Steroid and Gonadotrophin Action Flashcards
What is the function and location of myoid cells?
Surrounds the seminiferous tubules. Squeezing action transports sperm into the epididymis.
What is the function and location of leydig cells?
They are in the spaces between the tubules. They have pale bodies - clue that they are an important site of steroid production.
LH acts on the leydig cell to convert cholesterol to testosterone.
What happens to the testosterone produced by the leydig cell?
It is transferred across the basement membrane, across the myoid cell, into the seminiferous tubule where it is taken up into the sertoli cell.
In the sertoli cell, it is converted by 5-alpha reductase to DHT.
FSH stimulates production of the 5-alpha reductase.
What are symptoms of 5-alpha reductase deficiency.
-alpha reductase deficiency is a condition that affects male sexual development before birth and during puberty.
• People with this condition are genetically male, with one X and one Y, and have male testis.
• Their bodies however, do not produce enough DHT
• DHT has a critical role in sexual development, and a shortage of this hormone disrupts the formation of the external sex hormones before birth.
• Many people with this deficiency are born with external genitalial that appear female. In other cases, the genitalia do not look clearly male or female (is ambiguous). Other infants have predominantly male genitalia, but often unusually small, or with hypospadias.
• During puberty, people with this condition develop some secondary sex characteristics, but not much facial or body hair.
• Most affected males are infertile
• Children with this deficiency are often raised as girls, and about half of these individuals adopt a male gender role in adolescence.
What do LH receptor knockouts tell us about LH function?
• Causes a total lack of postnatal sexual maturation → small testits, no Leydig cells, arrest of spermatogenesis
Why?
• If you cant respond to LH, you don’t get signal to produce testosterone – you have impaired steroid production
• Testosterone replacement in juveniles can partially rescue the phenotype (only partially, because injecting testosterone into the circulation is not quite the same as testosterone produced by the testis) → proves that the action of gonadotrophin LG is required for androgen production and sexual function in the male.
What is the androgen receptor distribution in the testis?
- Sertoli cells – thought to be the major target
- Leydig cells
- Myoid cells
- → androgens can potentially influence all cell types in the testis.
- → its presence in germ cells is controversial. Studies suggest that if it is present, it is not required.
What do ARKOs tell us about testosterone function in the testis?
• The ARKO mouse develops with very small testis (20% are normal)
• Spermatogenesis is arrested at the spermatocyte stage:
− Stage where cell is beginning to develop morphological features
− Testosterone required for germ cells to progress beyond meiosis,and for the release of mature spermatids
− Withdrawal of testosterone/ARKO in sertoli cells results in 3 major impairments to fertility
− Blood testis barrier compromised → exposes post meiotic germ cells, formerly in a secluded specialized environment, to autoimmune attack
− Block in conversion of round spermatids to elongated spermatids due to a defect in cell adhesion that causes premature detatchment of round spermatids from sertoli cells
− Fully mature spermatozoa cant be released from sertoli cells, and are phagocystosed
- They have a female appearance
- The ARKO female has reduced litter sizes – androgens are important in the females too
What cell functions are dependent on the AR?
- People with mutations in AR show complete or partial ‘androgen insentivity’
- Testosterone levels are normal or elevated, but there are developmental defects affecting sexual differentiation.
- Phenotypes in these individuals vary widely: predominantly male, female external genitalia, ambiguous genitalia etc… depending on the mutation.
• The AR has different functions in different cell populations in the testis, shown by disabling the AR gene in specific cell populations in the mouse testis:
− Sertoli cells → nurse developing gametes and converts steroid to DHT
− Leydig cells → steroid production
− Myoid cells → mobilization of sperm along the tubules
• The loss of the AR from any one of these cells impairs male fertility
How do males produce estrogen?
- Androstenedione is the precursor to testosterone → androstenedione can be transferred to the sertoli cells and converted to estrogen by aromatase.
- So, in both the production of DHT and estrogen, the final step occurs in the sertoli cell.
- Male production of estrogen in the testis is 20% of the amount found in non-pregnant women.
What do aromatase knockouts tell us is the role of estrogens in male reproduction?
• No change in gonadotrophins or androgens (as you would expect)
• However, mice show highly impair spermatogenesis:
− Spermatogenesis begins, but then degenerative changes are seen in the early spermiogenic stages
− Spermatogenesis primarily arrested at early spermiogenic stages, as characterized by an increase in apoptosis and the appearance of multinucleated cells, and reduction in elongated spermatids.
− No changes in sertoli cells and earlier germ cells
− Leydig cell hyperplasiahypertrophy evidence, presumably as a consequence of increased circulating LH
− Findings indicate that local expression of aromatase is essential for spermatogenesis and provide evidence for a direct action of estrogen on male germ cell development.
Other than inducing cyclical proliferation and regression in the uterus, what other actions to estrogens have?
− Development of female secondary sex characteristics
− Sexual behavior
− Bone formation
− Blood vessel formation
− Immune function
− Wound healing – wound healing gets slower in post-menopausal women, as the skin has estrogen receptors.
What consequence does alpha-ERKO have?
normal lifespan, but is infertile with a very small uterus
What consequence does beta-ERKO have?
subfertile with disrupted ovarian function, but a normal looking uterus.
What are the actions of progesterone?
- Regulates the rate of transport of the egg through the fallopian tube
- Prepares the uterus to receive the implanting blastocyst
- Sustains the uterine liing throughout pregnancy
- inhibits myometrial contractility
- Influences the ovary
- Has effects on the brain and sexual behavior
What does the PRKO mouse tell us about the progesterone receptor actions?
- Two P receptors, A and B are derived from a single gene by alternative splicing
- Ablation of PR-A (PRAKO) results in severe abnormalities of uterine and ovarian function, leading to infertility
- the PRBKO has normal uterine and ovarian function and is fertile, but defective at the mammary gland
