1. Sexual Differentiation
By - dr shafali singh

2. Learning objectives
Outline the role of chromosomes, hormones, and related factors in sex determination and development.
Diagnosing aberrant sexual differentiation.
Summarize the hormonal changes that occur at puberty in males and females.

3. Sexual Differentiation
Includes the development of the gonads, the internal genital tract, and the external genitalia.
"Maleness" or "femaleness" can be characterized in three ways:
(1) genetic sex, whether the sex chromosomes are XY or XX;
(2) gonadal sex, whether the gonads are testes or ovaries
(3) phenotypic or genital sex, whether the person looks like a male or a female

4. GENETIC SEX
Determined by the sex chromosomes-XY in males and XX in females

5. The Y chromosome is necessary and sufficient for the production of testes, and the testis-determining gene product is called SRY (for sex-determining region of the Y chromosome).
SRY is a DNA-binding regulatory protein. It bends the DNA and acts as a transcription factor that initiates transcription of a cascade of genes necessary for testicular differentiation, including the gene for müllerian inhibiting substance.

6. karyotyping
Human chromosomes can be studied in detail. Human cells are grown in tissue culture; treated with the drug colchicine, which arrests mitosis at the metaphase; exposed to a hypotonic solution that makes the chromosomes swell and disperse; and then "squashed" onto slides. Staining techniques make it possible to identify the individual chromosomes and study them in detail .There are 46 chromosomes: in males, 22 pairs of autosomes plus an X chromosome and a Y chromosome; in females, 22 pairs of autosomes plus two X chromosomes. The individual chromosomes are usually arranged in an arbitrary pattern (karyotype). The individual autosome pairs are identified by the numbers 1–22 on the basis of their morphologic characteristics.

7. Sex Chromatin
The inactive X chromosome condenses and can be seen in various types of cells, usually near the nuclear membrane, as the Barr body, also called sex chromatin
Left: Barr body (arrows) in the epidermal spinous cell layer. Right: Nuclear appendage ("drumstick") identified by arrow in white blood cells.
some of the somatic cells in adult females contain an active X chromosome of paternal origin and some contain an active X chromosome of maternal origin.

8. Development of the Gonads
A primitive gonad arises from the genital ridge
The gonad develops a cortex and a medulla.
During the first 5 weeks of gestational life, the gonads are indifferent or bipotential-they are neither male nor female
Until the sixth week of development, these structures are identical in both sexes

9. At gestational weeks 6 to 7 in genetic males, the testes begin to develop;
In genetic males, the medulla develops during the seventh and eighth weeks into a testis, and the cortex regresses. Leydig and Sertoli cells appear, and testosterone and MIS are secreted.
At gestational week 9 in genetic females, the ovaries begin to develop
In genetic females, the cortex develops into an ovary and the medulla regresses. The embryonic ovary does not secrete hormone.

12. Differentiation of the internal genitalia and the primordial ducts
In males, the internal genital tract includes the prostate, seminal vesicles ,
vas deferens, and epididymis.
In females, the internal genitalia are the fallopian tubes, uterus, upper one-third of the vagina.
MIS causes regression of the müllerian ducts by apoptosis on the side on which it is secreted, and testosterone fosters the development of the vas deferens and related structures from the wolffian ducts. The testosterone metabolite dihydrotestosterone induces the formation of male external genitalia and male secondary sex characteristics

13. Differentiation of the external genitalia from bipotential primordial structures.
external genitalia in females are the clitoris, labia majora, labia minora, and lower 2/3rd of the vagina
The external genitalia in males are the scrotum and the penis

14. Which step in steroid hormone biosynthesis occurs in the accessory sex target tissues of the male and is catalyzed by 5α-reductase?
(A) Cholesterol → pregnenolone
(B) Progesterone → 11-deoxycorticosterone
(C) 17-Hydroxypregnenolone → dehydroepiandrosterone
(D) Testosterone → estradiol
(E) Testosterone → dihydrotestosterone

15. Q The principal androgen responsible for transforming undifferentiated fetal external genitalia into male external genitalia is a. Müllerian-inhibiting substance b. Androstenedione c. Dihydrotestosterone d. Testosterone e. Androsterone

16. Phenotypic/Genital Sex
Phenotypic sex is defined by the physical characteristics of the internal genital tract and the external genitalia.
In males, the internal genital tract includes the prostate, seminal vesicles ,vas deferens, and epididymis.
The external genitalia in males are the scrotum and the penis.
In females, the internal genitalia are the fallopian tubes, the uterus, and the upper one-third of the vagina.
The external genitalia in females are the clitoris, labia majora, labia minora, and lower 2/3rd of the vagina.

17. Aberrant Sexual Differentiation
Chromosomal disorders
Gonadal dysgenesis (XO and variants) /Turner syndrome
"Superfemales" (XXX)
Seminiferous tubule dysgenesis (XXY and variants) /Klinefelter syndrome.
True hermaphroditism
A pseudohermaphrodite is an individual with the genetic constitution and gonads of one sex and the genitalia of the other

18. Defects produced by maternal nondisjunction of the sex chromosomes at the time of meiosis

19. Ovarian agenesis/ gonadal dysgenesis or Turner syndrome
In individuals with the XO chromosomal pattern, the gonads are rudimentary or absent, so that female external genitalia develop,
Stature is short, other congenital abnormalities are often present
No sexual maturation occurs at puberty

20. Seminiferous tubule dysgenesis or Klinefelter syndrome
Individuals with the XXY pattern, the most common sex chromosome disorder, have the genitalia of a normal male.
Testosterone secretion at puberty is often great enough for the development of male characteristics,
However the seminiferous tubules are abnormal, and the incidence of mental retardation is higher than normal.

21. Hormonal Abnormalities
A pseudohermaphrodite is an individual with the genetic constitution and gonads of one sex and the genitalia of the other.
Male genital development may occur in genetic females exposed to androgens from some other source during the 8th to the 13th weeks of gestation. The syndrome that results is female pseudohermaphroditism.

22. (male pseudohermaphroditism)
defective testicular development
androgen resistance- ex- 5-α reductase deficiency. (defects in receptor function range from minor to severe. Mild defects cause infertility with or without gynecomastia).
When the loss of receptor function is complete, the testicular feminizing syndrome, now known as complete androgen resistance syndrome, results.
androgen resistance syndrome,  In this condition, MIS is present and testosterone is secreted at normal or even elevated rates. The external genitalia are female, but the vagina ends blindly because there are no female internal genitalia. Individuals with this syndrome develop enlarged breasts at puberty and usually are considered to be normal women until they are diagnosed when they seek medical advice because of lack of menstruation.

23. Aberrant Sexual Differentiation-Developmental disorders
Female pseudohermaphroditism
Male pseudohermaphroditism
Congenital virilising adrenal hyperplasia of fetus
Maternal androgen excess
Virilizing ovarian tumor
Iatrogenic: Treatment with androgens or certain synthetic progestational drugs
Androgen resistance
Defective testicular development
Congenital 17-hydroxylase deficiency

24. CASE 1
A girl who is apparently normal begins to develop breasts at age 11 However, by age 16, she has not begun to menstruate and has scant pubic and axillary hair. Upon pelvic examination, a gynaecologist notes the presence of testes and a short vagina, but no cervix, ovaries, or uterus. Chromosomal evaluation reveals that the girl has an XY genotype.

25. CASE 1
Suspecting a form of androgen insensitivity syndrome (testicular feminization), the physician orders androgen-binding studies in genital skin fibroblasts. The studies show no binding of testosterone or dihydrotestosterone, suggesting that androgen receptors in the tissue are absent or defective. She has mildly elevated levels of plasma testosterone and elevated levels of luteinizing hormone(LH).
This girl has a female phenotype with female
external genitalia (lower vagina, clitoris, and labia). At puberty, she
develops breasts. However, she has a male genotype (XY) and male
gonads (testes).
The basis for her disorder, a form of androgen insensitivity syndrome, is
lack of androgen receptors in target tissues, which results in resistance to
androgens. Her testes, which are normal, secreted both antimüllerian
hormone and testosterone in utero. As in normal males, antimüllerian
hormone suppressed development of the müllerian ducts in utero;
therefore, the girl has no fallopian tubes, uterus, or upper vagina. The
testes also secreted testosterone in utero, which should have stimulated
growth and differentiation of the wolffian ducts into the male genital tract
and development of the male external genitalia. The male genital tract
and external genitalia did not develop, however, because the target
tissues lack androgen receptors. Thus, although the testes secreted
normal amounts of testosterone , testosterone could not act on the
tissues of the male genital tract. (Lack of androgen receptors also explains
the girl's scant body hair at puberty.) The female phenotype (short vagina,
labia, and clitoris) is present because, in the absence of testosterone
receptors, the fetus became a phenotypic female by "default."
The girl's breasts developed at puberty because her testes are producing
estradiol from testosterone , stimulated by the high circulating levels of
LH. The estradiol then promotes breast development.

26. CASE 1 - Management
The young woman's testes are removed, and she is treated with intermittent estrogen replacement therapy. She is advised, however, that she will never have menstrual cycles or be able to bear children
TREATMENT. In androgen insensitivity syndrome, because the testes can
develop a neoplasm, they are removed. Following removal of the testes
(and, therefore, removal of the testicular source of estradiol ), the girl is
treated with estrogen therapy to maintain her breasts. She will not be able
to bear children, however, because she lacks ovaries and a uterus.

27. CASE 2
At birth, a baby is found to have ambiguous external genitalia. There is no penis, and a clitoris is significantly enlarged. Chromosomal evaluation reveals that the baby has an XX genotype. She is found to have ovaries, but no testes.

28. CASE 2
Tests confirm that the baby has a form of adrenal hyperplasia in which there is congenital lack of the adrenal cortical enzyme 21 -hydroxylase. .

29. CASE 2- management
Treatment involves surgical reconstruction of the external genitalia to conform to the female phenotype and the administration of glucocorticoids and mineralocorticoids.
The child will be raised as a female
Surgical correction of the ambiguous external genitalia
involves reconstruction to conform to a phenotypic female. Because the
baby has normal ovaries, fallopian tubes, and uterus, she should begin
normal menstrual cycles at puberty and have a normal reproductive
capacity. Hormone replacement therapy has two goals: (1) to replace the
missing adrenal glucocorticoids and mineralocorticoids, and (2) to
suppress ACTH secretion (by the negative feedback of glucocorticoids on
the anterior pituitary) to reduce the adrenal output of androgens and
prevent further masculinization

30. A baby is born with a penis, a scrotum with no testes, no vagina, and XX chromosomes. This condition is referred to as hermaphroditism. Which of the following could cause this abnormality? A) Abnormally high levels of human chorionic gonadotropin production by the trophoblast cells B) The presence of a testosterone-secreting tumor in the mother’s right adrenal gland C) Abnormally high levels of luteinizing hormone in the maternal blood D) Abnormally low levels of testosterone in the maternal blood E) Abnormally low rates of estrogen production by the placenta

31. Puberty

32. Growth of different tissues at various ages as a percentage of size at age 20

33. Rate of growth in boys and girls from birth to age 20
The first period of accelerated growth is partly a continuation of the fetal growth period. The second growth spurt, at the time of puberty, is due to growth hormone, androgens, and estrogens, and the subsequent cessation of growth is due in large part to closure of the epiphyses in the long bones by estrogens .After this time, further increases in height are not possible. Because girls mature earlier than boys, this growth spurt appears earlier in girls. Of course, in both sexes the rate of growth of individual tissues

34. Relative importance of hormones in human growth at various ages.

35. PULSATILE SECRETION OF GNRH, FSH, AND LH
The primary event at puberty is the initiation of pulsatile secretion of GnRH.
This new pattern of GnRH secretion drives a parallel pulsatile secretion of FSH and LH
Initiation
Genetically programmed
Neuronal maturation
Nutrition and stress
Melatonin

36. Reproductive Changes
Hypothalamic pulse generator increases activity just before physical changes at puberty.
First noted sign in a female is breast development; first by estrogen(promotes duct growth) then progesterone (promotes development of milk-producing alveolar cells).
First noted sign in a male is enlargement of the testes. Mainly FSH stimulating seminiferous tubules
Pubic hair development in males and females is dependent on androgen

37. CHARACTERISTICS OF PUBERTY
In males:
Leydig cell proliferation in the testes, and increased synthesis and secretion of testosterone
There is growth of the testes, prostate.
There is a pronounced linear growth spurt, and the epiphyses close when adult height is attained.
pubic and axillary hair appears, and there is growth of the penis, lowering of the voice, and initiation of spermatogenesis.

38. a burst of testosterone secretion occurs in male fetuses before birth In the neonatal period there is another burst, with unknown function, but thereafter the Leydig cells become quiescent. There follows in all mammals a period in which the gonads of both sexes are quiescent until they are activated by gonadotropins from the pituitary to bring about the final maturation of the reproductive system. This period of final maturation is known as adolescence

39. Changes in plasma hormone concentrations during puberty in boys and girls
Stage 1 of puberty is preadolescence in both sexes. In boys, stage 2 is characterized by beginning enlargement of the testes, stage 3 by penile enlargement, stage 4 by growth of the glans penis, and stage 5 by adult genitalia. In girls, stage 2 is characterized by breast buds, stage 3 by elevation and enlargement of the breasts, stage 4 by projection of the areolas, and stage 5 by adult breasts

40. Stage 1 of puberty is preadolescence in both sexes
In boys
In girls
stage 2 is characterized by beginning enlargement of the testes,
stage 3 by penile enlargement,
stage 4 by growth of the glans penis, and
stage 5 by adult genitalia
stage 2 is characterized by breast buds,
stage 3 by elevation and enlargement of the breasts,
stage 4 by projection of the areolas, and
stage 5 by adult breasts

41. In females:
Synthesis of estradiol by the ovaries.
The first event is thelarche, the development of breasts, followed by pubarche, the development of axillary and pubic hair, and then by menarche, the first menstrual period..
The growth spurt and closure of the epiphyses typically begin and end earlier in girls than in boys.

42. Growth Changes
During puberty, androgens promote the secretion in the following anabolic sequence:
At puberty, if T4 is normal, ↑ androgens drive ↑ growth hormone, which drives ↑ IGF-I.
In males, the increased androgen arises from the testes (testosterone); in females, from the adrenals (adrenarche).
Near the end of puberty, androgens promote the mineralization (fusion or closure) of the epiphyseal plates of long bones. Estrogen can also cause plate closure, even in men.
In females, the growth spurt begins early in puberty and is near completion by menarche.
In males, the growth spurt develops near the end of puberty.
IGF-I is the major stimulus for cell division of the cartilage-synthesizing cells located in the epiphyseal plates of long bones.