ABNORMAL PRENATAL SEXUAL DEVELOPMENT

Nondisjunction of the sex chromosomes (XO, XXX, XXY, etc.):

• Often results in ________________, but individuals typically have _______________ external genitalia
• Problem is usually not recognized until puberty, when the individual often fails to undergo normal sexual maturation or fails to menstruate

(review previous lecture notes on nondisjunction)

True Hermaphrodites: possess both ovarian and testicular tissue

• Extremely rare condition, in which individuals possess a ___________________ of both male and female ______________ tissue.
• External genitalia may be normal, but often varies from micropenis to enlarged clitoris. Vagina often present, but may be located underneath an ambiguous _________________________________.
• May be raised as either males or females, depending primarily on the appearance of the genitalia.
• May result in ___________________, but not necessarily.
• Two forms are known:

1. Possession of a testis on one side and an ovary on the other:

o Cause is poorly understood. May result from mitotic errors during cleavage that lead to a genetic mosaic (XY/XX or XY/XO).

o On one side of the body (__________):

Gonadal medulla - develops into a _____________
Gonadal cortex - ____________________
Wolffian duct – _________________ into male derivatives (due to local action of testosterone)
Mullerian duct – _________________ (due to local release of MIS)

o On the other side of the body (_______ or ________):

Gonadal cortex – develops into an __________________
Gonadal medulla - _________________
Mullerian duct – ___________________ into a partial uterus, cervix and vagina
Wolffian duct – ___________________ (due to local absence of testosterone)

2. Possession of two "______________________":

· Cause is poorly understood. Most affected individuals are XX.

· Gonadal medulla and cortex - _____________________________, yielding both testicular and ovarian tissue in each gonad (called an "ovotestis")

· Wolffian and Mullerian ducts – ____________________________ on each side of body

· Most menstruate and develop breasts at puberty, along with some facial, pubic & body hair.

Pseudohermaphrodites: gonads agree with chromosomal sex, but external genitalia are either ambiguous or appear as the opposite sex

(See http://www.isna.org/ for general information on intersex conditions and http://www.isna.org/faq/frequency.html for a table of their estimated frequencies in the population)

A. Male Pseudohermaphrodites: XY individuals with testes but external genitalia are either female or ambiguous (at least at birth)

1. Complete Androgen Insensitivity Syndrome (CAIS) (formerly called testicular feminization syndrome)

(= "XY individuals that possess testes, but who look, behave, and feel like normal females")

· Inherited disorder (__________________________________) in 80-90% of cases (spontaneous mutation in the remaining 10-20%).

· Affected individuals lack ________________________________________. (Therefore, the body is unable to recognize or respond to testosterone and DHT.)

· Gonadal medulla – develops into _______________ ______________________, which produce normal amount of testosterone (but testes fail to descend from abdominal position)

· Gonadal cortex – ___________________

· Wolffian and Mullerian ducts- _________________________________ (so there is no internal reproductive anatomy except for testes)

· External genitalia – _________________

· Secondary sex traits at puberty – _____________________ (estrogen is produced by testes)

· Problem is often first detected at puberty when the individual _____________________________________

· Usually quite feminine in appearance and behavior, with well-developed breasts, long legs, clear facial complexion, luxurious scalp hair, and little or no pubic and underarm hair

· Vagina shorter than average, and may require surgical lengthening to allow normal intercourse

· Testes are more likely to develop malignant cancer, and so are usually removed after puberty ends.

2. Partial Androgen Insensitivity Syndrome (PAIS)

· More common than CAIS.

· Affected individuals possess some, but not the usual amount of androgen receptors; therefore, the body ______________________________________________ to androgen stimulation.

· Degree of androgen insensitivity varies greatly, and as such, the degree of feminization also varies along a gradient.

· Genitalia are usually _______________________.

3. Guevodoces Syndrome (also called "5 alpha-reductase (5AR) Deficiency")

(= XY individuals that may look like girls at birth, but "turn into men" at puberty)

· Inherited disorder (autosomal recessive), in which affected individuals are unable to convert testosterone to DHT because they lack the appropriate conversion enzyme [5-alpha-reductase (5AR)]

· Gonadal medulla – develops into _______________________, which produce normal amount of testosterone (but remain undescended until puberty)

· Gonadal cortex – ___________________

· Wolffian ducts - __________________________

· Mullerian ducts – _________________

· External genitalia - resemble __________________ at birth, but change to ________________ at ________________________

· At puberty, blood levels of testosterone become so high that DHT-dependent tissues can respond to testosterone directly, even without conversion to DHT. Consequently, the clitoris grows to penis size, and is capable of normal erections. The testes descend into the labia majora, which now fuse to become a ______________________. Ejaculation is now possible, although they are unable to impregnate women because the urethral opening is not at the tip of the penis but is still an opening near the anus. Can be surgically corrected.

· Secondary sexual characteristics - _____________ (except less facial and body hair)

· At puberty, exhibit normal heterosexual ______________ behavior and sexual preference, even though they are nearly always initially raised as girls. This is probably best explained by ______________________________ of the fetal brain to _________________________.

· Very rare in the general population, but common in some remote, isolated island societies.

· As in AIS, there can be _____________ guevodoces syndrome, in which some areas of the body lack the enzyme or there are fewer receptors than normal. In these cases, external genitalia may be ambiguous at birth, but will resemble that of a normal male at puberty. Medical professionals recognize 5 grades of this disorder, depending on degree of feminized genitalia at birth.

B. Female Pseudohermaphrodites: XX individuals with normal ovaries and normal female internal anatomy; however, external genitalia are at least partially ________________________.

· 1. Congenital Adrenal Hyperplasia (CAS) (formerly called androgenital syndrome) Click here for more info

· Inherited disorder (autosomal recessive), in which affected individuals possess defective_________________________________. When the adrenals fail to secrete cortisol, this causes the pituitary gland to secrete large amounts of another hormone, which overstimulates the adrenals. They respond by secreting large amounts of testosterone into the bloodstream, which causes varying degrees of masculinization of the external genitalia.

· Gonadal cortex – ____________________

· Gonadal medulla – ___________________

· Mullerian ducts – _______________

· Wolffian ducts – ________________, despite the high levels of testosterone! (Why? Adrenals don’t begin producing testosterone until the 12 week. Wolffian ducts have already begun to degenerate by then, and are no longer capable of responding to testosterone.)

· External genitalia – __________________________ (often an elongated clitoris or "penoclitoris" with enough labial fusion to eliminate any vaginal orifice). Pubic and underarm hair growth can occur only a few years after birth.

· Failure to menstruate at puberty, unless treated with cortisol hormone therapy. Affected individuals may then get pregnant and give birth vaginally (after corrective surgery to open the fused labia majora).

· Individuals usually exhibit tomboy-like behavior during childhood, and are often lesbian as adults (1/3 of cases).

· Accounts for ½ of all cases of human intersexuality (ambiguous genitalia).

· Can also occur in ____________, who may appear to enter puberty very prematurely (as early as age 2 or 3), with enlarged penis, pubic and underarm hair, and deepened voice.

2. Progestin-induced Virilization

o Caused by administration of a synthetic _______________________ during pregnancy, which has an ____________________________ effect on the external genitalia, resulting in varying degrees of masculinization of genitalia.

o Was once prescribed to prevent miscarriage, but practice was banned in 1974

o Very rare today. Occurs primarily when women who are unaware of their pregnancy continue to take ___________________________________________ (= synthetic estrogen + progestin) after the 7^th week.

Other disorders in embryonic sexual development:

Male disorders:

Various types of penile and testicular abnormalities may result from fetal testosterone deficiencies or genetic mutations in growth:

1. Undescended testes (3% of full-term newborn males and _________% of premature males). If they don’t descend in early childhood, surgery is needed to prevent infertility.

2. Hypospadia (results from incomplete fusion of urogenital folds) - Urethral opening is located on the underside of the penis instead of at the tip. (1/300 male births)

3. Double penis or bifid (forked) penis (extremely rare)

Female disorders:

Various types of uterine and vaginal abnormalities usually result from incomplete fusion of the lower Mullerian ducts:

1. Double, branched, or septate uterus, with a single or double vagina

2. Absence of uterus and vagina

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