Sexual Differentiation

By - dr shafali singh

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.

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

GENETIC SEX

• Determined by the sex chromosomes-XY in males and XX in females

• 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.

karyotyping

Sex ChromatinThe 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

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

• 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.

Differentiation of the internal genitalia and the primordial ducts

In females, the internal genitalia are the fallopian tubes, uterus, upper one-third of the vagina.

In males, the internal genital tract includes the prostate, seminal vesicles ,vas deferens, and epididymis.

Differentiation of the external genitalia from bipotential primordial structures.

The external genitalia in males are the scrotum and the penis

external genitalia in females are the clitoris, labia majora, labia minora, and lower 2/3rd of the vagina

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

Q The principal androgen responsible for transforming undifferentiated fetal external genitalia into male external genitalia is

a. Müllerian-inhibiting substanceb. Androstenedionec. Dihydrotestosteroned. Testosteronee. Androsterone

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.

Aberrant Sexual Differentiation

1. Gonadal dysgenesis (XO and variants) /Turner syndrome

2. "Superfemales" (XXX) 3. Seminiferous tubule dysgenesis (XXY and

variants) /Klinefelter syndrome. 4. True hermaphroditism

Chromosomal disorders

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

Ovarian agenesis/ gonadal dysgenesis or Turner syndrome

Seminiferous tubule

dysgenesis or Klinefelter syndrome

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.

(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.

Aberrant Sexual Differentiation-Developmental disorders

Female pseudohermaphroditism

1. Congenital virilising adrenal hyperplasia of fetus

2. Maternal androgen excess 3. Virilizing ovarian tumor 4. Iatrogenic: Treatment with

androgens or certain synthetic progestational drugs

Male pseudohermaphroditism

1. Androgen resistance 2. Defective testicular

development 3. Congenital 17-hydroxylase

deficiency

CASE 1

A girl who is apparently normal begins to develop breasts at age 11However, 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.

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).

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

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.

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. .

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

A baby is born with a penis, a scrotum with no testes,no vagina, and XX chromosomes. This condition isreferred to as hermaphroditism. Which of the followingcould cause this abnormality?A) Abnormally high levels of human chorionicgonadotropin production by the trophoblast cellsB) The presence of a testosterone-secreting tumor inthe mother’s right adrenal glandC) Abnormally high levels of luteinizing hormone inthe maternal bloodD) Abnormally low levels of testosterone in the maternal

bloodE) Abnormally low rates of estrogen production bythe placenta

Puberty

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

Rate of growth in boys and girls from birth to age 20

Relative importance of hormones in human growth at various ages.

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

• InitiationGenetically programmed

Neuronal maturationNutrition and stress

Melatonin

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

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.

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

• 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.

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.