anterior pituitary disorders Flashcards
5 types of endocrine cells in the anterior pituitary that are defined by the hormones they secrete:
somatotrophs = GH
lactotrophs = LH
gonadotrophs = LH & FSH
corticotroph = ACTH
thyrotroph = TSH
Inadequate production of Anterior Pituitary Hormones
hypopituitarism
causes of hypopituitarism
- congenital
- gene mutations
- Prader Willi
- Kallmann syndrome - acquired
- Radiation
- TBI
- Chemotherapy
- Ischemic stroke - functional
- Opioid use
- Aging
- Malnutrition
- CKD
what hormone deficiency would cause:
growth disorders in children and abnormal body composition in adults
GH deficiency - Hypopituitarism
what hormone deficiency would cause:
menstrual disorders and infertility in women and decreased sexual function, infertility, and loss of secondary sex characteristics in men
Gonadotropin deficiency -Hypopituitarism
what hormone deficiency would cause:
Hypothyroidism in children and adults
TSH deficiency - Hypopituitarism
what hormone deficiency would cause:
Hypocortisolism
ACTH deficiency - Hypopituitarism
what hormone deficiency would cause:
Failure of lactation
Prolactin deficiency - Hypopituitarism
what anterior pituitary hormone is released do these hypothalamic releasing hormones trigger?
CRH
TRH
GnRh
GHRH
Dopamine (inhibits)
ACTH
TSH
LH & FSH
GH
Prolactin
Significant lactotrope cell hyperplasia develops during when?
- pregnancy
- first months of lactation
what state is PRL usually in?
inhibited
PRL is mediates by what?
dopamine
(D2 receptors)
Serum PRL levels rise mildly and transiently with the following:
- Exercise, meals, sexual intercourse
- Breast exam, chest wall injury
- Minor surgical procedures, general anesthesia
- Stress of any kind
PRL secretion is pulsatile, with the highest secretory peaks occurring ?
non-REM sleep
- Peak serum levels 4:00 - 6:00 a.m.
- Circulating ½ life ~ 50 min
PRL levels increase about tenfold during ____ and decline rapidly within 2 weeks of _____.
pregnancy
parturition
The magnitude of PRL increase is directly proportional to
the degree of preexisting lactotroph hyperplasia due to estrogen
The surge in prolactin in response to sucking is due to ?
decrease in the amount of dopamine released by the hypothalamus
what hormone is responsible for the milk release from the breast?
oxytocin
acts to induce and maintain lactation, decrease reproductive function, and suppress sex drive
PRL
how does PRL inhibit reproductive function
- suppresses hypothalamic GnRH and pituitary gonadotropin secretion
- impairs gonadal steroidogenesis in both women and men.
In the ovary, PRL leads to what?
hypoestrogenism and anovulation.
MC pituitary hormone hypersecretion syndrome in both men and women
Hyperprolactinemia
MC cause of PRL levels >200 μg/L
(normal = ~ 10-20 (M) and 10-25 for (W))
PRL-secreting pituitary adenomas (prolactinomas)
More common in women
Less pronounced PRL elevation can also be seen with microprolactinoma but is more commonly caused by:
drugs, pituitary stalk compression, hypothyroidism, or renal failure
a woman presents with:
Amenorrhea, galactorrhea, and infertility
what could it be?
other s/s?
- hyperprolactinemia
- s/s
- decreased libido
- wt gain
- hirsutism
- vaginal dryness/atrophy
- irritability, anxiety and depression (due to estrogen deficiency)
- long-lasting - osteopenia, reduced muscle mass
a male pt presents with:
Decreased libido
Impotence/erectile dysfunction
Infertility
Gynecomastia
Galactorrhea
what could it be?
- hyperprolactinemia
- long-lasting - osteopenia, reduced muscle mass, and decreased facial hair growth
work up for hyperprolactinemia
-
Serum Prolactin concentration
- Basal, fasting morning PRL levels (normally <20 μg/L)
- MOST ACCURATE - TSH and T4 levels - r/o hypothyroidism
- Serum hCG
- CMP - r/o liver and kidney disease
- serum total and free testosterone, LH, and FSH
- for men evaluated for hypogonadism - serum estradiol, LH, and FSH
- Women who have amenorrhea are assessed for hypogonadism -
MRI
- if PRL level elevated w/ no other cause, or if PRL > 200
Pt has a slightly high value for their serum prolactin of 30 (normal: 21 to 40 ng/mL)
what is the next step?
repeated to confirm before the patient is considered to have hyperprolactinemia.
(A persistently elevated serum prolactin value should prompt a search for its cause)
a mass lesion in the region of the sella turcica was found in an MRI for possible hyperprolactinemia, what is the next step?
secretion of other pituitary hormones should also be evaluated
an MRI shows normal hypothalamic-pituitary anatomy and there is no identifiable secondary cause of hyperprolactinemia, what is the diagnosis?
idiopathic hyperprolactinemia
(Can be due to microadenomas that are too small to be seen on imaging)
tx for hyperprolactinemia
- treat identifiable cause (if there is one)
-
Dopamine agonists - Most effective
- Cabergoline
- Bromocriptine - estrogen, estrogen/progesterone, or testosterone replacement
- for microprolactinomas (< 1cm)
- AVOID MACROprolactinomas (risk of progressive growth)
what med is a LA dopamine agonist and suppresses PRL for >14 d after a single dose
Cabergoline
what med is SA dopamine agonist and is preferred when pregnancy is desired
Bromocriptine
administer a low dose PM with snack, followed by gradually increasing the dose
which dopamine agonist has SE and drug intolerance less commonly encountered than the other?
Cabergoline (than Bromocriptine)
SE of dopamine agonists
- constipation, nasal stuffiness/congestion, dry mouth, nightmares, insomnia, and vertigo
- N/V and postural hypotension may occur. Give at bedtime.
- rare: leukopenia, thrombocytopenia, pleural fibrosis, arrhythmias, and hepatitis
Patients with Parkinson’s disease who receive at least 3 mg of cabergoline daily have been reported to be at risk for development of
cardiac valve insufficiency
(Recommend echo prior to starting to document no valvular abnormalities and repeat if clinically warranted)
Women with ademonas who desire fertility / are pregnant who take dopamine agonists, what are the considerations?
- Microadenoma – safe with dopamine agonist held, conceive, and even safely breastfeed
-
Macroadenoma – if dopamine agonist is stopped, monitor with:
- serum PRL levels
- visual-field testing
Low serum prolactin levels due to damaged lactotroph cells in ant. pit.
hypoprolactinemia
the inability to lactate after delivery is the hallmark manifestation of what condition?
hypolactinemia
most pts with acquired prolactin deficiency have evidence of other pituitary hormone deficiencies, indicative of ?
panhypopituitarism or possibly macroadenoma of another cell line
causes of hypoprolactinemia
- Sheehan’s Syndrome
- Meds
- Dopamine agonists
— antiparkinsonian drugs - Tumors
postpartum hypopituitarism caused by necrosis of the pituitary gland
Usually the result of severe hypotension or shock caused by massive hemorrhage during or after delivery
Sheehan’s Syndrome
tx for hypoprolactinemia
- Dopamine antagonists
- Surgery
direct effects of GH
stimulates cellular metabolism
1. adipose tissue
- lipolysis - fuels metabolism
2. liver
- promotes gluconeogenesis and glycogenolysis
3. tissues
- diabetogenic: insulin resistance - insulin is less effective in moving glucose into cells
indirect effects of GH
- muscles
- stimulates AA uptake into muscle cells = protein production and muscle growth - growth of long bones
- acts on epiphyseal cartilage = stimulates osteoblasts and chondrocytes = boosts growth
the most abundant anterior pituitary hormone
GH
GH-secreting somatotrope cells constitute up to 50% of the total anterior pituitary cell population
GH secretion is controlled by what 2 factors
complex hypothalamic and peripheral factors
- GHRH stimulates GH synthesis and release
- Somatostatin is synthesized in the medial preoptic area of the hypothalamus and inhibits GH secretion
GH secretion is pulsatile, with highest peak when?
at night, generally correlating with sleep onset.
GH secretory rates decline markedly with what?
age
hormone levels in middle age are about 15% of pubertal levels
- These changes are paralleled by an age-related decline in lean muscle mass.
A potent growth and differentiation factor
Somatomedin C (Insulin-like growth factor 1)
what organ is the major source of circulating IGF-1
liver
what is the relationship between GH and IGF-1?
proportional:
As GH levels increase, the liver synthesizes more IGF-1. As GH levels decrease, the liver synthesizes less IGF-1.
Serum IGF-I concentrations are affected by physiologic factors:
- Levels increase during puberty, peak at 16 years, and subsequently decline by >80% during the aging process.
- IGF-I concentrations are higher in women than in men.
- Abnormalities of GH synthesis or action (pituitary failure, GHRH receptor defect, GH receptor defect) reduce IGF-I levels.
what condition may result from disruption of the growth hormone axis in the hypothalamus or pituitary, and can be congenital or acquired.
GH deficiency
Acquired growth hormone deficiency may result from ?
- trauma
- infections (encephalitis, meningitis)
- cranial irradiation (somatotrophs are the most radiation-sensitive cells)
- other systemic disease
short stature, micropenis, increased fat, high-pitched voice, and hypoglycemia are characteristics commonly in what condition?
Isolated GH deficiency
what are the familial modes of inheritance of GH deficiency aka how can it be passed down?
autosomal dominant, recessive, or X-linked
- Genetic mutations of GH producing or secreting cells
- May also involve other pituitary hormone deficiencies
- Recessive mutations of the GHRH receptor gene can lead to severe dwarfism
Caused by defects of GH receptor structure or signaling
GH insensitivity
GH insensitivity is diagnosed based on what?
normal or high GH levels, with decreased circulating growth hormone binding protein (GHBP), and low IGF-I levels
growth failure is an important clinical manifestation for what condition
GHD
careful documentation of growth rate is critical to making the correct diagnosis
hx in pts with suspected GHD should focus on the following issues:
Birth weight and height
Height of parents
Timing of puberty in parents
Previous growth points
General health of child
Nutritional history
PE for GHD should focus on the following:
-
Proper height and wt measurement
- The best way to evaluate height or weight measurements is to plot the points on a growth chart - Proportionality
- Pubertal status
- Evidence of genetic syndromes
when should GHD evaluation be done for children?
- Marked short stature, more than 2.5 SD below the mean for age, sex, and ethnic background.
- Growth failure, defined as height velocity < 25th percentile whether or not short stature is present.
- Less severe short stature for age, sex and ethnic background, combined with growth failure in the absence of an alternative explanation.
- Evidence suggesting hypothalamic-pituitary dysfunction (hypoglycemia, microphallus, cryptorchidism, optic nerve hypoplasia, intracranial tumor, or history of cranial irradiation), with decelerating growth, even if the child’s height is within the normal range.
- Evidence for deficits in other hypothalamic-pituitary hormones, either congenital or acquired.
work up for GHD
- evaluate for other causes of growth failure
- chronic systemic disease, hypothyroidism, Turner Syndrome, and skeletal disorders - If there is no evidence, investigate for GHD with: (diagnostic)
- GH stimulation test -
- Insulin-like growth factor-1 (IGF-I)
- Insulin-like growth factor binding protein-3 (IGFBP-3). Main carrier of IGF-I in body.
- Bone age - MRI/CT
- genetic testing - if no other causes found
Why is assessing GH production difficult?
GH secretion is pulsatile
the most consistent surges during stages 3 and 4 of sleep
- Between normal pulses, serum GH levels are too low for sensitivity of most conventional assays
— a random serum GH level is not helpful in diagnosing GHD
what is also a useful predictor of response during the first year of treatment with GH
Provocative testing
GH Stimulation Test relies upon the use of what 2 factors?
physiological or pharmacological stimuli
1. physiological - sleep, fasting, and exercise
2. Pharmacological - L-dopa, clonidine, propranolol, arginine, and insulin-induced hypoglycemia
A diagnosis of impaired GH secretion can be confirmed only if ?
subnormal GH secretion is observed during two different GH stimulation tests
- tests are performed after an overnight fast
- Lack of increase of GH = positive test
tx for GHD
-
Recombinant GH
- Somatropin (Genotropin, Humatrope, Norditropin, Nutropin, Omnitrope, Saizen, TevTropin) - correct associated hormones with pituitary insufficiency - esp adrenal steroids
- GH insensitivity or mutations of the GH receptor = IGF-I
- GH levels normal or elevated in these pts
This disorder usually is caused by hypothalamic or pituitary somatotrope damage.
GHD (adults)
The sequential order of hormone loss is usually GH →
FSH/LH → TSH → ACTH
an adult pt notes:
changes in body composition, lipid metabolism, and cardiovascular dysfunction
what could be their condition?
what other signs could be found on PE
AGHD
- reduced lean body mass, increased fat mass, increased waist-to-hip ratio
- Hyperlipidemia, LV dysfunction, and HTN
- increased fractures
- Depression, social isolation, fatigue
Testing for AGHD should be limited to pts with the following predisposing risk factors:
pituitary surgery
pituitary or hypothalamic tumor or granulomas
history of cranial irradiation
radiologic evidence of a pituitary lesion
childhood requirement for GH replacement therapy
unexplained low age- and sex-matched IGF-I levels
tx for AGHD
dosing?
-
recombinant human GH (rhGH, somatropin)
- starting dose of 0.1–0.3 mg/d should be titrated (up to a max 1.25 mg/d) to maintain IGF-I levels in the mid-normal range for age- and sex-matched controls
CI of recombinant human growth hormone therapy
presence of an active neoplasm
intracranial HTN
uncontrolled DM and retinopathy
what tx assists growth of linear bone, skeletal muscle, and organs by stimulating chondrocyte proliferation, lipolysis, protein synthesis, and hepatic glucose output
Recombinant human growth hormone rhGH (Somatropin)
indications and dosing for rhGH (somatropin)
- indications
- children - growth failure, short stature
- adults - GH deficiency, hypopituitarism - dosing:
- Adults: IGF-1 every 1-2 months during titration, then semiannually at maintenance
- Children: Monitor growth curve and physical exam with skeletal assessment with every visit
monitoring for rhGH (somatropin)
fundoscopic exam
start of therapy and periodically during tx (intracranial hypertension)
SE and what to watch for during AGHD tx
SE: HA, Increased ICP (usually in first 8-12 weeks of treatment), HTN, Tinnitus, Slipped Capital Femoral Epiphysis
what to watch for:
1. fluid retention
2. joint pain
3. CTS
4. myalgias
5. paresthesias
Patients requiring insulin need careful monitoring for dose adjustments
- GH is a potent counter-regulatory hormone for insulin action = Hyperglycemia and DM can develop
A result of too much GH / excess GHRH production
acromegaly/gigantism
GH hypersecretion is usually the result of a ?
somatotrope adenoma
but may rarely be caused by extrapituitary lesions
ectopic GH secretion can happen by tumors of ?
pancreatic, ovarian, lung, or hematopoietic origin
The most common cause of GHRH-mediated acromegaly is ?
chest or abdominal carcinoid tumor
frontal bossing, increased hand and foot size, mandibular enlargement with prognathism, and widened space between the lower incisor teeth
Acral bony overgrowth
Manifestations of GH and IGF-I hypersecretion are ___ and often are not clinically diagnosed for ____
slow-moving
10 yrs or more
initiation of GH hypersecretion before epiphyseal long bone closure is associated with development of
pituitary gigantism
Generalized visceromegaly occurs, including ?
cardiomegaly, macroglossia, and thyroid gland enlargement
The most significant clinical impact of GH excess occurs with what?
CV system
- Cardiomyopathy with arrhythmias, left ventricular hypertrophy, decreased diastolic function, and hypertension ultimately occur in most patients if untreated.
clinical features with GH excess
- arrhythmias
- sleep apnea
- DM
- colon polyps
work up for GH excess
- elevated age- and sex-matched serum IGF-I (in acromegaly)
-
the failure of GH suppression to <0.4 μg/L within 1–2 h of an oral glucose load (75 g)
- High glucose stimulates somatostatin release - Thyroid function, gonadotropins, and sex steroids may be attenuated because of tumor mass effects
Measurement of a single random GH level is not useful
tx for GH excess
-
Transsphenoidal surgical resection
- for both micro- and macroadenomas
- GH levels return to normal within an hour, and IGF-I levels are normalized within 3–4 days. - radiation
- External radiation therapy or high-energy stereotactic techniques = adjuvant therapy - Somatostatin analogues: Decrease GH secretion
- lanreotide, octreotide, pasireotide, Sandostatin, Sandostatin LAR, Signifor, Somatuline Depot - Dopamine Agonists
- Combined tx with octreotide and cabergoline may induce additive biochemical control compared with either drug alone.
SE of Somatostatin analogues
N/D, abd discomfort, fat malabsorption, and flatulence
- happens in 1/3 of patients
- remits within 2 weeks.
what Somatostatin analogues
suppresses postprandial gallbladder contractility and delays gallbladder emptying;
octreotide
The most common presenting feature of adult hypopituitarism
Hypogonadism
a woman presents:
oligomenorrhea, amenorrhea, infertility, decreased vaginal secretions, decreased libido, osteoporosis
what could be the condition?
Hypogonadism
a male presents with:
testicular failure associated with decreased libido, impotency, infertility, decreased muscle mass, reduced beard and body hair growth
what could be the condition?
Hypogonadism
labs with hypogonadism
- low or inappropriately normal serum gonadotropin levels in the setting of low sex hormone concentrations (testosterone/estradiol)
- IV GnRH should stimulate secretion of LH/FSH = increased serum levels
- normal response to GnRH indicates intact pituitary function with hypothalamic abnormality
Lab Evaluation of Hypogonadism for males and females
males
1. AM serum testosterone and free testosterone
- Low - repeat testosterone, along with serum LH and PRL levels.
females
1. hCG (r/o pregnancy)
2. serum PRL
3. FSH and LH
4. TSH
tx for hypogonadism
male
1. Testosterone replacement
2. human chorionic gonadotropin (hCG) (equivalent to LH) - infertility due to oligospermia
3. leuprolide (GnRH analog) - with intact pituitary
4. Clomiphene - stimulate men’s own pituitary gonadotropins (if pituitary is intact)
female
1. estrogen and progesterone
- Gonadotropin therapy - ovulation induction
— human menopausal gonadotropin (hMG) or recombinant FSH - Follicular growth and maturation
— LH - induce ovulation
2 Pulsatile GnRH therapy - treat hypothalamic causes of infertility
synthesized in the hypothalamus and stimulates the release of ACTH by the anterior pituitary
CRH
ACTH is released by the anterior pituitary and stimulates the adrenal cortex to secrete ?
corticosteroids (cortisol)
ACTH secretion is pulsatile and peaks at
~ 6 A.M.
ACTH levels are increased by:
physical and psychological stress, exercise, acute illness, and insulin-induced hypoglycemia
how does cortisol affect CRH and ACTH
Cortisol provides negative regulation and inhibits both CRH in the hypothalamus and ACTH release by the pituitary
