What is another name for klinefelter syndrome?
•XXY Seminiferous Tubule Dysgenesis
What promotes the intrauterine development of the testes?
SRY gene produces TDF (testes determining factor)
What cells produce antimullerian hormone?
Sertoli cells
What hormone action is needed for the wolfian duct to develop?
Testosterone
What are the wolfian duct structures?
seminal vesicles
ejaculatory duct
vas deferens
epididymus
Which cells in the testes produce testosterone?
Leydig cells
What hormone stimulates fetal leydig cell production of testosterone during development prior to fetal pit. LH?
HCG
•What is required for the development of the penis, scrotum and prostate?
–DHT (Dihydrotestosterone)
•What enzyme is required for the conversion of testosterone à DHT?
–5α-reductase-2
–5α-reductase-1 is more expressed in skin, so in what condition might this come into play?
Acne treatment
Which binds tighter to their shared receptor, DHT or testosterone?
DHT
5α-reductase-2 deficiencies lead to what phenotypical changes?
ambiguous or feminized external genitalia
What goes down at 6-8 weeks gestation in the male differentiation
Differentiation of testes
[SRY transcription factor]
What happens in weeks 8-9 of male gestational development (UG tract)
- Retention of wolffian ducts
- [Testosterone]
- Regression of müllerian ducts
- [Antimϋllerian hormone]
What happens in weeks 9-13 of male genital development?
Male-type external genitalia
[DHT]
In klinefelters, why the gynecomastia?
–Elevated estradiol levels and increased estradiol-to-testosterone ratio
–Peripheral conversion of testosterone à estradiol
•Which enzyme converts androgen to estrogen?
–CYP19-aromatase
•What hormone is considered to be responsible for the normal initiation of puberty?
–Resurgence of pulsatile sleep-associated GnRH secretion from the hypothalamus during adolescence, along with increased gonadotrope sensitivity to GnRH.
In this patient with Klinefelter Syndrome, increased levels of gonadotropins failed to induce normal testicular growth and spermatogenesis.
What happpens to the testes?
Seminiferous tubules?
- The testis became fibrotic and hyalinized and remain small and firm.
- The seminiferous tubules are largely destroyed and he is infertile.
What hormones are affected and how in primary hypogonadism?
–Gonadotropin levels are elevated
–Androgen production is reduced
What hormone is the key player in development of secondary sex characteristics, such as penis size, bear development, etc?
DHT
What percent of testosterone circulates as….
–SHBG (sex hormone-binding globulin) bound:
–Serum albumin bound:
–Free:
–SHBG (sex hormone-binding globulin) bound: 45-60%
–Serum albumin bound: 38-55%
–Free: 2-5%
•Which cells are the primary site for the production of testosterone in males?
LEydig cells
•What protein is responsible for maintaining testosterone concentration in the testes?
–ABP (androgen-binding protein)
•Why is it important for testosterone to be concentrated within the testes?
–Maintenance of adequate concentration [~ 100x > circulating levels] within the testes is essential for the promotion of adequate spermatogenesis.
From cholesterol to testosterone, elaborate the intermediates in the production pathway.
- Cholesterol
- pregnenolone
- progesterone
- androstenedione
- testosterone
Maintenance of adequate concentration [~ 100x > circulating levels] within the testes is essential for the promotion of adequate spermatogenesis. Describe how this is accomplished.
Androgen binding protien (ABP) in the seminiferous tubules binds testosterone with high affinity.
What is testosterone converted to in peripheral tissues and by what?
Estradiol (CYP19-aromatase)
DHT (5α-reductase-2)
•What promotes LH and FSH secretion?
–Pulsatile hypothalamic GnRH release stimulates anterior pituitary LH and FSH secretion
•Which cells are the target of LH in the testes?
–Leydig cells
•Which cells are the target of FSH in the testes?
–Sertoli cells
Sertoli cells have a number of functions, what general actions do these functions fall undeR?
Supportive function
Exocrine function
Endocrine function
What are the supportive functions of the sertoli cells?
• Maintaining blood-testis barrier
- Phagocytosis
- Transfer of nutrients to sperm
• Receptors for hormones & paracrines
What are the exocrine functions of the sertoli cells?
- Fluid produced for sperm mobilization
- Production of ABP (Androgen binding protein)
- Spermination: release of sperm from seminiferous tubule
What are the endocrine functions of the sertoli cells?
- Expression of testosterone, ABP and FSH receptors
- Production of AMH (Antimϋllerian hormone)
- CYP19 Aromatase: testosterone à estradiol-17β (local)
- Production of inhibin B to regulate FSH levels
In klinefelter, you will see low serum testosterone levels and elevated gonadotropin levels (LH and FSH). What is the explanation for elevated LH and FSH levels?
–Reduction in androgen production results in decreased negative feedback on the hypothalamic-pituitary-testicular axis
What does inhibin provide negative feedback on in men?
FSH
•Which 3 key hormones have an important function to promote adequate spermatogenesis in the normal male?
–Testosterone from Leydig cells
–FSH & LH (necessary for Leydig and Sertoli function)
How does FSH contribute to spermatogenesis?
stimulates the Sertoli cells (nursing cells) to nurse and form sperm
Does estradiol have a role in spermatogenesis?
Yes, unclear what though
What role does GH have in development of sperm?
•. GH promotes early division of the sperm. Without it, as seen in pituitary dwarfs, spermatogenesis is severely deficient or absent resulting in infertility.
•What treatment might be suggested for this patient with Klinefelter Syndrome?
–Androgen replacement therapy
•What would be the likely effect of administering exogenous testosterone to a klinefelter patient?
Can exogenous testosterone promote fertility in these patients? explain your answer.
–Virilization of secondary male sexual traits
–No
–Seminiferous tubule tissue is likely destroyed and the cause of infertility
Also, in more detail…
–Exogenous testosterone (T, DHT, and estradiol-17β) promotes negative feedback on gonadotropin secretion
–↓ LH –> further ↓ T production by Leydig cells –> ↓ testicular [T] –> ↓ spermatogenesis
What impact does defective steroidogenesis have on spermatogenesis?
•Normal spermatogenesis almost never occurs when steroidogenesis is defective
May still have defective spermatogenesis though
In klinefelters why does a female phenotype fail to develop despite the presence of multiple X chromosomes?
–Antimϋllerian hormone –> Mϋllerian duct regression
