Endocrinology

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Endocrinology genetic sex established at
conception Direction of differentiation due to
hormones Gonadal sex regulates the phenotypic
sex Devt of brain dependent on hormones
present Compared to female, male devt of
reproductive system is uncomplicated. After
puberty-male is tonic Female is cyclic in
hormonal output and gonadal function Also she can
become pregnant Unique female hormones Milk
production after delivery

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Sex Determination Genetic Sex, determine at
conception governs the development of the gonadal
sex of the individual Gonadal sex regulates
development of phenotypic sex Differential of
internal and external sex organs as well as
attainment of adult sexual characteristics.

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Chromosomal (genetic) basis of sex
determination No matter what chromosome is-lack
of Y-get a female Although the genetic sex of the
species determine the direction in which the
gonads initially differentiate, the exogenous
administration of sex steroids at a critical time
(varies among species) can induce permanent
gonadal sex reversal

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Sex Chromosomes and Determination of Sex Humans
usually have 46 chromosomes per diploid cell
consisting of 22 sets of autosomes and a set of
sex chromosomes - either XX or XY. In the usual
course of events, individuals with the karyotype
46, XX are female and individuals with 46, XY,
are male. How is the sex of an individual is
determined. Is sex determined by the number of X
chromosomes - with one X you are male or with 2
X's you are female? NO Or is sex determined by
the presence or absence of the Y chromosome - the
presence of a Y makes for a male or the absence
of a Y produces a female?

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Sex Chromosomes and Determination of Sex One way
the answer was provided by individuals resulting
from non-disjunction of the sex chromosomes. Some
individuals have 45 chromosomes and have only one
X chromosome other individuals have 47
chromosomes and have two X chromosomes and a Y.
The table below indicates the sex of these
individuals. ChromosomeConstitution Name of
Syndrome Sex Frequency in Population 46,
XX
Normal Female 0.511 46, XY

Normal Male 0.489 45, XO
Turner's Syndrome Female
1/5,000 47 XXY Klinefelter's
Syndrome Male
1/700Female (46,XX) and Male (46,XY)
frequencies taken from the US Census
projectionof July 1, 1996 with no correction for
chromosome constitution. It is clear that the
presence of a Y chromosome is necessary for male
sexual characteristics to develop. The number of
X chromosomes present does not play a significant
role in sex determination.

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SRY Sex determination We have come a long way
in our understanding of sexual dimorphism since
355 BC. In those days, Aristotle suggested that
the difference between the two sexes was due to
the heat of semen at the time of copulation hot
semen generated males, whereas cold semen made
females. Thankfully, we now know a little more
about the molecular events of sex determination.
Usually, a woman has two X chromosomes (XX) and
a man one X and one Y (XY). However, both male
and female characteristics can sometimes be found
in one individual, and it is possible to have XY
women and XX men. Analysis of such individuals
has revealed some of the molecules involved in
sex determination, including one called SRY,
which is important for testis formation.

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SRY Sex determination SRY (which stands for
sex-determining region Y gene) is found on the Y
chromosome. In the cell, it binds to other DNA
and in doing so distorts it dramatically out of
shape. This alters the properties of the DNA and
likely alters the expression of a number of
genes, leading to testis formation. Most XX men
who lack a Y chromosome do still have a copy of
the SRY region on one of their X chromosomes.
This copy accounts for their maleness. However,
because the remainder of the Y chromosome is
missing they frequently do not develop secondary
sexual characteristics in the usual way. Since
human SRY is similar to SRY of mice, a model of
SRY function has been developed in mice. This has
been particularly important in discovering the
interactions of SRY with other genes in male sex
determination.

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Mammalian testicular organogenesis dependent on
protein TDF or SRY Female mice embryos with
normal pair of XX Are injected with a small piece
of Y containing SRY, they grow up as males with
testis and male behavior Y triggers the genital
ridges in embryo to develop into testes rather
than ovaries Once that happens, all other changes
that make a male follow under the influence of
hormones produced by the testes SRY gene is only
a SWITCH

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SRY is only a switch because testes can develop
in XX women who have no portion of the Y In
cattle, some genetic females have testes So,
genes found in females
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Gonadal Steroid and Brain Differentiation Expts
have shown that transplantation of the pit from a
male to a female rat to the opposite sex did not
alter the normal reproductive processes in either
sex. Pits are equivalent We know tonic in males
and cyclic in females
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Neonatal male develop into adult make with male
behavior But if castrate at critical period
becomes a feminized male with female
behavior Neonate female develops into adult
female with female behavior But if put in
testosterone at critical period then get
masuclinized female with male behavior

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These results suggest that control of pit hormone
secretion and subsequent gonadal function depend
on a system that is programmed early in
development was not localized to the pit or the
gonads.
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Steroid hormones derived from Cholesterol Andros
tenedione (testis) Testosterone
Estradiol
5a reductase
DHT

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A single treatment of a chick embryos with an
aromatase inhibitor at a stage when gonads are
bipotential causes genetic females to
permanently develop a male phenotype Aromatase
is key developmental switch in the sex
determination of chickens

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Many breast tumors are highly "estrogen
sensitive," so estrogen stimulates their
growth Aromatase inhibitors (AIs) can help block
the growth of these tumors by lowering the amount
of E in the body. Estrogen is produced by the
ovaires and other tissues of the body, via
aromatase. AIs do not block estrogen production
by the ovaries, but they can block other tissues
from making this hormone. That's why AIs are used
mostly in women who have reached menopause, when
the ovaries are no longer producing
estrogen. Currently (2003), 3 AIs approved by the
U.S. Food and Drug Administration anastrazole
(Arimidex), exemestane (Aromasin), and
letrozole (Femara).

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Males The principal androgen (male sex hormone)
is testosterone. This steroid is manufactured by
the interstitial (Leydig) cells of the testes.
Secretion of testosterone increases sharply at
puberty and is responsible for the development of
the so-called secondary sexual characteristics
(e.g., beard) of men. Testosterone is also
essential for the production of sperm.
Production of testosterone is controlled by the
release of LH from the anterior lobe of the
pituitary gland, which is in turn controlled by
the release of GnRH from the hypothalamus. LH is
also called interstitial cell stimulating hormone
(ICSH).

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Males Hypothalamus?GnRH? Pituitary?LH?Testes?Te
stosterone The level of testosterone is under
negative-feedback control a rising level of
testosterone suppresses the release of GnRH from
the hypothalamus. This is exactly parallel to the
control of estrogen secretion in females.

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Males Males need estrogen, too! In 1994, a man
was described who was homozygous for a mutation
in the gene encoding the estrogen receptor. A
single nonsense mutation had converted a codon
(CGA) for arginine early in the protein into a
STOP codon (TGA). Thus no complete ER could be
synthesized. This man was extra tall, had
osteoporosis and "knock-knees", but was otherwise
well. His genetic defect confirms the important
role that estrogen has in both sexes for normal
bone development.

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Males It is not known whether this man (or any
of the few other men who have been found with the
same disorder) is fertile or not. However, an
article in the 4 December 1997 issue of Nature
reports that male mice whose ER gene has been
"knocked out" are sterile.

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Males Anabolic steroids A number of synthetic
androgens are used for therapeutic purposes.
These drugs promote an increase in muscle size
with resulting increases in strength and speed.
This has made them popular with some athletes
(weight lifters, cyclists, runners, swimmers,
professional football players). Usually these
athletes (females as well as males) take doses
far greater than those used in standard therapy.
Such illicit use carries dangers (besides being
banned from an event because of a positive drug
test) acne, a decrease in libido, and in males
testicle size and sperm counts to name a few.

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Males Genetic abnormalities of gonadal
function. Many things can go wrong with sexual
development in both males and females
fortunately rarely. only a few that clearly
result from the inheritance of single-gene
mutations. Inherited mutations in both copies of
the gene encoding the GnRH receptor result in
failure to develop at puberty. Mutations in the
gene encoding the LH receptor prevent normal
sexual development in both sexes.

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Males Genetic abnormalities of gonadal
function. Mutations in the gene encoding the FSH
receptor block development of the gonads in both
males and females. Mutations in any of the genes
encoding the enzymes for synthesis and metabolism
of testosterone interfere with normal sexual
function in males. A similar spectrum of
disorders in males can be caused by mutations in
the genes encoding the androgen receptor.

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Females The ovaries of sexually-mature females
secrete a mixture of estrogens of which
17ß-estradiol is the most abundant (and most
potent) and progesterone.

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Females Estrogens Estrogens are steroids.
primarily responsible for the conversion of
girls into sexually-mature women. development of
breasts further development of the uterus and
vagina broadening of the pelvis growth of pubic
and axillary hair increase in adipose (fat)
tissue participate in the monthly preparation of
the body for a possible pregnancy participate in
pregnancy if it occurs

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Females Estrogens also have non-reproductive
effects. They antagonize the effects of the
parathyroid hormone, minimizing the loss of
calcium from bones and thus helping to keep bones
strong. They promote blood clotting.

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Females Progesterone Progesterone is also a
steroid. It has many effects in the body, some
having nothing to do with sex and reproduction.
We already discussed the role and regulation of
progesterone in the menstrual cycle and pregnancy

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How estrogens and progesterone achieve their
effects Steroids like estrogens and progesterone
are small, hydrophobic molecules that are
transported in the blood bound to a serum
globulin. In "target" cells, i.e., cells that
change their gene expression in response to the
hormone, they bind to receptor proteins located
in the cytoplasm and/or nucleus. The
hormone-receptor complex enters the nucleus (if
it formed in the cytoplasm) and binds to
specific sequences of DNA, called the estrogen
(or progesterone) response elements

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How estrogens and progesterone achieve their
effects Response elements are located in the
promoters of genes. The hormone-receptor complex
acts as a transcription factor (often recruiting
other transcription factors to help) which turns
on (sometimes off) transcription of those genes.
Gene expression in the cell produces the
response.

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Regulation of Estrogen and Progesterone The
synthesis and secretion of estrogens is
stimulated by follicle-stimulating hormone (FSH),
which is, in turn, controlled by the hypothalamic
gonadotropin releasing hormone (GnRH).
Hypothalamus?GnRH? Pituitary?FSH?Follicle?Estroge
ns

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Hermaphroditism is a term referring to being of
both sexes (intersexual). True hermaphroditism
requires the presence of both ovarian (female)
and testicular (male) reproductive tissue and is
relatively rare and poorly understood.
Pseudo-hermaphroditism is more common. From a
medical standpoint, hermaphroditism suggests two
factors ambiguous external genitalia genitalia
that do not match the genetic make-up of the
person (example female genitalia in a
genetically male individual)

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The following conditions can produce ambiguous
genitalia and hermaphroditism congenital
adrenal hyperplasia fetal exposure to sex
hormones testicular feminization syndrome XY
gonadal dysgenesis XY gonadal agenesis
chromosomal abnormalities cryptophthalmos
Smith-Lemli-Opitz 4p syndrome 13q syndrome

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Congenital adrenal hyperplasia refers to a group
of inherited disorders relating to the adrenal
glands, characterized by a deficiency in the
hormones cortisol and aldosterone and an
overproduction of androgen. Alternative Names
Adrenogenital syndrome 21-hydroxylase deficiency


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Congenital adrenal hyperplasia Causes,
incidence, and risk factors The different types
of adrenogenital syndrome are inherited as
autosomal recessive diseases and can affect both
boys and girls. The defect is lack of an enzyme
needed by the adrenal gland to make the major
steroid hormones of the adrenal cortex cortisol
and aldosterone. Due to the block in synthesis of
these hormones, there is abnormal 'feedback' and
steroids are 'diverted' to becoming androgens, a
form of male sex hormones.

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Congenital adrenal hyperplasia This causes
early appearance of male characteristics. In a
newborn girl with this disorder, the clitoris is
enlarged with the urethral opening at the base
(ambiguous genitalia, often appearing more
male-like than female). The internal structures
of the reproductive tract (ovaries, uterus, and
fallopian tubes) are normal. As she grows older,
masculinization of some features takes place,
such as deepening of the voice, the appearance of
facial hair, and failure to menstruate at
puberty. In a newborn boy no obvious abnormality
is present, but long before puberty normally
occurs, the child becomes increasingly muscular,
the penis enlarges, pubic hair appears, and the
voice deepens. Affected males may appear to enter
puberty as early as 2-3 years of age. At
puberty, the testes are small.

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Congenital adrenal hyperplasia Some forms of
congenital adrenal hyperplasia are more severe
and cause adrenal crisis in the newborn due to
salt wasting. In this salt-losing form of
congenital adrenal hyperplasia, newborns develop
symptoms shortly after birth. These include
vomiting, dehydration, electrolyte changes, and
cardiac arrhythmias. Untreated, this condition
can lead to death within 1-6 weeks after
birth. About 1 in 10,000 to 18,000 children are
born with congenital adrenal hyperplasia.

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Turner syndrome A disorder in women caused by a
chromosomal defect. This disorder inhibits sexual
development and causes infertility. Alternative
NamesBonnevie-Ullrich syndrome Gonadal
dysgenesis Monosomy X Causes, incidence, and
risk factorsTurner syndrome is usually caused by
a missing X chromosome. It affects 1 out of 3,000
live births. It is usually sporadic meaning that
it is not inherited from a parent.
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Turner syndrome Rarely, a parent silently
carries rearranged chromosomes that can result in
Turner syndrome in a daughter this is the only
situation in which Turner syndrome is inherited.
There are many manifestations of this syndrome,
but the main features are short stature, webbing
of the skin of the neck, absent or retarded
development of secondary sexual characteristics,
absence of menstruation, coarctation (narrowing)
of the aorta, and abnormalities of the eyes and
bones. The condition is either diagnosed at
birth because of the associated anomalies, or at
puberty when there is absent or delayed menses
and delayed development of normal secondary
sexual characteristics.
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Ambiguous genitalia A congenital physical
abnormality where the outer genitals do not have
the typical appearance of either sex.
ConsiderationsThe genetic sex of a child is
determined at conception. The egg cell (ovum)
contains a chromosome called the X chromosome.
Sperm cells contain either an X chromosome or one
called the Y chromosome. These determine the
child's genetic sex. Normally an infant will
inherit ONE PAIR (one from the mother and one
from the father) of these "sex chromosomes" (two
chromosomes).

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Ambiguous genitalia Thus, it is the father who
"determines" the genetic sex of the child. An
infant who inherits the X chromosome from the
father is a genetic female (XX pattern) and one
who inherits the Y chromosome is a genetic male
(XY pattern).The reproductive organs and
genitals associated with "female" or "male" arise
from the same initial (fetal) tissue. If the
process that causes this fetal tissue to become
"male" or "female" is disrupted, ambiguous
genitalia can develop.

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Ambiguous genitalia Ambiguous genitalia are
those in which it is difficult to classify the
infant (by physical examination) as male or
female. The extent of the ambiguity varies. In
very rare instances, the physical appearance may
be fully developed as the opposite of the genetic
sex (e.g., a genetic male may have normal female
appearance).Typical ambiguous genitalia in
genetic females include an enlarged clitoris that
has the appearance of a small penis. The urethral
opening (where urine comes out) can be anywhere
along, above, or below the surface of the
clitoris, which may be considered normal or
common abnormalities of anatomic urethra
placement (such as hypospadias, when the urethra
is on the underside of the penis, instead of at
the tip).

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Ambiguous genitalia The labia may be fused,
resembling a scrotum. The infant may be thought
to be a male with undescended testicles
sometimes a lump of tissue is felt within the
fused labia, further making it look like a
scrotum with testicles.

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Ambiguous genitalia In a genetic male, findings
of ambiguous genitalia include a small penis,
less than 2 to 3 centimeters (0.8 to 1.2 inches)
that may appear to be an enlarged clitoris (the
clitoris of a newborn female is normally somewhat
enlarged at birth). The urethral opening may be
anywhere along, above, or below the penis it can
be placed as low as on the peritoneum, further
making the infant appear to be a female. There
may be a small scrotum with any degree of
separation, resembling labia. Undescended
testicles commonly accompany ambiguous
genitalia.Uncertain or mistaken sex is not a
physical threat to life, but can create social
upheaval for the child and the family.

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Ambiguous genitalia Common Causes pseudohermap
hroditism (when the genitalia are of one sex, but
some physical characteristics of the other sex
are present) true hermaphrodism (very rare --
both ovarian and testicular tissue is present and
the child may have parts of both male and female
genitalia) mixed gonadal dysgenesis (where some
cells in the body have only a single X
chromosome--gtfemale, and some cells in the body
have XY chromosomes--gtmale. This syndrome is
variable, and depends on which cells are female,
which cells are male, and what percent of each
there are

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Ambiguous genitalia Common Causes congenital
adrenal hyperplasia (several forms, but the most
common form causes the genetic female to appear
male. Male infants with the most common form
appear normal at birth, but may show premature
sexual development as early as 6 months of age)
-- many states test for this as part of the
newborn screen (the blood test a baby has at
24-48 hours of life) To look for chromosomal
abnormalities

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Ambiguous genitalia Common Causes Klinefelter'
s syndrome (XXY--male, usually has small testes
causes infertility may be associated with
learning defects or mental retardation affects
1/500-1/1000 live male births) Turner's syndrome
(XO--female usually does not cause ambiguous
genitalia (usually looks female at birth), but
may have webbed neck, swelling of the hands and
feet and other characteristic physical findings
at birth may not be diagnosed until later in
life when sexual maturation does not take place
infertile)

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Ambiguous genitalia Common Causes maternal
ingestion of certain medications (particularly
androgenic steroids) -- may make a genetic female
look more male lack of production of specific
hormones, causing the embryo to develop with a
female body type regardless of genetic sex lack
of testosterone cellular receptors (so even if
the body makes the hormones needed to develop
into a physical male, the body is unable to
respond to those hormones, and therefore, a
female body-type is the result even if the
genetic sex is male)

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Puberty-Time to Change When your body reaches a
certain age, your brain releases GnRH that starts
the changes of puberty. When GnRH reaches the
pituitary gland, this gland releases into the
bloodstream two more puberty hormones LH and
FSH. Guys and girls have both of these hormones
in their bodies. And depending on whether you're
a guy or a girl, these hormones go to work on
different parts of the body.

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Puberty Guys- these hormones travel through the
blood and give the testes the signal to begin the
production of testosterone and sperm.
Testosterone is the hormone that causes most of
the changes in a guy's body during puberty. Sperm
cells must be produced for men to reproduce. In
girls, FSH and LH target the ovaries, which
contain eggs that have been there since birth.
The hormones stimulate the ovaries to begin
producing another hormone called estrogen.
Estrogen, along with FSH and LH, causes a girl's
body to mature and prepares her for pregnancy.