1. Regulation of the development of the gonads in intrauterine life Physiology Unit

2. Objective The objective of the lecture is to discuss the development of gonads : hormones produced by the embryonic testes: role of testosterone, dihydrotestosterone, Mullerian inhibiting substance in the development of gonads: Male and female psudohermaphrodism and congenetal adrenal hyperplasia and testicular feminizing syndrome.

3. At the end of the lecture, students should be able to: -Describe the development of gonads List and explain the role of hormones produced by the embryonic testes. -Describe the role of testosterone, dihydrotestosterone and mullerian inhibiting substance in the development of gonads. -Describe the defect and clinical presentation of male and female pseudohermaphrodism. -Describe the features of congenital adrenal hyperplasia and testicular feminizing syndrome.

4. 1. Primitive gonad: (identical in both sexes) - cortex - medulla 2. Primitive genital tracts: (identical in both sexes) - Müllerian tract - Wolffian tract -Up to 6 weeks of intra uterine life the indifferent gonads exist. Sex Differentiation ?

5. Levels of Sexual Development There are 3 levels to sexual development: – chromosomal sex: presence or absence of the Y chromosome. – 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. – 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.

6. 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. Human karyotype: chromsomes stained to show bands, from a male

7. The presence and absence of “Y” Chromosome determines the sex of an individual in the intra uterine life. Primitive gonads contains both the Mullarian ductal system as well as the Wolffian ductal system. Further development of these ductal systems into either male and female internal and external genitilia is possible after 7 th week of intra utirine life and it depends upon the existence of Y chromosome. In the presence of Y chromosome, The sex determining gene ( SRY gene) present in the short arm of the Y - Chromosome that codes for Testes determining factor (TDF) is responsible for the development of Wolffian system. The embryonic teste’s Leydig cells secrets the male sex hormone testosterone. The Seratoli cells secrets Mullerian inhibitary factor (MIF), this is responsible for the regreession of Mullerian system. In the absence of Y chromosome as there is no TDF, the cortex of the premitive gonads develops in to the overies automatically.

8. *In the absence of Y chromosome the female ductal system ( Mullerian ductal system develops. *Up to week 7 the embryo has both male and female primordial genital ducts (internal genitalia) *After week 7, in females: müllerian duct system differentiates  uterine tubes, uterus, upper third of vagina. wolffian duct system degenerates *External genitalia bipotential up to week 8. *Then, in females: urogenital slit remains open, female type external genitalia develop *By week 12: ovaries are present, müllerian ducts develop, external genitalia remain feminine and wolffian duct regresses

9. Hormones produced by the embryonic testes: -Testicular androgens : -Testosterone -Androtestosteron -dehydroepiandrosterone -17-hydroxyprogesterone -insulin-like hormone 3 -Progesteron -pregnenolone

10. 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.

11. Development of gonads

12. T HE C HROMOSOMAL A BNORMALITIES

13. Klinefelter Syndrome: 47,XXY Occurs about 1 per 500 male births. It is the most common type of sex chromosome variant. The presence of the Y chromosome causes a 47,XXY person to be male, both externally and internally, because the testes are formed. Root symptom: small testes, leading to low testosterone levels. Most, but not all, are sterile. At puberty, reduced facial and body hair, broader hips, breast development. 47,XXY children tend to be taller, less physically strong and coordinated, and more quiet and shyer than their peers. Some language and learning problems are common: often slow to learn to speak and read. Testosterone replacement therapy helps with some of the physical symptoms. Speech therapy and educational services also help. 46,XX males, with the SRY gene on the X, have the Klinefelter appearance.

14. Turner Syndrome: 45,X Only one X chromosome, sometimes called XO. Since there is no Y chromosome, the primary gonad is the ovary, and 45,X people are female. About 1 in 2500 live female births. – 10% of all spontaneous abortions (miscarriages) are due to Turner syndrome; about 98% of all Turner’s embryos die before birth Ovaries completely non-functional, so 45,X women are sterile, with no production of sex hormones and development of secondary sexual characteristics at puberty. Some characteristic physical abnormalities: short stature, low hairline, webbed skin at neck. Kidney and circulatory system problems Often have problems with spatial reasoning and mathematics. Also social difficulties: inability to understand others’ emotions. Can be treated with growth hormone and estrogen. You need 2 X chromosomes for proper ovarian development. 46,XY females (non-functional SRYgene) resemble Turner’s

15. 47,XYY About 1 in 1000 live male births. Most XYY’s are never detected: a very mild condition. since 1960, newly discovered chromosome variants aren’t given the discoverer’s name It was once thought to create hyper-aggressive males with a tendency towards criminal behavior. – Richard Speck, the killer of eight student nurses in 1966, pretended (falsely) to be an XYY to obtain leniency. – A 1968 letter to the Lancet claimed that XYY men were in prison at a rate "25-60 times as high as the prevalence in the general population”, based on finding 2 XYY’s. – the plot of Aliens 3 involves a prison planet for XYY’s. XYY’s are generally normal in appearance, but with average height about 7 cm above expected and normal build. Perhaps acne is more common than average, but this is disputed. They are often more physically active, somewhat delayed in emotional maturity, and have a slight increase in learning and speech problems. Fertile, normal sex drive, very rarely pass 2 Y’s to sons. 1970’s British TV series: He had an extra Y, which made him a macho criminal!

16. 47,XXX (Super Female ) About 1 in 1000 live female births. So mild as to be only rarely detected. Also called triplo-X. Originally called “superfemale” (early 1960’s). Widely varying symptoms, including none at all. Slightly more passive and quiet as babies, less assertive, delayed motor and linguistic skills. Delayed emotional maturity and social skills. Some have slightly decreased intelligence and learning difficulties. Lower back problems are common. Fertility normal, don’t generally pass 2 X’s to children.

17. True hermaphrodites They have both testes and ovaries Due to 44XX/XY pattern

18. Pseudohermaphrodites They have genetic constitution and gonads of one sex but the external genitalia of other. It is of two types. 1. Female pseudohermaphrodite 2. Male pseudohermaphrodite

19. 1.Female pseudo hermaphrodite: Genetic female with male genitalia Reason may be exposure of female embryo to androgens during 8 th to 13 th week of intra uterine life. 2.Male pseudo hermaphrodism: Genetic male with both internal and external female genitalia. Defect in androgen and MIF secretion

20. Congenital Adrenal Hyperplasia

21. The adrenal glands sit on top of the kidneys and secrete a variety of steroid hormones, including cortisone (stress response), aldosterone (salt balance) and androgens (male sex hormones). Steroid hormones are made from cholesterol through a series of biochemical steps. Any one of these steps can be inactivated by mutation. However, about 95% of CAH cases involve defects in the enzyme 21-hydroxylase. 21-hydroxylase is needed to make cortisol and aldosterone (but not androgens). Cortisol is secreted in response to the pituitary hormone ACTH, in a feedback loop. So, if there isn’t enough cortisol being made, more ACTH is made, and this causes the adrenal gland to grow larger (hyperplasia). And, all of those steroid molecules that were destined to become cortisol and aldosterone get diverted into male sex hormones (androstendione and testosterone), which don’t need the 21- hydroxylase. Very little effect on male fetus, which is already making testosterone, except that after birth the lack of salt regulation can lead to death from excess salt secretion (salt-wasting).

22. CAH Female fetuses with 21-hydroxlase deficiency have some problems due to the flood of androgens released by the adrenal gland. The ovaries are normal, and the female (Mullerian) ducts are also normal (since no MIS is made). Main effects are on the external genitalia: enlarged clitoris, sometimes with an enclosed urethra (i.e. like the penis), labia can fuse and become scrotum-like, vaginal opening can be partly or completely closed. Appearance at birth varies a lot. Some appear to be normal male with undescended (because non-existent) testes. However, the chromosomes are XX, the gonads are ovaries, and the uterus and fallopian tubes are usually intact. Normally, very little androgen is made in childhood. CAH causes excess androgens throughout life, leading to rapid growth, but an early closure of the bone growth plates: a very short adult. Also: early puberty, with menstrual problems (and poor sperm production in males). The other hormones, aldosterone and cortisol, need to be replaced. The cortisol replacement calms the ACTH activity, leading to less androgen production. CAH is the most frequent cause of non-standard genitals in genetically female (XX) children.

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