The document discusses human sexual development from fertilization through the three trimesters of pregnancy. It covers the formation of gonads and duct systems, factors that determine chromosomal and phenotypic sex, and the roles of genes and hormones in sexual differentiation. The timeline of organ formation and growth is provided for each trimester, noting that all major organ systems are developed by the end of the first trimester.

1. sex differentiation.TDF,
Disorders of sexual
Development.

2. Introduction
• Zygote is formed as a result of fusion of sperm
(male gamete) and oocyte (female gamete)
• Gametes are produces in gonads
• Gonads are paired organs with associated ducts
and accessory glands
• The fertilization of the male and female gamete
lead to the formation of zygote

3. Human Life cycle

4. Stages of development
• The development of human fetus is divided into
3 trimesters
• First trimester
• Second trimester
• Third trimester

5. 1st
t•
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• Three tissue layers form starting from first week and
at the end of third week the organ systems begin to
take shape
• by 4th week the body is 5mm long and composed
of paired segments of body
• In 5th week the embryo dramatically increase in size
of about 3cm long. Most of the organ systems like
heart are formed
• Limb buds develop into complete arms and legs with
fingers and toes
• Head is larger than other body due to rapid
development of the nervous system

6. • After 7 weeks the embryo is called as a fetus
• Though the sex of the fetus is determined at the
time of fertilization but the physical appearance
of sex is not strict until start of the 9th week
• After 9th week a set of genes is activated which
initiates the sexual development
• Ultrasound scans can reveal the external sex
organs by 12th to 13th week
• At the end of first trimester the fetus is 9cm long
• It weighs about 15g
• All the major organ systems are formed and are
functional to their full extent

7. 2nd
t•
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ima
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sc
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ea
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s
include the increase in the size
and maturation of the respiratory system
• Bony parts of skeleton begin to form
• Heartbeat becomes notable with aid of a
stethoscope
• Fetal movements become notable
• At the end of 2nd trimester the fetus weighs 700g
and is 30-40cm in length
• A well formed face arms and legs with finger

8. 3rd
t•
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ime
t
u
essg
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to
ew
rsrapidly
• Respiratory and circulatory system grow and
prepare to get functional for air breathing
• Maternal nutrition in this period accounts for the
skeletal system development and nervous
development
• Fetus doubles in size in the last two months
• The last month accounts for the immune system
development as maternal antibodies pass into fetus
these antibodies are utilized to be safe from the
diseases until baby’s immune system develops
shortly after birth

10. Factors in Sexual Differentiation
• The formation of male and female reproductive
structures depends on:
▫Gene action
▫Interactions within the embryo
▫Interactions with other embryos in the uterus
▫Interactions with the maternal environment

11. Levels of sex development
• There are 3 levels to sexual development:
1. chromosomal sex: presence or absence of the Y
chromosome
2. gonadal sex (primary sex determination): whether the
gonads develop as testes or ovaries depends on the
presence or absence of the SRY gene, usually found on
the Y chromsome
3. phenotypic sex (secondary sex determination): all of
the internal and external structures develop along
male or female lines depending on which hormones
are secreted by the gonads.
• Phenotypic sex also has a couple of distinct systems: the
internal ducts, and the external genitalia
• Two important times: pre-natal development and
puberty

12. Chromosomal sex determination
• We have 46 chromosomes: 23 pairs, one set
from each parent.
• One pair of chromosomes is the sex
chromosomes, X and Y.
• the other chromosomes just have numbers: 1-22.
• A person with 2 X chromosomes (46,XX) is
female, and a person with an X and a Y (46,XY)
is male.

13. The mammalian pattern-Primary and secondary sex
dertermination.
Primary- gonads. ovaries and testis,
Chromosomal. and not influenced by the envt.
XX-XY
Every indl carry at least one X chromosome.
Y chromosome crucial factor for determining
sex in mammals.
Y chromosome causes a gene that encodes a
testis determining factor .
A person with five X chromosomes and one Y
chromosome male
Single X chromosome and no second x or y
(XO)female.

14. Secondary sex determination-affects phenotype
outside gonads,
Duct systems and external genitalia.
Usually determined by hormones secreted by
gonads
If y chromosome is absent,the gonadial
primordia develop into ovaries
Ovaries produce estrogen enable mullerian duct
into uterus ,oviduct,and upper end of the
vagina
If Y present testes forms secrete 2 major AMH
and testosterone(functions).

15. Primary thesex determination developing gonad.
Mammalian gonads embody a unique embryological
situation.
All other organ rudiment normally can differentiate into
only one type.of organ
But gonadial rudiment bipotential
SRY-The y chromosome sex determinant.—the major gene
for testis determination resides on the short arm of y
chromosome.
Sry encodes the human testis determining factor.
SRY activate transcription factor SF1(Making bipotential
gonad).
SFI appears to be active in masculanising Leydig and Sertoli
cells.
In Sertoli cells ,SF1 working with SOX9,is needed to elevate
the levels of anti-mullerian transcription.
In Leydig cells ,SF1 activates the encoding the enzymes that
make testosterone.
SRY maintains SF1 expression ,sf1 protein then involved in
the production of testosterone in Leydig cells.and activation
of AMH in the Sertoli cells

17. DAX-1 a potential testis-suppressing gene on the x-chromosome.
There is no gene ovary specific
Dax 1 antagonize the function of sry and sox
9and down regulate SFI expression.
WNT4 –A potential ovary determining gene
on an autosome.
These respresses male devt.in the female
gonad.
SRY may form testes by repressing WNT4
expression in the genital ridge ,as well as
promoting FGF9

19. Male-XY
SRY gene-Y chromosome-Sex determining region of Y
chromosome
DAX-1-X-Chromosome
SF1-11 chromosome-Steroidogenic factor 1
FgF-9-13 chromosome-Fibroblast growth factor
SOX-9-17 chromosomeSRY related HMG Box
WT1-11 chromosome-Wilms tumor protein

20. Female XX
DAX-1-X chromosome-Dosage sensitive Sex
reversal,adrenal hyperplasia critical region ,on
chromosome X
WNT-4-1 chromosome Wingless related integration site
RSPO1-1 chromosome-R-SPONDIN-1

23. Chromosomal basis of sex
determination
Male or female?

24. SRY GENE
HG
owe
the
n
Ye
chromosome determines sex.
The SRY gene, located on the Y chromosome, is the
primary determinant of sexual development.
That is, if a developing embryo has a functional SRY
gene in its cells, it will develop as a male. And, if there
is no functional SRY, the embryo develops as female.
Although the SRY gene is usually on the Y
chromosome, it occasionally gets transferred to the X.
this leads to 46,XX males
Also, sometimes the SRY gene is inactivated by
mutation.
Leading to 46,XY females (Swyer syndrome)
it is also possible to have a partially inactive SRY gene,
leading to ambiguous genitalia

25. (Swyer syndrome) XY gonadal dysgenesis, also known as
Swyer syndrome, is a type of hypogonadism in a person whose
karyotype is 46,XY. They typically have normal female
external genitalia, but functionless gonads (fibrous tissue termed "streak
gonads"), and if left untreated, will not experience puberty. Such gonads
are typically surgically removed (as they have a significant risk of
developing cancer). The typical medical treatment is hormone
replacement therapy.The syndrome was named after Gerald Swyer, an
endocrinologist based in London.
people with Swyer syndrome are born with the appearance of a normal
female in most anatomic respects except that the child has nonfunctional
gonads instead of ovaries or testes. As their ovaries produce no important
body changes before puberty, a defect of the reproductive system typically
remains unsuspected until puberty fails to occur. They appear to be normal
girls and are generally considered so. They are usually diagnosed in their
teens when they fail to begin having a menstrual period (primary
amenorrhea)

26. The first known step of sexual differentiation of a normal XY fetus is
the development of testes. The early stages of testicular formation in
the second month of gestation requires the action of several genes,
one of the earliest and most important of which is SRY: the
sex-determining region of the Y chromosome. Mutations of SRY
account for many cases of Swyer syndrome.
When such a gene is defective, the indifferent gonads fail to
differentiate into testes in an XY fetus. Without testes,
no testosterone or antimüllerian hormone (AMH) is produced. Without
testosterone, the wolffian ducts fail to develop, so no internal male
organs are formed. Also, the lack of testosterone means that
no dihydrotestosterone is formed and consequently the
external genitalia fail to virilize, resulting in normal female genitalia.
Without AMH, the Müllerian ducts develop into normal internal female
organs (uterus, fallopian tubes, cervix, vagina)

27. XX male syndrome, also known as de la Chapelle syndrome, is a rare
congenital intersex condition in which an individual with a 46,
XX karyotype (otherwise associated with females) has phenotypically male
characteristics that can vary among cases.
In 90 percent of these individuals, the syndrome is caused by the Y
chromosome's SRY gene, which triggers male reproductive development,
being atypically included in the crossing over of genetic information that
takes place between X and Y chromosomes during meiosis in the
father.] When the X with the SRY gene combines with a normal X from the
mother during fertilization, the result is an XX male. Less common
are SRY-negative XX males, which can be caused by a mutation in
an autosomal or X chromosomal gene.

28. Males typically have one X chromosome and one Y chromosome in
each diploid cell of their bodies. Females typically have two X
chromosomes. XX males that are SRY-positive have two X
chromosomes, with one of them containing genetic material (the SRY
gene) from the Y chromosome; this gene causes them to develop a
male phenotype despite having chromosomes more typical of
females. Some XX males, however, do not have the SRY gene
(SRY-negative) and the male phenotype may be caused by another
gene on one of the autosome. Autosomes still contain sexual
determination genes even though they are not sex chromosomes. For
example, the SRY gene on the Y chromosome encodes the
transcription factor TDF and is vital for male sex determination during
development. TDF functions by activating the SOX9 gene
on chromosome 17, so mutations of the SOX9 gene can cause
humans with an ordinary Y chromosome to develop as females.[

29. SRY Positive-The SRY gene, normally found on the Y chromosome,
plays an important role in sex determination by initiating testicular
development. In about 80 percent of XX males, the SRY gene is
present on one of the X chromosomes.The condition results from an
abnormal exchange of genetic material between chromosomes
(translocation). This exchange occurs as a random event during the
formation of sperm cells in the affected person's father. The tip of the
Y chromosome contains the SRY gene and, during recombination,
a translocation occurs in which the SRY gene becomes part of the X
chromosome.If a fetus is conceived from a sperm cell with an X
chromosome bearing the SRY gene, it will develop as a male despite
not having a Y chromosome. This form of the condition is called
SRY-positive 46,XX testicular disorder of sex development.[3]

30. An example of translocation between two
chromosomes.

31. SRY-negative-About 20 percent of those with 46 XX testicular
disorder of sex development do not have the SRY gene. This form of
the condition is called SRY-negative 46,XX testicular disorder of sex
development. The cause of the disorder in these individuals is often
unknown, although changes affecting other genes have been
identified. Individuals with SRY-negative 46,XX testicular disorder of
sex development are more likely to have ambiguous genitalia than are
people with the SRY-positive form.]
The exact cause of this condition is unknown but it has been
proposed that mutations in the SOX9 gene may contribute to this
syndrome since SOX9 plays a role in testes differentiation during
development. Another proposed cause is mutations to
the DAX1 gene, which encodes a nuclear hormone
receptor.[20][21] DAX1 represses masculinizing genes; therefore, if
there is a loss of function of DAX1, then testes can develop in an XX
individual.Mutations in SF1 and WNT4 genes have also been studied
in connection with SRY-negative XX male syndrome.

33. • Testosterone
▫ A steroid hormoneproduced by the testisMale sex hormone.Leydig cells
.Masculinizes the fetus.stimulating the formation of the penis,male duct
system,scrotum,and other portions of the male anatomy,inhibiting the devt. Of
breast primordia.

34. • Müllerian inhibiting hormone (MIH).AMH-is a member of the
TGF beta family of growth and differentiation factors .
▫ Hormone produced by developing testis that causes breakdown of
Müllerian (female) ducts in the embryo.Secreted by Sertoli cells.AMH
thought to bind to mesenchyme cells surrounding the Mullerian duct
,causing these cells to secrete a paracrine factor that induces apoptosis
in the ducts epithelium.
TGF-beta (Transforming growth factor beta / TGF-β) is a type of
cytokine that controls proliferation, cellular differentiation, and other
functions in most cells.
When proteins synthesized by one cell can diffuse over small distances to
induce changes in neighboring cells, the event is called
a paracrine interaction, and the diffusible proteins are called paracrine
factors or growth and differentiation factors (GDFs

36. Early Gonad Development
• Before 6-7 weeks of
development, the gonad is
indifferent: neither male nor
female.
• It develops from the same
tissue as the kidneys and
adrenal glands.
• Also developing by this time: 2
sets of ducts that will
eventually lead to the outside
world.
▫ Wolffian ducts = male
▫ Mullerian ducts = female

37. Gonad Differentiation
• If SRY is present in the
indifferent gonad at 6
weeks, it gets activated.
This in turn activates
other genes, and the
indifferent gonad is
converted to a testes.
• In the absence of SRY, a
different set of genes is
activated, and the
indifferent gonad
becomes an ovary.
• The germ cells, which
actually become sperm
or eggs, migrate into the
gonad about this time.

39. Development of Phenotypic
Se•xThecells of the newly formed testes start secreting
the hormone testosterone.
▫ Testosterone secretion peaks about week 16, with levels similar
to those found in adult males. After this, the testosterone level
drops to about the same level as female fetuses.
▫ The testes also secrete another hormone: Mullerian inhibiting
substance (MIS) (aka anti-Mullerian hormone, AMH).
• Another important process in the developing male:
during the last trimester of pre-natal life, the testes
migrate (“descend”) from the kidney region into the
scrotum.
▫ Under the control of a third testes hormone: “insulin-like
hormone 3”INSL3-Leydig cells
• The developing ovary secretes estrogen, which is
important after birth, but estrogen from the mother
completely swamps it out before birth.

40. Internal Ducts
• In the early embryo, two duct
systems form. After the gonad
differentiates into a testis or
ovary, one set of ducts develops
further while the other set
degenerates.
• Testosterone causes the Wolffian
ducts to develop into male
structures: epididymus, vas
deferens, seminal vesicles.
▫ In the absence of testosterone, the
Wolffian ducts disappear (except a
bit becomes the adrenal glands in
both sexes)
• Mullerian inhibiting substance
causes the Mulerian ducts to
disappear.
▫ In the absence of MIS, the
Mullerian ducts develop into
the Fallopian tubes, uterus,
and upper vagina.

42. Another Duct
Picture

43. Development of the External Genitalia
• This process is controlled by the
presence or absence of dihydrotestosterone
(DHT).
• Testosterone gets converted into DHT by the
enzyme 5-alpha reductase, which is found in
the testes and the skin.
• Both sexes start out with the same structures,
which develop along different lines under the
influence of testosterone and DHT.
• The default condition in male: in the absence
of DHT, the external genital structures develop
along female lines.
• DHT also causes hair loss: male pattern
baldness. Testosterone is converted to DHT
locally. Rogaine works by blocking 5-alpha
reductase. C9H15N5O

44. High levels of androgens, including DHT, can shrink
your hair follicles as well as shorten this cycle,
causing hair to grow out looking thinner and more
brittle, as well as fall out faster. DHT can also make it
take longer for your follicles to grow new hairs once
old hairs fall out.

45. External Development
• In the absence of DHT, the
genital swellings form the
labia majora; the genital
folds remain unfused and
form the labia minora; the
genital tubercle forms the
clitoris and the urogenital
sinus forms the lower part
of the vagina.
• With DHT present, the
genital swellings migrate
and become the scrotum;
the urogenital folds enlarge
and enclose the penile
urethra and become the
shaft of the penis; the
genital tubercle becomes
the glans penis; and the
urogenital sinus forms the
prostate gland

47. Persistent Müllerian duct syndrome (PMDS) is the presence
of Müllerian duct derivatives (fallopian tubes, uterus, and/or the upper
part of the vagina)[1] in what would be considered a genetically and
otherwise physically normal male animal by typical human based
standards. In humans, PMDS typically is due to
an autosomal recessive.congenital disorder and is considered by
some to be a form of pseudohermaphroditism due to the presence of
Müllerian derivatives.Typical features include undescended testes
(cryptorchidism) and the presence of a small, underdeveloped uterus
in an XY infant or adult. This condition is usually caused by deficiency
of fetal anti-Müllerian hormone (AMH) effect due to mutations of
the gene for AMH or the anti-Müllerian hormone receptor, but may
also be as a result of insensitivity to AMH of the target organ.

48. Pseudohermaphroditism is an old clinical term for an organism that
is born with primary sex characteristics of one sex but develops
the secondary sex characteristics[1][2] that are different from what
would be expected on the basis of the gonadal tissue (ovary or testis).
It can be contrasted with the term true hermaphroditism, which
described a condition where testicular and ovarian tissue were
present in the same individual. This language has fallen out of favor
due to misconceptions and pejorative connotations associated with
the terms,[3] and also a shift to nomenclature based on genetics.
The term male pseudohermaphrodite was used when a testis is
present, and the term female pseudohermaphrodite was used when
an ovary is present.[4]
In some cases, external sex organs associated with
pseudohermaphroditism look intermediate between a
typical clitoris and penis. In other cases, the external sex organs have
an appearance that would be expected to be seen with the "opposite"
gonadal tissue. Because of this, pseudohermaphroditism is
sometimes not identified until puberty or adulthood.

49. Müllerian agenesis, also known
as Mayer–Rokitansky–Küster–Hauser syndrome (MRKH)
or vaginal agenesis, is a congenital malformation characterized by a
failure of the Müllerian duct to develop, resulting in a
missing uterus and variable degrees of vaginal hypoplasia(lack of
cells) of its upper portion. Müllerian agenesis (including absence of
the uterus, cervix and/or vagina) is the cause in 15% of cases of
primary amenorrhoea.[2] Because most of the vagina does not
develop from the Müllerian duct, instead developing from
the urogenital sinus, along with the bladder and urethra, it is present
even when the Müllerian duct is completely absent.
Because ovaries do not develop from the Müllerian ducts, affected
people might have normal secondary sexual characteristics but
are infertile due to the lack of a functional uterus. However,
parenthood is possible through use of gestational surrogates.
WNT4 (found on the short arm (p) of chromosome 1) has been clearly
implicated in the atypical version of this disorder. A genetic mutation
causes a leucine to proline residue substitution at amino acid position

50. Androgen insensitivity syndrome (AIS) is an intersex condition with
an estimated prevalence of about 1:20,000-64,000 in XY
(chromosomally male) births, resulting in the partial or complete
inability of the cell to respond to androgens.[1] The unresponsiveness
of the cell to the presence of androgenic hormones can impair or
prevent the masculinization of male genitalia in the developing fetus,
as well as impairing or preventing the development of male secondary
sexual characteristics at puberty, but does not significantly impair
female genital or sexual development.[2][3] As such, the insensitivity to
androgens is clinically significant only when it occurs in genetic males
(i.e. individuals with a Y-chromosome, or more specifically, an SRY
gene).[4] Clinical phenotypes in these individuals range froma
typical male habitus with mild spermatogenic defect or reduced
secondary terminal hair, to a full female habitus, despite the presence
of a Y-chromosome.[5] The human androgen receptor (AR) is a protein encoded by
a gene located on the proximal long arm of the X chromosome.. Testicular
feminization is the syndrome when a male, genetically XY, because
of various abnormalities of the X chromosome, is resistant to the
actions of the androgen hormones, which in turn stops the forming of
the male genitalia and gives a female phenotype.

51. Intersex people are individuals born with any of several variations
in sex characteristics including chromosomes, gonads, sex
hormones or genitals that, according to the Office of the United
Nations High Commissioner for Human Rights, "do not fit the typical
definitions for male or female bodies.Though the range of atypical sex
characteristics may be obvious from birth through the presence of
physically ambiguous genitalia, in other instances, atypical
characteristics may go unnoticed, presenting as ambiguous internal
reproductive organs or atypical chromosomes that may remain
unknown to an individual all of their life.

52. The words used to describe intersex people are contested, and
change over time and place. Intersex people were previously referred
to as "hermaphrodites" or "congenital eunuchs.In the 19th and 20th
centuries, some medical experts devised new nomenclature in an
attempt to classify the characteristics that they had observed, the first
attempt to create a taxonomic classification system of intersex
conditions. Intersex people were categorized as either having "true
hermaphroditism", "female pseudohermaphroditism", or "male
pseudohermaphroditism".[13] These terms are no longer used, and
terms including the word "hermaphrodite" are considered to be
misleading, stigmatizing, and scientifically specious in reference to
humans.In biology, the term hermaphrodite is used to describe an
organism that can produce both male and female gametes.[15][16]
Some people with intersex traits use the term intersex, and some
prefer other language.In clinical settings, the term "disorders of sex
development" (DSD) has been used since 2006,[

53. According to the UN Office of the High Commissioner for Human Rights:
Intersex people are born with sex characteristics (including genitals, gonads
and chromosome patterns) that do not fit typical binary notions of male or
female bodies. Intersex is an umbrella term used to describe a wide range of
natural bodily variations. In some cases, intersex traits are visible at birth while
in others, they are not apparent until puberty. Some chromosomal intersex
variations may not be physically apparent at all.[2]
According to World Health Organization: Intersex is defined as a congenital
anomaly of the reproductive and sexual system.

54. Mutations can cause Sex Phenotypes to
Change at Puberty
• Pseudohermaphroditism
▫ An autosomal genetic condition that causes XY
individuals to develop the phenotype of females
▫Caused by mutations in several different genes
▫ Affected individuals have both male and female
structures, but at different times of life
▫At puberty, females change into males

57. Thanks
☺