Male hormones in development and reproduction Flashcards
Case 1: A 17 y/o female presents to her pediatrician with complaint that she has not had a menstrual period yet. She reports breast development but scant axillary and pubic hair. On exam, she is noted to have a blind vaginal pouch with no evidence of a uterus or cervix.
46,XY.
- lack of cervix, utuers and tubes: AMH
What cells secrete AMH?
Sertoli cells of testes
what does AMH do?
causes regression of female mullerian structures
what promotes development of testes?
SRY gene causes transcription factor TDF (testis determining factor) to be expressed.
- SRY gene is located on Y chromosome
what promotes development of male external genitalia? what enzyme is required?
DHT (dihydrotestosterone)
- 5alpha- reductase-2
5-alpha reductase 2 deficincies
results in ambiguous or feminzed external genitalia with not internal female structures
what cells secrete testosterone
Leydig cells
- action stimulated by LH
Before fetal pituitary LH action is initiated, which hormone stimulates fetal Leydig cell production of T?
hCG
- Note: 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.
Androgen insensitivity?
- patient does not develop a penis, scrotum or prostate but is secreting testosterone and has no 5alpha reductase 2 deficiency
- DHT is required for external male genitalia and prostate
- DHT binds same androgen receptor as testosterone, but with great afinity
- if patient is missing androgen receptors then target tissues do not respond to DHT/T
- this is an X-linked recessive trait
Do you expect a patient with androgen insensitivity to have seminal vesicles, ejaculatory ducts, and vas deferens/epididymis associated with the testes?
No, testosterone action required for these Wolffian duct structures to develop
Defective androgen receptors
What is required for formation of prostate gland and scrotum/penis?
DHT!!!!
Testosterone is converted to DHT via 5 alpha reductase 2
What is required for formation of prostate gland and scrotum/penis?
DHT!!!!
Testosterone is converted to DHT via 5 alpha reductase 2
What is required for formation of epididymis, Vas deferens, ejaculatory duct and seminal vesicle?
Just testosterone, secreted from Leydig cells
What is required for formation of epididymis, Vas deferens, ejaculatory duct and seminal vesicle?
Just testosterone, secreted from Leydig cells
What is required for development of Sertoli cells and Leydig cells?
SRY gene –> TDF –> development of testes –> development of these cell types –> secrete AMH and testosterone
What is required for development of Sertoli cells and Leydig cells?
SRY gene –> TDF –> development of testes –> development of these cell types –> secrete AMH and testosterone
when is SRY made?
6-8 weeks
when is SRY made?
6-8 weeks
When is testosterone/AMH made?
8 weeks
When is testosterone/AMH made?
8 weeks
when is DHT made?
9-12 weeks
when is DHT made?
9-12 weeks
why would patient with 46 XY and androgen receptor insufficiency present with breast development?
- production of testosterone still occurs, peripherally body converts the testosterone to estradiol via cyp19-aromatase
why would patient with 46 XY and androgen receptor insufficiency present with breast development?
- production of testosterone still occurs, peripherally body converts the testosterone to estradiol via cyp19-aromatase
what is required for pubertal hair growth in males?
testosterone secretion –> DHT
- If have receptor insensitivity, then pubic hair will devleop
what is required for pubertal hair growth in males?
testosterone secretion –> DHT
- If have receptor insensitivity, then pubic hair will devleop
What hormone is thought to initiate puberty?
- GnRH
- Resurgence of pulsatile, sleep-associated GnRH secretion from the hypothalamus during adolescence
- Initial increase during gestation, again within the first 2 years of life, and then inhibition of GnRH neurons by the CNS until puberty; lower hypothalamic and pituitary set-point
- Increased pituitary gonadotrope sensitivity to GnRH
What hormone is thought to initiate puberty?
- GnRH
- Resurgence of pulsatile, sleep-associated GnRH secretion from the hypothalamus during adolescence
- Initial increase during gestation, again within the first 2 years of life, and then inhibition of GnRH neurons by the CNS until puberty; lower hypothalamic and pituitary set-point
- Increased pituitary gonadotrope sensitivity to GnRH
What promotes LH/FSH secretion and Testosterone secretion? where are the receptors?
- pulsatile hypothalamic GnRH release stimulates anterior pituitary LH And FSH secretion
- LH receptors on Leydig cells
- FSH receptors are on Sertoli cells
What are androgenic actions of testosterone?
- Fetal differentiation of male internal (T) and external genitalia (DHT)
- Growth, development of secondary sexual characteristics at puberty
- Maintenance of reproductive tract & production of semen
- Initiation and maintenance of spermatogenesis
What are the anabolic actions of testosterone?
- 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
What are the anabolic actions of testosterone?
- 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
What are important hormonal factors that stimulate spermatogenesis?
Luteinizing hormone (LH): stimulates Leydig cells to secrete testosterone
Testosterone (T): essential for growth and division of testicular germinal cells, beginning of sperm formation
Follicle-stimulating hormone (FSH): stimulates the Sertoli cells which are essential for supporting spermatogenesis
Estradiol (T is converted by aromatase to E): ER expressed on sperm cells, some evidence for a role in optimizing spermatogenesis
Growth hormone (GH): necessary for controlling background metabolic functions of the testes. Promotes early division of sperm. (Pituitary dwarfs: spermatogenesis is severely deficient or absent rendering them infertile)
know tanner stages
- Preadolescent: no pubic hair
- scrotum and testes enlarge and scrotal skin changes texture: sparse, long downy hair at base of penis
- growth of penis in length and further growth of testes/scrotum; darker coarser hair
- growth of penis in length; darkening of scrotal skin; adult type hair but less area
- adult-sized genitalia; adult texture and quantity of pubic hair
* ** puberty of male starts around 10 years of age, and ends at 17 years.
how is circulating testosterone bound?
- SHBG (sex hormone-binding globulin): binds about 45-60% of testosterone
- 38-55% bound to serum albumin
- 2-5% is free
how is circulating testosterone bound?
- SHBG (sex hormone-binding globulin): binds about 45-60% of testosterone
- 38-55% bound to serum albumin
- 2-5% is free
What protein is responsible for maintaining adquate testosterone concentration in testes?
ABP (androgen-binding protein)
Why must Testosterone be concnetrated in testes?
- Adequate concentration within the testes is essential for maintaining normal rate of spermatogenesis
- 100 : 1 (intra-testicular : circulating)
Case 2: 16 y/o male with no signs of puberty. lower in height and weight. no secondary sex characteristics. little muscle mass. high pitched voice. sparse pubic hair, underdeveloped testes.
LH: low
Testosterone: low
MRI: normal hypothalamus and pituitary
hypogonadotropic hypogonadism
- testes are immature and have no sperm due to low LH, FSH and testosterone plasma levels
- congenital disease
Kallman syndrome
decreased or absence GhRH secretion
- results in low LH/FSH and low testosterone
- testes are immature and have no sperm
hypogonadism
defects in spermatogenesis or steroidogenesis
- usually due to endocrine factors
What promotes LH/FSH secretion and Testosterone secretion? where are the receptors?
- pulsatile hypothalamic GnRH release stimulates anterior pituitary LH And FSH secretion
- LH receptors on Leydig cells
- FSH receptors are on Sertoli cells
GnRH therapy?
given for prostate cancer
- continuous high doses of GnRH will suppress gonadotropin secretion
- inhibition of GnRH receptor replenishment –> results in decreased levels of LH/FSH and decreased Testosterone
What are main functions of 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
Spermination: release of sperm from seminiferous tubule - Endocrine Function:
Expression of testosterone, ABP and FSH receptors
Production of AMH
CYP19 Aromatase: testosterone estradiol-17β (local)
Production of inhibin B to regulate FSH levels
Which hormones are important for adequate spermatogenesis?
- testosterone from Leydig cells (req. ABP from Sertoli cells for sufficient concentration)
- FSH and LH (necessary for Leydig and sertoli fn.)
What are important hormonal factors that stimulate spermatogenesis?
Luteinizing hormone (LH): stimulates Leydig cells to secrete testosterone
Testosterone (T): essential for growth and division of testicular germinal cells, beginning of sperm formation
Follicle-stimulating hormone (FSH): stimulates the Sertoli cells which are essential for supporting spermatogenesis
Estradiol (T is converted by aromatase to E): ER expressed on sperm cells, some evidence for a role in optimizing spermatogenesis
Growth hormone (GH): necessary for controlling background metabolic functions of the testes. Promotes early division of sperm. (Pituitary dwarfs: spermatogenesis is severely deficient or absent rendering them infertile)
In patient with hypogonadic hypogonadism what would be the effect of administering exogenous testosterone?
Virilization of secondary male sex traits
- would not promote fertility because testosterone feeds back negatively to decrease LH secretion which is already low in this patient
- decreased LH –> decreased Testosterone production by Leydig cells –> decreased testicular concentration –> decreased spermatogenesis
primary testicular failure
removes negative feedback from hypothalamic-pituitary axis
- see low levels of T, thus high levels of plasma gonadotropins
in contrast:
- decreased gonadotrpoin and steroid levels and reduced testicular size almost always accompany hypothalamic and pituitary failure
gonad failure before puberty
results in absence of secondary sex characteristics (eunuchoidism)
- men with a postpubertal testicular failure retain masculine featues, but exhibit low sperm counts later in life
