lateral aspects of the
pituitary which are surrounded by a pseudo capsule which
contains secretory granules of prolactin. Microadenomas are < 1
cm; macroadenomas are > 1 cm. Hypotheses for their origin
include reduced pituitary dopamine concentrations and/or a
vascular isolation of the adenoma cells.
Outline
- Prolactin - The hormone of lactation
Prolactin was first identified as a product of the anterior
pituitary in 1933 (1). Since that time, it has been found in
nearly every vertebrate species. The specific activities of
human prolactin (hPRL) have been further defined by the
separation of its activity from growth hormone (2) and
subsequently by the development of radioimmunoassays (3-5).
Although the initiation and maintenance of lactation is a
primary function, many studies document a significant role
for prolactin activity both within and far beyond the
reproductive system.
Prolactin Secretion
There are 199 amino acids within hPRL with a molecular
weight of 23,000 daltons. Although human growth hormone and
placental lactogen have significant lactogenic activity,
they have only a 16% and 13% amino acid sequence homology
with prolactin, respectively.
In the basal state three forms are released: a monomer, a
dimer, and multimeric species called little , big and
big-big PRL, respectively (6-8). The two larger species
can be degraded to the monomeric form by reducing disulfide
bonds (9). The proportions of each of these prolactin
species vary with physiologic, pathologic, and hormonal
stimulation (9,10-12). The heterogeneity of secreted forms
remains an active area of research. Overall, these studies
indicate that little prolactin (MW 23,000) constitutes
more than 50% of all combined prolactin production (8,11-12)
and is most responsive to extra pituitary stimulation or
suppression. The bioactivity and immunoreactivity of
little prolactin is influenced by glycosylation (13-16).
It appears that the glycosylated form is the predominant
species secreted, but the most potent biological form
appears to be the 23,000 MW nonglycosylated form of
prolactin (15). To some degree, the heterogeneity of
prolactin forms may explain the biologic heterogeneity of
this hormone, but it further complicates the physiologic
evaluation of prolactin's myriad effects.
In contrast to other anterior pituitary hormones, which are
controlled by hypothalamic-releasing factors, prolactin
secretion is primarily under inhibitory control mediated by
dopamine. Multiple lines of evidence suggest dopamine, which
is secreted by the tuberoinfundibular dopaminergic neurons
into the portal hypophyseal vessels, is the primary
prolactin-inhibiting factor. Dopamine receptors have been
found on pituitary lactotrophs (17),and treatment with
dopamine or dopamine agonists suppresses prolactin secretion
(18-23). The dopamine antagonist metaclopramide abolishes
the pulsatility of prolactin release and increases serum
prolactin levels (19,20,24). Interference with dopamine
release from the hypothalamus to the pituitary routinely
raises serum prolactin levels. -Aminobutyric acid(GABA) and
other neuropeptides may also function as prolactin-inhibiting
factors (Table 1) (25-28). Several hypothalamic polypeptides
that increase prolactin-releasing activity as well as
physiologic and pathologic drugs in hyperprolactinemia are
also listed in Table 1.
- Mammary gland - A target of prolactin
action
The mammary glands are specialized skin structures which
retain the relatively simple tubulosecretory units of the
sweat glands. At approximately 35 days of embryonic
development, a thickening in the malpighian layer on the
ventrolateral surface begins the development of the breast
(mammary ridges). Mammalian differentiation is mainly
characterized by the development of increasingly complex
branching and ductal systems which vary by species according
to whether the ducts from each lobule join together before
opening onto the nipple or if they remain separate. The
basic component of the breast lobule is the hollow alveolus
or milk gland lined by a single layer of milk-secreting
epithelial cells. Each alveolus is encased by a
crisscrossing skeleton of contractile myoepithelial cells,
and encasing this structure is a rich capillary network. The
lumen of the alveolus connects to a collecting intralobular
duct by means of a thin nonmuscular duct. Contractile muscle
units line the intralobular ducts that eventually reach the
surface via 15 to 25 openings in the areola. Each breast has
15 to 20 lobes.
Despite gross anatomical differences, histologic features
are similar in all species. The alveoli are embedded in a
stroma of loose intralobular connective tissue, adipose
tissue, and denseinterlobular connective tissue. Thick septa
lie between the lobes. In those forms with pendulous udders,
the septa connect with suspensory ligaments anchored to the
abdominal wall and skeleton to support the breast. Small
ducts are lined by secretory cells whereas larger ducts and
sinuses are lined by a nonsecretory two-layered cuboidal
epithelium.
A few days after birth, the breast occasionally demonstrates
its functional capacity by secreting witches milk which is
due to elevated prolactin in the newborn. The breast
requires a substantial fat pad for appropriate early
development. Another mesenchymal element required for
development is adequate capillary vasculature.
Mammary development is essentially the same in male and
females at birth. In some species(horse) no nipple formation
occurs because testosterone causes a proteolytic digestion
of the connection of the mammary bud from the epithelium.
Exposure of female embryos to testosterone during nipple
differentiation can result in failed mammary development.
Conversely, exposure of a male embryo to cyproterone
acetate, an anti-androgen, results in mammary development.
It is hypothesized that the testosterone production of the
developing male embryo desensitizes the mammary bud to
eventual stimulation by estrogen. This is not an all or none
effect, however, as gynecomastia can occur in 60% of
pubertal boys and is hypothesized to be an alteration in the
estradiol-to-testosterone ratio occurring at puberty.
The number of mammary glands in mammals ranges from the
usual two in the human to 25 in the opossum. Glands are
distributed along the axillalinguinal embryonic milk line
(rat and pig)and restricted to the thoracic region (man,
gorilla, elephant), abdominal region (whales, seals),and
inguinal regions (horses and cows) in other species.
Polythelia (accessory nipples) and polymastia (accessory
glands) can occur anywhere from the knee to the neck in man.
It occurs in 1% of the population with a racial predilection
(Japanese, above the midthoracic; European,below the
midthoracic region).Athelia or amastia are rare, but
unilateral failure of breast development during puberty or
extreme asymmetry is not uncommon. This may result from
abnormal development of the mammary bud or from traumatic or
surgical destruction of the bud postpartum.
Support,education, and eventual augmentation mammoplasty are
required. Biopsy of the breast bud before or during puberty
must be avoided.
- Breast changes during physiological
hormonal fluctuations influencing the actions of prolactin
- Puberty
The major influence on breast growth during puberty is
estrogen, which acts by the development of prolactin-dependent
estrogen receptors. In most women the first response to
rising estrogen levels is an increase in size,
pigmentation of the areola, and the formation of abreast
mass beneath the areola (thelarche). The primary effect
of estrogen is to stimulate growth in the ductal portion
of the gland. This growth can begin at any age between 8
to 14 years and normally occurs in a span of four years.
Normal development requires prolactin,estrogen,
progesterone, growth hormone, insulin, cortisol, thyroid
and parathyroid hormone,and growth factors; but this
growth is only in anticipation of the development of the
fully functional status characterized by full
development of the alveoli which occurs only during
pregnancy.
Premature thelarche is characterized by the
nonprogressive nature and absence of other secondary
sexual characteristics. Confirmation is obtained by a
normal FSH, LH, prepubertal estrogen concentration,
immature vaginal maturation index, and a negative
ultrasound exam to rule out ovarian pathology. If other
secondary sexual characteristics are noted, a hand film
for bone age and a GnRH stimulation test are performed
to document precocious puberty.
Cyclic changes in estrogen/progesterone during the
normal menstrual cycle result in continued development
of breast structures. As estrogen and progesterone
levels fall near the end of the cycle, prolactin-induced
secretory changes become evident in the alveolar lumen
during the first few days of the menses. The breasts are
largest in this phase and are smallest on days 4to 7 of
the cycle, which is the ideal time for breast self-exam.
- Pregnancy
Differentiation of the breast to its mature functional
status occurs by the third month of pregnancy. The true
glandular acini (true alveoli) develop under the
influence of prolactin,human placental lactogen,
estradiol, progesterone, insulin, cortisol, growth
hormone, IGF-1,and EGF. Thyroid hormones also promote
alveolar growth of the glands.
Pregnancy provides a unique opportunity to evaluate the
facilitator and inhibitory actions of various hormones;
specifically, the interactions of prolactin, estradiol,
and progesterone on the development of the lactating
breast.
In humans, prolactin acts to (1) increase arginase
activity, (2) stimulate ornithine decarboxylase
activity, and (3) enhance the rate of transport of
polyamines into the mammary gland. All result in
increased spermine and spermidine synthesis (polyamines)
which are required for milk production. The polyamines
stabilize membrane structures, increase transcriptional
and translational activities, and regulate enzymes.
Prolactin in cultured mammary gland explants also
elicits increased messages and synthesis of casein,
spermidine,lactose, and phospholipids which are all
required for lactation. Estradiol levels, rising
throughout pregnancy, act at the hypothalamic level to
increase prolactin secretion.
Progesterone interferes with prolactin action at the
alveolar cell's prolactin receptor level. While estrogen
and progesterone are required to get full activity of
the prolactin receptor,progesterone antagonizes the
positive action of prolactin on its receptor by (1)
inhibiting up regulation of the prolactin receptor, (2)
reducing estrogen binding (lactogenic activity), and
(3)competing for binding at the glucocorticoid receptor.
Actual lactation occurs after birth by allowing
prolonged prolactin elevation without progesterone
inhibition because of the more rapid clearance of
progesterone in contrast to prolactin. It takes
approximately seven days for prolactin to reach
non-pregnant levels, while estrogen and progesterone
elevations are cleared in three to four days postpartum.
In the first week postpartum, prolactin levels decline
50% (to about 100 ng/ml). Suckling results in increased
prolactin, which is important in the initiation of
lactation. Until approximately two to three months
postpartum, basal levels are 40 to 50 ng/ml in the
lactating female, and there are large (10 to 20-fold)
increases with suckling. Basal prolactin levels remain
normal or slightly elevated with a twofold increase with
suckling in the third to sixth months postpartum.
Increased prolactin levels are required for lactogenesis;
however,nonpregnant levels are adequate to maintain
lactation.
Progesterone, while still present postpartum, has less
effect once lactation has begun because the number of
progesterone receptors has decreased significantly (also
related to the precipitous drop in estrogen). Once
lactation has begun, progesterone, which has a greater
affinity for milk fat than for the progesterone
receptor, is cleared rapidly.
Inhibition of lactation postpartum can be accomplished
medically by utilizing bromocriptine(an ergot alkaloid
which is a dopamine agonist) at 2.5 mg bid for two
weeks, although this not necessary and may be dangerous
in women with hypertension. Breast-binding, ice, and
avoidance of nipple stimulation will result in cessation
of lactation in one week.
- Prolactin Actions
- Evaluation of Prolactin
When evaluating prolactin levels, physiologic
alterations or conditions may result in transient as
well as persistent elevations in prolactin levels.
Disorders categorized as physiologic conditions and
drug-related do not always require intervention.
Plasma levels of immunoreactive prolactin are 5-27 ng/ml
during the menstrual cycle. Samples should not be drawn
soon after the patient awakes or after procedures.
Prolactin is secreted in a pulsatile fashion with a
pulse frequency ranging from about 14 pulses per 24
hours in the late follicular phase to about nine pulses
per 24 hours in the late luteal phase. There is also a
diurnal variation with the lowest levels occurring the
midmorning after the patient awakes. Levels rise 1 hour
after the onset of sleep and continue to rise until peak
values are reached between 5:00 and 7:00 AM (29,30). The
pulse amplitude of prolactin appears to increase from
early to late follicular and luteal phases (31-33).
Because of the variability of secretion and inherent
limitations of radioimmunoassay, an elevated level
should always be rechecked. This is preferably drawn
midmorning and not after stress, venipuncture,breast
stimulation, or physical examination, which increases
prolactin levels.
Prolactin and TSH determinations are basic evaluations
in infertile women. Infertile men with hypogonadism also
should be tested. Likewise, prolactin levels should be
measured in the evaluation of amenorrhea, galactorrhea,
galactorrhea with amenorrhea, hirsutism with amenorrhea,
anovulatory bleeding, and delayed and precocious
puberty.
- Lactation
Prolactin, the major hormone in lactogenesis, is
modulated by a combination of second messenger
activities which include cyclic nucleotides,
prostaglandin, and calcium ion charges,polyamine
production, and growth factors. In pregnancy cAMP and
cGMP increase progressively and may be involved in
stimulation of mitogenic and morphogenic processes that
occur with pregnancy. At delivery cAMP levels fall
precipitously, and cGMP levels continue to rise and stay
elevated in the lactational period. cAMP stimulators
abolish prolactin effects,while cGMP increases
(marginally) the activity of prolactin. Prolactin
certainly does not work via cAMP nor cGMP, but its
activity may be modulated by cGMP.
Prolactin can cause perturbations in phospholipid
metabolism via the activation of phospholipase enzymes
in the cell membrane. Consequent to this action, protein
kinase C maybe activated and modulate prostaglandin
production and/or intracellular calcium ions.
As mentioned previously, prolactin increases enzyme
activities and results in increased polyamine synthesis
with resultant increased message and synthesis of
products required for lactation.
Growth factors, such as insulin-like growth factor and
epidermal growth factor, have been reported to cause
mitogenesis in mammary cells and may play a role in the
effects of prolactins.
- Galactorrhea
- Etiologies
Galactorrhea refers to the secretion of milky fluid from
the breast at times other than pregnancy (six months
after delivery and not nursing) or breast-feeding (six
months after cessation). Prolactin is under chronic
inhibition by prolactin-inhibiting factor (PIF) which is
mediated by dopamine, in contrast to the
peptide-releasing hormones for other hypothalamic
hormones. PIF is released by specialized neurons in the
hypothalamus into the pituitary portal system and is
transported to the anterior pituitary where it inhibits
the synthesis and release of prolactin by the
lactrotrophs. Prolactin in converse inhibits the
pulsatile secretion of GnRH. Prolactin has short loop
positive effects on dopamine which reduce GnRH by
suppressing arcuate nucleus function, perhaps in a
method mediated by endogenous opioid activity. PIF
appears to be released as a package with GnRH from the
hypothalamus. Galactorrhea can result from any of the
following mechanisms:
- Activation of the afferent limb of the
neuroendocrine arc. Examples include stimulation of
the breast by suckling, excessive manual
stimulation, thoracotomy incisions, herpes zoster of
thoracic nerves, spinal cord lesions, breast
surgery.
- Decreased dopamine or PIF release or transport
or interference with dopamine binding. Commonly used
drugs such as phenothiazines, tranquilizers, opiates
(B enkephalin and morphine), reserpine derivatives,
amphetamines, estrogens (BCP) can interfere with
dopamine metabolism and result in galactorrhea.
Numerous drugs interfere with dopamine secretion
(Table 1). The same principles utilized in the
management of pituitary microadenomas or hyperplasia
can be applied in these situations. If
discontinuation of the drugs is feasible, resolution
of hyperprolactinemia is uniformly prompt. Stress,
trauma, surgery, and marathon running can reduce
hypothalamic dopamine release. Galactorrhea can also
occur after pituitary stalk section or with a
hypothalamic or pituitary condition blocking
dopamine transport (Tables 1 and 2).
- Autonomous pituitary prolactin section.
Prolactinomas of the anterior pituitary may cause
elevated prolactin. Also, ectopic production of
prolactin can be found in tumors such as renal cell,
liver, and uterine fibroids.
- Elevated TRH, which acts as an enhancer of
prolactin release. TSH is the most sensitive method
to evaluate for hypothyroidism. Occasionally,
patients with hypothyroidism exhibit
hyperprolactinemia with remarkable pituitary
enlargement due to thyrotroph hyperplasia. These
patients respond to thyroid replacement with
reduction in pituitary enlargement and normalization
of prolactin levels (34).
- Chronic renal failure. Hyperprolactinemia occurs
in 20-75% of women with chronic renal failure.
Prolactin levels are not normalized through
hemodialysis but are normalized after
transplantation (35-38). Occasionally, women with
hyperandrogenemia also have hyperprolactinemia.
Elevated prolactin levels may alter adrenal function
by enhancing the release of adrenal androgens such
as DHEAS (39).
- Physical Findings Associated with Galactorrhea
The cessation of normal ovulatory processes attributed
to elevated prolactin levels may be related to the
following gonadal and hypothalamic-pituitary effects:
reduction in granulosa cell number and FSH binding (40);
inhibition of granulosa cell 17 estradiol production by
interfering with FSH action (40-42); inadequate
luteinization and reduced progesterone (43-45); and the
suppressive effects of prolactin on GnRH pulsatile
release which may mediate most of the anovulatory
effects (46-59).
Although isolated galactorrhea is commonly considered
indicative of hyperprolactinemia,prolactin levels are
within the normal range in nearly 50% of patients
(60-62). In such cases,an earlier transient episode of
hyperprolactinemia may have existed which triggered
persistent galactorrhea despite normal prolactin levels.
This situation is very similar to nursing mothers in
whom milk secretion, once established, continues despite
normal prolactin levels. Repeat testing is occasionally
helpful in detecting hyperprolactinemia. Approximately
one-third of women with galactorrhea have normal menses.
Conversely, hyperprolactinemia commonly(66%) occurs in
the absence of galactorrhea, which may result from
inadequate estrogenic or progestational priming of the
breast.
In patients with both galactorrhea and amenorrhea
(including the syndromes described and named by Forbes,
Henneman, Griswold, and Albright, 1951; Chiari and
Frommel, 1985; and Argonz and del Castilla, 1953),
approximately of that two-thirds will have
hyperprolactinemia. Of that group, approximately
one-third will have a pituitary adenoma (63).
Anovulatory women carrying the diagnosis of polycystic
ovarian disease are noted to be hyperprolactinemic in
3%to 10% (64,65).
In all cases of delayed puberty, pituitary abnormalities
including craniopharyngiomas and adenomas must be
considered. Additionally, the multiple endocrine
neoplasia type 1syndrome should be considered
particularly in patients who present with a family
history of multiple adenomas (65). Prolactin and
thyroid-stimulating hormone (TSH) levels should be
measured in all patients with delayed puberty.
Once an elevated prolactin level is documented, the
gynecologist must be familiar with neuroanatomy as well
as imaging techniques and their interpretation. Patients
can be reassured that hyperprolactinemia usually is
associated with a relatively benign condition (pituitary
microadenoma or hyperplasia) that requires only periodic
monitoring. However, it is critical for the physician to
exercise vigilance and to consider the evaluation of
other potential etiologies, particularly sellar/suprasellar
tumors (Table 1). Levels of TSH should be measured in
all cases of hyperprolactinemia.
- Imaging Techniques of the Pituitary
Prolactin levels in patients with larger microadenomas
and macrdoadenomas are usually higher than 100 ng/ml.
However, levels may be lower with smaller microadenomas
and other suprasellar tumors that may be missed on a
coned-down view of the sella turcica. Inpatients with
an identifiable drug-induced or physiological etiology
for hyperprolactinemia,scanning may not be necessary.
Coned-down views of the pituitary are occasionally
obtained as a screening technique to rule out a mass
effect in the sella. The community standard of
care,resources available, and expertise of the operator
will influence the imaging technique: coned-down view of
sella, CT scan, or MRI. An MRI is considered by neuro
radiologists to be the optimal technique to evaluate the
sella/suprasellar region (67). The cumulative radiation
dose from multiple CT scans may cause cataracts, and the
coned-down views or tomograms of the sella are very
insensitive and likewise expose the patient to
radiation. Even modest elevations of prolactin can be
associated with microadenomas or macroadenomas,
nonlactotroph pituitary tumors, and other central
nervous system abnormalities (Table 2).
For patients with hyperprolactinemia who desire future
fertility, MRI is indicated to differentiate a pituitary
microadenoma from a macroadenoma as well as to identify
other potential sellar-suprasellar masses. Although they
are infrequent when pregnancy-related complications
occur, sellar-suprasellar masses are associated with
macroadenomas twice as often as with microadenomas, and
patients should make informed decisions (Table 3).
- Prolactinomas
Prolactinomas retain their responsiveness to the inhibitory
effects of dopamine; therefore, their origin still remains
somewhat nebulous. Hypotheses include: reduced dopamine
concentrations in the pituitary portal system and vascular
isolation of the tumor which precludes dopamine inhibition.
These tumors originate in the lateral aspects of the
anterior pituitary and are surrounded by a pseudo capsule.
These tumors may be cystic or degenerating and are often
discolored (blue, brown, or gray) as the result of
hemorrhage. The parenchymal cells of the tumors are densely
arranged in small lobules which, in turn, are surrounded by
abasement membrane. Secretory granules of prolactin in these
tumors are 400 to 500 nm in diameter, with normal
lactotrophs containing 700 nm granules. Some have reported
prolactinomas in 12% to 25% of women with secondary
amenorrhea; however, the actual incidence is somewhat less.
The incidence of prolactinomas in women with galactorrhea
but regular menses is quite low.
- Microadenoma
Microadenoma. A pituitary microadenoma or
hyperplasia is the cause of hyperprolactinemia in most
patients. In over one-third of women with
hyperprolactinemia, a radiologic abnormality consistent
with an adenoma is found. In the remainder, simple
hyperplasia of the pituitary lactotrophs is assumed to
be the cause. Most of these abnormalities are
microadenomas (< 1 CM), and patients can generally be
reassured of a benign course of disease (68,69).
Hypotheses for the formation of microadenomas and
macroadenomas (> 1 cm) include are duction in dopamine
concentrations in the hypophyseal portal system,
vascular isolation of the tumor, or both. The tumors,
which originate in the lateral aspects of the anterior
pituitary,are surrounded by a pseudo capsule. They may
be cystic or degenerating and are often discolored
(blue, gray or brown) as a result of hemorrhage.
Treatment. Microadenomas rarely progress to
macroadenomas. Therapies include expectant, medical
and/or rarely surgical therapy. All women are advised to
notify their physician of chronic headaches, visual
disturbances (particularly tunnel vision consistent with
bitemporal hemianopsia), and extraocular muscle palsies.
Formal visual field testing is rarely necessary.
Expectant Management. In women who do not
desire fertility, expectant management can be utilized
for both microadenomas and hyperplasia if menstrual
function remains intact. Hyperprolactinemia-induced
estrogen deficiency, rather than prolactin itself, is
the major factor in the development of osteopenia (70).
Therefore, estrogen replacement or oral contraceptive
pills are indicated for patients with amenorrhea or
irregular menses. Patients with drug-induced
hyperprolactinemia can also be managed expectantly with
attention to the risks of osteoporosis. Repeat imaging
for microadenomas is usually performed in 6 to 12 months
to insure no further growth of the microadenoma.
Medical Treatment. Ergot alkaloids are the
mainstay of therapy. In the United States, bromocriptine
was approved for use in the United States to treat
hyperprolactinemia caused by a pituitary adenoma. The
ergot alkaloids increase dopamine levels, thus
decreasing prolactin levels. The serum half-life is 3.5
hours, and twice-a-day administration is required. Ergot
alkaloids are excreted via the biliary tree; therefore,
caution is required in the presence of liver disease.
The major adverse effects include nausea,headaches,
hypotension, dizziness, fatigue and drowsiness,
vomiting, headaches, nasal congestion, and constipation.
Many patients tolerate the drug on the following
regimen: one-half tablet every evening (1.25 mg) at
bedtime for one week, an increase of one-half tablet
every evening in the second week, and every morning in
the third week, and finally 2.5 mg twice a day. The
lowest dose that maintains the prolactin level in the
normal range is continued.
An alternative to oral administration is the vaginal
administration of bromocriptine tablets,which is well
tolerated (71). When cannot be used, other medications
such as pergolide, cabergoline, metergoline, and
CV205-502 may be used. In patients with a microadenoma
who are receiving bromocriptine therapy, a repeat MRI
scan may be performed at 6 to 12 months after prolactin
levels are normal. Normal prolactin levels and
resumption of menses should not be considered proof of
tumor response to treatment. Further MRI scans should be
performed only to evaluate new symptoms. Discontinuation
of bromocriptine therapy after two to three years may be
attempted because some adenomas undergo hemorrhagic
necrosis and cease to function. Further attempted, as
some adenomas undergo hemorrhagic necrosis and cease to
function.
- Macroadenomas
Macroadenomas are pituitary tumors greater than 1 cm in
size. Bromocriptine is the best initial and potentially
long-term treatment option, but transphenoidal surgery
may be required. Evaluation for other trophic hormone
deficiencies may be indicated. Macroadenoma symptoms
include severe headaches, visual field changes, and
rarely, diabetes in sipidus and blindness. After
prolactin has reached normal levels, a follow-up MRI is
indicated within six months to document shrinkage or
stabilization of growth. This may be performed earlier
if symptoms develop or exacerbate. Normalized prolactin
levels or resumption of menses should not be taken as
proof of tumor response to treatment.
Medical Treatment. Macroadenomas treated with
bromocriptine routinely show a decrease in prolactin
levels and size; nearly one-half show a 50% reduction in
size and another one-fourth show a 33% reduction after
six months of therapy. Tumor regrowth occurs in over 60%
of cases after discontinuation of bromocriptine therapy;
therefore, long-term therapy is the rule.
After stabilization of tumor size is documented, the MRI
scan is repeated six months later and,if stable, yearly
for several years. Serum prolactin levels are measured
every six months. Because tumors may enlarge despite
normalized prolactin values, re-evaluation of symptoms
at regular intervals (six months) is required.
Surgical Intervention. Tumors that are
unresponsive to bromocriptine or that cause persistent
visual field loss require surgical intervention.
Unfortunately, despite surgical resection,recurrence of
hyperprolactinemia and tumor growth are not uncommon.
Complications of surgery include cerebral carotid artery
injury, diabetes insipidus, meningitis, nasal septal
perforation, partial or pan hypopituitarism, spinal
fluid rhinorrhea, third nerve palsy, and recurrence. Pre
treatment with bromocriptine may result in fibrosis,
making resection more difficult. Periodic MRI scanning
after surgery is indicated, particularly in patients
with recurrent hyperprolactinemia.
Transphenoidal surgery achieves resolution of
hyperprolactinemia with resumption of menses in 40% with
macroadenomas, and 80% with microadenomas. Recurrence
after surgery is approximately 50% (range 10% to 70%).
Unfortunately, 10% to 30% of patients undergoing surgery
develop panhypopituitarism. Other problems of surgery
include CSF leaks,meningitis, and frequent diabetes
insipidus after surgery.
- Other Considerations in the Treatment of Pituitary
Adenomas
In rodents, rapid pituitary prolactin-secreting adenoma
(prolactinoma) occurs with high-dose estrogen
administration (72). However, even conditions associated
with high estrogen levels,such as pregnancy, do not
cause prolactinomas in humans. Indeed, pregnancy may
have a favorable influence on pre-existing prolactinomas
(73,74). Recent studies (75-77) and autopsy surveys (77)
indicate that estrogen administration is not associated
with clinical, biochemical,or radiological evidence of
growth of pituitary microadenomas or the progression of
idiopathic hyperprolactinemia to an adenoma status. For
these reasons, estrogen replacement or oral
contraceptive use for hypo estrogenic hyperprolactinemic
patients secondary to microadenoma or hyperplasia is
appropriate.
Pituitary Adenomas in Pregnancy. Prolactin-secreting
microadenomas rarely create complications during
pregnancy. However, monitoring of patients with serial
gross visual field examinations and fundoscopic
examination is recommended. If persistent
headaches,visual field deficits, or visual or
fundoscopic changes occur, MRI scanning is advisable.
Because serum prolactin levels are elevated throughout
pregnancy, prolactin measurements are of no value.
Although not recommended, bromocriptine use during
pregnancy in women with symptomatic(visual field
defects, headaches) microadenoma enlargement has
resulted in resolution of deficits and symptoms (79-82).
Women with previous transsphenoidal hypophysectomy and
macroadenomas are monitored, as are those with
microadenomas, with the addition of monthly Goldman
perimetry visual field testing. Periodic MRI scanning
may be necessary in women with symptoms or visual
changes. Bromocriptine has been used on a temporary
basis to resolve symptoms and visual field deficits in
symptomatic macroadenoma patients to allow completion of
pregnancy before initiation of definitive therapy.
Breast feeding is not contraindicated in the presence of
microadenomas or macroadenomas (79-82).
Take Home Points
Normal mammary development depends on
a critical interplay of appropriate fat deposition,vascular
supply, and hormone interactions. Estrogen stimulation of ductal
development and progesterone induced development of alveolar
growth and the modulating activities of estrogen, progesterone,
growth hormone, insulin, cortisol, thyroid and parathyroid
hormone with prolactin result in a functional gland. Lactation
postpartum occurs when the inhibitory activity of progesterone
is reduced through its more rapid clearance compared to
prolactin.
- Progesterone antagonizes the alveolar cells prolactin
receptor by:
a. Inhibiting the up regulation of the prolactin receptor
b. Reducing estrogen binding
c. Competing for binding at the glucocorticoid receptor
- Galactorrhea occurs with:
a. Stimulation of the afferent limb of the neuroendocrine
arc
b. Decreased dopamine release or transport or binding
c. Autonomous prolactin secretion
d. Hypothyroidism
e. Chronic renal failure
- Hyperprolactinemia may cause anovulation through:
a. A reduction in granulosa cell number and FSH binding
b. Inhibition of granulosa cell 17 estradiol production by
interfering with FSH action
c. Inadequate luteinization and reduced progesterone
d. The suppressive effects of prolactin on GnRH pulsatile
release.
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