Montemayor's review DSA Flashcards
Klinefelter Syndrome
XXY Seminiferous Tubule Dysgenesis
Most common genetic form of male hypogonadism (~1:500) (~250,000 men in the U.S.)
Most common symptoms:
Infertility
Gynecomastia
What promotes the intrauterine development of his testes?
SRY gene (sex-determining region on Y chromosome) SRY transcription factor (TDF: testis determining factor)
what keeps female phenotype from developing?
Antimϋllerian hormone Mϋllerian duct regression
Which cells produce Antimϋllerian hormone?
Sertoli Cells
What is required for the development of seminal vesicles, ejaculatory duct, and vas deferens/epididymis?
Testosterone action is required for these Wolffian duct structures to develop
Which cells in the testes produce testosterone?
Leydig cells
Which hormone stimulates fetal Leydig cell production of testosterone during development prior to fetal pituitary secretion of luteinizing hormone (LH)?
hCG (human chorionic gonadotropin)
Important concept: hCG can be substituted for LH in clinical attempts to stimulate spermatogenesis in oligospermic men due to its increased availability. hCG is structurally most similar to LH and binds LH receptors.
What is required for the development of the penis, scrotum and prostate?
DHT (Dihydrotestosterone)
DHT required for external male genitalia & prostate
DHT binds same androgen receptor as testosterone, with greater affinity
What enzyme is required for the conversion of testosterone to DHT?
5α-reductase-2
Summary: Male Sexual Differentiation
week
6-8- differentiation of testes (SRY transcription factor)
8- retention of wolffian ducts (testosterone) , regression of mullerian ducts (antimullerian hormone)
9-13- male-type external genitalia (DHT)
What promotes development of gynecomastia?
Elevated estradiol levels and increased estradiol-to-testosterone ratio
Peripheral conversion of testosterone 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.
(Initial increase during gestation, again within the first 2 years of life, and then low activity until puberty)
Primary hypogonadism:
Gonadotropin levels are elevated
Androgen production is reduced
major, normal actions of androgens
Androgenic:
Differentiation of male internal (T) and external genitalia (DHT) in fetus.
Growth, development of secondary sexual characteristics at puberty
Maintenance of reproductive tract & production of semen
Initiation and maintenance of spermatogenesis
Anabolic:
Stimulation of erythropoietin synthesis
Stimulation of sebaceous gland secretion
Control of protein anabolic effects (nitrogen retention)
Stimulation of linear body growth, bone growth and closure of the epiphyses
Promotion of ABP synthesis
Maintenance of secretions of sex glands
Regulation of behavioral effects, including libido
In which form is the majority of circulating testosterone found?
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 of the testes
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 within the testes is essential for the promotion of adequate spermatogenesis
development of testosterone in leydig cells
Cholesterol ↓ Pregnenolone ↓ Progesterone ↓ Androstenedione ↓ Testosterone (T) ↓ T + ABP (seminiferous tuble) T + SHBG (circulation) 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
GnRH Therapy for Prostate Cancer
Continuous and high doses suppresses gonadotropin secretion
Inhibition of GnRH receptor replenishment –> insufficient receptor availability
↓ LH/FSH levels –> ↓ T
What are some of the key functions of normal Sertoli cells?
Supportive Function: * Maintaining blood-testis barrier Phagocytosis Transfer of nutrients to sperm * Receptors for hormones & paracrines
Exocrine Function:
Fluid produced for sperm mobilization
Production of ABP * (Androgen binding protein)
Spermination: release of sperm from seminiferous tubule
Endocrine Function:
Expression of testosterone, ABP and FSH receptors
Production of AMH *(Antimϋllerian hormone)
CYP19 Aromatase: testosterone –> estradiol-17β (local)
Production of inhibin B to regulate FSH levels
our Klinefelter patient has 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
Feedback Regulation of the Hypothalamic-Pituitary-Testicular Axis in Males
This axis shows both the positive and negative feedback systems for the release of both LH and FSH and their action on specific cells to potentiate the release of testosterone (Leydig cells) and nursing cells that function to help mature and nurture sperm to maturity (Sertoli cells).
Summary of GnRH story
Pulsatile GnRH release
FSH (and T) –> Sertoli Cells
LH –> Leydig Cells
Note: hCG is structurally similar to LH and can act to stimulate Leydig cells
Inhibin: Negative feedback on FSH production (Inhibin B in men)
T, DHT, and E: Negative feedback mainly on LH (also FSH)
Which 3 key hormones have an important function to promote adequate spermatogenesis in the normal male?
Testosterone from Leydig cells
Sufficient testicular concentration of testosterone (ABP, androgen-binding protein; produced by Sertoli cells)
FSH & LH (necessary for Leydig and Sertoli function)
Hormonal Factors in Spermatogenesis
Luteinizing hormone, (LH), secreted by anterior pituitary, stimulates the Leydig cells to secrete testosterone.
Testosterone, secreted by Leydig cells. Essential for growth and division of the testicular germinal cells, beginning of sperm formation.
Follicle-stimulating hormone, (FSH), also secreted by anterior pituitary, stimulates the Sertoli cells (nursing cells) to nurse and form sperm. Process of spermatogenesis.
Estradiol, formed from the testosterone by the Sertoli cells when they are stimulated by FSH. Role in spermatogenesis. [Mechanism not completely understood]
Growth hormone is necessary for controlling background metabolic functions of the testes. 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 our patient with Klinefelter Syndrome?
Androgen replacement therapy
What would be the likely effect of administering exogenous testosterone to this patient with klinefelter?
Virilization of secondary male sexual traits
Would exogenous testosterone likely improve fertility of this patient?
No
Seminiferous tubule tissue is likely destroyed and the cause of infertility
AND, in general:
2. Exogenous testosterone (T, DHT, and estradiol-17β) promotes negative feedback on gonadotropin secretion
↓ LH –> further ↓ T production by Leydig cells ↓ testicular [T] –> ↓ spermatogenesis
Factors to Consider with Hypogonadism
Normal spermatogenesis almost never occurs when steroidogenesis is defective
Defective spermatogenesis can still occur despite normal steroidogenesis
Primary testicular failure: removes negative feedback from the hypothalamic-pituitary axis ↑ plasma gonadotropins
Hypothalamic and/or pituitary failure: generally result in decreased gondadotropin and steroid levels and reduced testicular size
Gonadal failure before puberty results in the absence of secondary sex characteristics (eunuchoidism)
Men with a postpubertal testicular failure retain masculine features but exhibit low sperm counts or reduced ability to produce functional sperm
failure of the testes to descend impairs what aspect of reproductive function?
maturation of spermatogonia (maintain good temp for those swimmers)
guy has decreased facial and axillary hair, decreased penile length, and hypogonadism. Deficiency of what androgen most directly explains his physical exam findings?
DHT- directly required for facial and axillary hair growth
antibodies bind and neutralize FSH bioactivity. These immunized men would have what change in hormone levels?
decreased serum inhibin B levels.
