Lecture 8 Flashcards
What are the 5 patterns of abnormal sexual development we must learn?
- 5-alpha reductase deficiency
- (Complete) Androgen Insensitivity Syndrome
- Congenital Adrenal Hyperplasia
- Klinefelter Syndrome (XXY men)
- XYY men
5-alpha reductase deficiency
5-alpha reductase converts testosterone (T) to dihydrotesoterone (DHT)
DHT more potent than T DURING development - it is responsible for male external genitalia
Leads to female morphology until puberty, followed by conversion to male at puberty
Raised female, but often develop male behavioral traits
What pattenr of heritability does 5-alpha reductase deficiency show?
It is autosomal recessive
Men only
What does it look like
Female genitals until puberty
Male after
5-alpha reductase deficiency (Treatment)
TREATMENT
-DHT topical cream to enlarge genitals in childhood
-Gender based on physiological sex to reduce difficult transition at puberty
(Raise as men)
-Not infertile, all physiological capabilities of typically developing man
Complete Androgen Insensitivity Syndrome
XY with female development
- Women never get it (2Xs)
- Gene for the androgen receptor is on the X chromosome
- We are only interested in complete although partial does exist
Action of the androgen on a target cell (with functional receptors)
Binds to receptor Influences genes These create proteins which influence: Voice Behavior Sperm production Sex differentiation Muscle and bone development Growth
Effects of knocking out the androgen receptor
NO development of the Wolffian system (test) so no internal male organs
No DHT signaling so no external genitalia
Testes also produce anti Mullerian hormone which DOES still work (So no female INTERNAL sex organs
Study on CAIS
Shows what affect at birth?
Wisniewski et al (2000) :
Looked at 14 women with confirmed CAIS
Physical measurements at birth:
CAIS babies no different from unaffected infants in terms of birth weight
External genitalia was completely female with no abnormalities
Essentially the same at birth as XX women
CAIS at puberty
What do you see?
Pubertal feminization still occurs because:
- CAIS DO respond to estrogen
- The testis are a source of androgen, converted to estrogen
- Normal female secondary sex characteristics
Physical indicators of CAIS in adolescence:
- Amenorrhea
- No virilization despite high circulating testosterone
- Absence of post-pubertal axillary hair as there are no receptors for DHEA and Androsenedione
Treatment of CAIS
Best practice is removal of testes after puberty, and feminization by:
Surgical creation of full vagina (in which dilation will still be necessary after surgery to
Vaginal dilation - prevent scarring and vaginal stricture
- Can be painful and distressing, length is the priority, then width
- Dilation is recommended before surgical creation
Typically these omen are infertile as they lack internal sexual organs
Congenital Adrenal Hyperplasia is characterized by
Excess androgens
Types of CAH (2)
Affects males and females
Classic = from conception, Non-classic = late onset
Females and CAH symptoms
FEMALES:
Classic: ambiguous genitalia because high androgens in utero
Non-classic: early pubic hair (hirtruism) (in childhood),
and possibly polycystic ovarian syndrome as the estradiol made by converting androgens to causes follicular development but not evolution (and so forms cysts eventually)
Males and CAH symptoms
MALES:
Often no signs of CAH at birth, possibly hyperpigmentation and penile enlargement
Age of diagnosis of males varies based on severity of aldosterone deficiency
Aldosterone: critical for controlling concentrations of salts
If there is very low aldosterone = salt-wasting disease: hyponatremia and hypovolemia and so this will be picked up earlier medically
No salt-wasting disease present later: virilization and hirtruism before the appropriate age
CAH inheritance/prevelance
Autosomal recessive
1%
What happens in CAH
The pituitary gland regulates the production of hormones in the adrenal glands
Two main parts of the adrenal glands:
Adrenal Medulla
Adrenal Cortex
The adrenal cortex is the part of the adrenal glands affected in CAH
Normally it produces 3 types of hormones:
Cortisol
Physical and emotional stress
Maintains adequate energy supply and blood sugar levels
Aldosterone
Maintains normal levels of sodium and potassium
Maintains normal blood volume of the body
Androgens
DHEA and Androstenedione
BUT in CAH
Deficiency of the enzyme 21-hydroxylase (21-OHD) in the adrenal cortex necessary for the production of cortisol and aldosterone
Non-classical CAH: commence from early childhood to early adulthood
Gradually lose ability to make 21-OHD
As a consequence the only thing the adrenal gland can successfully make is adrenal androgens
Why does negative feedback not prevent the excess androgens in CAH?
21-OHD deficiency dysregulates HPA axis
lack of negative feedback from cortisol to the pituitary
17-hydroxy-progesterone (17-OHP) to cortisol requires 21-hydroxylase
No cortisol means continued release of CRH and ACTH
Excess 17-OHP converted to androgens instead of cortisol
Androgens can be produced because based on 17,20-lyase, not hydroxylase
And so there is nothing preventing this being produced to excess.
The problems of CAH
Problems of those with CAH are threefold:
- Very little or no production of cortisol.
- Very low or no production of aldosterone.
- Overproduction of androgens
Excessive stimulation of adrenal cortex because NO negative feedback leads to
Enlarged glands
Symptoms of classic CAH in females
Ambiguous genitalia in girls
Enlarged clitoris and joined labia folds
Females born with CAH have XX chromosomes
No anti-mullerian hormone: internal female genitalia
May be infertile because androgens also stimulated Wolffian to develop
High levels of androgens masculinize external genitalia
Salt-wasting disease depending on aldosterone
Often infertile
Clasic CAH symptoms in males
-Salt-wasting or large penis at birth
If not: diagnosed at puberty
At puberty:
- Cystic acne
- Early beard growth
- The testes are small compared to the phallus
- Low sperm count
- Short stature
Puberty causes what in CAH?
Symptoms get worse
-There is an increase in gonadal hormones on top of excessive androgens
Premature development of, and excessive pubic hair
Accelerated bone aging
Severe acne
Early and strong body odor
Oily hair and skin
What about mental health at puberty in CAH?
Depression
Anxiety
CRH effects on brain
The brain has CRH receptors. These increase anxiety and depression when activated by excess CRH
Which sex is more obviously affected in CAH?
Females
-True in childhood and puberty
Shortly after the onset of menstruation women get:
- Thinning of hair on head and infertility.
- Facial hair that is dark and course on the upper lip and chin.
- Menstrual irregularities.
- Formation of ovarian cysts due to the disruption of the gonadotropin release so limited ovary stimulation
What are the psychological and behavioral affects of CAH? (of females)
Do these behaviors differ from the norm?
Childhood/Adolescence:
Increase in testosterone levels / increased male typical play
More aggressive
Females less interested in marriage, motherhood, feminine appearance than controls
Lower levels of empathy, intimacy
Less stereotypical female traits
Female sexuality
Less heterosexual activity
Homosexual fantasies and increased occurrence of homosexuality and bisexuality.
CAH-SW > CAH-nSW > control
Gender identity is more ambiguous with increased severity
Treatment of CAH
Provide glucocorticoids to reduce excess CRH and ACTH
Cortisol, etc… something to activate neg feedback
Hydrocortisone: infancy, childhood
Dex/Prednisone: adolescents, adults (bedtime dose)
Mineralocorticoids for salt-wasting form
e.g. fludrocortisone
Klinefelter Syndrome (KS)?
Trisomic Anomalies: 47 Chromosomes
Instead of having the usual XY chromosome, males have an extra X in their cells (only males)
**Note: Not every male with XXY chromosome has KS
Physical, endocrinologic, reproductive, cognitive, and behavioral disabilities.
This affects males over their development.
Prevalence of XXY
Between 1 in 500 and 1 in 1000 males
0 female
SRY region on Y chromosome means all are male
Other variants of Klinefelter syndrome:
1 out of 50,000 males
e.g. some are XXXY for example
Rare cos the effects of all these are cumulative and many do not survive
Causes of XXY
XXY syndrome is not clear
- Increased risk in mother over 35
- KS is NOT an inherited disorder
During meiosis 46 chromosomes divide into 2 cells with 23 chromosomes each
In female, each cell gets a X
In male, one cell gets the X and the other gets the Y
For XXY there is non-disjunction from one parent
Contribute an extra X
May be mosaic – 2 genotypes in 1 person
If this is so the relative concentration of XY vs XXY determines severity
XXY Severity (mosaic)
May be mosaic – 2 genotypes in 1 person
If this is so the relative concentration of XY vs XXY determines severity
Physical symptoms of XXY
Do not make as much testosterone (hypogonadism)
- Incomplete virilisation
- Can have normal sex lives, but they make little or no sperm (so often infertile if untreated)
- Penis does not reach adult size
- Small firm testicles (microorchidism)
- Enlarged breasts (gynecomastia)
- Less facial and body hair
- Less muscular body (underdeveloped muscles)
- Pear shaped (long arms and legs, narrow shoulders, broad hips)
- Taller (long legs)
- Weaker bones
XXY IQ and Gender Identity
IQ within normal range, but ~15pts lower
Verbal IQ < Performance IQ
Lower verbal IQ
Androgynous or feminine feelings that can develop at an early age
Higher proportion consider themselves transgendered
In individuals who ID as male and want treatment
testosterone can masculinize and may aid in fertility
XYY (Supermales, lol)
Has a bad rep but actually the best of the trisomys
History of XYY
XYY discovered in 1961 by Avery Sandberg
Incidental finding: man was karyotyped because daughter born with Down syndrome
47, XYY
last common sex chromosome abnormalities discovered
No consistent differences from general public
XYY Prevalence
The incidence is reported to be ~1 in 1,000 males
80-90% of the time will be 47, XYY
10-20% of the time 46,XY/47, XYY; also known as mosaic.
May be diagnosed both prenatally and postnatally
What stage in Meiosis causes XYY
A study by Robinson et al, 1999
28 47,XYY males
Error during meiosis, but where?
Prime illustration of the most common origin of this syndrome
~85% of cases additional Y chromosome was generated by non-disjunction at paternal meiosis II, after a normal meiosis I
Implications of XYY
Also affected by XYY:
Physical Attributes
Height
Psychological and Cognitive
Intelligence normal, but learning difficulties (verbal)
IQ lower than siblings…
Behavioral
Aggression/Criminality are not above normal but they get caught more
Explained by IQ deficit
Stress hormone in development
If stress hormones are given to the fetus, there is a change in stress responses later in life.
Greater hormonal stress response
Possibly set points in the brain-pit-adrenal axis are edited by prenatal stress and permanently change.
SRY gene causes the production of
testes determining factor
Verified male/female differences normally
Verified normal sex differences in behavior include the following:
Males are more aggressive than females across cultures and from childhood
through adulthood, more so in children. Boys are more active and display
more playful aggression. For toys, boys prefer vehicles, weapons, and building
toys, whereas girls prefer dolls, kitchen accessories, and cosmetics. As adults
in most cultures, women are more interested in parenting than men are.
Men are more likely to be left-handed than women, and women are less
likely to have exclusive left cerebral language dominance. Whereas there is
no sex difference in general intelligence, some differences in specific cognitive measures have been found. Females have slightly better overall verbal
ability. Males are slightly better on analogies, whereas females are slightly
better in speech production and verbal fluency. From childhood through
adulthood, males rotate mental images more accurately and rapidly than do
females. Females solve mathematical problems slightly better in childhood,
whereas males’ problem-solving ability is slightly better in adulthood. There
is no sex difference in comprehension of mathematical concepts at any age.
Finally, females show better perceptual speed and accuracy than do males,
but the magnitude of the difference has been declining since the 1940s,
likely related to evolution of the tests used to measure this performance
characteristic
Low thyroxine in development
Low IQ
Secondary sexual characteristics in 5-a-reductase deficiency
The anabolic events at puberty, in particular the increase ill muscle mass,
the growth of the phallus and scrotum, and the voice change, appear to be
mediated by testosterone and occur in the aSected males ( 11, 13 ) .
Prostate growth, facial hair, temporal recession of the hairline, and acne do not occur and appear to be mediated by dihydro-
testosterone (14).
Gender identity at puberty in 5ARD
Change from female (raised ) to male
Begin liking girls
Maybe sex drive is test mediated
