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CLINICAL CHEMISTRY

CHAPTER 20: HYPOTHALAMIC AND PITUITARY FUNCTION EMBRYOLOGY AND ANATOMY

§ Three distinct parts of the pituitary:
Chapter Outline: 1. Anterior pituitary (adenohypophysis)
§ Embryology and Anatomy - Largest portion of the gland
§ Functional Aspects of the Hypothalamic-Hypophyseal - Originates from Rathke pouch, an evagination
Unit of buccal ectoderm that progressively extends
§ Hypophysiotropic or Hypothalamic Hormones upward and is eventually enveloped by the
§ Anterior Pituitary Hormones sphenoid bone
§ Pituitary Tumors 2. Intermediate lobe (pars intermedialis)
ü GROWHT HORMONE - Poorly developed in humans
§ Actions of GH - Has little functional capacity other than to
§ Testing confuse radiologists by forming nonfunctional,
§ Acromegaly benign, cystic enlargements of the pituitary
§ GH Deficiency 3. Posterior pituitary (neurohypophysis)
ü PROLACTIN - It arises from the diencephalon
§ Prolactinoma - Responsible for the storage and release of
§ Other Causes of Hyperprolactinemia oxytocin and vasopressin (also called
§ Clinical Evaluation of Hyperprolactinemia antidiuretic hormone [ADH])
§ Management of Prolactinoma § Median eminence (inferior portion of the
§ Idiopathic Galactorrhea hypothalamus) and the pituitary stalk is the other
ü HYPOPITUITARISM critical event in the formation of the hypothalamic–
§ Etiology of Hypopituitarism hypophyseal unit
§ Treatment of Panhypopituitarism § Pituitary function can be detected between the
ü POSTERIOR PITUITARY HORMONES seventh and ninth weeks of gestation
§ Oxytocin § The pituitary resides in a pocket of the sphenoid (the
§ Vasopressin sella turcica, meaning “Turkish saddle”) and is
surrounded by dura mater
§ The reflection of dura that separates the superior
portion of the pituitary from the hypothalamus, the
 diaphragma sella, is penetrated by the infundibulum,
or pituitary stalk, that connects the adenohypophysis
to the median eminence and hypothalamus
§ The pituitary stalk contains neural and vascular
structures that terminate in the hypophysis
§ The posterior pituitary is connected to the supraoptic
and paraventricular hypothalamic nuclei (where
vasopressin and oxytocin are produced)
§ The anterior pituitary receives 80% to 90% of its
blood supply and many hypothalamic factors via the
hypothalamic–hypophyseal portal system, also
contained in the stalk
FUNCTIONAL ASPECTS OF THE HYPOTHALAMIC-
HYPOPHYSEAL UNIT
§ The hypothalamic response patterns are similar for
each specific pituitary hormone and characterized by
open-loop negative feedback mechanisms, pulsatility,
and cyclicity
§ An example of negative feedback is the relationship
between a thermostat and a home heating unit.
Because the thermostat set point can be adjusted for
the comfort of the occupants, the furnace–thermostat
functional relationship is termed an open-loop
negative feedback system
§ The feedback of thyroxine at the level of the pituitary
is called a short feedback loop, and feedback at the
level of the hypothalamus is called a long feedback
loop. Feedback between the pituitary and
hypothalamus (when present) is called an ultrashort
feedback loop
HYPOPHYSIOTROPIC OR HYPOTHALAMIC HORMONES
§ TRH stimulates the secretion of both TSH and prolactin
§ GnRH stimulates both LH and FSH production
§ Somatostatin (SS) inhibits GH and TSH release from
the pituitary
§ Vasopressin (ADH) can also stimulate ACTH secretion
§ The main stimulus for ACTH secretion is corticotropin-
releasing hormone. These hypophysiotropic hormones
are found throughout the central nervous system and
various other tissues, including the gut, pancreas, and
other endocrine glands
PITUITARY TUMORS
ANTERIOR PITUITARY HORMONES
§ These pituitary hormones are either tropic, meaning
their actions are specific for another endocrine gland,
or they are direct effectors, because they act directly
on peripheral tissue
§ TSH is an example of tropic and GH is an example of
direct effector
§ GH has direct effects on substrate metabolism in
numerous tissues and also stimulates the liver to
produce growth factors that are critical in enhancing
linear growth
§ The tropic hormones are LH, which directs
testosterone production from Leydig cells in men and
ovulation in women; FSH, which is responsible for
ovarian recruitment and early folliculogenesis in
women and spermatogenesis in men; TSH, which
directs thyroid hormone production from the thyroid;
and ACTH, which regulates adrenal steroidogenesis
§ Both GH and prolactin are direct effectors
§ Prolactin-secreting pituitary tumors are the most
common, followed by nonfunctioning or null cell
tumors, and tumors that secrete GH, gonadotropins,
ACTH, or TSH
§ WHO defined “atypical pituitary tumors” as tumors
that have an MIB-1 proliferative index greater than 3%,
excessive p53 immunoreactivity, and increased mitotic
activity
§ MIB-1 is a monoclonal antibody that is used to detect
the Ki-67 antigen, a marker of cell proliferation, and a
high “proliferation index” suggests higher degree of
atypia
 § Most of these “atypical” tumors are macroadenomas
(i.e., >1 cm in diameter) and show invasion into
surrounding structures like the cavernous sinuses
§ Physiologic enlargement of the pituitary can be seen
during puberty and pregnancy. The enlargement seen
during pregnancy is due to lactotroph hyperplasia
GROWTH HORMONE
§ Also called somatotropin
§ Structurally related to prolactin and human placental
lactogen
§ GH is secreted in pulses, with an average interpulse
interval of 2 to 3 hours, with the most reproducible
peak occurring at the onset of sleep
§ Ghrelin – an enteric hormone that plays important
roles in nutrient sensing, appetite and in glucose
regulation, is also a potent stimulator of GH secretion
ACTIONS OF GH
§ It allows an individual to effectively transition from a
fed state to a fasting state without experiencing a
shortage of substrates required for normal intracellular
oxidation
§ Directly antagonizes the effect of insulin on glucose
metabolism, promotes hepatic gluconeogenesis, and
stimulates lipolysis
§ Isolated GH deficiency in children may be accompanied
by hypoglycemia
TESTING
§ The current testing paradigms for GH are based on the
dynamic physiology of the GH axis
§ Definitive testing for determining the autonomous
production of GH relies upon the normal
suppressibility of GH by oral glucose loading
- This test is performed after an overnight fast,
and the patient is given a 100 g oral glucose
load
- GH is measured at time zero and at 60 and 120
minutes after glucose ingestion
ACROMEGALY
§ Acromegaly results from pathologic or autonomous GH
excess
§ Recent reports have documented mutations in the aryl
hydrocarbon–interacting protein gene (AIP) in cases of
familialacromegaly and polymorphisms in the SS
receptor type 5 gene in sporadic cases
§ If a GH-producing tumor occurs before epiphyseal
closure, the patient develops gigantism
§ Because GH is an insulin antagonist, glucose
intolerance or over diabetes can occur
§ Hypertension; accelerated atherosclerosis; and
proximal muscle weakness, resulting from acquired
myopathy, may be seen late in the illness
§ Sleep apnea is common
§ Organomegaly, especially thyromegaly, is
common, but hyperthyroidism is exceedingly rare
unless the tumor cosecretes TSH
 § Treatment of acromegaly can be challenging.
Transsphenoidal adenomectomy is the procedure of
choice
GH DEFICIENCY
§ Occurs in both children and adults
§ In children, it may be genetic or it may be due to
tumors, such as craniopharyngiomas
§ In adults, it is a result of structural or functional
abnormalities of the pituitary
§ Although GH deficiency in children is manifest by
growth failure, not all patients with short stature have
GH deficiency. There have been several genetic defects
identified in the GH axis. The most common type is a
recessive mutation in the GHRH gene that causes a
failure of GH secretion
§ An adult GH deficiency syndrome has been described
in patients who have complete or even partial failure
of the anterior pituitary. The symptoms of this
syndrome are extremely vague and include social
withdrawal, fatigue, loss of motivation, and a
diminished feeling of well-being
PROLACTIN
§ Prolactin is structurally related to GH and human
placental lactogen
§ Considered a stress hormone
§ Its major mode of hypothalamic regulation is tonic
inhibition rather than intermittent stimulation
§ Prolactin inhibitory factor (PIF) was once considered a
polypeptide hormone capable of inhibiting prolactin
secretion; dopamine, however, is the only
neuroendocrine signal that inhibits prolactin and is
now considered to be the elusive PIF
PROLACTINOMA
§ A prolactinoma is a pituitary tumor that directly
secretes prolactin
§ The clinical presentation of a patient with a
prolactinoma depends on the age and gender of the
patient and the size of the tumor
§ Premenopausal women most frequently complain of
menstrual irregularity/amenorrhea, infertility, or
galactorrhea; men or postmenopausal women
generally present with symptoms of a pituitary
mass, such as headaches or visual complaints
§ Occasionally, a man may present with reduced libido
or complaints of erectile dysfunction
OTHER CAUSES OF HYPERPROLACTINEMIA
§ Generally, substantial elevations in prolactin (>150
ng/mL) indicate prolactinoma, and the degree of
elevation in prolactin is correlated with tumor size
§ Modest elevations in prolactin (25 to 100 ng/mL) may
be seen with pituitary stalk interruption, use of
dopaminergic antagonist medications, or other medical
conditions such as primary thyroidal failure, renal
failure, or polycystic ovary syndrome
§ Breast or genital stimulation may also modestly
elevate prolactin. Significant hyperprolactinemia is also
encountered during pregnancy.
 § Under most circumstances, the principal form of § Radiotherapy is generally reserved for high surgical risk
prolactin is a 23-kD peptide; however, a 150-kD form patients with locally aggressive macroadenomas who
may also be secreted are unable to tolerate dopamine agonists

CLINICAL EVALUATION OF HYPERPROLACTINEMIA IDIOPATHIC GALACTORRHEA

§ It is essential to obtain TSH and free T4 to § Lactation occurring in women with normal prolactin
eliminate primary hypothyroidism as a cause for the levels is defined as idiopathic galactorrhea
elevated prolactin § This condition is usually seen in women
§ If a pituitary tumor is suspected, a careful assessment who have been pregnant several times and has no
of other anterior pituitary function (basal cortisol, pathologic implication, but may be a manifestation of a
LH, FSH, and gender-specific gonadal steroid localized increased sensitivity to prolactin in
[either estradiol or testosterone]) and an evaluation of breast tissue
sellar anatomy with a high-resolution MRI
should be obtained HYPOPITUITARISM
§ Complete loss of function is termed
MANAGEMENT OF PROLACTINOMA panhypopituitarism
§ The management of prolactinoma depends on the size § Here may be a loss of only a single pituitary hormone,
of the tumor (macroadenomas [tumor size >10 mm] which is referred to as a monotropic hormone
are less likely to be “cured” than are microadenomas deficiency
[tumor size <10 mm]) and the preferences of the
patient ETIOLOGY OF HYPOPITUITARISM
§ Dopamine agonists are the most commonly used
therapy for microprolactinomas. Tumor shrinkage is
noted in more than 90% of patients treated with either
bromocriptine mesylate (Parlodel) or cabergoline
(Dostinex), dopamine receptor agonists
§ A resumption of menses and restoration of fertility is
also frequently seen during medical therapy
§ Surgical cure rates are inversely proportional to tumor
size and the degree of prolactin elevation
TREATMENT OF PANHYPOPITUITARISM § Diabetes insipidus (DI), characterized by copious
§ In the average patient, replacement therapy for production of urine (polyuria) and intense thirst
panhypopituitarism is the same as for primary (polydipsia), is a consequence of vasopressin deficiency
target organ failure. Patients are treated with
thyroxine, glucocorticoids, and gender-specific sex
steroids

POSTERIOR PITUITARY HORMONES

§ It is an extension of the forebrain and represents the
storage region for vasopressin (also called ADH) and
oxytocin

OXYTOCIN
§ A cyclic nonapeptide, with a disulfide bridge
connecting amino acid residues 1 and 6
§ It has a critical role in lactation and plays a major role
in labor and parturition

VASOPRESSIN
§ Structurally similar to oxytocin, vasopressin is a cyclic
nonapeptide with an identical disulfide bridge
§ It regulates renal free water excretion and, therefore,
has a central role in water balance
§ The vasopressin receptors in the kidney (V2) are
concentrated in the renal collecting tubules and
the ascending limb of the loop of Henle
§ Vasopressin is also a potent pressor agent and effects
blood clotting by promoting factor VII release from
hepatocytes and von Wille brand factor release from
the endothelium
CHAPTER 22: GONADAL FUNCTION
Chapter Outline:
ü THE TESTES
§ Functional Anatomy of the Male Reproductive
Tract
§ Physiology of the Testicles
§ Disorders of Sexual Development and Testicular
Hypofunction
§ Diagnosis of Hypogonadism
§ Testosterone Replacement Therapy
§ Monitoring Testosterone Replacement Therapy
ü THE OVARIES
§ Early Ovarian Development
§ Functional Anatomy of the Ovaries
§ Hormonal Production by the Ovaries
§ The Menstrual Cycle
§ Hormonal Control of Ovulation
§ Pubertal Development in the Female
§ Precocious Sexual Development
§ Menstrual Cycle Abnormalities
§ Hirsutism
§ Estrogen Replacement Therapy
THE TESTES
Functional Anatomy of the Male Reproductive Tract
§ Adult testes are paired, ovoid organs that hang from
the inguinal canal by the spermatic cord, which
comprises a neurovascular pedicle, vas deferens, and
cremasteric muscle
§ The testes are located outside the body, encased by a
muscular sac
§ The testes are comprised of two anatomical units: a
network of tubules, known as the seminiferous
tubules, and an interstitium
§ The tubules contain germ cells and Sertoli cells and are
responsible for sperm production.
§ The testes serve dual functions: (1) production of
sperm and (2) production of reproductive steroid
hormones
§ The earliest sign of puberty in boys is testicular
enlargement that results from rising luteinizing
hormone (LH) and follicle-stimulating hormone (FSH)
§ After puberty, throughout adulthood, and until late in
old age, testosterone helps with sperm production and
maintains secondary sexual characteristics
Physiology of the Testicles
Spermatogenesis
- Formed from stem cells called spermatogonia
- Undergo mitosis and meiosis
- The mature sperm has a head, body, and tail,
which enables it to swim for the purpose of
forming a zygote with the haploid ovum
Hormogenesis
- Testosterone, secreted by the testes, is
controlled primarily by two pituitary hormones:
FSH and LH
- FSH acts primarily on germinal stem cells and
LH acts primarily on the Leydig cells
- Both hormones are produced by a single group
of cells in the pituitary called gonadotrophs
- Gonadotropins (LH and FSH) are glycoproteins
and share an alpha subunit with thyroid-
stimulating hormone (TSH) and hCG
Hormonal Control of Testicular Function
- The hypothalamus generates a hormone called
gonadotropin-releasing hormone (GnRH) ina
pulsatile fashion
- GnRH determines the production of LH and FSH
from the pituitary gland
- Impaired pulse generation of GnRH leads to
inadequate production of LH and FSH, resulting
in hypogonadism
- Testosterone and inhibin are the two
hormones secreted by the testes
- Leydig cell steroidogenesis of testosterone is
primarily controlled by LH secretion
- FSH acts on Sertoli cells to stimulate protein
synthesis, inhibin, and androgen-binding
protein
- The actions of both testosterone and FSH on
Sertoli cells are synergistic, permitting
completion of spermatogenesis
- Testosterone concentration fluctuates in a
circadian fashion
- This fact should be considered when
interpreting serum levels of testosterone: the
highest level is found at about 6 AM and
the lowest level is found at about 12 AM (in a
male with a normal sleep–wakecycle)
Cellular Mechanism of Testosterone Action
- Testosterone enters the cell and converts to
DHT in cells rich in 5α-reductase, such as some
hair follicles and prostate
Physiologic Actions of Testosterone
Prenatal Development
- The primitive gonads become distinguishable at
about the 7th week of embryonic stage
- In the fetus, the hypothalamo-hypophyseal
vascular connections are responsible for LH
release by hypothalamic GnRH and are
established between 11 and 12 weeks after
conception, which is 3 weeks after testosterone
production by the Leydig cells of the testis
Postnatal Development
- Testicular function is reactivated during
puberty after a period of quiescence to
produce testosterone that results in
development of secondary sex hair (face, chest,
axilla, and pubis), enhanced linear skeletal
growth, development of internal and external
 genitalia, increased upper body musculature,
and development of larynx and vocal cords with
deepening of the voice
Effect on Secondary Sexual Effects
- Failure to develop secondary sexual
characteristics should prompt evaluation for
hypogonadism or constitutional delay in boys
- Loss of secondary sexual characteristics might
occur gradually and should prompt evaluation
for hypogonadism because low testosterone
levels lead to loss of bone mass and
development of osteoporosis in males at any
age

Disorders of Sexual Development and Testicular

Hypofunction

Effect on Spermatogenesis
- Exogenous overuse or abuse of testosterone,
such as occurs with some athletes, will reduce
the high intratesticular concentration of
testosterone, leading to reduction of sperm
production

Hypergonadotropic Hypogonadism
- Hypergonadotropic hypogonadism incorporates
a group of disorders characterized by low
testosterone, elevated FSH or LH, and impaired
sperm production
Klinefelter's Syndrome
- Caused by the presence of an extra
chromosome
- The most common human sex chromosome
abnormality
- The most common karyotype is 47, XXY .11
- Men with this disorder have small (<2.5 cm),
firm testicles
- Gynecomastia (enlargement of the male
breast) is commonly present at the time of
diagnosis
- Men with Klinefelter's syndrome may have
reduced bone density and breast cancer risk
comparable to women
Testicular Feminization Syndrome
- The most severe form of androgen resistance
syndrome, resulting from mutations of the
androgen receptor and impaired androgen
actions in target tissues
- The testicles are often undescended, and
failure to promptly remove these organs is
essential to abort malignant transformation
5a-Reductase Deficiency
- Deficiency of 5α-reductase is a rare cause of
androgen insensitivity and results in a mutation
encoding the type 2 isoenzyme, maps to
chromosome 2p23, and is expressed in XY
males
Myotonic Dystrophy
- Myotonic dystrophy (type 1 caused by DMPK
gene mutation and type 2 caused by CNBP gene
mutation) is inherited in an autosomal
dominant fashion and presents with primary
hypogonadism, frontal balding, diabetes, and
muscle weakness, atrophy, and dystonia
(an inability of the muscle to relax adequately
after contraction
- Testicular failure typically presents in the
twenties and thirties

Testicular Injury and Infection
- Mumps orchitis develops in a third of post
pubertal males with mumps and is the most
frequent extra salivary manifestation of this
highly contagious infection
- Mumps outbreaks have been reported in
secondary schools, colleges, universities, and
military groups
Sertoli Cell–Only Syndrome
- Sertoli cell–only syndrome (SCO syndrome or
germ cell aplasia) is characterized by a lack of
germ cells
- Men present with small testes, high FSH levels,
azoospermia, and normal testosterone level
- Testicular biopsy shows lack (or complete
absence) of spermatozoa
- This disorder may arise from Y chromosome
microdeletions on Yq11 locus
Hypogonadotropic Hypogonadism
- Occurrence of low testosterone levels together
with low or inappropriately normal FSH or LH
levels
Kallmann's Syndrome
- Kallmann's syndrome is a result of an inherited,
X-linked recessive trait that manifests as
hypogonadism during puberty
- Certain men also have red-green color
blindness, congenital deafness, or cerebellar
dysfunction
Hyperprolactinemia
- Prolactin elevation resulting from any cause
(drug-induced or prolactin producing tumors of
the pituitary) can result in hypogonadotropic
hypogonadism due to impairment of both
frequency and amplitude of FSH and LH pulse
Type 2 Diabetes
- It is characterized by low free or total serum
concentrations of testosterone and
inappropriately low LH
Age
- There is a gradual reduction in testosterone
after age 30, with an average decline of about
110 ng/dL every decade
- Age is also associated with elevation of SHBG by
about 1%/year
Pituitary Disease
- Acquired hypogonadism can follow injury to
the pituitary as a result of tumors, surgical or
radiation-induced trauma, vascular injury,
autoimmune hypophysitis, or granulomatous or
metastatic disease
- Hemochromatosis is a rare cause of pituitary
dysfunction
Opioid Use
- Long-term or continuous use of narcotics has
been linked to severe hypogonadotropic
hypogonadism (due to μ-opioid receptor–
mediated decreased GnR pulsatile production)
and even decrease in male fertility
Obstructive Sleep Apnea
- It is to be noted that testosterone replacement
therapy (especially high-dose testosterone)
may worsen preexisting sleep apnea, possibly
due to increased oxygen consumption
Diagnosis of Hypogonadism
- Both clinical and biochemical features must be
met to make the diagnosis of hypogonadism
Testosterone Replacement Therapy
- Testosterone should be administered only to a
man who is hypogonadal, as evidenced by
clinical symptoms and signs consistent with
androgen deficiency and a distinctly subnormal
serum testosterone concentration
- The currently available modes of testosterone
administration in the United States are as
follows:
1. Parenteral testosterone
- The most widely available and cost-effective
mode of administration
- The cypionate and enanthate esters of
testosterone are available for intramuscular
injection
- The peak level is achieved in 72 hours and the
effect lasts for a period of 1 to 2 weeks
- Weekly administration provides for a lower
peak and less fluctuation within the normal
range of testosterone levels
- Usual dosing is 50 to 100 mg weekly or 150 to
250 mg once every 2 weeks
- Testosterone dose should be based on lean
body mass, not on body weight
2. Transdermal testosterone patch therapy
- This mode of administration provides more
physiologic levels of testosterone
 - The patch is permeability enhanced to aid in
the absorption of testosterone through normal
skin
- Local skin irritation can occur and often limits
the patch use
3. Testosterone gel
- This hydroalcoholic gel preparation is applied to
nongenital skin once daily
- The absorption is gradual and provides blood
levels of testosterone in the normal range for
24 hours
- The main concern with this preparation is
potential transmission to female partners or
children on close skin contact
4. Testosterone buccal pellet
- This plastic tablet is placed along the gum line
twice daily
- Local discomfort (irritated gums) and the need
for twice-daily dosing sometimes limit use
5. Subcutaneous testosterone pellet (Testopel)
- Involves implantation of three to six mg
testosterone pellets every 3 to 6 months, into
the subdermal fat of the buttocks, lower
abdominal wall, or thigh with a trocar under
sterile conditions using a local anesthetic
6. Nasal testosterone gel (Natesto)
- Natesto is administered into each nostril by a
metered-dose pump applicator three times
daily
- The risk of testosterone transfer from a patient
to his partner or children is mitigated, but the
complications of testosterone replacement are
acne, polycythemia, prostate enlargement,
possible growth-promoting effect on
undiagnosed prostate cancer, worsening of
obstructive sleep apnea (OSA), peripheral
edema, and gynecomastia
Monitoring Testosterone Replacement Therapy
- Prostate-specific antigen (PSA), blood counts
(for hematocrit), and lipid levels should be
checked 3 to 6 months after initiation of
testosterone replacement and at least yearly
thereafter
- Routine clinical evaluation for leg edema,
worsening of sleep apnea, and prostate
enlargement is also recommended
- If PSA elevation is noted after testosterone
replacement, prostate evaluation with possible
biopsy is recommended
THE OVARIES
Early Ovarian Development
- If no Y chromosome or TDF is present, the
gonad, by default, forms an ovary
- Estrogen formation in the fetal ovary begins in
early development despite primordial follicles
not having begun forming until the second
trimester of pregnancy
Pubertal Changes of Ovarian Function
- The ovaries are paired organs that perform the
dual functions of gamete (ovum) and steroid
hormone production
- Ovarian and menstrual events are carefully
synchronized by a complex interplay of
hormones among the hypothalamus, pituitary,
and ovaries to prepare the uterus for
implantation of an embryo
- In the absence of implantation, the uterine
lining is shed, resulting in menses
Hormonal Production by the Ovaries
Functional Anatomy of the Ovaries
- The ovaries are oval organs that lie in the pelvic
fossa
- They are positioned near the fimbrial end of the
fallopian tubes, which are connected to the
uterine cavity
- An adult ovary averages 2 to 5 cm in length,
weighs an average of 14 g, and typically
contains 2 to 4 million primordial follicles
- Typically, all but one of these follicles will then
atrophy, in a process termed the follicular
phase
- The single remaining follicle—known as the
graafian follicle—is composed of an outer and
inner layer encasing a central fluid-filled cavity
and a layer of cells known as the granulosa
layer
- The maturing ovum attaches to the inside of
the follicle via cells derived from granulosa
cells, called cumulus cells
- During the luteal phase of the ovarian cycle,
the graafian follicle releases its ovum in
response to ovarian stimulation by LH
- When the ovum is extruded, the graafian
follicle undergoes a morphologic change with
hypertrophy of the theca and granulosa cells to
become the corpus luteum. This process is
called luteinization
- As in the adrenal glands and the testes, the
steroidogenic pathway and synthetic enzymes
are present in the ovaries
- Cholesterol is either synthesized from acetate
or actively transported from the LDL particle in
blood and then used as a substrate for
hormonal production
Estrogen
- The principal estrogen produced in the ovary is
estradiol
- Estrogens promote breast, uterine, and vaginal
development and also affect the skin, vascular
smooth muscles, bone cells, and the central
nervous system
- The lack of estrogen that naturally occurs with
the onset of menopause leads to atrophic
changes in these organs
- During the reproductive period, it is estrogen
that is responsible for follicular phase changes
in the uterus
Progesterone
- Induces the secretory activity of those
endometrial glands that have been primed by
estrogen, readying the endometrium for
embryo implantation
- Progesterone is the dominant hormone
responsible for the luteal phase, and deficiency
results in failure of implantation of the embryo
Androgens
- Ovaries produce the androgens
androstenedione, dehydroandrostenedione,
testosterone, and DHT, all of which are carbon-
19 compounds.
- Excess production of ovarian androgens in
women leads to excess hair growth (hirsutism),
loss of female characteristics, and—in severe
cases—development of overt male secondary
sexual features (masculinization or virilization)
Others
- Inhibins A and B, which are produced by the
ovaries, are hormones that inhibit FSH
production
- Activin is a hormone that enhances FSH
secretion and induces steroidogenesis
The Menstrual Cycle
The Follicular Phase
- The follicular phase begins with the onset of
menses and ends on the day of LH surge
The Luteal Phase
- The start of the luteal phase is marked by the
extrusion of the ovum approximately 36 hours
after this LH surge, with subsequent
luteinization of the graafian follicle to form the
corpus luteum
Hormonal Control of Ovulation
- Positive and negative feedback responses exist
among estrogen, progesterone, LH, and FSH
production
Pubertal Development in the Female
- Puberty in females consists of a sequence of
hormonally mediated events resulting in the
development of secondary sexual
 characteristics and attainment of final adult Menstrual Cycle Abnormalities
height Amenorrhea
- Thelarche (development of breast tissue) is - Is defined as the absence of menses
typically the earliest sign of sexual Primary amenorrhea
development, followed by development of - is used to describe a woman who has never
pubic hair menstruated by age 16 years
- Menarche, or initiation of menses, occurs an secondary amenorrhea
average of 2 to 3 years after the onset of - is used to describe a woman who has had at
puberty least one menstrual cycle followed by absence
of menses for a minimum of 3 to 6 months
Precocious Sexual Development
- Precocious sexual development occurs in
response to premature exposure of tissues to
sex steroids from any source and is
distinguished from precious puberty, which can
be arrested by suppression of GnRH with
analogs of GnRH that will suppress LH

Oligomenorrhea
- refers to infrequent irregular menstrual
bleeding, with cycle lengths in excess of 35 to
40 days
- Uterine bleeding in excess of 7 days is
dysfunctional and is termed menorrhagia
Causes of Infertility
Polycystic Ovary Syndrome
Hypogonadotropic Hypogonadism
- Hypogonadotropic hypogonadism, or
gonadotropin (FSH and LH) deficiency resulting
in decreased sex steroid production, is a
common cause of secondary amenorrhea
Hypergonadotropic Hypogonadism
- Characterized by ovarian failure resulting in
elevation of FSH concentrations, with or
without LH elevations
- When the depletion of oocytes and follicles
occurs at the expected time, it is termed
menopause
- Menopause is a natural, inevitable event that
results in elevation of FSH and LH levels, with
low levels of estrogen
- Premature ovarian failure is defined as primary
hypogonadismin a woman before the age of 40
and can be a result of congenital chromosomal
abnormality (e.g., Turner's syndrome) or
premature menopause
- This common disorder can present in many
ways: infertility, hirsutism, chronic anovulation,
glucose intolerance, hyperlipidemia or
dyslipidemia, and hypertension
- Investigations for this disorder involve
estimation of free testosterone, SHBG, FSH, LH,
fasting glucose, insulin, lipid levels, DHEAS,
prolactin, and ± AMH levels
- Ovarian ultrasound reveals multiple cysts in
many patients (about 30% of patients do not
have ovarian cysts)
- Most patients with this disorder are
overweight; however, some patients with
polycystic ovary syndrome (PCOS), especially of
eastern Asian or South American descent, are
of normal weight
- Glucophage (metformin), commonly used for
the treatment of diabetes, is useful in this
condition, even in the absence of diabetes.
Although not U.S. Food and Drug
Administration approved for this use, it
 reportedly can normalize menstrual cycles and
improve conception rates

Hirsutism
- An abnormal, abundant, androgen-sensitive
terminal hair growth in areas in which terminal
hair follicles are sparsely distributed or not
normally found in women

Chapter 23
The Thyroid Gland
Thyroid gland is responsible for the
production of two hormones: thyroid
hormone and calcitonin
a) Calcitonin - secreted by parafollicular C
cells and is involved in calcium
homeostasis
b) Thyroid hormone - is critical in
regulating body metabolism, neurologic
development, and other body
functions.
I. Anatomy and Development
• Found in the lower anterior neck;
butterfly-like shaped.
• Consists of two lobes – resting on each
side of trachea, with a band of isthmus
(thyroid tissues)
• Parathyroid glands – posterior to the
thyroid glands; regulates serum calcium
thyroid cell by the Na+/I-
levels and the recurrent laryngeal
nerves that innervate the vocal cords.
• The fetal thyroid develops from an
outpouching of the foregut at the base
of the tongue and migrates to its
normal location over the thyroid
cartilage in the first 4 to 8 weeks of
gestation. By week 11 of gestation, the
thyroid gland begins to produce
T3 and T4 are stored in the
measurable amounts of thyroid
hormone
• Thyroid hormone is critical to
neurologic development of the fetus
Ø Iodine - essential component of
thyroid hormone
Ø Severe iodine deficiency -
neither the mother nor the
fetus can produce thyroid
hormone and both develop
hypothyroidism; which can
greatly affect the fetus because
hypothyroidism leads to mental
retardation and cretinism
II. Thyroid Hormone Synthesis
• made primarily of the trace element
iodine - found in seafood, dairy
products, iodine-enriched breads, and
vitamin
• 150 μg - recommended minimum daily
intake of iodine
Colloid, a viscous substance surrounded by
follicles (spheres of thyroid cells), consists
of thyroglobulin that is rich in the amino
acid tyrosine. Some of these tyrosyl
residues can be iodinated, producing the
building blocks of thyroid hormone
On the outer side of the
follicle, iodine is
Inside the thyroid cell,
iodide diffuses across the
Concentrated iodide is
oxidized and bound with
cell to the apical side of the
transported into the
follicle, which abuts the
tyrosyl residues on
thyroglobulin.
core of colloid.
TPO also aids in the
coupling of two tyrosyl monoiodothyronine (MIT)
Catalyzed by thyroid
and diiodothyronine (DIT)
residues to form
triiodothyronine (T3) or is produced.
peroxidase (TPO)
thyroxine (T4).
Endocytosis happens when
Inside folliclar cell, droplets
TSH signals follicular cells
thyroid follicle to ingest a microscopic
are digested by
intracellular lysosomes
droplet of colloid
T4, T3 and other products
Released into circulation
are produced
• Triiodothyronine (T3) (one MIT residue
+ one DIT residue) and thyroxine (T4)
 (two DIT residues) – two active forms of • The three major binding proteins:
thyroid hormone. 1. thyroxine-binding globulin
• The activity of thyroid hormone is (TBG) – most significant
dependent on the location and number 2. thyroxine-binding prealbumin
of iodine atoms 3. albumin
• T4 (approx. 80%) – metabolized into: • The quantity of T4 and T3 in the
a) T3 (35%) or circulation can be significantly affected
b) reverse T3 (rT3) (45%) by the amount of binding protein
• Outer ring deiodination of T4 (5ʹ- available for carrying these hormones.
deiodination) leads to the production of
3,5,3ʹ-triiodothyronine (T3).
• T4 - “pre” hormone
• T3 – more metabolically active than T4
• Thyroglobulin – “prohormone”
• There are three forms of iodothyronine
5ʹ-deiodinase:
a) Type 1 iodothyronine 5ʹ-
deiodinase, the most abundant
form, is found mostly in the
liver and kidney and is
responsible for the largest
contribution to the circulating
T3 pool.
b) Type 2 iodothyronine 5ʹ-
deiodinase is found in the brain
and pituitary gland; maintain
constant levels of T3 in the
central nervous system. Its
activity is decreased when
IV. Control of Thyroid Function
levels of circulating T4 are high This feedback loop requires a normally
and increased when levels are functioning hypothalamus, pituitary, and
low. thyroid gland, as well as an absence of any
interfering agents or agents that mimic TSH
action

III. Protein Binding of Thyroid Hormone

When released into the circulation, only

0.04% of T4 and 0.4% of T3 are unbound by
proteins and available for hormonal activity.
 circulation, TRH and TSH secretion
increases and will lead to increased
thyroid hormone production.
5) If thyroid hormone levels are high, TRH
and TSH release will be inhibited,
leading to lower levels of thyroid
hormone production and vice versa if
thyroid hormone levels are low.

V. Actions of Thyroid Hormone

• (T3) helps in the production of
messenger RNA – that in turn, leads to
the production of proteins that
influence metabolism and development
• Tissue growth
• brain maturation
• increased heat production
increased oxygen consumption
• increased number of β-adrenergic
receptors.
1) Thyrotropin-releasing hormone (TRH) is
synthesized by neurons in the
supraoptic and supraventricular nuclei
of the hypothalamus and stored in the
median eminence of the hypothalamus.
2) When secreted, this hormone
stimulates cells in the anterior pituitary
gland to manufacture and release
thyrotropin (TSH).
3) TSH, in turn, circulates to the thyroid
gland and leads to increased production
and release of thyroid hormone.
4) When the hypothalamus and pituitary
sense that there is an inadequate
amount of thyroid hormone in

VI. TESTS FOR THYROID EVALUATION

TEST DESCRIPTION METHOD

Blood tests
Thyroid- • most useful test for assessing thyroid function Assays
stimulating • capable of diagnosing primary hypothyroidism (thyroid gland
hormone disease leading to low thyroid hormone production) with
elevated levels of TSH

Serum T3 and • Measures free T4 and T3, the biologically active forms of thyroid radioimmunoassay (RIA);
T4 hormone. chemiluminometric assay;
• assay kits for measuring free T4 levels are not error proof and or
can still be affected by some binding protein abnormalities; similar immunometric
when this is suspected, measurement of free T4 levels is technique.
performed by dialysis
Thyroglobulin • This prohormone in the circulation is proof of the presence of doubleantibody RIA,
thyroid tissue, either benign or malignant enzyme-linked
• ideal tumor marker for thyroid cancer patients immunoassay,
• Accuracy is primarily dependent on the specificity of the immunoradiometric assay,
antibody used and the absence of antithyroglobulin and
autoantibodies. immunochemiluminescent
assay
Thyroid • In autoimmune thyroid disease, antibodies are directed at Bioassays
autoimmunity thyroid tissue with variable responses
• TSH receptor antibodies are being detected

Other tools
Nuclear • Assesses the metabolic activity of thyroid tissue and assisting in Radioactive iodine
medicine the evaluation and treatment of thyroid cancer
evaluation • When radioactive iodine is given orally, a percentage of the dose
is taken up by the thyroid gland. This percentage is called the
radioactive iodine uptake (RAIU).
a) High uptake suggests that the gland is metabolically
active and producing significant amounts of thyroid
hormone.
b) Low uptake suggests that the gland is metabolically
inactive
• can also be useful in the evaluation of thyroid nodules in the
presence of a low or undetectable TSH.
Thyroid • useful in assessing thyroid anatomy and characterization of Ultrasound
ultrasound palpable thyroid abnormalities
• capable of detecting even thyroid nodules of such a small size as
to be of unclear or even no clinical significance
Fine needle • often the first step and the most accurate tool in the evaluation can be performed
aspiration of thyroid nodules. through:
• allows prompt identification and treatment of thyroid a) using palpation if
malignancies and avoids unnecessary surgery in most individuals palpable
with benign thyroid lesions b) ultrasound imaging
• a small-gauge needle is inserted into the nodule and cells are in cases of
aspirated for cytologic evaluation nonpalpable nodules
• FNA biopsy results are reported according to six categories:
i. Nondiagnostic
ii. Malignant
iii. suspicious for malignancy
iv. indeterminate or suspicious for neoplasm
v. follicular lesion of undetermined significance
vi. benign

VII. Disorders of the Thyroid - defined as a low free T4 level with a

Hypothyroidism normal or high TSH; one of the most
common disorders of the thyroid gland
 a) Types § Hyponatremia can occur due to
inappropriate levels of antidiuretic
hormone
§ Myopathy
§ Elevated levels of creatine kinase (CK)
§ Anemia
§ Hyperlipidemia

d) Causes

b) Symptoms
§ cold intolerance
§ fatigue
§ dry skin
§ constipation
§ hoarseness
§ dyspnea on exertion
§ cognitive dysfunction
§ hair loss
§ weight gain American Thyroid Association Guidelines for
Hypothyroidism Screening:
Physical examination on severe cases may Measurement of TSH
have: • At age 35
§ may have low body temperature • Every 5 years after the age of 35
§ slowed movements • More frequently with risk factors or
§ bradycardia symptoms: goiter, family history,
§ delay in the relaxation phase of deep lithium use, amiodarone use
tendon reflexes
§ yellow discoloration of the skin (from
hypercarotenemia)
§ hair loss
§ diastolic hypertension
§ pleural and pericardial effusions
§ menstrual irregularities
§ periorbital edema

c) Clinical abnormalities

Because of the diffuse distribution of

thyroid hormone receptors and many
metabolic effects of thyroid hormone,
hypothyroidism can lead to a variety of Thyrotoxicosis
other abnormalities
 - result when peripheral tissues are
presented with, and respond to, an
excess of thyroid hormone
- can be the result of excessive thyroid
hormone ingestion, leakage of stored
Grave’s Disease
- Most common cause of thyrotoxicosis.
thyroid hormone from storage in the
It is an autoimmune disease in which
thyroid follicles, or excessive thyroid
antibodies are produced that activate
gland production of thyroid hormone
- Hyperthyroidism, latter form of
thyrotoxicosis

Signs and symptoms

- vary, depending on the degree of
thyroid hormone elevation and the
status of the affected individual

Typical symptoms:
§ anxiety
§ emotional lability
§ weakness
§ tremor
§ palpitations
§ heat intolerance the TSH receptor.
§ increased perspiration
§ weight loss despite a normal or
increased appetite a) Features
§ Goiter
§ Ophthalmopathy (eye changes
associated with inflammation and
infiltration of periorbital tissue)
§ Dermopathy (skin changes in the lower
extremities that have an orange peel
texture)
b) Treatment
§ Medication
§ radioactive iodine
§ surgery

Toxic Adenomas and Multinodular Goiter

- two relatively common causes of
hyperthyroidism
- caused by autonomously functioning
thyroid tissue

Treatment
§ surgery
§ radioactive iodine
§ medication (PTU or MMI)
VIII. Drug-Induced Thyroid Dysfunction
Amiodarone-Induced Thyroid Disease
- fat-soluble drug with a long half-life (50
days) in the body that interferes with
normal thyroid function
- Amiodarone also blocks T4-to-T3
conversion; the combination of these
two actions leads to hypothyroidism in
8% to 20% of patients on chronic
amiodarone therapy
- Amiodarone can also lead to
hyperthyroidism in 3% of patients
treated chronically with this medication
Subacute thyroiditis
Classifications:
a) postpartum thyroiditis
b) painless thyroiditis
c) painful thyroiditis
- These conditions are often associated
with a thyrotoxic phase when thyroid
hormone is leaking into the circulation,
a hypothyroid phase when the thyroid
gland is repairing itself, and a euthyroid
phase when the gland is repaired.
- These phases can last from weeks to
months
a. Postpartum thyroiditis
- most common form of subacute
thyroiditis.
- strongly associated with the presence of
TPO antibodies and chronic lymphocytic
thyroiditis. Patients may experience a
period of thyrotoxicosis followed by
hypothyroidism or simply
hypothyroidism or hyperthyroidism
- Thyroid hormone levels usually return
to normal after several months;
however, by 4 years’ postpartum, 25%
to 50% of patients have persistent
hypothyroidism, goiter, or both.
b. Painful thyroiditis
- also called subacute granulomatous
thyroiditis, subacute nonsuppurative
thyroiditis, or de Quervain’s thyroiditis
- Viral infections are felt to trigger this
condition.
- TPO antibodies are usually absent;
erythrocyte sedimentation rate and
thyroglobulin levels are often elevated
- characterized by neck pain, low-grade
fever, myalgia, a tender diffuse goiter,
and swings in thyroid function tests (as
discussed earlier).
IX. Nonthyroidal illness
- Typical laboratory pattern is one of low
total T4, free T4, and (sometimes) TSH;
because illness decreases 5ʹ-
monodeiodinase activity, less T4 is
converted to active T3. This leads to
decreased levels of T3 and higher levels
of rT3
X. Thyroid nodules
- The major concern with thyroid nodules
is that they may represent a thyroid
cancer
- FNA of these nodules, with cytologic
examination of the aspirate, has
become a routine practice to help
distinguish the nodules that require Chapter 24
surgical removal from those that do Calcium Homeostasis and Hormonal
not. Regulation

• Serum calcium level is maintained at a

constant level for the optimal
excitability of neural and muscular
tissue and the coordinated functioning
of various organ systems in the human
body
• 1,000 g of calcium – adult human body
contains
Ø 99% - in the form of
hydroxyapatite salt
Ø 1% - is in the extra-cellular
fluids and regulates various
biochemical events
• Exists in blood in 3 forms:
a) Ionized (50%)
b) Protein bound (40% to plasma
proteins)
c) Complexed (10% to citrate and
phosphate)
• Principal organs involved in calcium
homeostasis are the skin, liver, small
intestine, skeleton, parathyroid glands,
and kidneys.
• Diet is the only source of calcium.
• Skeleton - acts as a mineral repository,
releasing calcium into blood on demand
• Significant loss of calcium from the
body is into urine.

I. Hormonal regulation of calcium

metabolism
Two most important hormones that
regulate calcium and phosphate
homeostasis:
1) Vitamin D
2) Parathyroid Hormone (PTH)

A. Vitamin D
 - a steroid hormone that is synthesized in
the skin following exposure to UVB rays
from the sun
1) photo-biosynthesis from cholesterol;
2) hydroxylation in the liver and kidneys;
3) Enzyme 25-hydroxylase, metabolizes
vitamin D3 to 25-hydroxy vitamin D
4) renal 1α-hydroxylase, under PTH
regulation, completes the formation of
the active metabolite, 1,25-dihydroxy
vitamin D (1,25(OH)2D
Influences the synthesis of vitamin D:
§ amount of sun exposure; available
sunlight
§ skin covering
§ age of the individual
- The 1,25(OH)2D–vitamin D receptor
complex binds to the vitamin D
response element upstream (5ʹ) of the
transcription start site of vitamin D
genes and induces gene transcription.
Activated vitamin D, 1,25(OH)2D,
induces active absorption of calcium in
the small bowel cells, which is the
dominant mechanism of calcium
absorption in humans.
- Only about 5% to 10% of calcium is
absorbed passively
- In the bone, 1,25(OH)2D stimulates
differentiation of osteoclast precursors
to osteoclasts; 1,25(OH)2D also
stimulates osteoblasts to influence
osteoclasts to mobilize bone calcium
- 1,25(OH)2D plays an important role in
the mineralization of bone, and
abnormal bone results when vitamin D
is deficient or its metabolism is
defective
- 1,25(OH)2D increases blood calcium by
augmenting intestinal absorption of
calcium.
- 1,25(OH)2D has direct control over the
PTH secretion, and high levels reduce
secretion of PTH.
B. Parathyroid Hormone
- secreted from four parathyroid
glands that are located adjacent to
the thyroid gland.
- The parathyroid glands have
specialized calcium-sensing
receptors (CSRs) that respond to
rising or falling calcium levels by
 increasing or decreasing PTH
secretion, respectively.
- bone and kidneys: primary targets
for the PTH
- PTH mobilizes calcium from bone by
- increasing bone resorption.
Effects of PTH on kidneys:
1. Increase the reabsorption of renal
tubular calcium
2. Increase phosphate excretion
3. Enhance1α-hydroxylation of 25-hydroxy
vitamin D
As noted earlier, 1,25(OH)2D increases
blood calcium by augmenting intestinal
absorption of calcium – blood calcium feeds
back to parathyroid glands and regulates
the synthesis and secretion of PTH.
1,25(OH)2D has direct control also over the
PTH secretion, and high levels reduce
secretion of PTH. Elevated serum phosphate
levels reduce 1,25(OH)2D formation
Low blood calcium is sensed by the
parathyroid CSR, which in turn secretes PTH
and sets into motion a cascade of events
aimed at restoring normal blood calcium
levels. The multiple actions of PTH
described above are mediated via PTH
receptor, located on the cell membrane of
target tissues. This receptor activates
adenylate cyclase and the “second
messenger” pathway involving cyclic AMP
(cAMP), which modulates protein
phosphorylation.
II. Organ System Regulation of Calcium
Metabolism
Three organ systems that regulate calcium
metabolism:
• GI Tract
• Kidneys
• Bone
GI Regulation
Normal intestinal function is required for
calcium absorption in which 1,25(OH)2D
controls from the small bowel.
Conditions that may interrupt intestinal
function that may also affect calcium
absorption:
§ short bowel syndromes (following
resection)
§ gastric weight loss surgeries
§ intestinal mucosa disease (celiac
disease)
§ genetic defects
§ bowel fistula
Necessary for optimal calcium absorption:
§ Adequate dietary calcium intake
§ Availability of normal amounts of
vitamin D
§ Metabolism
Dietary phosphate can bind dietary calcium
in the intestinal lumen, forming calcium
phosphate (insoluble and nonabsorbable
precipitate). The insolubility of calcium
phosphate is the basis for the use of
calcium carbonate as a “phosphate binder”
in patients with renal failure. Likewise, a
diet rich in phosphate will tend to inhibit
calcium absorption by the same mechanism
Role of Kidneys
Under normal conditions, PTH increases
renal tubular reabsorption of calcium,
thereby reducing renal loss.
Persons who develop renal failure may
develop markedly disordered calcium and
phosphate metabolism. Impaired
hydroxylation of 25-hydroxy vitamin D to
form the active 1,25(OH)2D results in poor
calcium absorption from the gut.
Diseased kidneys fail to excrete phosphate,
leading to elevated serum phosphate levels.
Hyperphosphatemia triggers PTH and
fibroblast growth factor 23 (FGF 23)
secretion. FGF 23 is a powerful
phosphaturic hormone. Serum PTH levels
can be elevated into the thousands in
chronic renal failure patients. Once a critical
calcium/phosphate product is reached,
precipitation of these minerals occurs
within the tissues, leading to devastating
consequences.
Bone physiology
Bone turnover/ “remodeling”
- Coupled process of simultaneous bone
formation and breakdown that occurs to
varying degrees throughout the life and at
multiple sites in the skeleton.
This ensures that neither resorption nor
formation occurs in excess compared to the
other, thereby preventing imbalance
between formation and loss of bone.
• Too much resorption = weaker bones
• Too much bone formation = obliterates
marrow space
Osteoblasts – mediates bone formation
Osteoclasts – mediates bone
breakdown/resorption
When the net rates of osteoblast-mediated
bone formation and osteoclast-mediated
bone resorption are mismatched, or
uncoupled, such that resorption exceeds
formation, bone mass will ultimately
decrease
• Decreased bone mass = increased risk
of fracture
As bones turn over, several proteins are
released into the blood and eventually
excreted in the urine, collectively called as
bone turnover/resorption markers – useful
in the monitoring of clinical response to
osteoporosis therapies and for predicting
fracture risk; this includes:
§ Hydroxyproline
§ N telopeptides
§ C telopeptides
§ Cross-links
§ TRAP (tartrate-resistant acid
phosphatase)
Formation markers:
§ BSAP (bone-specific alkaline
phosphatase
§ Osteocalcin
§ Procollagen N-terminal extension
peptides
III. HYPERCALCEMIA
- results when blood calcium levels in
a subject are above the expected
normal range
a) patients with serum low albumin -
expected to have low total calcium and
normal ionized calcium
b) patients with high serum albumin –
normal total calcium and low ionized
calcium
 - The duration and the level of
calcium elevation determine the
severity of symptoms and the
degree of end-organ damage
Symptoms:
Acute Chronic mild Cancer-
hypercalcemia hypercalcemia mediated
§ Lethargy Symptom free often
§ Stupor
presents with
§ Coma
profound
central
nervous
system (CNS)
symptoms
Moderate calcium elevation is associated
with intellectual weariness, personality
changes, nausea, anorexia, polyuria, kidney
stones, hypertension, and
electrocardiogram (ECG) changes.
The signs and symptoms of hypercalcemia
are highly variable and depend upon the
rapidity of onset and severity of
hypercalcemia. Clinically, the signs and
symptoms also vary from patient to patient
and comorbid conditions may also influence
the development of symptoms.
Signs and symptoms are best described by
organ systems:
Organ system Signs and symptoms
CNS Impairment of CNS function,
including lethargy, decreased
alertness, depression,
confusion, forgetfulness,
obtundation, and coma
GI Patients may experience
anorexia, constipation, peptic
ulcers, and nausea and
vomiting
Renal Hypercalciuria leading to
kidney stone formation and
calcification of renal tubules
resulting in nephrogenic
diabetes insipidus.
Skeletal Increased bone resorption
and demineralization leading
to fractures
Cardiovascular Hypercalcemia may cause or
exacerbate hypertension. The
following ECG changes are
seen in hypercalcemia:
Increased PR interval, wide
QRS complex, and short QT
syndrome
Causes of hypercalcemia
1. Disorders of parathyroid glands and
CSRs:
§ PHPT (autonomous overproduction of
PTH): adenoma (>80%), hyperplasia (5%
to 10%), carcinoma (<1%), and familial
syndromes (MEN I, MEN 2a, and PHPT-
jaw tumor syndrome)
§ Secondary and tertiary
hyperparathyroidism: In chronic renal
failure patients, the sustained
hypocalcemic–hyperphosphatemic
stimuli result in parathyroid
hyperplasia, leading to sustained and
autonomous overproduction of PTH
with ensuing hypercalcemia.
§ CSR abnormalities (extracellular calcium
levels are sensed aberrantly resulting in
hypercalcemia): familial hypocalciuric
hypercalcemia (FHH) (inactivating
mutation of CSR), calcium receptor
antibodies, and lithium carbonate.
§ Other endocrine disorders: adrenal
insufficiency, hyperthyroidism,
pheochromocytomas, VIPoma.
2. Cancer-mediated hypercalcemia
(paraneoplastic hypercalcemia):
 § PTHrP production by tumors: Upper GI 3. Granulomatous diseases: Sarcoidosis,
adenocarcinomas, squamous cell tuberculosis, leprosy, fungal infections,
carcinomas of head and neck and lung, Crohn disease (granulomas express the
renal cell carcinoma, ovarian carcinoma, hydroxylation enzyme that is required
HTLV 1 lymphoma, adrenal cancer, to convert 25-hydroxy vitamin D to
carcinoid tumor, islet cell cancer, and active 1,25(OH)2D).
pheochromocytoma. Prostate and
colonic cancers rarely produce PTHrP.
4. Medications: Hydrochlorothiazide
§ 1,25 Hydroxylation of 25-hydroxy
(HCTZ), lithium, vitamin A and/or D
vitamin D: Various cell types of
toxicity, oral calcium excess (milk alkali
lymphomas.
syndrome [MAS]), tamoxifen,
§ Cytokine production by tumor cells
aminophylline toxicity.
leads to activation of bone resorption
(myeloma and diffuse bone metastasis):
Cytokines such as macrophage 5. Miscellaneous: William’s syndrome,
inflammatory protein 1 alpha, tumor chronic immobilization.
necrosis factor alpha, prostaglandins,
and IL-6 which activate osteoclasts
through RANK (receptor activator of
nuclear factor kappa B)

IIIA. Primary Hyperparathyroidism

- most common cause of hypercalcemia
- The hallmark of this disorder is the autonomous overproduction of PTH, most commonly by
a single adenoma in one of the parathyroid glands (>80%), less commonly by multiple gland
hyperplasia (~5% to 10%), and very rarely by parathyroid cancer.
- Diagnosis: biochemical testing
Ø elevated serum calcium (or ionized calcium) level with inappropriately normal or elevated PTH
level confirms the diagnosis

PTH Assays Biochemical findings in PHPT Management of PHPT

PTH assays use two antibodies that bind to § Hypercalcemia § Serum calcium levels >11.5
specific sites (one on each of the C- and N- § Hypophosphatemia: PTH mg/dL on at least two
terminal ends), which enable precise induces phosphaturia. determinations
detection of intact PTH. A few commonly
available assays include the following:
§ Intact PTH: measures 7 to 84 PTH
and 1 to 84 PTH
§ Bioactive PTH: measures 1 to 84
PTH
§ CAP assay: cAMP inducible PTH.
This assay detects biologically
active PTH by its ability to induce
formation of cAMP.
§ PRHrP assays and PTH assays are
exclusive to each other, by design.
There is no cross-reactivity.
Therefore, PTH levels are low in
subjects with cancers producing
PTHrP.
§ PTH can also be estimated in
needle biopsy specimens obtained
from parathyroid tumors. Hook
effect has not been observed
despite massive elevation of PTH
levels in these specimens obtained
by direct puncture of enlarged
parathyroid glands.
§ Elevated PTH relative to
serum calcium
(inappropriately normal PTH
in the face of hypercalcemia)
§ Low-normal 25-OH-D and
high normal or elevated (30%)
1,25(OH)2D due to PTH-
enhancing renal hydroxylation
§ Urinary calcium excretion is
elevated.
§ Metabolic hyperchloremic
acidosis (chloride is
exchanged for phosphate)
§ Elevated serum alkaline
phosphatase in severe
disease
§ Urinary calcium level of
>400 mg in 24 hours or
urine random calcium to
creatinine ratio of ≥0.4 on
two determinations. Newer
recommendations removed
this criterion.
§ Creatinine clearance that
has dropped >30%
(unexplained by other
reasons) corrected for age
and sex
§ Loss of bone density greater
than –2.5 standard
deviations (SDs) below
young normal (T-score);
cortical bone is
preferentially lost in PHPT
(e.g., wrist and hips)
§ Age
IIIB. Familial Hypocalciuric Hypercalcemia
(FHH)
- a benign condition that results from
germline mutation involving the
CSR
- PTH production and calcium
elevation in this condition are not
progressive and result in stable mild
hypercalcemia since birth
- The hallmarks of this disorder
include mild hypercalcemia,
hypocalciuria, mild elevation of
magnesium and low urinary calcium
excretion.
- The following are the salient clinical
and diagnostic features:
1) Serum calcium is elevated
(mild to moderate
elevation).
2) Serum magnesium is mildly
elevated.
3) PTH is mildly elevated
4) Urine calcium levels are
typically <100 mg in 24 hrs,
with fractional excretion of
urine calcium <1%
5) Mutant CSR can be
demonstrated.
6) End-organ dysfunction
(bone and kidney) is
uncommon; therefore,
surgery should not be
performed.
IIIC. Hyperthyroidism
- Due to the direct effects of
thyroxine on the bones, there is
increased resorption and
hypercalcemia. PTH levels are low
IIID. Addison’s Disease
- Hypercalcemia is commonly seen in
patients presenting with Addisonian
crisis. PTH levels are low. It gets
corrected promptly with fluid and
steroid replacement. It is thought to
be a result of hypovolemia and
dehydration. The exact mechanism
is truly unknown.
IIIE. Milk Alkali Syndrome
- (1930s) The hallmark of this
disorder includes hypercalcemia,
alkalosis, and renal impairment.
Serum phosphate is often elevated.
- Reappearance in 1990s:
Ø The presenting features are
hypercalcemia, alkalosis, dehydration,
and renal impairment with mental
status changes. Serum phosphate level
is low.
Ø Therapy includes intravenous and oral
hydration and cessation of excessive
calcium supplementation
Medications that cause Hypercalcemia
§ HCTZ and lithium – most common
§ Excessive intake of vitamin D – may
cause Hypervitaminosis D
§ Thiazide diuretics
§ Lithium carbonate
§ High doses of vitamin A, or vitamin A
analogs/metabolites in the retinoic acid
family
IV. HYPOCALCEMIA
- refers to low blood calcium levels
- It can result from a wide variety of
conditions, from organ system
dysfunction to lack of hormone
effect to acid–base disturbances
Organ system Signs and symptoms
Neuromuscular § Tetany (involuntary muscle
contraction) affecting
primarily the muscles in the
hands, feet, legs, and back
§ Percussion on cranial nerve
VII (facial nerve)
§ Numbness and tingling in
the face, hands, and feet
§ Inflation of a blood
pressure cuff to 20 mm Hg
above the patient’s systolic
blood pressure
CNS § Irritability
§ Seizures
§ Personality changes
§ Impaired intellectual
functioning
Cardiovascular § QT prolongation may be seen
on the ECG
§ In the extreme,
electromechanical dissociation
may be seen.
§ Cardiac contractile dysfunction
is rare but in the extreme can
result in congestive heart
failure
Causes of Hypocalcemia
1. Endocrine causes: hypoparathyroidism
(lack of PTH)
§ Postoperative
§ Autoimmune (isolated or part
of polyglandular autoimmune
syndrome)
§ Congenital (mutations of CSR,
PTH, and parathyroid aplasia)
§ Pseudohypoparathyroidism,
types 1a, 1b, and 2
2. Deficiency of vitamin D: malnutrition,
malabsorption due to celiac sprue,
weight loss, gastric surgeries, short
bowel syndrome, abdominal irradiation,
pancreatic disease, liver disease, and
renal disease
3. Hypomagnesemia: magnesium
depletion leads to lack of PTH synthesis
and release
One key concept should be emphasized
when considering hypocalcemia: when
functioning properly, the parathyroid glands
will not only correct falling blood calcium
but also prevent it, by increasing PTH
secretion.
Ø Secondary hyperparathyroidism - the
compensatory rise in PTH secretion, in
response to factors that would lower
blood calcium.
Ø The biochemical constellation includes
low blood calcium, elevated PTH, low
serum phosphate, elevated alkaline
phosphatase, hypocalciuria,
phosphaturia, and vitamin D deficiency
or lack of vitamin D effect
Ø Treatment of secondary
hyperparathyroidism is directed toward
correcting the process inducing
hypocalcemia and/or vitamin D
deficiency.
Endocrine causes of Hypocalcemia
Because proper PTH secretion and action
are necessary to maintain normocalcemia,
any inadequacy of parathyroid gland
function will cause hypocalcemia.
Ø Pseudohypoparathyroidism – results in
a lack of responsiveness to PTH in the
target tissue. This results from
uncoupling of the PTH receptor from
adenylate cyclase, due to a mutant
stimulatory G protein (Gs ). PTH binds
its receptor but cannot activate the
second messenger, cAMP, and thus
there is no response – hypocalcemia
develops.
Causes of hypoparathyoidism:
 § Neck surgery – most common
§ Autoimmune destruction of parathyroid
tissue (often associated with other
autoimmune diseases such as type 1
diabetes, Hashimoto’s thyroiditis, and
Addison’s disease)
Ø Hypovitaminosis D describes a
collection of conditions, including low
vitamin D availability, defective
metabolism of vitamin D, or mutations
in the vitamin D receptor, all of which
predispose to hypocalcemia.
Organ System Causes of Hypocalcemia
A variety of intestinal disorders can result in
malabsorption of calcium or vitamin D
resulting in hypocalcemia. Causes include
short bowel syndrome, abdominal
irradiation, weight loss surgeries, celiac
sprue, and bowel fistulation. Treatment end
points are normalization of urine calcium
excretion and normalization of PTH.
V. METABOLIC BONE DISEASES
Rickets and osteomalacia
- Diseases caused by abnormal
mineralization of bone.
- They result from vitamin D deficiency.
a) Rickets - disease state affecting growing
bones (in children); therefore,
permanent skeletal deformity can be
seen.
b) Osteomalacia - abnormal
mineralization of bone in adults, or
after completion of skeletal maturation
- Both conditions are associated with
similar biochemical findings of
secondary hyperparathyroidism.
- Hypocalcemia may be seen when the
response of secondary
hyperparathyroidism is inadequate to
counteract the threat of hypocalcemia
posed by the vitamin D deficiency
- Those of any age who live indoors, with
minimal or no sun exposure or who lack
dietary vitamin D, are at risk for
developing this condition.
- 25-hydroxy vitamin D., PTH and calcium
should be obtained to further confirm
the suspected diagnosis
Osteoporosis
- most prevalent metabolic bone disease
in adults
The following are validated risk factors for
the prediction of fracture, independent of
formal bone density evaluation:
§ decreased bone mass due to previous
fracture
§ advanced age
§ family history of osteoporosis or
fracture
§ body weight less than 127 lb
§ long-term glucocorticoid therapy
§ cigarette smoking or excess alcohol
intake.
Other conditions known to also alter
calcium metabolism and increase fracture
risk includes:
§ Cushing’s syndrome
§ hyperparathyroidism
§ disorders of vitamin D metabolism,
§ hyperthyroidism
§ certain malignancies
Diagnosis:
- The diagnosis rests on clinical risk
factors and dual-energy x-ray
absorptiometry (DEXA) scan.
 - The hallmark of osteoporosis is skeletal In early stages of CKD, in response to low
fragility; therefore, it can be diagnosed blood calcium and elevation of phosphate
without any additional testing when a levels, compensatory elevation of PTH and
fracture occurs at an inappropriate FGF 23 maintains near-normal calcium and
degree of trauma or following trivial phosphorus levels.21 As kidney disease
trauma or no trauma at all. becomes severe, the compensatory
mechanisms are overwhelmed, leading to
Treatment:
permanent abnormalities of calcium,
Treatment of osteoporosis is directed at
phosphorus, PTH, vitamin D, bone
prevention of the primary consequence of
mineralization, and vascular and soft tissue
this disease: fracture.
calcification. These biochemical changes
- All treatment plans should include
modification of preventable risk factors
completely resolve following renal
such as smoking and alcohol
transplantation. Renal replacement
consumption
therapies such as hemodialysis and
- They should also include an evaluation
peritoneal dialysis only induce partial
of fall risk and consideration of walkers, correction of these changes
hand rails, night lights, hip pads, etc.
Further, all patients with osteoporosis—
or those at high risk for developing
osteoporosis—should have adequate
dietary calcium (usually 1,200 to 1,500
mg daily) and vitamin D (usually 400 to
800 IU daily).

Antiresorptive agents – most commonly

used medications for the prevention and
treatment of osteoporosis

Secondary Hyperparathyroidism in Renal

Failure
Chronic kidney disease (CKD) results in
striking bone mineral and skeletal changes.
The diseased kidneys fail to excrete
phosphate; this along with the impaired
formation of 1,25(OH)2D leads to a vicious !
cycle of events resulting in parathyroid
gland stimulation and hyperplasia. The bone
mineral metabolic changes are progressive !
and proportional to the severity of renal
dysfunction and eventually ubiquitous in
patients with end-stage renal disease.