CM- Disorders of Sexual Differentiation Flashcards
What is the effect of testosterone on sexual differentation?
If the fetus is SRY+ it will develop testes. The testes has 3 cell types: - Leydig -Sertoli - gametes
Under the influence of hCG/LH, the Leydig cells secrete testosterone to:
- develop the Wolffian duct [epididymis, vas deferens, seminal vesicles]
- go to the periphery [skin] where 5a reductase converts it to DHT to make external male genitalia
What is the effect of AMH on sexual differentiation?
If the fetus is SRY+, it will develop testes.
Testes have gametes, Sertoli cells and Leydig cells.
Under the influence of FSH, Sertoli cells secrete AMH which leads to the regression of the Mullerian ducts [uterus, tubes, upper vagina]
In the absence of SRY gene, what will develop?
Ovaries
What is the effect of DHT on sexual differentiation?
LH–> Leydig cells –> testosterone
In the peripheral tissues, testosterone is converted to DHT by 5a-reductase.
DHT promotes the differentiation of external genitalia evidenced by:
- fusion and rugation of the scrotum
- elongation of the phallus with fusion of the urethra
What is the effect of estrogen on sexual differentiation?
It does not play a significant role in sexual differentiation.
Female genitalia [internal and external] are considered to be constitutive and persist in the absence male differentiating hormones.
No SRY –> ovaries
No AMH–> uterus, tubes, upper vagina
How do the effects of testosterone and AMH differ from DHT during in utero development?
AMH and testosterone:
- development of internal genitalia
- dependent on high local concentrations
- defects can be unilateral
DHT:
- external genitalia
- bilateral effects except with true hermaphrodites
What are the effects of testosterone on pubertal development?
Activation of the HPG axis stimulates gonad function.
LH –> Leydig cells –> testosterone
The testosterone has 4 major effects:
- sperm production
- enlargement of testes and phallus
- increase in muscle mass
- deepening of the voice
- facial and chest hair [with DHT]
What is the role of DHEA-S on pubertal development?
At puberty, the HPG axis is mature increasing activation of adrenal sex steroid production.
DHEA-S is responsible for the development of “sexual hair pattern” [axillary and pubic]
*DHEAS does NOT depend on functioning gonads, because it is secreted from the adrenals
What is the role of DHT on pubertal development?
DHT and testosterone increase facial and chest hair in men
[axillary and pubic hair result from DHEAS, an adrenal steroid]
What is the role of estrogen on puberty?
- breast development
- increased uterine size
- endometrial growth –> menstruation with cyclic ovulation
What is the role of AMH at puberty?
It is not present at puberty
What are the 4 main categories for disorders of sex development?
- 46XY DSD [male chromosomes, female phenotype]
- 46XX DSD [female chromosomes, male phenotype]
- Gonadal dysgenesis
- True hermaphrodite
What are the different types of gonadal dysgenesis?
Abnormal karyotype”
- Turner’s 45,X
- Klinefelters 47 XXY
- Mixed 45X, 46XY
Normal karyotype:
1. 46 XX or 46XY [pure gonadal dysgenesis]
What disorder of sex development is caused by mutation in 21 hydroxylase?
5a-reductase?
Mutation in 21-hydroxylase [CYP21] diverts the steroidogenic pathway away from cortisol and aldosterone and pushes the steroids to androgens.
This increases estrogen AND testosterone leading to 46 XX DSD [male external due to testosterone/DHT]
Mutation if 5a-reductase means DHT cannot be synthesized. In development, males will not develop external genitalia and at puberty there will not be facial hair or chest hair. This results in 46XY DSD
What is the definition of gonadal dysgenesis?
An ovary or testes which is functionally and/or anatomically absent.
Describe the internal and external genitalia for Klinefelter’s [XXY].
[in utero and pubertal changes]
Because there is a Y chromosome, the SRY gene is present and there will be testes.
Testes will secrete testosterone from Leydig cells and AMH from Sertoli cells so there will be no Mullerian features and present Wolffian features [seminal vesicles, vas deferens, epididymis]
By puberty, there has been loss of spermatogonia and hyalinization of the seminiferous tubules –> firm testes, low testosterone production.
The low testosterone is unable to counteract the estrogen dependent breast development resulting in gynecomastia.
A teen presents to you will small firm testes and gynecomastia. He is disproportionately tall because of his long limbs. His mother says he looked normal growing up, but has become odd with puberty.
What is it likely that he has? What is the genotype?
Klinefelter’s 47XXY
Testes
Wolffian ducts
gynecomastia [estrogen»_space; testosterone at puberty]
He has long limbs because low levels of testosterone result in inadequate local levels of estrogen at the bone to cause epiphyseal fusion
A 20yr old female presents with short stature, webbed neck, shield chest, hearing loss, renal and cardiac anomalies. She has not yet begun menstruating.
What is her likely problem? What is the genotype?
What is the effect on sexual development? Describe internal and external genitalia.
Turner syndrome 45X
The chromosomal abnormality leads to accelerated atresia of the oocytes so no follicles are present by the time of puberty.
Connective tissue remains in place of the functional ovary = streak gonad.
There is no estrogen surge at puberty so the uterus is small and the patient lacks breasts.
There is no Y so no testes, no AMH or testosterone so the Turner syndrome patient will have:
Ovaries [streak]
female external genitalia [no DHT]
axillary and pubic hair is scant [unknown reason]
What is the genotype for mixed gonadal dysgenesis?
Describe the internal and external genitalia.
What must be done in these patients?
45X/46XY
Internal:
- asymmetric gonadal development with a single testes [cryptorchid] and a streak gonad
- Some Mullarian development due to poor AMH production
External:
Can range from partial virilization and ambiguous genitalia to completely male or female phenotype.
Because there is a Y-cell line, the streak gonad must be removed bc it increases the risk of tumor development [dysgerminona, gonadoblastoma]
What mutation is thought to play a role in the development of gonadal dysgenesis?
46 XX or 46XY but with gonadal dysgenesis due to a mutation in SF-1 which regulates SRY in early development leading to gonadal and adrenal agenesis.
What are the 2 main causes of 46XX DSD?
- CAH - mutation in 21 hydroxylase, 11 hydroxylase or 3B-hydroxylase
- Exogenous maternal androgens
Describe the internal and external genitalia of a 46XX DSD due to CAH.
- ovaries - yes because no SRY
- Mullerian duct- yes because no AMH
- breasts - yes because estrogen is present
- pubic hair- yes because DHEA is made
The external genitalia can become virilized at puberty because of the extreme amount of androgens–>testosterone–> DHT
It can range from clitoromegaly to male genitalia
Scrotum WILL NOT contain testes [because they weren’t made] and the ovaries cannot descend
What are the 3 exogenous sources of androgens that can cause a patient to be 46XX DSD?
- drugs/medicines the mother is taking
- luteoma [high LH production]
- placental aromatase deficiency [can’t make estrogen from DHEAS]
What are the three main situations that cause 46XY DSD?
- AIS [androgen insensitivity sydrome]
- 5a reductase mutation
- AMH or AMH receptor mutations
What is androgen insensitivity syndrome? What is the genotype of someone with this?
Describe the external and internal genitalia.
This is an inherited X-linked recessive disorder where there is androgen insensitivity.
The phenotype is 46XY DSD
Internal:
- no Mullerian ducts because AMH is still made
- No wolffian ducts because testosterone doesn’t work
- testes
External:
- female external genitalia because irresponsive to DHT [vaginal dimple-derived from urogenital sinus]
- breasts - due to conversion of testosterone to estrogen
- NO pubic hair
Testes should be removed after puberty because Y cell lines are associated with cancer
What is the genotype associated with 5a-reductase mutation?
What are the internal and external genitalia?
It is associated with 46XY DSD.
Internal:
- AMH –> no mullerian
- testosterone–> wolffian
- testes
External:
- LOW DHT production so some degree of external masculinization
- At puberty, high testosterone increases DHT resulting in further masculinization
- pubic hair
NO uterus, breasts
What will the internal and external genitalia look like for a 46XY patient with AMH or AMHR mutations?
Internal:
- testosterone–> Wolffian
- no AMH –> Mullerian persists
External:
1. Testosterone–>DHT–> male external genitalia
Describe the phenotype and internal and external genitalia of a true hermaphrodite.
Genotype: 46XX or 46XX/46XY
- both expressing SRY
- despite SRY, menstruation can occur
Internal:
- ovary on the left
- ovatestes or testes on the right
- uterus due to inadequate AMH from the partial or uni-testes
- Mullerian and/or Wollfian [its complex]
External:
Complex phenotype
What is the diagnostic workup for an infant with ambiguous genitalia?
- PE -focused on genitalia [if there is a mass in the inguinal canal or scrotum, it is the testes]
- karyotype
- Imaging of pelvic structures
- ultrasound, MRI
- genitography [radioopaque dye in urogenital sinus]
- endoscopy - measure 17OH-P. If it is high -> CAH
What is the diagnostic workup for a post-pubertal patient with ambiguous genitalia?
- PE - focus on genitalia, feel for testes
- karyotype
- Imaging
- US, MRI
- genitgraphy
- endoscopy - 17OHP and electrolytes for CAH
- hormonal evaluation [FSH, LH, estradiol, testosterone]
What is treatment for disorder of sex differentiation?
- gender reassignment- if newborn is ambiguous, parents select a sex- of -rearing
- surgical correction - easier to poke a hole than make a pole. Time it to where there is psychosocial advantage for the child
- surgical excision of streak gonads in Y-containing cell lines
- hormone replacement
