Major Disorders of Sex Differentiation in Humans

1. Major Disorders of Sex Differentiation in Humans Dr. Salman Elawad Biology Instructor CVCC

2. Outlines • Sex Determination • Embryonic Sex Structures • Male Sex Disorders • Male Reproductive System • Klinefelter Syndrome (XXY) • 5-Alpha Reductace Deficiency (A-ARD) • Androgen Insensitivity Syndrome (AIS) • Female Sex Disorders • Female Reproductive System • Turners Syndrome XO) • Metafemales (XXX) • Transsexuals/Transvestites

3. Sex Determination • Humans have 46 chromosomes (23 pairs) in their somatic (body) cells, 23 inherited from the mother and 23 inherited from the father. • Pairs 1 – 22, called autosomes, are perfectly matched in both males and females. • Pair #23, called the sex chromosomes, consists of XX in females and XY in males. • In males, the Y chromosome is highly condensed and very few of its genes are expressed. • Some scientists believe that the Y chromosome is diminishing, and a day will come that it will disappear! • The gene SRY on the Y chromosome codes for a protein called testis-determining factor (TDF) which causes the fetal all-purpose gonads to develop into testes.

6. Embryonic Sex Structures • Sex structures in male and female embryos • All-purpose gonads→ testes in males (SRY gene on Y chromosome → TDF) and ovaries in females (absence of Y chromosome) • All-purpose sex structures→ glans penis, penis shaft, and scrotum in males (DHT); labia minora, labia majora, and clitoris in females (absence of DHT) • Müllerian ducts→ atrophy in males (MIF); uterus, fallopian tubes, and vagina in females • Wolffian ducts→ Epididymis, vas deferens, and seminal vesicles in males (testosterone); atrophy in females

7. Embryo Development • Between the 5th and 7th week after fertilization, the human embryo of either sex develops an all-purpose gonad that can later become either a testis or an ovary. • If a Y chromosome is present (male), the all-purpose gonad will begin to commit itself by the 8th week to become a testis due to the presence of TDF. • If there is no Y chromosome, the all-purpose gonad waits until the 13th week and then begins developing as an ovary. • The natural tendency of our primordial gonad is to develop as an ovary.

9. Embryo Development Website: http://visembryo.com/baby/index.html

10. When Something Goes Wrong • Since a Y chromosome specifies testes (TDF), and since the presence or absence of the testes’ secretions (testosterone and MIF) specifies the remaining sex structures, it might seem as if there’s no way that we could end up hermaphrodites. • In fact, a long series of further biochemical steps, programmed by genes on chromosomes other than X and Y, is required to produce all the structures other than testes and ovaries. • Every step involves the synthesis of one enzyme, specified by one gene. • If any one gene is altered by a mutation, the enzyme for which it’s responsible may be defective or absent. • Thus, an enzyme defect may result in a male pseudo-hermaphrodite with X and Y chromosomes, but with a mixture of both male and female structures. • Also, defective androgen receptors may cause development of female sex structures in males.

11. Turning A Man • Becoming a man is a struggle against inherent trends toward femaleness. • Chauvinists might hail becoming a man as heroic, and becoming a woman as the easy fallback position. • In reality, womanhood is the natural state of humanity. • A Y chromosome switches gonad development from the ovarian path to the testicular path.

12. Male Sex Disorders • Male Reproductive System • Klinefelter Syndrome (XXY) • 5-Alpha Reductace Deficiency (A-ARD) • Androgen Insensitivity Syndrome (AIS)

16. Klinefelter Syndrome (XXY) • Occurs as a result of nondisjunction during the formation of gametes by meiosis. • Genetically male with 47, XXY or 48, XXXY chromosomes. • Symptoms • Usually tall • Some degree of breast growth at puberty • Small penis and testes • Diminished mental capacity in some cases • Sterile with many female body characteristics • Occurrence: 1 in 500 males

17. 5-Alpha Reductase Deficiency (5-ARD) • An autosomal recessive condition resulting in the inability to convert testosterone into the more physiologically active dihydrotestosterone (DHT). • All-purpose sex structures fail to develop into male structures (glans penis, penis shaft, and scrotum); and develop into female equivalents (clitoris, labia majora, and labia minora) by default. • Condition varies from • infertility with normal male genital anatomy • to underdeveloped male hypospadias (urethral opening on side of penis) • to predominantly female sex genitalia, most often with mild clitoromegaly (clitoral enlargement).

18. 5-Alpha Reductase Deficiency (5-ARD) (cont.) • Since the external genitals appear largely female at birth, many, but not all, 5-ARD pseudo-hermaphrodites are raised at first as females. • Testes and Wolffian structures (epididymis, vas deferens, seminal vesicles) are intact. • Male internal ducts are present but terminate in a blind pseudovaginal pouch or on the perineum. • At puberty, these children become much more malelike─the presence of testosterone causes muscle development, growth of the penis and scrotum, erections, and ejaculation.

19. 5-Alpha Reductase Deficiency (5-ARD) (cont.) • Pubic/underarm and body hair appears, and voice deepens. • The lack of DHT causes less-than-normal growth of the beard and body hair. • Finally, at middle age, lack of DHT helps prevent prostate enlargement and male pattern baldness. • Suffer from psychological problems.

21. Androgen Insensitivity Syndrome (AIS)/ Testicular Feminization • Inherited condition that affects sexual development before birth and during puberty. • Caused by a defective X-linked recessive gene (AR gene) inherited from the mother. • People with AIS are genetically male (XY). • Because their bodies are unable to respond to androgens, they may have mostly female sexual characteristics or signs of both male and female development.

22. Androgen Insensitivity Syndrome (cont.) • The process by which the usual male machinery is activated by testosterone is interrupted due to a biochemical block in cell receptors. • Since the Y chromosome is normal, testes form normally and produce normal MIF, which forestall development of the Müllerian ducts into uterus, fallopian tubes, and internal vagina. • Development of the remaining all-purpose embryonic sex organs follows the female channel by default: female rather than male external genitalia, atrophy of the Wolffian ducts, and hence no development of male internal genitalia (epididymis, vas deferens, and seminal vesicles). • The result, then, is a genetic male who can’t become male─in short, a genetic male whose visible sexual parts are those of a female.

23. Types of AIS • There is complete androgen insensitivity syndrome (CAIS), partial androgen insensitivity syndrome (PAIS), and mild androgen insensitivity syndrome (MAIS) • CAIS affects 2 to 5 per 100,000 live male births. PAIS is as common as CAIS. MAIS is much less common • An individual with any type of AIS is sterile.

24. General Features • This type of pseudo-hermaphrodite looks like a normal female. • Indeed, “she” often conforms to the male ideal of feminine beauty even more than the average woman does because • Her breasts tend to be well developed • Her legs long and graceful • Her complexion is usually flawless • She tends to have the added height of a man • Sparse to absent pubic/underarm and body hair • Hence, cases have turned up repeatedly among female movie stars and fashion models. • Frequency is 2-5 in 100,000 in normal population, and 25 in 100,000 among fashion models.

26. Clinical Diagnosis • Clinical diagnosis of AIS reveals • Presence of a Y chromosome (i.e., genetically male) • Two hidden nondysplastic (normal) testes • Normal male testosterone levels • Absent or rudimentary Müllerian structures (i.e., no fallopian tubes, uterus, or internal vagina) • Presence of a short external vagina • Normal female external genitalia • No menstruation or ovulation

27. No Emotional Stress • Almost all such people unquestionably view themselves, and are viewed by others, as women. • Most find husbands and marry. • Naturally, without a uterus or ovaries, they can’t bear children, but many adopt. • Most are well adjusted to their role as women and show no signs of unusual emotional stress. • In these cases, not only do testes fail to make a man, but they fail to interfere with much of the happiness available to women as wives and mothers.

28. Management • The modalities of management─surgery, hormone replacement or supplementation, and psychologic support─depend on the individual’s phenotype. • A common practice is to remove the testes (gonadectomy) after puberty when feminization of the affected individual is complete. • If prepubertal gonadectomy is performed, estrogen replacement therapy is necessary to initiate puberty, maintain feminization, and avoid osteoporosis. • Vaginal length may be sufficiently short to require dilatation in an effort to avoid dyspareunia (pain during intercourse). • Systematic disclosure in an empathic setting is much preferable to systematic concealment or self-discovery of the diagnosis in an environment devoid of support from family, professionals, and other affected individuals.

29. Jamie Lee CurtisTrue Lies!!!

31. Female Sex Disorders • Humans are genetically programmed to develop into women. • Embryonic sex structures develop into female sex structures by default. • Pseudo-hermaphroditism does not occur in genetically defined women (XX). • Some sex disorders may occur including Turner Syndrome (XO) and Metafemales (XXX).

33. Turner Syndrome (XO) • Caused by nondisjunction during gamete formation by meiosis • Afflicted individuals are always sterile females. • Immature sex organs that do not undergo puberty changes. • Vaginal hypoplasia (underdevelopment). • Short stature and webbed neck. • May develop pectus excavatum • Mental abilities in the low-normal range. • Occurrence: 1 in 5,000 females.

34. Pectus excavatum

35. Metafemale (XXX) • Caused by nondisjunction during gamete formation by meiosis • Afflicted individuals are always females. • Vaginal hypoplasia. • Sterile but usually normal in other respects. • Occurrence: 1 in 3,000 females.

36. Transsexuals (Gender Dysphoria) • A transsexual is a person with gender dysphoria. • These are individuals who feel they were born with the wrong body-men who feel they should have been born women and vice versa. • Individuals with gender dysphoria experience anxiety, uncertainty or uncomfortable feelings with their birth gender. • They want to change their body to match their brain. • Occurrence: • Male to female: 1 in 10,000 males • Female to male: 1 in 40,000 females • Transvestites (TVs) are individuals who just cross dress occasionally.

37. Gender Dysphoria: Treatment • Treatment of gender dysphoria includes: • Hormone therapy: Estrogen/testosterone • Surgical reconstruction • Counseling and other psychotherapeutic approaches • Speech therapy • Facial therapy (male to female) • Electrolysis to remove beard and other body hair