The Pituitary Gland

Getting a handle on the Master Gland

Drugs affecting Pituitary or to test Pituitary function

Chorionic gonadotropin (hCG) (generic, Profasi, A.P.L., Pregnyl, others)

Corticotropin (generic, ACTH, Acthar, H.P., Acthar Gel, others)
Cosyntropin (Cortrosyn)
Gonadorelin hydrochloride [GnRH] (Factrel)
Gonadorelin acetate [GnRH] (Lutrepulse)
Goserelin acetate (Zoladax)
Leuprolide (Lupron.)
Histrelin (Supprelin)
Lypressin (Diapid)
Menotropins [hMG] (Pergonal)
Nafarelin (Synarel)
Octreotide (Sandostatin)
Oxytocin (generic, Pitocin, Syntocinon)
Protirelin (Thypinone, Relefact TRH)
Sermorelin [GHRH] (Geref)
Somatrem (Protropin)
Somatropin (Humatrope)
Thyrotropin [TSH] (Thytopar)
Urofollitropin (Metrodin)
Vasopressin (Pitressin Synthetic)
Vasopressin Tannate (pitressin Tannate in oil)

The Pituitary is a gland about as big as the tip of your index finger, but may be the
most important control center in the body after the brain. It produces more varied
hormones than any other gland. It sits directly under the brain in a pocket called the
sella turcica. It has three main parts the anterior (adenohypophysis), posterior
(neurohypophysis) and the intermediate. The posterior pit. is derived from an
outpocketing of the ventral brain called the infundibulum and it, thus, an extension of
the CNS. It contains the nerve endings, or axon terminals of neurons located in the
hypothalamus.
The anterior pituitary is derived from an outpocketing from the top of the mouth
cavity called. Rathkes pouch. It is therefore, made up of rather different cells than the
brain, with which it is not directly connected. It sits in a web of blood vessels which
are fed partially by a portal system. (What is a portal system?) The other end of this
one is in the base of the brain in an area called the median eminence which is a
section of the arcuate nucleus. Substances produced in the brain are released near the

capillary bed in the med. eminence from which they may descend to the ant. pituitary
by way of the portal system in the infundibular stalk.

Hypothalamic control of the Pituitary

Some of the first endocrine experiments done were to remove glands and observe
what happened. With the pituitary a whole host of things happened when this was
done including death. Therefore they decided to cut the infundibular stalk. When this
was done and they assayed for things in the blood they found that some hormone
levels went up and others went down. For example, Prolactin went up while LH, TSH,
ACTH, oxytocin went down. They therefore concluded that elements were released
from the brain to either inhibit or release each hormone and started searching for what
these were. It was proposed, therefore that there would be a corticotropin releasing
factor (CRF), an LH releasing factor (or LHRF) and an inhibiting factor for prolactin
(PIF). Much of endocrinology in the 50s through the 70s has been the search for
what are the releasing and inihibiting factors.

Production of protein hormones

Hormones in the pituitary are either proteins or peptides. They are synthesized like
other proteins, DNA to RNA etc. but they are almost always chopped up after they are
synthesized, from larger proteins called prohormones. This probably takes place
somewhere in the golgi or the vesicles as was described in the first lecture. (Go to
handout with some prohormones). Discuss POMC briefly, concentrate on GH and
PRL (lookup prohormones).

Growth hormone (Somatotropin)

GH is an 191-amino acid peptide with 2 sulfydryl bridges. It has direct metabolic
effects direct metabolic effects on lipolysis in adipose tissue and on insulin action and
indirect anabolic effects mediated through another class of factors known as
somatomedins. Two drugs are used on this system, somatotropin, which is GH and
somatrem, which has an extra methionine residue at the amino terminal end.

Absorption, Metabolism and excretion

Human GH can be administered im with peak levels occurring in 2-4 hours and active
blood levels persisting for 36 hours.

Pharmacodynamics
GH has cell membrane receptors, but does not appear to act via any of the known
second messengers (cAMP, Ca++ etc.). The immediate effect of injected GH is similar
to insulin with increased uptake of glucose and amino acids and decreased lipolysis.
Within a few hours, however, it has the opposite effects of insulin with increased
lipolysis and impaired glucose uptake.
The major anabolic effects of GH are mediated by somatomedins or insulin-like
growth factors (IGFs). GH promotes release of IGF-I and II predominantly from the
liver which in turn increases uptake of sulfate into cartilage and are probably the
actual mediators of the cellular processes associated with bone growth. GH results in
increases in thymidine uptake into DNA and uridine into RNA which are indicators of
cellular proliferation along with increased conversion of proline into hydroxyproline
indicating cartilage synthesis. No effect of GH in bone after closing of epiphyseal
plates.

Clinical usage of GH
Children with GH deficiency can attain full adult height if given GH in a timely
fashion. GH deficiency is: 1) a growth rate below 4 cm per year and 2) the absence of
a serum GH response to two growth secretagogues. (1:4000 have GH deficiency). (In
infants seizures and hypoglycemia can occur as a result of GH deficiency). GH def.
caused by either diseases of the hypothalamic-hypophyseal region or
craniopharygiomas, but is most often due to lack of GH - releasing factors.

Experimental use of GH
NICHHD is conducting a 10 year study until 1999 to see if final adult height can be
affected in normal GH level short children with GH treatment. [Girls with Turners
syndrome respond.] Short-term trt. of GH-def. adults with GH increased lean body
mass, decreased fat mass and improved psychological well-being. Its safety in adults
in under study. Cost of GH in children is $10,000-$30,000/year.

Somatostatin (GH-IH, somatropin-release inhibiting

hormone)
Somatostatin is a 14 aa. peptide isolated from the CNS. It produces a decrease in
circulating insulin levels and interferes with the ability of TRH to release TSH. Also
identified in the pancreas and other sites in the GI tract. Inhibits release of glucagon,
insulin and gastrin. Inhibits release of GH in acromegalics. Receptors are membrane
glycoproteins. Somatostatin has a shorter half-life and less specificity for actions on

GH than an eight aa. analogue Octreotide (SMS 201-995), which is used instead. It is
24 times more potent than somatostatin in inhibiting GH release but only twice as
potent as somatostatin in inhibiting insulin secretion making it better at treating
acromegaly without causing hyperglycemia.

GHRH (GHRH, Sermorelin)

This is a 40 amino acid peptide (researchers have also found a 44 and a 29 aa.
sequence with effects) that releases GH from somatotrophs. GHRH can be given with
continuous infusion to release GH without down-regulating its receptors. This, like
insulin-induced hypoglycemia, levodopa or iv arginine, is a GH releaser and is used to
test whether the pituitary is capable of making and releasing GH. GHRH can be used
to treat slow-growth. In this action it has some advantages over GH: 1) it preserves
feedback on the pituitary, 2) patients may recover their ability to release GH after this
treatment and the drug can be discontinued for the last phase of growth stimulation, 3)
potentially lower cost, since it is smaller. The disadvantages compared to GH are that
it requires multiple doses per day (vs. once/day or one per two days with GH), not
everyone will respond to GHRH and insufficient studies have been done to assess its
safety.

Octreotide (Sandostatin)

Symptoms associated with VIP tumors and metastatic carcinoid

tumors are reduced.
Non-approved uses: AIDs-associated diarrhea and pituitary tumors.

Actions of Octreotide

Acts like somatostatin and inhibits: serotonin, gastrin, VIP, insulin,

glucagon, secretin, motilin, GH & TSH.
Decreases VIP therefore good with VIPomas: Decreases stool volume
and improves hypokalemia.
Inhibits 5-HT therefore counteracts carcinoid stimulation of 5-HT
which causes flushing, diarrhea and wheezing.
It reduces GH levels in acromegalics.

Prolactin
Prolactin (PRL) is a 198 amino acid peptide synthesized in the anterior pituitary. Its
release is characterized by a circadian rhythm with a nocturnal surge. Production of
milk in all mammals is stimulated by prolactin. It has also been associated with
stimulation of both maternal and female sexual behaviors although a clearcut

demonstration of prolactin synthesis in the brain is still missing. PRL also induces
mitogenesis of lymphocytes and thus has a role in immune responses.
Dopamine,probably of tubero-infundibular origin, is commonly accepted as a PRL
inhibiting factor.
Therefore, the ergot derivative with agonist properties bromocriptine, lowers PRL
levels. Bromocriptine acts by inhibiting PRL release by directly inhibiting pituitary
cells and reducing TRH-induced PRL release. (Bromocriptine stimulates pituitary GH
release in normal subjects and, paradoxically and for unknown reasons, suppresses
GH in acromegalics.
Hyperprolactinemia can produce galactorrhea and hypogonadism and may be
associated with symptoms of a pituitary mass. No preparation is available for use in
PRL-deficient patients. For patients with symptomatic hyperprolactinemia, inhibition
of PRL secretion can be achieved with bromocriptine.

PRL-secreting adenomas
PRL-secreting are the most common of pituitary tumors. Bromocriptine is an accepted
initial treatment for such adenomas. Significant reduction in both tumore size and
serum PRL levels can be demonstrated with bromocriptine treatment. For definitive
therapy of such tumors, eventual surgical excision with or without radiation therapy
probably remains necessary because the effects of long-term bromocriptine therapy
are not known, and expansion of those tumors may occur if bromocriptine is
discontinued.

Amenorrhea-Galactorrhea
Bromocriptine is approved for treatment of these PRL-secreting conditions.

Bromocriptine (Ergoset, Parlodel)

synthetic dopamine agonist (ergot alkaloid)

Used in a variety of hyperprolactinemia syndromes.
Stimulates DA2 receptors (associated with psychosis)

Other uses of Bromocriptine

Approved therapy for amenorrhea-galactorhea, reduces PRL effectively.

alone or in combination with surgery or irradiation may be used for
acromegaly.

Is approved for infertility (1981), acromegaly (1984) and PRL-secreting

pituitary tumors (1985).

Acromegaly
Bromocriptine alone or in combination with surgery or irradiation may be used for
acromegaly.
Acromegalics rarely achieve remission with bromocriptine alone, however, so that
there is still question about its pharmacologic effectiveness in this condition.

Woman, 43, With Recent Amenorrhea

Posted 12/23/2003
Quannetta T. Edwards, BSN, MSN, DNSc,WHCNP, FNP, (Col, ret,
USAF, NC), Sherri Saunders-Goldson, (Major, USAF, NC)

Introduction
A 43-year-old woman presented to a gynecology clinic with a chief complaint of having
missed two menstrual periods. Prior cycles occurred every 30 days with normal flow. She
denied menopausal symptoms or nipple discharge, headaches, visual disturbances,
symptoms of pregnancy, life changes, or stress. History included a tubal ligation but no
medication use or medical problems. Family history was unremarkable.
Findings of a complete physical examination, including a gynecologic examination, were
unremarkable. Laboratory data were ordered, including serum human chorionic gonadotropin
(HCG), blood urea nitrogen (BUN), thyroid-stimulating hormone (TSH), and serum prolactin.
Medroxyprogesterone 10 mg/d was prescribed for five days to start menses if the pregnancy
test should prove negative.
On recommended follow-up three weeks later, the patient returned to report no withdrawal
bleeding. Laboratory data included a negative pregnancy test, normal TSH and BUN levels,
and elevated serum prolactin of 60.0 ng/mL (normal range for nonpregnant females, 1.0 to
25.0 ng/mL[1]; however, lab values can differ).[2-4] A repeat serum prolactin test with morning
fasting yielded similar results, confirming a diagnosis of hyperprolactinemia. Accordingly, an
MRI of the sella turcica was ordered to rule out a pituitary adenoma. A 5-mm nodule was
detected on the pituitary gland, consistent with a pituitary microadenoma.
The patient was referred for further evaluation and management to an endocrinology clinic,
where she was started on 5 mg cabergoline, once weekly. At three months' follow-up, the
patient's serum prolactin level had fallen to 23.8 ng/mL, and she reported a return of normal
menstrual cycles. A repeat MRI was scheduled in six months to confirm resolution of the
adenoma.

Discussion
Prolactin is a hormone secreted primarily by the lactotrophs of the anterior pituitary gland; it is
also expressed by the decidualized endometrium and the myometrium. Prolactin, whose main

function is to stimulate milk production, is regulated by dopamine. Thus, any condition that
alters dopamine's effect on the anterior pituitary can result in elevated prolactin levels. [2,3,5,6]
Prolactin secretion can also be stimulated by thyrotropin-releasing hormone. Possible causes
of prolactin excess include autonomous production by an adenoma (prolactinoma) and
decreased prolactin clearance secondary to renal failure. [6]
Hyperprolactinemia (elevated serum prolactin) was first noted in the 1970s with the discovery
that prolactin is a hormone distinct from growth hormone. [5,6] The most common endocrine
disorder to affect the hypopituitary axis, hyperprolactinemia can affect men but is mostly seen
in women.[5] Among the varying laboratory values for serum prolactin, accepted ranges include
1.0 to 25.0 ng/mL for women and 1.0 to 20.0 ng/mL for men. [1]
Diagnosis of hyperprolactinemia is made by performing serum prolactin levels on two
separate occasions, with the second verifying specimen taken in a morning fasting state. [1,3]
Once the condition is diagnosed, its underlying cause or causes must be determined and
managed.[3-7]

Physiologic Causes
Pregnancy is one of the most common reasons for hyperprolactinemia; a serum HCG level
should be ordered on any affected woman of reproductive age. Other physiologic factors that
may cause mild or transient elevations in serum prolactin include breast-feeding, stress,
sleep, nipple stimulation, and sexual activity.[3,5-7]

Pharmacologic Causes
Drugs that block the synthesis, release, or action of dopamine (eg, metoclopramide,
risperidone, phenothiazines, thioxanthenes, methyldopa) have the greatest potential for
causing prolactin excess.[3-5,7] High-dose estrogens, but not low-dose contraceptives, have
been associated with hyperprolactinemia, as has chronic cocaine use. [1,7] Even some
antihypertensives, such as calcium channel blockers and angiotensin-converting enzyme
(ACE) inhibitors, can elevate serum prolactin.[7] Thus, drug- induced prolactin excess should
be ruled out in the patient history.

Pathologic Causes
The most common pathologic cause of hyperprolactinemia is a pituitary adenoma. [4-8] This
functional tumor of the pituitary gland is classified according to size by radiographic scan:
Tumors measuring less than 1 cm are called microadenomas; larger tumors,
macroadenomas.[3-5,7,8]
Microadenomas, which represent the majority of pituitary adenomas, usually do not progress
in size, but follow-up is warranted and medical treatment may be needed. Patients with
macroadenomas are at risk for tumor growth and symptoms effected by the tumor's mass.
Macroadenomas demand close monitoring and treatment. [3,4]
Also detectable by radiographic scans[3] are non-prolactin-secreting sellar lesions, which affect
the hypothalamic and pituitary stalk (stalk hyperprolactinemia). These lesions, too, can
interfere with dopamine conduction to the pituitary gland and influence prolactin inhibition. [6,7]
Patients with elevated prolactin levels should also be screened for primary hypothyroidism
and chronic renal disease, which are both associated with elevated prolactin levels. [3-5,7,8] Other
conditions that may explain serum prolactin excess include granulomatous diseases (such as
sarcoidosis), aneurysm and other vascular abnormalities, cirrhosis, and trauma to the chest
wall (including surgery).[1]

Clinical Manifestations
In women, hyperprolactinemia has been closely associated with hypogonadism and
galactorrhea.[5,7] Symptoms of hyperprolactinemia may include mild hirsutism and acne, which
suggest chronic mild hyperandrogenism due to direct stimulation of prolactin on the adrenal
glands; and infertility or decreased libido, which are explained by hypo gonadism resulting
from increased prolactin levels.[5,7,8]
Neurologic symptoms may include headache and visual disturbances. These warrant close
evaluation to rule out the mass effect of a macroadenoma or other tumor. However, headache
may also be reported in patients with microadenomas and in those with normal head scans. [7]

Because hyperprolactinemia is often associated with hypogonadism, affected patients may be

at risk for osteopenia or osteoporosis.[9-11] In recent research, women with prolactinomas had a
relative risk of 4.5 of developing osteoporosis, compared with healthy controls. [12]

Diagnosis
Once physiological and pharmacologic causes have been excluded, a pituitary tumor or other
sellar mass must be ruled out.[3-8,13] Imaging of the brain is performed by MRI or CT (with MRI
preferred because it is better detailed[3]) if even mildly elevated serum prolactin levels have
not been explained.[6] However, if other identifying causes are noted or suspected for the
hyperprolactinemia (eg, pharmacologic agents), elevated prolactin levels exceeding 200
ng/mL still warrant imaging to rule out a concomitant mass lesion. [6]
Patients with macroprolactinomas require further evaluation to rule out lesions near the optic
chiasm and hypopituitarism (the possible result of compression on the pituitary). [3] Close
follow-up and treatment are warranted to prevent and possibly reverse tumor growth. [5]
Referral to a pituitary disorder center is recommended to rule out panhypopituitarism and to
perform additional testing and treatment.[4] Additionally, diagnosis of hyperprolactinemia due to
stalk lesions or sellar masses, as well as signs of visual field defects or cranial nerve palsies
(which may indicate a mass), warrant immediate referral to a neurosurgeon or other
specialist.[3]

Management of Hyperprolactinemia
General objectives of hyperprolactinemia therapy are to lower serum prolactin levels,
eradicate symptoms, reduce tumor mass (if a tumor is present), preserve residual pituitary
function, and prevent disease progression or recurrence. [7] Indications for therapy include
irregular menses/amenorrhea, anovulation/ infertility, hypogonadism, bothersome
galactorrhea, acne, hirsutism, osteopenia, and/or headache. [4,6]
A dopamine agonist is the recommended first-line treatment for hyperprolactinemia [6,7,13,14]
because it reduces prolactin levels, shrinks prolactinomas, and restores gonadal functioning
thus decreasing or eliminating symptoms and reducing the risk of osteopenia/osteoporosis.
[7,14-16]

Two types of dopamine agonist routinely used in the United States are bromocriptine and
cabergoline.[6,7,13,15] Bromocriptine, introduced in the early 1970s, has a short half-life, requiring
two to three daily doses. The drug may cause adverse effects such as nausea, dizziness, and
headache, often leading patients to discontinue use.[7,13,14]
Though more expensive, cabergoline, a newer dopamine agonist, is long-acting and can be
taken once or twice weekly. It is more tolerable to patients, and it reduces prolactin and
shrinks adenomas more effectively than bromocriptine.[17,18]
If use of an antidepressant or other psychotropic agent is a suspected cause of
hyperprolactinemia, the patient's psychiatrist must be consulted before medication is
discontinued or a dopamine agonist is added. An inappropriate medication change could
precipitate a psychosis.[6]
Patients diagnosed with primary hypothyroidism should be treated appropriately. Doing so will
eradicate symptoms and lower serum prolactin levels. [3]
Treatment of hyperprolactinemic amenorrheic patients has been shown to increase bone
mass.[10,11] Thus, treating estrogen deficiency secondary to hyperprolactinemia should prevent
long-term consequences of osteopenia or osteoporosis. [9-11,19]
For all patients, repeat serum prolactin levels should be obtained at three, six, and 12 months
after initiating therapy (or changing medication) and yearly thereafter,[6] unless prolactin levels
rise or symptoms increase. Otherwise, medication may be discontinued after two years.
Radiographic studies should be repeated in cases of rising prolactin levels, increasing
symptoms, or signs or symptoms that suggest a growing pituitary lesion. [3]
Surgery for prolactinomas, though rare, may be required in patients with lesions that do not
respond to therapy, symptoms of a mass effect, intolerance to medication, or psychiatric
illness in which use of a dopamine agonist could precipitate psychosis. Mac roadenomas may
warrant surgery if there is a risk of tumor enlargement secondary to pregnancy.[6]
Referral to a specialist is indicated when diagnostic tests or clinical responses are difficult to
interpret; when the patient has severe symptoms, extremely high prolactin levels, or a
comorbid medical condition; or if the patient wishes to become pregnant. [6]

Conclusion
In women who present with complaints of menstrual irregularities, infertility, acne, hirsutism,
or galactorrhea, a diagnosis of hyperprolactinemia should be considered. Advanced practice
clinicians must be knowledgeable of the many signs and symptoms of hyperprolactinemia to
order appropriate laboratory and/or radiologic testing, confirm the diagnosis, and initiate
effective management. Early recognition of the disorder can lead to immediate consultation
(when needed) and/or prevent potentially serious complications, as when a pituitary mass or
hypogonadism is present.