CLINICAL CHEMISTRY Jolan F.

Herce
BSMT-3B
LECTURE / 2nd SEMESTER
 Due to inhibition by
Adrenal steroid (glucocorticoids)
CHAPTER 30: Therapeutic Drug Monitoring
o
INTRODUCTION o cytokines
Therapeutic drug monitoring (TDM) - to measure and monitor - TYPES OF FEEDBACK LOOP
circulating drug levels primarily in serum, plasma, or whole blood  SHORT feedback loop
The purpose of TDM: o bet. thyroxine and pituitary
1. ensure that a given drug dosage is within a range that  LONG feedback loop
produces maximal therapeutic benefit and o bet. thyroxine and hypothalamus
2. identify when the drug is above or below a therapeutic range  ULTRASHORT feedback loop
which may lead to either inefficacy or toxicity o bet. hypothalamus and pituitary
The following are common indications for TDM:
 Identifying non-compliance in patients.
 Preventing the consequences of overdosing and underdosing.
 Maximizing therapeutic effect, particularly when there is a
narrow dose range between a therapeutic and toxicity.
 Optimizing a dosing regimen based on drug–drug
interactions or a change in the patient’s physiologic state that
may unpredictably affect circulating drug concentrations.

ROUTES AND ADMINISTRATION

A drug must be at the proper concentration at its site of action to
provide therapeutic benefit. It would be excellent to measure drug
concentration at the site of action.
 Bioavailability is defined as the unaltered percentage of the
injected dose as it enters systemic circulation.
 The goal of most therapeutic regimens is to acquire (blood,
plasma, or serum) concentration
Drugs can be administered by several routes:
a. Intravenous (IV) - Directly into the circulation
b. Intramuscular (IM) - Into the muscles
c. Subcutaneous (SC) - Under the skin
d. Transcutaneous - Inhalation or absorbed through the skin
e. Suppository - Rectal delivery 2. PULSATILITY
- All ANTERIOR PITUITARY hormones are secreted in a
FUNCTIONAL ASPECTS OF pulsatile fashion.
THE HYPOTHALAMIC–HYPOPHYSEAL UNIT  Pulse frequency of secretion is regulated by neural
2 PATHWAYS modulation and is specific for each pituitary end-organ
• Afferent = inputs unity
• Efferent = outputs - Ex. secretion of hormones for gonadal function
- characterized by  Luteinizing hormone (LH)
 negative feedback mechanisms o Normal values for MALE:
o OPEN-LOOP = subject to external modulation and  Median interpulse interval =
generally influenced by higher neural input or other 55 minutes
hormones  Average LH peak duration =
 Pulsatility 40 minutes
 Diurnal variation  Follicle-stimulating hormone (FSH)
1. NEGATIVE FEEDBACK MECHANISM - The pulse frequency of the gonadotropin-releasing
HYPOTHALAMIC-PITUITARY-THYROIDAL AXIS hormone (GnRH), has profound effects on LH secretion
- example of feedback loop profiles:
- hypothalamus produces the hypophysiotropic hormone, • ↑ frequency GnrH pulses = ↓ gonadotrope secretory response
THRYOTROPIN RELEASING HORMONE (TRH) • ↓ frequency GnrH pulses = ↑ LH pulse
 directs the TYROTROPHS (TSH-producing cells) in
the anterior pituitary 3. DIURNAL VARIATIONS
o secrete THYROID STIMULATING regulated by external changes such as
HORMONE  Light-dark changes
 involved in the production and release  Daylight to darkness ration
of thyroid hormones ZEITGEBER
✓ T3  “time giver”
✓ T4  Process of entraining or synchronizing the external
- THYROXINE suppress further production of: cues into the function of internal biologic clock –
 TRH = hypothalamus diurnal variations are typified by
o long feedback loop  Adenocorticotropic hormone (ACTH)
 TSH = pituitary gland o Nadir (trough) = 11pm – 3am
o short feedback loop o Peak = 6am – 9am
- hormone production may decline during severe physiologic stress  Morning or “awakening”

TRANSCRIBED BY: JOLAN HERCE

CLINICAL CHEMISTRY Jolan F. Herce
BSMT-3B
LECTURE / 2nd SEMESTER
 TSH secretion - FREQUENCY
o Nocturnal = 2x the daytime levels  Prolactin-secreting pituitary tumors = most common
 Due to increased pulse amplitude  Nonfunctioning or null cell tumors
 Other pituitary tumors
HYPOPHYSIOTROPIC OR HYPOTHALAMIC o GH
HORMONES o Gonadotropins
- most products are peptides o ACTH
 Bioactive amines are also synthesized and transported o TSH
- hypothalamic hormones may have multiple actions - Physiologic enlargement can be seen during:
 TRH = stimulates secretion of TSH and prolactin  puberty
 GnRH = stimulates LH and FSH production  pregnancy = LACTOTROPH HYPERPLASIA
 Somatostatin (SS) = inhibits GH and TSH - can also be seen in longstanding primary:
 AVP = water retention and stimulate ACTH secretion  thyroidal failure = THYROTROPH hyperplasia
o Corticotropin-releasing hormone (CRH) = main  gonadal failure = LACTOTROPH hyperplasia
stimulus for ACTH secretion
-hypophysiotropic hormones are found through the CNS and other
tissues
 Gut, pancreas, other endocrine glands

ATYPICAL PITUITARY TUMORS

- tumors that have:
 MIB-1 proliferative index <3%
o MIB-1 = monoclonal antibody used to detect the Ki-
HORMONE STRUCTURE ACTION 67 antigen
TRH 3 Amino acids Release TSH and  Marker of proliferation
prolactin ✓ ↑ “proliferation index = ↑ degree of atypia
GnRH 10 AA Release LH and FSH  excessive p53 immunoreactivity
CRH 41 AA Releases ACTH  increased mitotic activity
GHRH 44 AA Release GH -most are MACROADENOMAS
Somatostatin 14 & 28 AA Inhibits GH and TSH  >1cm in diameter
release  Show invasion into surrounding structures like cavernous
Dopamine 1 AA Inhibits prolactin sinuses
(prolactin inhibitory release -may or may not be hormonally active
factor)  may not produce clinically evident syndromes
-commonly stain for
ANTERIOR PITUITARY HORMONES  GH
- hormones secreted are larger and more complex than those  ACTH
synthesized in the hypothalamus
-TYPES BASED ON ACTION GROWTH HORMONES
 Tropic = specific for another gland -growth ceases if:
o TSH = thyroid hormone production from the thyroid  Pituitary gland is removed
o ACTH = adrenal steroidogenesis  Hormonal products from other endocrine glands are
o FSH replaced
 Women: ovarian recruitment and early o Thyroxine
folliculogenesis o Adrenal steroids
 Men: spermatogenesis o Gonadal steroids
o LH -growth is not restored until GROWTH HORMONE (GH) is
 Women: Ovulation administered
 Men: Testosterone production from Leydig - it takes complete functioning of the anterior pituitary and its
cells hormones to establish conditions ripe for growth of the individual
 Direct effectors = directly on peripheral tissue  But, w/o other hormones = no growth
o GH = stimulates liver produce growth factors  Other factors:
o Prolactin o Adequate nutrition
o Normal insulin levels
PITUITARY TUMOR o Overall good health
-STATISTICS
-also called SOMATOTROPIN
 20% = clinically silent pituitary adenomas
 Structurally related to
 10-30% = pituitary tumors in normal individuals undergoing o Prolactin
MRI
o Lactogen = placental hormone for growth and
 91% of lesions removed during transsphenoidal surgery are
metabolism
pituitary rumors
- Single peptide with 2 intramolecular disulfide bridges

TRANSCRIBED BY: JOLAN HERCE

CLINICAL CHEMISTRY Jolan F. Herce
BSMT-3B
LECTURE / 2nd SEMESTER
- DIRECT EFFECTOR - single, random measurement of GH is rarely diagnostic
- SOMATOTROPHS = pituitary cells that produce GH • MORE ACCURATE TEST = measure GH at timed intervals
 1/3 of normal pituitary weight o Suppression test
-release is stimulated by the hypothalamic peptide GROWTH ▪ For diagnosing acromegaly
HORMONE-RELEASING HORMONE (GHRH) o Stimulation test
 GHRELIN = potent stimulator of GH secretion ▪ For diagnosing GH deficiency
o enteric hormone for nutrient sensing, appetite and -REFERENCE RANGES
glucose regulation • 0.01 – 1.0 ng/mL = males
- inhibited by SOMATOSTATIN (SS) • 0.01 – 3.5 ng/mL = females
- average interpulse interval = 2-3 hours
 Peak = onset of sleep
 Below detectable limit = GH DEFICIENCY

B. INSULIN-LIKE GROWTH FACTOR 1 (IGF-1)

- preferred for assessing GH deficiency or excess during
childhood and/or adolescent development
- used for monitoring recombinant human growth hormone
treatment and for treatment follow-up for acromegaly and
ACTION OF GH gigantism
- considered an AMPHIBOLIC hormone - lower diagnostic sensitivity and specificity
 Directly influence both anabolic and catabolic processes  More sensitive than albumin for monitoring nutritional
-allows an individual to effectively transition from a fed state to a status
fasting state without experiencing a shortage of substrates required o ↓ IGF-1 = malnutrition
for normal intracellular oxidation - based on GH AXIS
 Antagonizes effect of INSULIN on glucose metabolism  IGF-1 (and IGFBP-3) integrate the peaks of GH secretion
(glucose catabolism) o ↑ IGF-1 / IGFBP-3 = consistent with excess GH
 Promotes hepatic gluconeogenesis -CONDITIONS
 Stimulates lipolysis  ↑ IGF-1 = hepatoma
o Provides oxidative substrates for skeletal muscle
 Normal IGBP-3 = acromegaly
o Conserves glucose for CNS
 ↓ IGF-1 = ↓ GH
-HYPOGLYCEMIA
 GH deficiency in children ORAL GLUCOSE LOADING
 GH and ACTH deficiency - Definitive testing for determining the autonomous production of
- The anabolic effects of GH are reflected by enhanced protein GH
synthesis in skeletal muscle - PROCEDURE
 Causes:  performed after an overnight fast
o Positive nitrogen balance  patient is given a 75g oral glucose load
o Phosphate retention  GH measured at time:
-indirect effects is mediated by INSULIN-LIKE GROWTH o 0 (time of consumption)
FACTOR (IGF) o 30 minutes
 Initially called SOMATOMEDINS o 60 minutes
o Somatomedin C → IGF-1 o 90 minutes
 Has structural homology to INSULIN o 120 minutes
o Cell receptors are distinct from insulin; except -RESULTS
o ↑ IGF-2 → cross reacts with insulin receptors →  Undetectable = normal individuals
hypoglycemia  Increase = acromegaly
o Hyperinsulinemia can partially activate IGF-1
receptors *TEST FOR GH DEFICIENCY
 IGF-BINDING PROTEIN 3 (IGFBP-3) = best studied -EXAMPLES
member of the IGFBP family  insulin-induced hypoglycemia = once considered the gold
o directly play a role in the pathophysiology of standard
several human cancers  Combination infusion = most widely used and better
o ↑ IGFBP-3 w/ ↑IGF-1 = cancer tolerated by the patient
 Prostate o GHRH + L-arginine
 Colorectal o L-arginine w/ Ievodopa (L-DOPA)
 Lung REFERENCE VALUE: >3-5mg/mL
 Premenopausal breast
o tumor suppressor gene (p53) upregulate active ACROMEGALY
IGFBP-3 secretion acromegaly result from
 inhibits IGF1-signaled mutagenesis and  pathologic or autonomous GH excess
neoplastic cell proliferation  pituitary tumor = majority
 ectopic GHRH production = rare
TESTING
- FAMILIAL ACROMEGALY
A. GROWTH HORMONE
 mutations in the aryl hydrocarbon–interacting protein gene

TRANSCRIBED BY: JOLAN HERCE

CLINICAL CHEMISTRY Jolan F. Herce
BSMT-3B
LECTURE / 2nd SEMESTER
(AIP)  Pegvisomant
 polymorphisms in the SS receptor type 5 gene = rare
- If a GH-producing tumor occurs before epiphyseal closure of the
long bones, the patient develops gigantism
GH DEFICIENCY
-occurs in both children and adults
 Children = may be
o Genetic
o Tumors (ex. craniopharyngiomas)
FEATURES OF ACROMEGALY
 Adults
 progressive enlargement of hands and feet
o Structural or functional abnormality
 growth of facial bones, mandible, and skull
o Age = ↓ GH production
 significant gap between teeth
- Although GH deficiency in children is manifested by growth
 arthritis = diffuse overgrowth of the ends of long bones or failure, not all patients with short stature have GH deficiency.
spine -due to genetic defects
 glucose intolerance or overt diabetes  recessive mutation in the GHRH gene = most common
o since GH is insulin antagonist
 loss of GH gene
 suppress insulin → ↓ glucose catabolism
 GH INSENSITIVITY
→ ↑ glucose level
o Mutations in the
 acquired myopathy = late stage
 GH receptor,
o hypertension
 IGF-1 biosynthesis
o atherosclerosis  IGF-1 receptors
o proximal muscle weakness  GH signal transduction
 Sleep apnea - due to structural lesion of the pituitary or hypothalamus
 Organomegaly  associated with other anterior pituitary hormone
o Thryomegaly = common deficiencies
 Hyperthyroidism is rare unless tumor co-
secretes TSH GH DEFICIENCY SYNDROME
 Excessive sweating or heat intolerance o GH excess is a  complete or partial failure of the anterior pituitary
hypermetabolic condition  symptoms
- features develop slowly over time o social withdrawal,
 Facial changes may go unrecognized o careful, o fatigue
retrospective review of older photographs may be crucial o loss of motivation
- If left untreated, acromegaly shortens life expectancy because of o diminished feeling of well-being
increased risk of heart disease
 ↑ mortality in children
 Greater lifetime risk of cancer
 Adult:
o Osteoporosis
DIAGNOSIS
o Alteration in body composition (ex. reduced lean
 GLUCOSE LOADING = definitive test
body mass)
o (+) = nonsupressibility of GH
 some patients with acromegaly have normal random levels TREATMENT
of GH
 GH REPLACEMENT THERAPY = uses recombinant
o ↑ IGF-1 = acromegaly
GH
o Relatively simple but expensive
-TREATMENT
o Used by athletes as
 Goal: tumor ablation with continued function of the
 performance-enhancing substance
remainder of the pituitary
 aid in injury recovery
 TRANSSPHENOIDAL ADENOMECTOMY =  combat the effects of aging
procedure of choice
o Normal GH levels and suppressibility = cured
 EXTERNAL BEAM or FOCSED IRRADIATION PROLACTIN
o Tumors may be too large or invaded local -structurally related to
structures  growth hormone (GH)
o Produces smaller but hormonally active tumor
 Lactogen = human placenta
 Takes several years before GH level -considered as stress hormone
declines
 has vital functions in relationship to reproduction
 SUPRESSIVE AGENTS -direct effector hormone
o SS analogs
 Lacks a single endocrine end organ
 Octreotide - major mode of hypothalamic regulation is TONIC INHIBITION
 Pasireotide
 PROLACTIN INHIBITORY FACTOR (PIF) = once
 lanreotide
considered capable of inhibiting prolactin secretion
o Dopaminergic agonists
 cabergoline
 bromocriptine
o GH receptor agonists

TRANSCRIBED BY: JOLAN HERCE

CLINICAL CHEMISTRY Jolan F. Herce
BSMT-3B
LECTURE / 2nd SEMESTER
 DOPAMINE = only neuroendocrine signal that inhibits  25 -100 ng/mL (moderate increase) o Pituitary stalk
prolactin; Considered as the ELUSIVE PIF interruption o Dopaminergic antagonist medication o
-OTHER REGULATING HORMONES Primary thyroidal failure o Renal failure o Polycystic
 GnrH ovary syndrome o Breast or genital stimulation
o ↑ Estrogen = ↑ Prolactin - Significant hyperprolactinemia is also encountered during
 TRH pregnancy
o ↑ TRH = ↑ Prolactin - principal prolactin form: 23-kd peptide
 Vasoactive intestinal polypeptide  Other form: 150-kD
o Larger prolactin molecule has markedly reduced
HYPERPROLACTINEMIA biologic potency
 There are many physiologic, pharmacologic, and pathologic o MACROPOLACTENEMIA = 150-kD > 23-kD
causes of hyperprolactinemia, and a common error by  Most are relatively asymptomatic
clinicians is to ascribe any elevation in prolactin to a  10-22% of hyperpolactinemic samples
“prolactinoma.”  Can be excluded by precipitating serum
-MEDICATION CAUSING HYPERPOLACTINEMIA samples with polyethylene glycol
 phenothiazines,
 butyrophenones HYPOPITUITARISM
 metoclopramide PANHYPOPARAPITUITARISM - complete cessation of pituitary
 reserpine function
 tricyclic antidepressants MNEMONICS: 5 I’s (eyes) saw me in 2Ps (two-piece) so I Run To
 α-methyldopa the Family
 antipsychotics SHEEHAN’S SYNDROME - postpartum ischemic necrosis of the
- disruption in pituitary stalk causes increase prolactin pituitary following a complicated delivery
 due to interruption of flow of dopamine from the 1 Immunologic
hypothalamus to the lactrotrophs 2 Infarction
o lactotroph = prolactin secreting cell 3 Infection
- CAUSES OF HYPERPROLACTINEMIA 4 Infiltrative disease
 Chest wall injuries = pathologic stimulation of neural 5 Idiopathic
suckling reflex 6 Parapituitary tumors/ hypothalamic tumors
 Renail failure 7 Pituitary tumor
 Polycystic ovary syndrome 8 Radiation therapy/ surgery
 Physiologic stress (ex. exercise and seizure) 9 Trauma
- Physiologic effect of prolactin is lactation 10 Familial
- prolactin excess causes HYPOGONADISM by:
 Suppression of gonadotropin secretion from the pituitary POSTERIOR PITUITARY TUMOR
 Inhibition of gonadotropin action at the gonad o -includes
 suppression of ovulation in lactating postpartum  Oxytocin
mothers  Vasopressin (ADH)
A. OXYTOCIN
PROLACTINOMA - Cyclic nonapeptide, with a disulfide bridge connecting amino acid
- pituitary tumor that directly secretes prolactin residues 1 and 6
 Most common functional pituitary tumor - Has a critical role in lactation and plays a major role in labor and
-clinical presentation depends on age, gender, and size of tumor parturition
 Premenopausal women B. VASOPRESSIN (ADH)
o menstrual irregularity/amenorrhea, - a cyclic nonapeptide with an identical disulfide bridge
o infertility, o galactorrhea - Major action of AVP (formerly called antidiuretic hormone) is to
 Men regulate renal free water excretion
o Reduced libido - A 5% to 10% fall in arterial blood pressure in normal humans will
o Erectile dysfunction trigger vasopressin release
- AVP excess may also occur and is much more difficult to treat
 Men and premenopausal women
- Since excess AVP leads to the pathologic retention of free water.
o Headaches
o Visual complaints
- One recently recognized complication of prolactin induced
hypogonadism is osteoporosis

OTHER CAUSES OF HYPERPROLACTINEMIA

- Generally, substantial elevations in prolactin (>150 ng/mL)
indicate prolactinoma, degree of elevation in prolactin is correlated
with tumor size

TRANSCRIBED BY: JOLAN HERCE