sexual differentiation by - dr shafali singh. learning objectives outline the role of chromosomes,...
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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.